（2026.V3）NCCN临床实践指南：多发性骨髓瘤

指南血液内科· 淋巴瘤与骨髓瘤 · 2026

NCCN Guidelines Version 3.2026 Multiple Myeloma

*Shaji K. Kumar, MD/Chair $\ddagger$ Novo Clinic Comprehensive Cancer Center

*Natalie S. Callander, MD/Vice Chair $\notin $ University of Wisconsin Carbone Center

Kehinde Adekola,MD,MSCI‡ Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Larry D. Anderson, Jr., MD, PhD $\ddagger$ UT Southwestern Simmons Comprehensive Cancer Center

*Muhamed Baljevic, MD P≠p Vanderbilt-Ingram Cancer Center

Rachid Baz,MD $\ddagger$ Moffitt Cancer Center

Erica Campagnaro, MD $\ddagger$ University of Michigan Rogel Cancer Center

Caitlin Costello, MD PδP UC San Diego Moores Cancer Center

Christopher D'Angelo,MD $\ddagger$ Fred & Pamela Buffett Cancer Center

Benjamin Derman, MD † The UChicago Medicine Comprehensive Cancer Center

Srinivas Devarakonda, MD $\ddagger$ The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute

Noura Elsedawy,MD t St. Jude Children's Research Hospital/The University of Tennessee Health Science Center

NCCN Guidelines Panel Disclosures

Amandeep Godara, MD D Huntsman Cancer Institute at the University of Utah

Kelly Godby,MD‡O'ONal Comprehensive Cancer Center at UAB

Jens Hillengass, MD, PhD $\ddagger$ Roswell Park Comprehensive Cancer Center

Leona Holmberg, MD, PhD $\ddagger$ Fred Hutchinson Cancer Center

Myo Htut,MD‡P City of Hope National Medical Center

Carol Ann Huff, MD+±John Hopkins Kilmel Cancer Center

Malin Hultcrantz, MD PhD $\ddagger$ Memorial Sloan Kettering Cancer Center

Yubin Kang,MD#+t&Duke Cancer Institute

Sarah Larson, MD++ t UCLA Jonsson Comprehensive Cancer Center

Hans C. Lee, MD $\_$ The University of Texas MD Anderson Cancer Center

Michaela Liedtke, MD‡ Stanford Cancer Institute

Thomas Martin,MD‡UCSF Helen Diller Family Comprehensive Cancer Center

James Omel, MD ¥Patient Advocate

Timothy J.Robinson,MD,PhD §Yale Cancer Center/Smilow Cancer Hospital

Aaron Rosenberg,MD $\sharp$

Shayna R. Sarosiek, MD $\ddagger$ Dana-Farber/Brigham and Women's Cancer Center

Mark A. Schroeder, MD $\ddagger$ Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Daniel Sherbenou,MD,PhD t University of Colorado Cancer Center

Attaya Suvannasankha, MD $\ddagger$ Indiana University Melvin and Bren Simon Comprehensive Cancer Center

Jason Valent, MD $\ddagger$ Case Comprehensive Cancer Center/University Hospitals Seldman Cancer Center and Cleveland Clinic Taussig Cancer Institute

Asya Nina varshavsky-Yanovsky, MD, PhD‡ Fox Chase Cancer Center

Dan Vogl,MD $\ddagger$ Abramson Cancer Center at the University of Pennsylvania

Jing Christine Ye, MD, MSc‡The University of Texas MD Anderson Cancer Center

NCCN Emily Kovach Rashmi Kumar, PhD

§Bone marrow translation

↑Medical oncology

§Hematology/Hematologic Oncology P Internal medicine

§ Radiation oncology *Discussion section writing committee

NCCN Guidelines Version 3.2026 Multiple Myeloma

Version 3.2026, 11/03/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index Table of Contents Discussion

NCCN Multiple Myeloma Panel Members

Summary of Guidelines Updates

Initial Diagnostic Workup and Clinical Findings (MYEL-1)

Solitary Plasmacytoma or Solitary Plasmacytoma with Minimal Marrow Involvement:

Primary Treatment and Follow-up/Surveillance (MYEL-2)

Smoldering Myeloma (Asymptomatic): Primary Treatment and Follow-up/Surveillance (MYEL-3)

Multiple Myeloma (Symptomatic): Primary Treatment and Follow-up/Surveillance (MYEL-4)

Multiple Myeloma (Symptomatic): Response After Primary Therapy and Follow-up Surveillance (MYEL-5)Multiple Myeloma (Symptomatic): Treatment for Relapse or Progressive Disease (MYEL-6)

Multiple Myeloma with CNS Disease (CNSM-1)

Definitions of Myeloma and Related Plasma-Cell Disorders (MYEL-A)

Disease Staging and Risk Stratification Systems for Multiple Myeloma (MYEL-B)

Principles of Imaging (MYEL-C)

Principles of Radiation Therapy (MYEL-D)

Response Criteria for Multiple Myeloma (MYEL-E)

Considerations for Myeloma Therapy (MYEL-F)

Myeloma Therapy (MYEL-G)

Principles of Management of CNS Disease in Patients with MM (MYEL-H)

Supportive Care for Multiple Myeloma (MYEL-I)

Management of Infections in Patients with Multiple Myeloma (MYEL-J)

Management of Venous Thromboembolism (VTE) in Multiple Myeloma (MYEL-K)

Management of Renal Disease in Multiple Myeloma (MYEL-L)

Monoclonal Gammopathy of Clinical Significance

• Monoclonal Gammopathy of Renal Significance (MGRS-1)

• Monoclonal Immunoglobulin Deposition Disease (MIDD-1)

• Monoclonal Gammopathy of Neurological Significance (MGNS-1)

POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Protein, Skin Changes) (POEMS-1)Abbreviations (ABBR-1)

Find an NCCN Member Institution: https://www.nccn.org/home/memberinstitutions

NCCN Categories of Evidence and Consensus: All recommendations

are category 2A unless otherwise

indicated.

See NCCN Categories of Evidence and Consensus.

NCCN Categories of Preference: All recommendations are considered appropriate.

See NCCN Categories of Preference.

The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to

treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2025.

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

UPDATES CONTINUED

Updates in Version 3.2026 of the NCCN Guidelines for Multiple Myeloma from Version 2.2026 include:

MYEL-G (4 of 5)

• Other Recommended

Regimen added: After two prior therapies including a PI and IMiD, Belantamab mafodotin-blmf/Bortezomib/Dexamethasone (category 1)

MYEL-G (5 of 5)

• Useful in Certain Circumstances

Bullet 1, regimen modified: Belantamab mafodotin-blmf (as available through expanded access program)

Updates in Version 2.2026 of the NCCN Guidelines for Multiple Myeloma from Version 1.2026 include:MYEL-G (5 of 5)

• Therapy for Previously Treated Multiple Myeloma

Preferred, After at least four prior lines of therapy, including an Anti-CD38 monoclonal antibody, a PI, and an IMiD:

◊ Regimen added: Linvoseltamab-gcpt

Updates in Version 1.2026 of the NCCN Guidelines for Multiple Myeloma from Version 2.2025 include:GLOBAL

• Added new sub-section: "Considerations for Special Populations" including Older Adults and Black/African American Individuals on MYEL-F.

• Footnotes referencing MYEL-A have been changed to reflect the new title: Definitions for Myeloma and Related Plasma-Cell Disorders.

MYEL-1

• Initial Diagnostic Workup

Bullet 12 added: Next-generation sequencing (NGS) to assess for TP53 mutation.

• Useful in Certain Circumstances

Bullet 5 revised: Consider Obtain baseline clonotype identification at diagnosis and storage of or store an aspirate sample for future clonotype

identification to enable minimal residual disease (MRD) testing by NGS.

Bullet 9 added: Renal biopsy if albuminuria or abnormal renal function.

Bullet removed: Single nucleotide polymorphism (SNP) array on bone marrow, and/or next-generation sequencing (NGS) panel on bone marrow.

• Clinical Findings

For Renal Significance, bullet added: For Monoclonal Immunoglobulin Deposition Disease (MIDD), MIDD-1.

• Footnote b, first sentence modified: These tests are essential for R-ISS staging.

• Footnote h added: Dimopoulos MA, et al. Lancet Oncol 2023;24:e293-e311.

MYEL-2

• Follow-Up/Surveillance

Bullet 5 modified: 24-h urine for total protein and UPEP with UIFE as needed.

Bullet removed: Tests as needed.

• Footnote k, last sentence added: Consider FISH testing on plasmacytoma biopsy if clonal cells are absent or inadequate in the marrow.

• Footnote o, last sentence modified: Patients with soft tissue and head/neck plasmacytoma could be followed less frequently as clinically indicated after initial 3-month follow-up.

MYEL-3

• Primary Treatment

High risk

◊ Header added: Select patients.

◊ Bullet 1, regimen added: Daratumumab (category 1).

◊ Bullet 2, modified: Lenalidomide in select patients (category 2B).

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

UPDATES CONTINUED

Updates in Version 1.2026 of the NCCN Guidelines for Multiple Myeloma from Version 2.2025 include:

MYEL-3 (continued)

• Follow-Up/Surveillance

Bullet 1, sub-bullet 5 modified: 24-h urine for total protein, UPEP, and UIFE as clinically indicated, if abnormal at baseline, or if there is significant

change in FLC levels. (Also for MYEL-4).

Bullet 2 modified: Bone marrow aspirate and biopsy with FISH, SNP array, NGS, or multi-parameter flow cytometry as clinically indicated.

• Footnote r modified: BMPCs >20%, M-protein >2 g/dL, and serum FLC ration (FLCr) >20 are variables used to risk stratify patients at diagnosis.

Patients with two or more of these factors are considered to have high risk of progression to MM. For risk criteria, refer to Lakshman A, et al. Blood

Cancer J 2018;8:59 and Mateos MV, et al. Blood Cancer J 2020;10:102.

• Footnote u modified: Consider consultation for hematopoietic cell transplant (HCT) and collection of hematopoietic stem cells for future use transplant procedures.

MYEL-4

• Clinical Findings, first column, row added: For CNS disease, see CNSM-1.

• Primary treatment

Top row, link to NCCN Guidelines for Supportive Care added.

• Footnote x modified: See General Considerations for Myeloma Therapy(MYEL-F) for considerations for myeloma therapy and for specific populations(eg, Black/African American individuals). (Also for MYEL-5 and MYEL-6)

MYEL-5

• Response After Primary Therapy, third row modified:

Header added from below text: Useful in Certain Circumstances for patients with high risk of progression/relapse under certain circumstances..

• Footnote ee added: Whole-body FDG-PET/CT is recommended on day 100 after autologous HCT.

• Footnote removed: Allogeneic HCT should preferentially be done in the context of a trial when possible. (Also for MYEL-6).

MYEL-6

• Multiple Myeloma (Symptomatic)

First column, row added: For CNS disease, see CNSM-1.

Treatment column

◊ Bullet 1 modified: Discuss the patient's preferences and goals of care through a shared decision-making process.

◊ Bullet 2, sub-bullet 2 modified: Palliative care specialist and supportive care for symptom management (See NCCN Guidelines for Palliative Care and NCCN Guidelines for Supportive Care).

• Footnote y added: Supportive Care Treatment for Multiple Myeloma (MYEL-H).

CNSM-1

• Multiple Myeloma with CNS Disease section added.

MYEL-A

• Table reformatted.

• Definitions for solitary plasmacytoma with and without minimal marrow involvement and plasma cell leukemia added.

MYEL-B (1 of 2)

• Table reformatted.

• Column 2, row 3, bullet 2 modified: And either high-risk chromosomal abnormalities [del(17p) or translocation (4;14) or translocation (14;16)]

abnormalities by FISH or Serum LDH > the ULN.

• IMS-IMWG column added.

• Reference 3 added: Avet-Loiseau H, Davies FE, Samur MK, et al. International Myeloma Society/International Myeloma Working Group Consensus Recommendations on the Definition of High-Risk Multiple Myeloma. J Clin Oncol 2025:Jco2401893.

MYEL-B (2 of 2)

• Column 1, bullet 6 added: Markers of high proliferation rate.

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

UPDATES CONTINUED

Updates in Version 1.2026 of the NCCN Guidelines for Multiple Myeloma from Version 2.2025 include:

• Footnote moved to MYEL-A table: Presence of ≥5% of plasma cells in circulation is defined as plasma cell leukemia.

MYEL-C

• Imaging for Initial Diagnostic Workup...

Bullet 1 modified: Whole-body FDG-PET/CT (preferred)...

• Imaging of Solitary Plasmacytoma

Bullet 1, sentence 2 modified: For solitary osseous plasmacytoma, whole-body MRI (or FDG-PET/CT if MRI not available) is the first choice for initial

evaluation of solitary osseous plasmacytoma.

• Imaging for Follow-up of MM

Bullet 1, sentence 1 modified: Advanced whole-body imaging (ie, FDG-PET/CT, low-dose CT, whole-body MRI without contrast) is recommended as

needed.

MYEL-D (2 of 2)

• General Principles, bullet 6 added: For principles of RT for CNS disease in patients with MM, see Principles of Management of CNS Disease in Patients with MM (MYEL-H).

MYEL-F

• Pages extensively revised.

MYEL-G (1 of 5)

• Header revised: Primary Therapy for Transplant HCT Candidates.

Preferred, regimen added: Isatuximab-irfc/Bortezomib/Lenalidomide/Dexamethasone (category 1).

Other Recommended

◊ Regimen moved from Useful in Certain Circumstances: Daratumumab/Carfilzomib/Lenalidomide/Dexamethasone.

◊ Regimen moved from Useful in Certain Circumstances: Isatuximab-irfc/Carfilzomib/Lenalidomide/Dexamethasone.

• Maintenance Therapy

Useful in Certain Circumstances, regimen added: Daratumumab.

• Footnote c modified: See General Considerations for Myeloma Therapy(MYEL-F) for considerations for myeloma therapy and for specific populations(eg, Black/African American individuals). (Also for MYEL-G 2, 3, 4, and 5)

• Footnote removed: Preferred primarily as initial treatment in patients with acute renal insufficiency or those who have no access to proteasome inhibitor(PI)/lenalidomide/dexamethasone. Consider switching to PI/lenalidomide/dexamethasone after renal function improves. (Also for MYEL-G [2 of 5]).

MYEL-G (2 of 5)

• Header revised: Primary Therapy For if HCT Deferred or Non-Transplant Candidates if HCT is not Indicated.

• Preferred, regimen added: Daratumumab/Bortezomib/Lenalidomide/Dexamethasone (for patients <80 years old who are not frail) (category 1).

• Other Recommended

Regimen added: Bortezomib/Lenalidomide/Dexamethasone (category 1).

Regimen added: Isatuximab-irfc/Lenalidomide/Dexamethasone.

• Useful in Certain Circumstances: Regimen Added: Ixazomib/Lenalidomide/Dexamethasone.

• Footnote i added: Strongly consider collecting and storing stem cells for future HCT.

MYEL-G (4 of 5)

• Other recommended, regimen removed: Carfilzomib (twice-weekly)/dexamethasone (category 1).

• Useful in Certain Circumstances, regimen modified: Carfilzomib (weekly)/Dexamethasone (category 1).

MYEL-G (5 of 5)

• Useful In Certain Circumstances

Bullet 1 modified: Belantamab mafodotin-blmf (as if available through compassionate use expanded access program).

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

UPDATES

Updates in Version 1.2026 of the NCCN Guidelines for Multiple Myeloma from Version 2.2025 include:

Bullet 3, 4, 5, 6: regimens moved from Other Recommended.

MYEL-H

• Section added: Principles of Management of CNS Disease in Patients with MM.

MYEL-I

• Footnote removed: An FDA-approved biosimilar is an appropriate substitute.

MYEL-J (1 of 2)

• Page sub-header added: For additional recommendations on infection management, see NCCN Guidelines for Prevention and Treatment of CancerRelated Infections. (Also for MYEL-J [2 of 2])

• Common Bacterial Infections

Levofloxacin row, BsAb indication modified: Consider starting with therapy and administer throughout the first cycle Start when ANC <500 or per

clinician discretion and continue until neutrophil recovery.

Immunoglobulin replacement row

◊ BsAb indication modified: Consider for the duration of BsAb therapy based on clinical context.

◊ Other Indications modified: For IgG <400 mg/dL and/or recurrent life-threatening infections.

MYEL-J (2 of 2)

• Common Viral and Fungal Infections

Pneumocystis jirovecii pneumonia (PJP) row, CAR-T and BsAb indication modified: Start with therapy and continue for at least 6 months after the

infusion until end of therapy or until CD4 ≥200/mm3 (whichever is longer).

MYEL-L

• Treatment options, bullet removed: Use other plasma cell-directed therapy with caution.

• Bone-Modifying Agent Dosing in Patients with Multiple Myeloma who Have Renal Impairment Table

Dosing timing removed from table.

None row, Zoledronic Acid column entry modified: 4 mg IV every 3-4 wks 1–3 months.

• Footnote b modified: Consider other diagnosis such as amyloid and light chain disease for patients with significant proteinuria. Dimopoulos MA, et al.

Lancet Oncol 2023;24:e293-e311.

• Footnote removed: An FDA-approved biosimilar is an appropriate substitute.

MIDD-1

• Monoclonal Immunoglobulin Deposition Disease section added.

POEMS-2

• Treatment

Bullet 3 and sub-bullets modified:

◊ In patients who are not candidates for HCT transplant ineligible, options include:

– All regimens listed above– Lenalidomide/dexamethasone– Bortezomib/Dexamethasone– Melphalan/Dexamethasone– Cyclophosphamide/Dexamethasone– Pomalidomide/Dexamethasone

Header added: Useful in Certain Circumstances

◊ Bullet added: Myeloma systemic therapy options can be used in certain circumstances (see MYEL-G).

National Comprehensive Cancer Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

INITIAL DIAGNOSTIC WORKUPa

●History and physical (H&P) exam

●CBC,differential, and platelet count

●Peripheral blood smear

●Serum BUN/creatinine, electrolytes, liver function tests,album,b${}^{b}$ calcium, serum uric acid, serum lactate dehydrogenase(LDH),${}^{b}$ and beta-2 microglobulinb

●Creatinine clearance (calculated or measured directly)c

●Serum quantitative immunoglobulins, serum protein electrophoresis(SPEP), and serum immunofixation electrophoresis(SIFE)

●24-h urine for total protein, urine protein electrophoresis(UPEP),and urine immunofixation electrophoresis(UIFE)

●Serum free light chain (FLC) assay

●Whole-body FDG-PET/CT(preferred) or low-dose CTd

●Unilateral bone marrow aspirate and biopsy,including immunohistochemistry (IHC) and/or multi-parameter flow cytometry

●Plasma cell fluorescence in situ hybridization(FISH)b panel on bone marrow®[del(13), del(17p13),t(4;14),t(11;14),t(14;16),t(14:20),1q21 gain/1q21 amplification,1f1p deletion]

●Next-generation sequencing(NGS) to assess for TP53 mutation

●N-terminal prohormone B-type natriuretic peptide(NT-proBNP)/BNP9

aFrailty assessment should be considered in older adults.

See NCCN Guidelines for Older Adult Oncology.

bThese tests are essential for staging. See Disease Staging and Risk Stratification for Multiple Myeloma(MYEL-B).

cManagement of Renal Disease in Multiple Myeloma(MYEL-L).

dPrinciples of Imaging(MYEL-C).

CLINICAL FINDINGS

Useful in Certain Circumstances

●If whole-body low-dose CT or FDG-PET/CT is negative, consider whole-body MRI without contrast to discern smoldering myeloma from multiple myeloma (MM)d

●Tissue biopsy to confirm suspected plasmacytoma

●Echocardiogram

●Evaluation for light chain amyloidosis,if appropriate(See NCCN Guidelines for Systemic Light Chain Amyloidosis)

●Obtain baseline clonotype identification at diagnosis or store an aspirate sample for future clonotype identification to enable minimal residual disease(MRD) testing by NGS

●Serum viscosity

●Hepatitis B and hepatitis C testing and human immunodeficiency virus(HIV)screening as required

●Assess for circulating plasma cells as clinically indicated

●Renal biopsy if albuminuria or abnormal renal function

Solitary plasmacytoma(MYEL-2)

Smoldering myeloma(asymptomatic)i(MYEL-3)

Multiple myeloma(symptomatic)i(MYEL-4)

Significance,see MGRS-1$\bullet$ For Monoclonal Immunoglobulin Deposition Disease(MIDD),see MIDD-1$\bullet$ For Neurological Neurological Significance,see MGNS-1

Polyneuropathy,Organomegaly,Endocrinopathy, Monoclonal Protein, Skin Changes(POEMS-1)

eCD138-positive selected sample is strongly recommended for optimized yield.

f1q21 amplification is defined as≥4 copies detected by FISH, and a gain is defined as 3 copies of 1q21.

g If NT-proBNP is not available, BNP can be performed.

h Dimopoulos MA,et al. Lancet Oncol 2023;24:e293-e311.

i Definitions of Myeloma and Related Plasma-Cell Disorders(MYEL-A).

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

CLINICAL FINDINGS

PRIMARY TREATMENT

FOLLOW-UP/SURVEILLANCE

![Solitary plasmacytoma or\n8\nRt'±surgery^{m,n} \nRT^{l}±surgery^{m,n}\n8\nRt'sly 1±s\nSerum quantum tunioglobulins, SPEP, with SIFE\n8\nMultiple Myeloma\nSeral\n8\nRt'sly 1±s\nyery 2\n8\nRt'sly 1±s\nSerum quantum tunioglobulins, SPEP, with SIFE\n8\nRt'sly 1±s\nyery 2\n8\n\n00\nCorrene 0\n4\n\n\n8\nSolitary plasmacytoma with minimal marrow involvement1,k\nConsider clinical trial\nFollow-up interval, 6\n2-6\n months: 0\nCBC, differential, and platelet count\nSerum chemistry for creatinine and corrected calcium\n\nSerum quantitative immunoglobulins, SPEP, with SIFE\n\nMultiple SIFE\n\nSerum FLC assay\n●Serum quantitative immunoglobulins, SPEP, with SIFE\n\nSife\nProgressive Disease\nor\n\nor\nProgressive with UPEP with UIFE, as needed\nor\nResponse followed by workup\nResponse\nof\nMyeloma workup\n(MYEL-4)\nMultiple (MYEL-4)\nResponse\n\nProgressive\nwith\nmyeloma (symptomatic) (MYEL-4)\nMultiple (MYEL-4) workup\nResponse\nfollowed by progression^{q}\n](2/aj0YEe4oUhYkBdfpda0fYP/figurebe1aba25e8ff43649917c80d4bc890f3_0_7.png) d Principles of Imaging(MYEL-C).

J All criteria must be present for the diagnosis. For diagnostic criteria, see Definitions Myeloma and Related Plasma-Cell Disorders (MYEL-A).

${}^{k}$ Solitary plasmacytoma with 10% or more bone marrow plasma cells (BMPCs)is regarded as active (symptomatic) MM and systemic therapy should be considered. Consider FISH testing on plasmacytoma biopsy if clonal cells are absent or inadequate in the marrow.

${}^{1}$ Principles of Radiation Therapy(MYEL-D).

m Consider surgery if structurally unstable or if there is neurologic compromise due to mass effect.

${}^{n}$ Systemic therapy may be indicated in patients with high risk of progression based on the clinical context.

°Reassess after at least 3 months following radiation as the assessment of response with imaging may not be accurate if the scans are performed sooner.Patients with soft tissue and head/neck plasmacytoma could be followed less frequently as clinically indicated after initial 3-month follow-up.

P Whole-body FDG-PET/CT is the first choice for initial and continued evaluation of solitary extraosseous plasmacytoma. Whole-body MRI (or PET/CT if MRI is not available) is the first choice for initial evaluation of solitary osseous plasmacytoma (If whole-body MRI is not available, then consider MRI of the spine and pelvis, whole-body FDG-PET/CT, or low-dose whole-body CT).

q Response Criteria for Multiple Myeloma (MYEL-E).

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

CLINICAL FINDINGS

PRIMARY TREATMENT

FOLLOW-UP/SURVEILLANCE

![Smoldering myeloma (asymptomatic)is High riskrs.\nLow risk\nRisk\nor\nObserve at 3- to 6-month intervals (category 1)\nLow risk\nor\nObserve at 3-month intervals (expected 1)\nClinical trial'the preferred 4-month and 2013 intervals for 3-month intervals as clinically indicated s\nCheck patients: Daratumab (category 1)\nDaratumumab (loaded: Lenalidomide (category 2B)"\nEvery 3-6 months: CBC, differential, platelet count Creatinine, corrected calcium Serum quantitative immunoglobulins, SPEP, SIFE Serum FLC assay\n24-hour urine for total protein, UPEP, and UIFE as clinically indicated\nBone marrow aspirate and biopsy with FISH, NGS, or multi-parameter flow cytometry as clinically indicated sERum of TFE. \nUEE of DNA-MODE to contrast, whole-body MRI without contrast, low-dose CT, FDG-PET/CT annually or as needed, ideally with the same technique used at diagnosisd\nSee NCCN Guidelines for Survivorship\nMultiple Myeloma (symptomatic)Myeloma (symptomatic) (MYEL-4)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure8950a978ba6f4a8399dc3eaaa0b828a2_0_7.png) d Principles of Imaging(MYEL-C).

Definitions of Myeloma and Related Plasma-Cell Disorders (MYEL-A).

For risk criteria, refer to Lakshman A, et al. Blood Cancer J 2018;8:59 and Mateos MV,et al. Blood Cancer J 2020;10:102.

${}^{s}$ Patients with rising parameters are considered high risk and should be closely monitored.

${}^{t}$ The NCCN Panel strongly recommends enrolling eligible patients with smoldering myeloma in clinical trials.

${}^{u}$ Consider collection of hematopoietic stem cells for future use.

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

CLINICAL FINDINGS

PRIMARY TREATMENT

FOLLOW-UP/SURVEILLANCE

![## \n Initiate myeloma therapy w,x and bone-targeting treatmenty +\n Supportive care treatment as indicated for symptom managementc,y (also see NCCN Guidelines for Supportive Care)\n Laboratory assessments appropriate for monitoring treatmentactivities may include: complete blood count (CBC) with differential and metabolic panel\n - Serum quantitative immunoglobulins, SPEP, and SIFEbb \n 24 - hour urine for total protein, UPEP, and UIFEbb as clinically indicated\n System\neq, y (also also clinically for SACE)\n - Serum FLC assay\n - Whole-body MRI without contrast, low-dose CT, FDG-PET/CT annually or as clinically indicated, ideally with the same technique used at diagnosisd\n - Bone marrow aspirate and biopsy at relapse with FISH as clinically indicated \n - Bone marrow aspirate and biopsy at relapse with FISH as clinically indicated\n - Bone marrow aspirate, SPEP, and SIFEbb \n 24 - hour urine for total protein, UPEP, and UIFEbb as clinically indicated\n Response^\n Response^\n - Response\n After primary therapy (MYEL-5)\n $ (MYEL-6)\n 4 - System FLC assay\n](2/aj0YEe4oUhYkBdfpda0fYP/figureebf5a2b11e834532825416418d5325fb_0_7.png) c Management of Renal Disease in Multiple Myeloma(MYEL-L).

d Principles of Imaging(MYEL-C).

i Definitions Myeloma and Related Plasma-Cell Disorders(MYEL-A).

gResponse Criteria for Multiple Myeloma(MYEL-E).

vDisease Staging and Risk Stratification for Multiple Myeloma(MYEL-B).

w Myeloma Therapy(MYEL-G).

× See MYEL-F for considerations for myeloma therapy and for specific populations (eg, Black/African American individuals).

y Supportive Care Treatment for Multiple Myeloma (MYEL-I).

z Autologous transplantation: Category 1 evidence supports proceeding directly after primary therapy to high-dose therapy and HCT. Collecting stem cells and delaying HCT is also an option. See Discussion.

aa Renal dysfunction and advanced age are not contraindications to transplant.

bb Needed only if protein electrophoresis is negative during follow-up.

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

MULTIPLE MYELOMA(SYMPTOMATIC)

FOLLOW-UP/SURVEILLANCE

![\nResponse after primary therapy\nAutologous z, aa, cc,dd,ee\nHCT(category 1)\nMaintenance therapy\nstable disease^q\n(category 1)^{w,x,dd,ff\n\nResponse\nContinuous myeloma therapy\nor maintenance therapyw,x,dd,ff\nprimary\ntherapyq,cc\nUseful in Certain Circumstances\nfor patients with high risk of progression/relapse:\n\nTandem autologous or allogeneic HCTdd,ee\nContinuous myeloma therapy\nstable disease^q\nMaintenance therapy (category 1)^{w,x,dd,ff\n0\nnc}$$\|W(x, x, dd, ff\nprogressive therapy\nPerformance\nOKY-6.4\nNCCN\nGeneral dysfunction and advanced age are not contraindications to transplant. \n${cc}$\nPatients with stable disease can be considered for autologous HCT. \ndd Follow up with the tests listed on \`\`MYEL-4 under Follow-up/Surveillance. \nee Whole-body FDG-PET/CT is recommended around day 100 after autologous HCT.\nff The length of therapy should be balanced with toxicity and depth of response and disease status. \nMYEL-5\nMYEL-6\n](2/aj0YEe4oUhYkBdfpda0fYP/figurefa1e72b868a843ee88917ae4f8a7b7e4_0_6.png) 9Response Criteria for Multiple Myeloma(MYEL-E).

w Myeloma Therapy(MYEL-G).

× See MYEL-F for considerations for myeloma therapy and for specific populations (eg, Black/African American individuals).

zAutologous transplantation: Category 1 evidence supports proceeding directly after primary therapy to high-dose therapy and HCT. Collecting stem cells and delaying HCT is also an option. See Discussion.

${}^{a}$ Renal dysfunction and advanced age are not contraindications to transplant. ${ }_{c}^{\text {Renal dysfunction and advanced age are not contraindications to transplant. }}$CC Patients with stable disease can be considered for autologous HCT.

ee Whole-body FDG-PET/CT is recommended around day 100 after autologous HCT.

f The length of therapy should be balanced with toxicity and depth of response and disease status.

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

MULTIPLE MYELOMA(SYMPTOMATIC)

![Relapse^ or\n· Discuss the patient's preferences and goals of care\n-Chinese the patient's preferences and goals of care\n-Chimeric antigen receptor (CAR) T-cell therapy specialist\nChimeric antigen receptor (Palliative care specialist and supportive care' for symptom management (See NCCN Guidelines for Palliative Care) AND NCCN Guidelines for Supportive Care)\n Or\n Autologeneic HCTdd,gg\n Allogeneic HCTdd,gg/hh\n](2/aj0YEe4oUhYkBdfpda0fYP/figure3b6664e683fb48e2b43656c7ff08ec6a_0_5.png) Response Criteria for Multiple Myeloma(MYEL-E).

w Myeloma Therapy (MYEL-G).

See MYEL-F for considerations for myeloma therapy and for specific populations (eg, Black/African American individuals).

ySupportive Care Treatment for Multiple Myeloma (MYEL-H).

dd Follow up with the tests listed on MYEL-4 under Follow-up/Surveillance.

ggAss for HCT candidacy).

hh Donor lymphocyte infusion can be considered in patients with disease relapse after allogeneic HCT.

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma with CNS Disease

NCCN Guidelines Index Table of Contents Discussion

CLINICAL PRESENTATION OF CNS INVOLVEMENTa

![####Confusion,headache,visual visual symptoms,weakness,cranial nervebalsies palsies\nEssential - Brain and spine MRI with and without contrast.●Lumbar puncture with flow cytometry,cytopathology,cell count, total protein infections for use\n####Useful in Certain Circumstances\nBiopsy of affected tissue if above test results are negative and suspicion is high\n####High\nUseful in Certain Circumstances\nBiopsy of affected tissue if above test results are negative and suspicion is high\n\nMultimodality therapy (CNSM-2)\nand\n####Multimodality therapy CNSM-2)\n● Multimodality therapy (CNSM-2)\nwith flow cytometry,cytopathology,cell enhancement or enhancement or parenchymal lesions on MRI without definitive clonal plasma cells demonstrated\nFor example Diagnosis of skull or spinal plasmacytoma without meningeal infiltration and neurologic disease is not considered central nervous system (CNS) disease and should be treated per treatment guidelines for MM (MYEL-G)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure54cdd5b43834465ea0f25bc650ce4752_0_5.png) a Hyperammonemic encephalopathy is a rare presentation of myeloma-this is not considered CNS involvement and resolves with systemic plasma cell-directed therapy.In addition, hyperviscosity and hypercalcemia may also cause neurologic symptoms but is not considered CNS involvement. CNS involvement may occur as part of initial myeloma presentation or relapse with or without systemic involvement.

b Cerebrospinal fluid (CSF) SPEP is not appropriate for diagnosis of CNS disease in patients with MM.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

DEFINITIONS OF MYELOMA AND RELATED PLASMA-CELL DISORDERS

|Disease|Definition| |---|---| |Smoldering Myeloma a,b (Asymptomatic)|●Serum monoclonal protein ≥ 3 g/dL or ●Bence-Jones protein ≥ 500 mg/24 h and ●Clonal bone marrow plasma cells (BMPCs) 10%-59% and ●Absence of myeloma-defining events or amyloidosis| |Multiple Myeloma a,c (Symptomatic)|●Clonal BMPCs≥10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma- defining events: ● Myeloma-defining events: Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: $\diamond$ Hypercalcaemia: serum calcium>0.25 mmol/L(>1 mg/dL) higher than the upper limit of normal or $>2.75 mmol/L(>11 mg/dL) \diamond$ Renal insufficiency: creatinine clearance <40 mL per min or serum creatinine >177 μmol/L (>2 mg/dL) \diamond Anaemia: haemoglobin value of >20 g/L below the lower limit of normal, or a haemoglobin value <100 g/L \diamond Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT Anyone or more of the following biomarkers of malignancy: Clonal bone marrow plasma cell percentage ≥ 60% $\diamond$ Involved:uninvolved serum free light chain ratio ≥ 100 >1 focal lesions on MRI studies| |Solitary Plasmacytoma ${}^{a}$|●Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells ●Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion) ●Absence of myeloma defining events| |Solitary Plasmacytoma with minimal marrow involvement ${}^{a}$|$\bullet$ Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells ●Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion) ●Absence of myeloma defining events ●Clonal bone marrow plasma cells <10%| |Plasma Cell Leukemia|$\bullet$ Presence of $\geq 5\%$ of plasma cells in circulation|

a Adapted with permission from Rajkumar SV, Dimopoulos MA, Palumbo, A et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014;15:e538-e548.

bBMPCs>20%,M-protein>2 g/dL, and FLCr>20 are variables used to risk stratify patients at diagnosis. Patients with two or more of these risk factors are considered to have a high risk of progression to MM. Lakshman A, Rajkumar SV, Buadi FK, et al. Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J 2018;8:59.

c Other examples of active disease include: repeated infections, amyloidosis, light chain deposition disease, or hyperviscosity.

NCCN

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

DISEASE STAGING AND RISK STRATIFICATION SYSTEMS FOR MULTIPLE MYELOMA

|International Staging System (ISS)|Revised-ISS (R-ISS)1|R2-ISS2,a|IMS-IMWG3| |---|---|---|---| |ISS Stage I ·Serum beta-2 microglobulin <3.5 mg/L ·Serum albumin ≥3.5 g/dL|R-ISS Stage l ●ISS stage l and standard risk chromosomal l risk abnormalities by FISH ●Serum LDH ≤ the ULN ●Serum LDH ≤ the ULN ●Serum LDH ≤ the ULN|Low-risk:0 pointsb ●Not ISS stage Il or II ● Serum LDH ≤ the ULN ● del(17p),t(4;14),1q+:Not detected|Standard Risk ● All patients not meeting criteria for HR| |ISS Stage II ·Not ISS stage l or III|R-ISS Stage l ● Not R-ISS stage l or III|Low-intermediate risk: 0.5-1 pointsb ●ISS stage Il or ● Serum LDH > the ULN ● or ●del(17p) or t(4;14) or 1q+:Detected|Standard Risk ● All patients not meeting criteria for HR| |ISS Stage III ·Serum beta-2 microglobulin ≥5.5 mg/L|R-ISS Stage l ●.SS stage III ●And either high-risk chromosomal abnormalities [del(17p) or translocation (4;14) or translocation (14;16)] by FISH or Serum (14;16)] by FISH or serum LDH >the ULN|Intermediate-high risk: 1.5-2.5 pointsb ●Any combination of high-risk features that equals a score of 1.5-2.5|High-Risk IMS-IMWG ·Del(17p)(>20% of plasma cells) and/or TP53 mutation ● One of these translocations co- occurring with 1q+ and/or del(1p32): t(14;16) t(14;10) t(14;20) ● Monoallelic del(1p32) along with 1q+ or biallelic del(1p32) ●High $\beta$ 2M(>5.5 mg/dL) with normal creatinine(<1.2 mg/dL)| |||High-risk:3-5 pointsb ●Any combination of high-risk features that equals a score of 3-5|High-Risk IMS-IMWG ·Del(17p)(>20% of plasma cells) and/or TP53 mutation ● One of these translocations co- occurring with 1q+ and/or del(1p32): t(14;16) t(14;10) t(14;20) ● Monoallelic del(1p32) along with 1q+ or biallelic del(1p32) ●High $\beta$ 2M(>5.5 mg/dL) with normal creatinine(<1.2 mg/dL)|

1 Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for Multiple Myeloma: A Report from International Myeloma Working Group. J Clin Oncol 2015;33:2863-2869.

2D'Agostino M, Cairns DA, Lahuerta JJ, et al. Second revision of the international staging system(R2-ISS) for overall survival in multiple myeloma: A European Myeloma Network(EMN) report within the harmony project. J Clin Oncol 2022;40:3406-3418.

$^{3}$ Avet-Loiseau H, Davies FE, Samur MK, et al. International Myeloma Society/International Myeloma Working Group Consensus Recommendations on the Definition of High-Risk Multiple Myeloma. J Clin Oncol 2025:14) is

a R2-ISS is only validated for newly diagnosed Multiple Myeloma.

b For R2-ISS classification a numerical value is assigned to each risk factor based on their influence on OS: ISS-III is 1.5 points, ISS-II is 1 point, del(17p) is 1 point,t(4;14) is 1 point, 1q+ is 0.5 points, and serum LDH > the ULN is 1 point.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

DISEASE STAGING AND RISK STRATIFICATION SYSTEMS FOR MULTIPLE MYELOMA

|Factors Considered as High Risk for Progression/Relapse|| |---|---| |For Those with Newly Diagnosed MM|For Those with Relapsed MM| |●R-ISS III (MYEL-B 1 of 2) ● Extramedullary disease ●Circulating plasma cells ●Cytogenetic abnormalitiesc Del(1p32) t(4;14) t(14;16) t(14;20) Del(17p)/monosomy 17/TP53 mutation 1q21 gain/1q21 amplification,4 MYC translocation5 ●High-risk gene expression profile ●Markers of high proliferation rate|●Disease relapse within 2 years of initial therapy when transplant and maintenance are used. ●Relapse within 18 months in case of non-transplant-based treatment. ●Acquisition of 1q gain/amplification and/or del(17p)/TP53 mutation ●Extramedullary disease at relapse and/or circulating plasma cells|

$4\text{Schmidt TM, Fonseca R, Usmani SZ. Chromosome 1q21 abnormalities in}$ multiple myeloma. Blood Canc J 2021;11:83.

${}^{5}$ Abdullah N., BaughnL, Rajkumar SV, et al. Implications of MYC Rearangements in Newly Diagnosed Multiple Myeloma. Clin Cancer Res 2020;26:6581-6588.

${}^{c}$ Patients presenting with two or more of these cytogenetic abnormalities are considered to have very high risk of disease progression/relapse.

d Sole abnormality in $1 q 21$ is not considered a marker for high risk of progression/relapse.

Abstract

Note: All recommendations are category 2A unless otherwise indicated.

References

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF RADIATION THERAPY

Note: All recommendations are category 2A unless otherwise indicated.

MYEL-D 1 OF 2

Solitary Plasmacytoma

General Principles:

• Radiation therapy (RT) is the intervention of choice for solitary plasmacytoma.

• Treatment of solitary plasmacytomas should be performed using modern treatment principles including imaging-based delineation (MRI,CT with contrast, and/or FDG-PET/CT) of a gross tumor volume (GTV), clinical target volume (CTV), and planning target volume (PTV) and adjacent organs at risk (OARs). CTV expansions should generally include at least 0.5 cm of margin for microscopic extent, and up to 2–3 cm for involvement of long bones. PTV margins should be minimized using modern daily image guidance. Treatment of adjacent vertebral bodies for spine lesions is not required if there is no suspicion of clinical involvement.

• RT should be utilized with advanced technology (ie, intensity-modulated RT [IMRT], VMAT, protons) when these modalities can help limit

radiation doses to surrounding OARs. Principles of involved-site RT (ISRT) should be used to avoid large radiation fields and inappropriately

including uninvolved sites, which will increase the risk of toxicity.

Treatment Information/Dosing:

• Solitary plasmacytoma (MYEL-2)

RT (40–50 Gy in 1.8–2.0 Gy fractions [20–25 total fractions]) to involved site.

Treatment with 35–40 Gy is an acceptable alternative for solitary plasmacytomas <5 cm in size, due to the high rates of local control

reported for smaller tumors.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF RADIATION THERAPY

Multiple Myeloma

General Principles:

●Treatment recommendations should be made after joint consultation and/or discussion by a multidisciplinary team including surgical, radiation, and medical oncologists, and radiologists.

.RT is primarily used for palliation in patients with MM.

● Careful planning in defining the radiation field and radiation technique must be utilized to minimize toxicity to the spinal cord, brain, bone marrow, and adjacent OARs as patients may be treated multiple times during their disease course.

●Careful planning of radiation fields for cord compression in the thoracic area at the level of the heart should be utilized to avoid radiation dose exiting into the heart structures, which could lead to cardiac toxicity.

●If surgical intervention is not indicated for impending fracture, structural instability, or emergent decompression, it should be avoided to circumvent potential complications and delays in systemic therapy.RT can result in functional re-ossification in a large proportion of patients.

●For principles of RT for CNS disease in patients with MM, see Principles of Management of CNS Disease in Patients with MM(MYEL-H).

Timing and Sequencing of Therapy:

●Systemic therapy should not be delayed for RT. Data suggest that systemic therapy and palliative RT can be used concurrently without evidence of increased toxicity, but that patients should be carefully monitored for toxicities.

●If urgent surgical intervention is indicated,RT should be delivered postoperatively to improve pain control and prevent local recurrence. Patients in a resource-limited setting with access to systemic therapy may consider forgoing postoperative RT.

Palliative RT Dosing for MM:

●Low-dose RT(8 Gy x 1 fraction) or 20-30 Gy in 5-15 total fractions can be used as palliative treatment for indications such as uncontrolled pain, for impending pathologic fracture, or for impending cord compression. Moderately fractionated courses of 20-25 Gy in 8-10 fractions are generally preferred over higher doses (30 Gy) absent extenuating circumstances (eg, severe symptomatic cord compression) to limit toxicity risk and reduce future toxicity risk in the event additional irradiation is needed to adjacent or overlapping sites (eg, overlapping sites in the spine/spinal cord.

●Limited involved sites should be used to limit the impact of irradiation on hematopoietic stem cell harvest or impact on potential future treatments.

●For RT dose constraint suggestions regarding bone marrow and other OARs,see NCCN Guidelines for Hodgkin Lymphoma.

References

Elhammali A, Amini B, Ludmir EB, et al. New paradigm for radiation in multiple myeloma:Lower yet effective dose to avoid radiation toxicity. Haematologica 2020;105:e355-e357.

Guerini AE, Tucci A, Alongi F, et al. RR Myelo POINT: A Retrospective Single-Center Study Assessing the Role of Radiotherapy in the Management of Multiple Myeloma and Possible Interactions with Concurrent Systemic Treatment. Cancers(Basel).2022;14:2273.

Resende Salgado L, Wang S, Adler A, et al. The Safety Profile of Concurrent Therapy for Multiple Myeloma to

Tsang RW,Campbell BA,Goda JS,et al.Radiation Therapy for Solitary Plasmacytoma and Multiple Myeloma: Guidelines From the International Lymphoma Radiation Oncology Group Int J Radiat Oncol Biol Phys 2018;101:794-808.

Tsang RW,Gospodarowicz MK,Pintilie M,et al.Solitary plasmacytoma treated with radiotherapy: impact of tumor size on outcome. Int J Radiat Oncol Biol Phys 2001;50:113-120.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

RESPONSE CRITERIA FOR MULTIPLE MYELOMA

(Revised based on the new criteria by International Myeloma Working Group [IMWG])

|IMWG criteria for response assessment including criteria for minimal residual disease (MRD)|| |---|---| |Response Category|Response Criteria| |IMWG MRD criteria (requires a complete response as defined below)|| |Sustained MRD-negative|MRD negativity in the marrow (next-generation flow [NGF],next-generation sequencing [NGS],or both) and by imaging as defined below, confirmed minimum of 1 year apart. Subsequent evaluations can be used to further specify the duration of negativity (eg, MRD-negative at 5 years).| |Flow MRD-negative|Absence of phenotypically aberrant clonal plasma cells by NGFc on bone marrow aspirates using the EuroFlow standard operation procedure for MRD detection in multiple myeloma (or validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells or higher.| |Sequencing MRD-negative|Absence of clonal plasma cells by NGS on bone marrow aspirate in which presence of a clone is defined as less than two identical sequencing reads obtained after DNA sequencing of bone marrow aspirates using a validated equivalent method with a minimum sensitivity of 1 in 105 nucleated cells or higher.| |Imaging plus MRD-negative|MRD negativity as defined by NGF or NGS plus disappearance of every area of increased tracer uptake found at baseline or a preceding FGP-TCT or decrease to less mediastinal blood pool standardized uptake value (SUV) or decrease to less than that of surrounding normal tissue.e| |Standard IMWG response criteria|| |Stringent complete response|Complete response as defined below plus normal FLC ratio ${}^{9}$ and absence of clonal cells in bone marrow biopsy by immunohistochemistry (k/A ratio≤4:1 or ≥1:2 for k and /x patients, respectively, after counting ≥ 100 plasma cells).| |Complete response|Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow aspirates.| |Very good partial response|Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 h.| |Partial response|≥50% reduction of serum M-protein plus reduction in 24-h urinary M-protein by ≥90% or to <200 mg per 24 h. If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference between involved and uninvolved flC levels is required in place of the M-protein criteria. If serum and urine M-protein are unmeasurable, and serum-free light assay is also unmeasurable, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma-cell percentage was ≥30%. In addition to these criteria, if present at baseline, a ≥50% reduction in the size (sum of the products of the maximal perpendicular diameters [SPD] of measured lesions) of soft tissue plasmacytomas is also required.| |Minimal response|≥25% but ≤49% reduction of serum M-protein and reduction in 24-h urine M-protein by 50%-89%. In addition to the above listed criteria, if present at baseline, a 25%-49% reduction in SPD of soft tissue plasmacytomas is also required.|

Reprinted with permission from The Lancet Oncology, 17: Kumar S, Paiva B, Anderson K, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma, e328-e346, Copyright(2016), with permission from Elsevier.

Note: All recommendations are category 2A unless otherwise indicated.

Footnotes

MYEL-E 1 OF 3

NCCN Guidelines Index Table of Contents Discussion

National Comprehensive Cancer Cancer Network®

Multiple Myeloma

RESPONSE CRITERIA FOR MULTIPLE MYELOMA(Revised based on the new criteria by International Myeloma Working Group [IMWG])

|Standard IMWG response criteriaf (continued from previous page)|| |---|---| |Stable disease|●Not recommended for use as an indicator of response; stability of disease is best described by providing the time-to-progression estimates. Not meeting criteria for complete response, very good partial response, partial response, minimal response, or progressive disease.| |Progressive diseasekI|Any one or more of the following criteria: ●Increase of 25% from lowest confirmed response value in one or more of the following criteria: ●Serum M-protein (absolute increase must be≥0.5 g/dL); ●Serum M-protein increase ≥1 g/dL, if the lowest M component was ≥5 g/dL; ●Urine M-protein (absolute increase must be ≥200 mg/24 h); ●In patients without measurable serum and urine M-protein levels, the difference between involved and uninvolved FLC levels (absolute increase must be >10 mg/dL); ●In patients without measurable serum and urine M-protein levels and without measurable involved FLC levels, bone marrow plasma-cell percentage irrespective of baseline status (absolute increase must be ≥10%); ●Appearance of a new lesion(s), ≥50% increase from nadir in SPD of >1 lesion, or ≥50% increase in the longest diameter of a previous lesion >1 cm in short axis; ●≥50% increase in circulating plasma cells (minimum of 200 cells per $\mu$ L) if this is the only measure of disease.| |Clinical relapse|Clinical relapse requires one or more of the following criteria: ●Direct indicators of increasing disease and/or end organ dysfunction(calcium elevation, renal failure, anemia, lytic bone lesions [CRAB features]) related to the underlying clonal plasma cell proliferative disorder. It is not used in calculation of time to progression or progression-free survival but is listed as something that can be reported optionally or for use in clinical practice; ●Development of new soft tissue plasmacytomas or bone lesions (osteoporotic fractures do not constitute progression); ●Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a 50% (and ≥1 cm) increase as measured serially by the SPD of the measurable lesion; ●Hypercalcemia (>11 mg/dL); ●Decrease in hemoglobin of≥2 g/dL not related to therapy or other non-myeloma-related conditions; ●Rise in serum creatinine by 2 mg/dL or more from the start of the therapy and attributable to myeloma; ●Hyperviscosity related to serum paraprotein.| |Relapse from complete response (to be used only if the endpoint is disease-free survival)|Any one or more of the following criteria: ●Reappearance of serum or urine M-protein by immunofixation or electrophoresis; ●Development of≥5% plasma cells in the bone marrow; ●Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or hypercalcemia) (see above).| |Relapse from MRD negative (to be used only if the endpoint is disease-free survival)|Any one or more of the following criteria: ●Loss of MRD negative state (evidence of clonal plasma cells on NGF or NGS, or positive imaging study for recurrence of myeloma); ●Reappearance of serum or urine M-protein by immunofixation or electrophoresis; ●Development of ≥5% clonal plasma cells in the bone marrow; ●Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or hypercalcemia).|

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

RESPONSE CRITERIA FOR MULTIPLE MYELOMA FOOTNOTES

aAll response categories require two consecutive assessments made any time before starting any new therapy; for MRD there is no need for two consecutive assessments, but information on MRD after each treatment stage is recommended (eg, after induction, high-dose therapy/autologous HCT, consolidation, maintenance). MRD tests should be initiated only at the time of suspected complete response. All categories of response and MRD require no known evidence of progressive or new bone lesions if radiographic studies were performed. However, radiographic studies are not required to satisfy these response requirements except for the requirement of FDG-PET if imaging MRD-negative status is reported.

bSustained MRD negativity when reported should also annotate the method used (eg, sustained flow MRD-negative, sustained sequencing MRD-negative).

Cone marrow MFC should follow NGF guidelines. The reference NGF method is an eight-color two-tube approach, which has been extensively validated.The two-tube approach improves reliability, consistency, and sensitivity because of the acquisition of a greater number of cells. The eight-color technology is widely available globally and the NGF method has already been adopted in many flow laboratories worldwide. The complete eight-color method is most efficient using a lyophilised mixture of antibodies, which reduces errors, time, and costs. Five million cells should be assessed. The Flow Cytometry Method(FCM) method employed should have a sensitivity of detection of at least 1 in 10° plasma cells. Paiva B, Gutierrez NC, Rosinol L, et al, for the GEM (Grupo Espanolde MVM)/PETHEMA (Programa para el Estudio de la Terapeutica en Hemopatias Malignas) Cooperative Study Groups. High-risk cytogenetics and persistent minimal residual disease by multiparameter flow cytometry predict unsustained complete response after autologous stem cell transplantation in multiple myeloma. Blood 2012;119:687-691.

dDNA sequencing assay on bone marrow aspirate should use a validated assay.

eCriteria used by Zamagni and colleagues, and expert panel (IMPetUs; Italian Myeloma Criteria for PET Use). Baseline positive lesions were identified by presence of focal areas of increased uptake within bones, with or without any underlying lesion identified by CT and present on at least two consecutive slices. Alternatively, an SUV max=2.5 within osteolytic CT areas>1 cm in size,or SUV max=1.5 within osteolytic CT areas≤1 cm in size were considered positive. Imaging should be performed once MRD negativity is determined by MFC or NGS. Zamagni E, Nanni C, Mancuso K, et al. PET/CT improves the definition of complete response for multiple myeloma. skeletal progression in multiple myeloma. Clin Cancer Res 2015;21:4384-4390.

f Derived from international uniform response criteria for multiple myeloma.

Minor response definition and clarifications derived from Rajkumar and colleagues. When the only method to measure disease is by serum FLC levels: complete response can be defined as a normal FLC ratio of 0.26 to 1.65 in addition to the complete response criteria listed previously. Very good partial response in such patients requires a≥90% decrease in the difference between involved and uninvolved FLC levels. All response categories require two consecutive assessments made at any time before the institution of any new therapy; all categories also require no known evidence of progressive or new bone lesions or extramedullary plasmacytomas if radiographic studies were performed. Radiographic studies are not required to satisfy these response requirements. Bone marrow assessments do not need to be confirmed. Each category, except for stable disease, will be considered unconfirmed until the confirmatory test is performed. The date of the initial test is considered as the date of response for evaluation of time dependent outcomes such as duration of response. Durie BG, Harrousseau JL, Miguel JS, et al, for the International Myeloma Working Group. International uniform response criteria for multiple myeloma.Leukemia 2006;20:1467-1473.

9 All recommendations regarding clinical uses relating to serum FLC levels or FLC ratio are based on results obtained with the validated serum FLC assay.

Presence/absence of clonal cells on immunohistochemistry is based upon the k/A/L ratio.An abnormal k/A ratio by immunohistochemistry requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is k/A of>4:1 or

Special attention should be given to the emergence of a different monoclonal protein following treatment, especially in the setting of patients having achieved a conventional complete response, often related to oligoclonal reconstitution of the immune system.These bands typically disappear over time and in some studies have been associated with a better outcome. Also, appearance of monoclonal IgG k in patients receiving monoclonal antibodies should be differentiated from the therapeutic antibody.

J Plasmacytoma measurements should be taken from the CT portion of the PET/CT, or MRI scans, or dedicated CT scans where applicable. For patients with only skin involvement,skin lesions should be measured with a ruler. Measurement of tumor size will be determined by the SPD.

k Positive immunofixation alone in a patient previously classified as achieving a complete response will not be considered progression. For purposes of calculating time to progression and progression-free survival, patients who have achieved a complete response and are MRD-negative should be evaluated using criteria listed for progressive disease. Criteria for relapse from a complete response or relapse from MRD should be used only when calculating disease-free survival.

In the case where a value is felt to be a spurious result per physician discretion (eg, a possible laboratory error), that value will not be considered when determining the lowest value.

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

CONSIDERATIONS FOR MYELOMA THERAPY

Note: All recommendations are category 2A unless otherwise indicated.

MYEL-F 1 OF 2

General Principles:

• Systemic therapy should not be delayed for advanced imaging if diagnosis of active myeloma is otherwise clear.

• Quadruplet regimen is preferred. Based on functional status, patients may be started with a 2- or 3-drug regimen with additional drugs added as performance status improves.

• Consider dose modifications based on functional status and age.

• Consider discontinuing dexamethasone at earliest possible timepoint, based on response, frailty, and toxicity considerations.

• For additional supportive care while on myeloma therapy, see Supportive Care Treatment for Multiple Myeloma (MYEL-I).

Considerations for Special Populations:

• Older Adults

Frailty assessment should be considered in older adults. See NCCN Guidelines for Older Adult Oncology.

For the Myeloma Frailty Score Calculator developed by IMWG for the prognosis, see http://www.myelomafrailtyscorecalculator.net/1

• Black/African American Individuals

Black/African American individuals have the highest rate of myeloma of any race/ethnic group and twice the incidence of all other races

and ethnicities, earlier age at diagnosis, and present with more severe symptoms at diagnosis including increased anemia, higher calcium

levels, worse renal dysfunction, and more extramedullary disease at presentation.

The biology of myeloma in these individuals can also differ. Black/African American individuals are more likely to have chromosome 14

translocations such as t(11;14), t(14;16), and t(14;20), and are less likely to have high-risk mutations such as del17p and gain/amp 1q

compared to white individuals.

Decreased participation in clinical trials exists based on race, ethnicity and age, which leads to limited understanding of whether results of

the studies apply to all patients.

A study of outcomes of patients with MM showed that without disparities in the overall use of novel agents or autologous HCT, Black/

African American individuals and age <65 years had a superior median overall survival (OS) (7.07 years; 95% CI, 6.36–7.70 years) compared

with white patients (5.83 years; 95% CI, 5.44–6.09 years; P < .001) (Fillmore NR, et al. Blood 2019;133:2615-2618).

Toxicity of drugs can vary in Black/African American individuals, including hyperpigmentation of skin with use of IMiDs and higher risk for

cytokine release syndromes (CRS) during CAR T-cell therapy (Blevins F, et al. Blood 2020;136:23-24; Peres LC, et al. Blood Adv 2024;8:251-

259).

Due to these differences, in order to reflect populations most affected, it is recommended to conduct equitable and inclusive clinical trials.

1 Palumbo A, Bringhen S, Mateos MV, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: An International Myeloma Working Group report. Blood 2015;125:2068-2074.

NCCN

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

CONSIDERATIONS FOR MYELOMA THERAPY

Additional Consideration for Relapsed/Refractory Disease:

●Consideration for appropriate regimen in previously treated myeloma should be based on the context of clinical relapse.

●In order to maximize benefit of systemic therapy, agents/regimens may be reconsidered or repeated if relapse is after at least 6 months after stopping therapy.

●A new triplet regimen should preferably include drugs or drug classes in patients who have not been exposed to, or not exposed to for at least 6 months.

●Clinical trials with these triplet regimens primarily included patients who were naive or sensitive to the novel drug in the doublet comparator arm. Patients with disease refractory to the novel drug in the doublet backbone should be considered for triplet therapy that does not contain the drug they are progressing on.

●Immunoglobulin replacement should be considered for patients with an IgG<400 mg/dL a or at a higher level for supportive care as clinically indicated.(See MYEL-J)

●Patients may be candidates for TCR Therapy.(See MYEL-G).

For HCT and Stem Cell Storage:

●Exposure to myelotoxic agents (including alkylating agents and nitrosoureas) should be limited to avoid compromising stem cell reserve prior to stem cell harvest in patients who may be candidates for HCT.

●Consider harvesting autologous peripheral blood stem cells within the first 6 cycles of therapy initiation prior to prolonged exposure to lenalidomide and/or daratumumab in patients for whom HCT is being considered.

●If delayed HCT is considered, then autologous stem cells should be collected and stored.

Dosing and Administration:

●An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.

●Subcutaneous bortezomib is the preferred method of administration.

●Both weekly(preferred) and twice-weekly dosing schemas of bortezomib may be appropriate.

●Carfilzomib may be used weekly(preferred) or twice-weekly and at different doses.

●For any regimen that includes daratumumab, this could be daratumumab for intravenous infusion or daratumumab and hyaluronidase-fihj for subcutaneous injection. Daratumumab and hyaluronidase-fihj for subcutaneous injection has different dosing and administration instructions compared to daratumumab for intravenous infusion.

●Steroids should be reduced to 20 mg weekly in patients who are older and should be decreased or discontinued with treatment response plateau and/or toxicity.

Side Effects and Lab Interference:

●Daratumumab and isatuxim-irfc may interfere with serologic testing and cause false-positive indirect Coombs test.

●Type and screen should be performed before using daratumumab or isatuximab-irfc.

●Monoclonal antibodies can produce a false positive serum immunofixation if the monoclonal protein is IgG kappa and special interference testing or mass spectrometry based assessment can differentiate between the two.

●Carfilzomib can potentially cause cardiac,renal, and pulmonary toxicity,especially in patients who are older.

●Agents such as bendamustine can impact the ability to collect T cells for CAR T-cell therapy. See NCCN Guidelines for Management of Immunotherapy-Related Toxicities.

a In assessing the need for gammaglobulin replacement in patients with IgG myeloma, it is important to take into the account the portion of IgG that is clonal. To estimate the normal IgG levels, subtract the M spike value from the IgG.

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

MYEL-G 1 OF 5

PRIMARY THERAPY FOR HCT CANDIDATESa-d

Preferred

• Daratumumab/Lenalidomide/Bortezomib/Dexamethasone (category 1)

• Isatuximab-irfc/Bortezomib/Lenalidomide/Dexamethasone (category 1)

Other Recommended

• Bortezomib/Lenalidomide/Dexamethasone (category 1)

• Carfilzomib/Lenalidomide/Dexamethasone

• Daratumumab/Carfilzomib/Lenalidomide/Dexamethasone

• Isatuximab-irfc/Carfilzomib/Lenalidomide/Dexamethasone

Useful in Certain Circumstances

• Bortezomib/Cyclophosphamide/Dexamethasone

• Carfilzomib/Cyclophosphamide/Dexamethasonee

• Daratumumab/Bortezomib/Cyclophosphamide/Dexamethasone

• Dexamethasone/Thalidomide/Cisplatin/Doxorubicin/Cyclophosphamide/Etoposide/Bortezomibf (VTD-PACE)

MAINTENANCE THERAPYg Preferred

• Lenalidomideh (category 1)

Other Recommended

• Carfilzomib/Lenalidomideh

• Daratumumab/Lenalidomideh

Useful in Certain Circumstances

• Bortezomib ± Lenalidomideh

• Daratumumab

• Ixazomib (category 2B)

a Selected, but not inclusive of all regimens. The regimens under each preference category are listed by

order of NCCN Category of Evidence and Consensus alphabetically.

b Supportive Care Treatment for Multiple Myeloma (MYEL-I).c See MYEL-F for considerations for myeloma therapy and for specific populations (eg, Black/African

American individuals).

d Management of Renal Disease in Multiple Myeloma (MYEL-L).e Treatment option for patients with renal insufficiency and/or peripheral neuropathy.f Generally reserved for the treatment of aggressive MM.g Two-drug maintenance recommended for high-risk MM.h There appears to be an increased risk for secondary cancers, especially with lenalidomide maintenance following transplant. The benefits and risks of maintenance therapy versus secondary cancers should be discussed with patients.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

PRIMARY THERAPY IF HCT-DEFERRED OR IF HCT IS NOT INDICATEDa-d,j

In general, continue primary therapy until progression with de-escalation of therapy(modification of dose and duration) as needed.

Preferred

●Daratumumab/Lenalidomide/Dexamethasone(category 1)

●Daratumumab/Bortezomib/Lenalidomide/Dexamethasone(for patients<80 years old who are not frail)(category 1)

●Isatuximab-irc/Bortezomib/Lenalidomide/Dexamethasone(for patients<80 years old who are not frail)(category 1)

Other Recommendeded

●Carfilzomib/Lenalidomide/Dexamethasone

●Bortezomib/Lenalidomide/Dexamethasone(category 1)

●Isatuximab-irfc/Lenalidomide/Dexamethasone

Useful In Certain Circumstances

●Lenalidomide/Low-Dose Dexamethasone(category 1)

●Bortezomib/Cyclophosphamide/Dexamethasone

●Bortezomib/Dexamethasone

●Bortezomib/Lenalidomide/Dexamethasone(VRD-lite) for patients assessed as being frail

●Carflizomib/Cyclophosphamide/Dexamethasone

●Daratumumab/Cyclophosphamide/Bortezomib/Dexamethasone

●Isatuximab-irfc/Carfilzomib/Lenalidomide/Dexamethasone(category 2B)

●Ixazomib/Lenalidomide/Dexamethasone

●Lenalidomib-irfc/Carfilzomib/Lenalidomide/Dexamethasone

a Selected, but not inclusive of all regimens. The regimens under each preference category are listed by order of NCCN Category of Evidence and Consensus alphabetically.

b Supportive Care Treatment for Multiple Myeloma (MYEL-I).

c See MYEL-F for considerations for myeloma therapy and for specific populations (eg, Black/African American individuals).

d Management of Renal Disease in Multiple Myeloma(MYEL-L).

e Treatment option for patients with renal insufficiency and/or peripheral neuropathy.

i Strongly consider collecting and storing stem cells for future HCT.

Bortezomib or carfilzomib may be substituted with ixazomib in select patients in case of intolerance/logistical reasons.

NCCN

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

|THERAPY FOR PREVIOUSLY TREATED MULTIPLE MYELOMA${}^{a\text{-}d\text{-}l\text{-}o}$ Relapsed/Refractory Disease After 1-3 Prior Therapies||| |---|---|---| |Preferred* Order of regimens does not indicate comparative efficacy||| |Anti-CD38 Refractory|Bortezom-Refractory|Lenalidomide-Refractory| |●Carfilzomib/Lenalidomide/Dexamethasone (category 1)|●Carfilzomib/Lenalidomide/Dexamethasone(category 1)|●Daratumumab/Bortezomib/Dexamethasone(category 1)| |●Carfilzomib/Pomalidomide/Dexamethasone|●Daratumumab/Lenalidomide/Dexamethasone(category 1)|●Isatuximab-irfc/Carfilzomib/Dexamethasone(category 1)| |●Pomalidomide/Bortezomib/Dexamethasone (category 1)|●Isatuximab-irfc/Carfilzomib/Dexamethasone(category 1)|●Pomalidomide/Bortezomib/Dexamethasone(category 1)| |(category 1)|●Carfilzomib/Pomalidomide/Dexamethasone|●Carfilzomib/Pomalidomide/Dexamethasone| |After two prior therapies including|After one prior therapy including Lenalidomide and a PI|After one prior therapy including Lenalidomide and a PI| |Lenalidomide and a proteasome inhibitor(PI) Elotuzumab/Pomalidomide/Dexamethasone|●Daratumumab/Pomalidomide/Dexamethasone(category 1)|Daratumumab/Pomalidomide/Dexamethasone(category 1)| |After two prior therapies including an IMiD and a PI and with disease progression on/ within 60 days of completion of last therapy Ixazomib/Pomalidomide/Dexamethasone|After two prior therapies including Lenalidomide and a PI Isatuximab-irfc/Pomalidomide/Dexamethasone(category 1)|Itotuximab-irfc/Pomalidomide/Dexamethasone therapy| |△Ixazomib/Pomalidomide/Dexamethasone|After two prior therapy including IMiD and a PI, and refractory to lenalidomide Ciltacabtagene autoleuc(category 1)|Ixazomib/Pomalidomide/Dexamethasone|

*For Other Recommended regimens and for regimens Useful in Certain Circumstances for Relapsed/Refractory Disease After 1-3 Prior Therapies, see MYEL-G 4 of 5

aSelected, but not inclusive of all regimens.The regimens under each preference category are listed by order of NCCN Category of Evidence and Consensus alphabetically.

b Supportive Care Treatment for Multiple Myeloma (MYEL-I).

c See MYEL-F for considerations for myeloma therapy and for specific populations (eg, Black/African American individuals).

d -Management of Renal Disease in Multiple Myeloma (MYEL-L).

${}^{1}$ Regimens included under 1-3 prior therapies can also be used later in the disease course. Attempt should be made to use drugs/drug classes the patients have not been exposed to or exposed to>1 line prior.

m Autologous HCT should be considered in patients who are eligible and have not previously received HCT or had a prolonged response to initial HCT.

n In order to maximize benefit of systemic therapy, agents/regimens may be reconsidered or repeated if relapse is after at least 6 months of stopping therapy.

° Alkylating agents can impact the ability to collect T cells for CAR T-cell therapy.See NCCN Guideline for Management of Immunotherapy-Related Toxicities.

NCCN

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

|THERAPY FOR PREVIOUSLY TREATED MULTIPLE MYELOMaa-d,l-p Relapsed/Refractory Disease After 1-3 Prior Therapies|| |---|---| |Other Recommended|Other Recommended| |- Elotuzumab/Lenalidomide/Dexamethasone(category 1)|After two prior therapies including an IMiD and a PI| |- Ixazomib/Lenalidomide/Dexamethasone(category 1)|Belantamab mafodot-blmf/Bortezomib/Dexamethasone(category 1)| |- Selinexor/Bortezomib/Dexamethasone(category 1)|After two prior therapies including an IMiD and a PI| |- Bortezomib/Cyclophosphamide/Dexamethasone|progression on/within 60 days of completion of last therapy| |- Carfilzomib/Cyclophosphamide/Dexamethasone|Pomalidomide/Cyclophosphamide/Dexamethasone(category 1)| |- Daratumumab/Cyclophosphamide/Bortezomib/Dexamethasone|Doxamethasone| |- Daratumumab/Carfilzomib/Pomalidomide/Dexamethasone|| |- Elotuzumab/Bortezomib/Dexamethasone|| |- Ixazomib/Cyclophosphamide/Dexamethasone|| |●Lenalidomide/Cyclophosphamide/Dexamethasone|| |Useful in Certain Circumstances|| |-|Bortezomib/Dexamethasone(category 1)| |-|Pomalidomide/Dexamethasone(category 1)| |●Carfilzomib/Cyclophosphamide/Thalidomide/Dexamethasone|Selinexor/Pomalidomide/Dexamethasone| |●Selinexor/Carfilzomib/Dexamethasone|For treatment of aggressive MM| |●Selinexor/Daratumumab/Dexamethasone|Dexamethasone/Cyclophosphamide/Etoposide/Cisplatin(DCEP)| |●Venetoclax/Dexamethasone± Daratumumab or PI only for t(11;14)|Dexamethasone/Thalidomide/Cisplatin/Doxorubicin/Cyclophosphamide/ patients(Etoposide(DT-PACE)±Bortezomib(VTD-PACE)| ||After at least three prior therapies including a PI and an IMiD or are double-refractory to a PI and an IMiD|

a Selected, but not inclusive of all regimens. The regimens under each preference category are listed by order of NCCN Category of Evidence and Consensus alphabetically.

m Autologous HCT should be considered in patients who are eligible and have not previously received HCT or had a prolonged response to initial HCT.

b Supportive Care Treatment for Multiple Myeloma (MYEL-I).

c See MYEL-F for considerations for myeloma therapy and for specific populations (eg, Black/African American individuals).

nIn order to maximize benefit of systemic therapy, agents/regimens may be reconsidered or repeated if relapse is after at least 6 months of stopping therapy.

d Management of Renal Disease in Multiple Myeloma(MYEL-L).

Regimens included under 1-3 prior therapies can also be used later in the disease course. Attempt should be made to use drugs/drug classes the patients have not been exposed to or exposed to >1 line prior.

° Alkylating agents can impact the ability to collect T cells for CAR T-cell therapy.See NCCN Guideline for Management of Immunotherapy-Related Toxicities.

P Consider single-agent lenalidomide or pomalidomide for patients with steroid intolerance.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

|THERAPY FOR PREVIOUSLY TREATED MULTIPLE MYELOMA a-d,l-o Relapsed/Refractory Disease After 3 Prior Lines of Therapy|| |---|---| |Preferred|| |CAR T-cell Therapy:|| |Ciltacabtagene autoleucel|| |Idecabtagene vicleucel|| |After at least four prior therapies, including an anti-CD38 monoclonal antibody, a Pl, and an IMiD|| |Bispecific Antibodies(BsAb)r:|| |Elranatamab-bcmm|| |Linvoseltamab-gcpt|| |Talquetamab-tgvs|| |Teclistamab-cqyv|| |Other Recommendeded|Other Recommendeded| |●High-Dose or Fractionated Cyclophosphamide|| |After at least four prior therapies and whose disease is refractory to at least two Pls, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody|| |●Selinexor/Dexamethasone|| |Useful in Certain Circumstances|| |●Belantamab mafodotin-blmf|| |●Bendamustine|| |●Bendamustine/Carfilzomib/Dexamethasone|| |●Bendamustine/Lenalidomide/Dexamethasone|| |●Talquetamab+ Teclistamab||

a Selected, but not inclusive of all regimens. The regimens under each preference category are listed by order of NCCN Category of Evidence and Consensus alphabetically.

m Autologous HCT should be considered in patients who are eligible and have not previously received HCT or had a prolonged response to initial HCT.

n In order to maximize benefit of systemic therapy, agents/regimens may be reconsidered or repeated if relapse is after at least 6 months of stopping therapy.

°Alkylating agents can impact the ability to collect T cells for CAR T-cell therapy.See NCCN Guideline for Management of Immunotherapy-Related Toxicities.

b Supportive Care Treatment for Multiple Myeloma(MYEL-I).

c See MYEL-F for considerations for myeloma therapy and for specific populations(eg, Black/African American individuals).

${}^{9}$ Patients can receive more than one B-cell maturation antigen(BCMA) targeted therapy. Optimal sequencing of sequential BCMA targeted therapies is not known;however accumulated data suggests immediate follow on with second BCMA directed therapy after relapse may be associated with lower response rates

d Management of Renal Disease in Multiple Myeloma(MYEL-L).

r Prophylactic tocilizumab may be considered prior to first dose to reduce the risk of CRS.

National Comprehensive Cancer Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma with CNS Disease

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF MANAGEMENT OF CNSDISEASE IN PATIENTS WITH MM

General

●Multimodality therapy (radiation and systemic therapy) has been associated with improved outcomes.

●Incorporation of palliative care along with multimodal therapy is strongly recommended.

Radiation Therapy (RT)

.RT can be part of multimodality therapy.

●Focal RT can be used to rapidly reverse or prevent progression of focal neurologic deficits resulting from localized disease within the brain, spine, or cranial nerves while awaiting further workup or if alternative therapies are not immediately available.

●Whole brain radiation therapy (WBRT) can be considered for patients with poorly localized or cranial nerve disease.

Doses of WBRt ≤23.4 Gy in 13 fractions are associated with low toxicity.

Consider adding craniosinal irradiation (CSI) for patients with negative or otherwise well-controlled extra-CNS involvement.

If using CSI: conformal volumetric modulated arc therapy (VMAT)or protons can spare bone marrow.

◇CSI serves as an effective bridge to consolidation therapy like CAR T-cell therapy or autologous HCT.

Intratheal(IT) Chemotherapy

●Consider as part of multimodality therapy.

●Concurrent IT Methotrexate and radiation can increase risk of myelopathy and should be given no less than 2 weeks apart.

●Other concurrent combinations such as T-Cell Redirecting (TCR)therapies and systemic therapy are considered safe.

●Recommended IT regimens:

Thiotepa/Hydrocortisone

Methotrexate/Cytarabine/Hydrocortisone

Systemic Chemotherapy

●Systemic chemotherapy can be considered in combination with immunomodulatory drug (IMiD) as part of multimodal therapy if there are no other alternatives.

●Limited data on efficacy supports the use of systemic chemotherapy (high-dose methotrexate, cytarabine, or bendamustine).Bendamustine and other alkylating agents can impact the ability to collect T cells for CAR T-cell therapy. See NCCN Guidelines for Management of Immunotherapy-Related Toxicities.

Novel Agents

●Consider as part of multimodality therapy (with IT chemotherapy and RT).

IMiDs

◆ Blood brain barrier penetration has been observed clinically with pomalidomide and lenalidomide.

●Retrospective studies incorporating IMiDs have demonstrated improved outcomes.

Selinexor

Can penetrate blood brain barrier but has not been tested in management of CNS disease in patients with MM.

Venetoclax

◇ Preclinical data supports blood brain barrier penetration.

Consider in t(11;14) if no other options are available.

Immunotherapy: CAR T-cell and BsAb Therapy

A history of treated CNS disease should not preclude use of CAR T-cell and BsAb therapy.

$\diamond$ CAR T-cell and BsAb therapies may be useful as consolidative therapy to treat extra-CNS disease in patients receiving multi-modality CNS-directed therapy, including RT.

◆In general, there is limited data available regarding the ability of current immunotherapies to penetrate the CNS.

Monoclonal antibody (mAbs) therapy

○In general there is limited data of mAbs to penetrate blood brain barrier

$\diamond$ Can use if systemic therapy required, but no clear data to support use in management of CNS disease in patients with myeloma.

●Proteasome inhibitors(PI)

●Commercially available agents exhibit limited penetration of the blood brain barrier.

●No clear signal for activity of PI in CNS disease.

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

SUPPORTIVE CARE FOR MULTIPLE MYELOMA

Bone Disease

●All patients receiving primary myeloma therapy should be given bone-targeting treatment(bisphosphonates[category 1a] or denosumabb).

A baseline dental exam is strongly recommended.

Assess vitamin D status.

●Monitor for renal dysfunction with use of bisphosphonate therapy.

Monitor for osteonecrosis of the jaw.

●Continue bone-targeting treatment(bisphosphonates or denosumab) for up to 2 years.The frequency of dosing(monthly vs. every 3 months) would depend on the individual patient criteria, response to therapy, and agent used.Continuing beyond 2 years should be based on clinical judgment.

Patients receiving denosumab for bone disease who subsequently discontinue therapy should be given maintenance denosumab every 6 months or a single dose of bisphosphonate to mitigate risk of rebound osteoporosis.c

●DEXA scans are not useful to assess myeloma bone disease.

●For RT recommendations see Principles of Radiation Therapy(MYEL-D).

●Orthopedic consultation should be sought for impending or actual long-bone fractures or bony compression of spinal cord or vertebral column instability.

●Consider vertebroplasty or kyphoplasty for symptomatic vertebral compression fractures.

Hypercalcemia

●Hydration,bisphosphonates (zoledronic acid preferred),denosumab,steroids, and/or calcitonin are recommended.

Hyperviscosity

●Plasmapheresis should be used as adjunctive therapy for symptomatic hyperviscosity.

Anemia

●See NCCN Guidelines for Hematopoietic Growth Factors.

●Consider erythropoietin for anemic patients.d

Infections

●See NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.

●See CDC for Use of COVID-19 Vaccines in the US.

●For prophylaxis and management of infections in patients with multiple myeloma, see MYEL-J.

Renal Dysfunction

●See Management of Renal Disease in Multiple Myeloma (MYEL-L).

Venous Thromboembolism(VTE)

●For management of VTE,risk stratification, and VTE prophylaxis, see MYEL-K.

a Both pamidronate and zoedronic acid have shown equivalence in terms of reducing risk of skeletal-related events in randomized trials.

b Denosumab is preferred in patients with renal insufficiency, caution for risk of hypocalcemia.

cThis is based on observations with denosumab discontinuation in non-myeloma settings.Cummings SR,Ferrari S,Eastell R,et al. Vertebral fractures after discontinuation of denosumab: A post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res 2018;33:190-198.

d Increased risk of VTE has been reported in patients receiving erythropoiesis-stimulating agents(ESAs).

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

MANAGEMENT OF INFECTIONS IN PATIENTS WITH MULTIPLE MYELOMA1

For additional recommendations on infection management, see NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections

Factors associated with increased infection risk in patients with MM

|Infection Risk|Increased Device Infection Risk|Increased Bacterial Infection Risk|Increased Viral Infection Risk|Increased Fungal Infection Risk| |---|---|---|---|---| |Contributing Factors|● Autologous HCT ● BsAb therapy ● CAR T-cell therapy ●CD38 antibodies ● Cytotoxic chemotherapy|● Diagnosis of MM ● BsAb therapy ● CAR T-cell therapy|● Proteasome inhibitors ● Monoclonal antibodies ●BsAb therapy ● CAR T-cell therapy|● High-dose steroids ● Prolonged Neutropenia ●BsAb therapy ● CAR T-cell therapy|

|Common Bacterial Infections|Indication & Duration|||| |---|---|---|---|---| |Interventions & Prophylaxis|Indication & Duration|||| |Interventions & Prophylaxis|CAR-T|BsAb|AutoHCT|Other Indications| |Levofloxacin: 500 mg PO daily Alternatives: Cefdinir 300 mg PO twice a day or augmentin 875 mg PO twice a day|Start when ANC < 500 or per clinician discretion and continue until neutrophil recovery.|Start when ANC < 500 or per clinician discretion and continue until neutrophil recovery.||Newly diagnosed MM: Consider levofloxacin for 12 weeks after diagnosis. ${}^{2}$| |Immunoglobulin replacement|After CAR T-cell therapy, regular IVIG infusions based on clinical context.|Consider for the duration of BsAb therapy||For IgG <400 mg/dL and/ or recurrent life-threatening infections. ${}^{a}$| |Pneumococcal vaccination|Revaccination starting 3-6 months after treatment.|Update vaccination status prior to starting BsAb treatment.|Revaccination starting 3-6 months after treatment.|The CDC recommends1 dose of PCV20 or 1 dose of PCV15 followed by 1 dose of PPSV23 at least 1 year later.|

a In assessing the need for gammaglobulin replacement in patients with IgG myeloma, it is important to take into the account the total portion of IgG that is derived from clonal plasma cells. To estimate the normal IgG levels, subtract the M spike value for the IgG. If IgG<400 mg/dL, is not polyclonal, than replacement can be considered.

1 Mohan M,et al.Blood Adv.2022;6:2466-2470.

2 Drayson MT,et al. Lancet Oncol 2019;20:1760-1772.

NCCN

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

MANAGEMENT OF INFECTIONS IN PATIENTS WITH MULTIPLE MYELOMA1

For additional recommendations on infection management, see NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections

|Common Viral and Fungal Infections||||| |---|---|---|---|---| |Interventions & Prophylaxis|Indication & Duration|||| |Interventions & Prophylaxis|CAR-Tb|BsAbb|AutoHCT|Other Indications| |Herpes simplex virus or Varicella-zoster virus: Acyclovir 400-800 mg PO twice/day or valacyclovir 500 mg PO once or twice/ day.|A minimum of 1 year; indefinite (preferred), irrespective of uncertainty status.|Indefinite, irrespective of vaccination status.|For 1 year post-HCT or as clinically indicated.|While receiving a regimen with Pls or monoclonal antibody and for at least 3 months beyond end of therapy or per institutional practice.| |Hepatitis B virus and HIV: Screening|● HBsAg-positive ● HBsAg-negative ● HBcAb-IgG positive ● See NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections for HBV and HIV treatment|See NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections for HBV and HIV treatment||| |Pneumocystis jirovcell pneumonia (PJP): Trimethoprim-sulfamethoxazole (TP-SMX) therapy or pentamidine or atovaquone|Start with therapy and continue for at least 6 months after the infusion or until CD4 ≥200/mm3 (whichever is longer).|When equivalent dexamethasone dosing is >40 mg/day for 4 days per week or as clinically indicated per institutional practice.||| |SARS-CoV-2: COVID-19 vaccination|See The CDC's Staying Up to Date with COVD-19 Vaccines for specific guidance and see NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections for treatment.|||| |Influenza virus: Vaccination|Per CDC for patients who are immunosuppressed.|||| |RSV: Bivalent vaccine|●Single dose of bivalent vaccine for patients with MM aged ≥60 years. ● See CDC guidance for all other patient populations.|||| |CMV: Prophylaxis|●Monitor viral load (by PCR) only in patients with suspected CMV-related disease (eg, colitis, pneumonitis, hepatitis) or otherwise unexplained fever and/or cytopenias or in patients with high risk of infections.b ● See NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections for Treatment of Cancer-Related Infections for treatment indication and treatment duration.|||| |Adenovirus, EBV,JCV, parvovirus: No prophylaxis|Routine monitoring of viral load is not recommended.|||| |Yeast: Fluconazole 400 mg PO daily|Start when ANC < 500 or per clinician discretion and continue until neutrophil recovery.|||| |Mold: Azole|In patients with high risk of infectionsb: Consider ongoing prophylaxis with anti-mold azole.||||

b Patients receiving CAR T-cell and BsAb treatment, recipients of>1 dose of tocilizumab, use of second line agents such as anakinra or siltuximab for management of CRS and ICANS, prolonged and/or high-dose steroid use(requiring>3 days of 10 mg dexamethasone per day with a 7-day period or receiving higher doses of methylprednisolone>1 g per day) are at high risk of infection.

1 Mohan M, et al. Blood Adv 2022;6:2466-2470.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

MANAGEMENT OF VENOUS THROMBOEMBOLISM(VTE) IN MULTIPLE MYELOMA

VTE RISK STRATIFICATION USING IMPEDE OR SAVED SCORING SYSTEM

|IMPEDE Score1 for Risk Stratification (points assigned)|||| |---|---|---|---| |Individual Risk Factors|Points|Myeloma Risk Factors|Points| |Positive Factors|Positive Factors|Positive Factors|Positive Factors| |Central venous catheter/Tunneled central line|+2|Immunomodulatory drug(IMiD)|+4| |Pelvic, hip, or femur fracture|+4|Erythropoiesis-stimulating agent|+1| |Obesity (body mass index ≥25)|+1|Dexamethasone ≤160 mg/month|+2| |Previous VTE|+5|Dexamethasone >160 mg/month|+4| |||Doxorubicin or multiagent chemotherapy|+3| |Negative Factors|Negative Factors|Negative Factors|Negative Factors| |Ethnicity/Race = Asian/Pacific Islander|-3||| |Existing thromboprophylaxis: prophylactic LMWH (low-molecular-weight heparin) or aspirin|-3||| |Existing thromboprophylaxis: therapeutic LMWH or warfarin|-4|||

|SAVED Score2 for Risk Stratification| |---| |Variable| |Surgery within 90 days| |Asian race| |VTE history| |Age≥80 years| |Dexamethasone(regimen dose) ●Standard dose(120-160 mg/cycle) ●High dose(>160 mg/cycle)|

1Adapted with permission from Sanfilippo KM, et al. Am J Hematol 2019;94:1176-1184.

2 Adapted with permission from Li A, et al. J Natl Compr Canc Netw 2019;17:840-847.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

MANAGEMENT OF VENOUS THROMBOEMBOLISM(VTE) IN MULTIPLE MYELOMA

General Principles:

●The highest risk for VTE is in the first 6 months following new diagnosis of MM.

●VTE prophylaxis is administered assuming there are no contraindications to anticoagulation agents or anti-platelets(see VTE-A within the NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease).

●All anticoagulants carry increased risk of bleeding; careful consideration needs to be made regarding risks and benefits for each patient.

●Warfarin at international normalized ratio(INR) 2-3 is not directly comparable to the other agents listed at prophylactic doses with respect to bleeding and thrombotic risks.

●Patients already on therapeutic anticoagulants for other reasons(eg, atrial fibrillation) should continue anticoagulation therapy.

●If no other coagulopathy, full-dose anticoagulation is contraindicated with thrombocytopenia<50,000/μL; in patients with high risk for VTE, prophylactic anticoagulation may be appropriate even if platelet count is as low as 25,000/μL.

●Indications for long-term anticoagulation include unprovoked VTE or provoked VTE in the presence of a risk factor that is still present.

●For any patients who develop VTE on IMID-based therapy, continue using therapeutic dose anticoagulants for as long as IMiD-based therapy is indicated.

Factors Impacting the Choice of Optimal VTE Prophylaxis Agent:

●Bleeding risk(eg, concurrent coagulopathy, disseminated intravascular coagulation, hyperviscosity)

●Cytopenias(eg, platelet count± hemoglobin)

●Concurrent medications(eg, strong cytochrome P inducers/inhibitors, single/dual anti-platelets)

●Current renal function(eg, creatinine clearance)

●Patient choice(eg, preference for mode of administration, dietary restrictions)

●Insurance coverage/restrictions(including cost of therapy)

● Availability of reversal agents in case of emergency bleeding

● History of heparin-induced thrombocytopenia

● Extremes of body weight

●Carflizombib+IMID therapy

References

Carrier M,Abou-Nassar K,Mallick R,et al.Apixaban to Prevent Venous

Khorana AA, Soff GA, Kakkar AK, et al. Rivaroxaban for Thrombophyraxis in High-Risk Ambulatory Patients with Cancer. N Engl J Med 2019;380:720-728.

Kristinson SY. Thrombosis in multiple myeloma. Hematology Am Soc Hematol Educ Program 2010;2010:437-444.

Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2008;22:414-423.

Piedra K, Peterson T,Tan C,et al. Comparison of venous thromboembolism incidence in newly diagnosed multiple myeloma patients receiving bortezomib, lenalidomide, dexamethasone(RVD) or carfilzomib, lenalidomide,dexamethasone(KRD) with aspirin or rivaroxaban thromboprophylaxis. Br J Haematol 2022;196:105-109.

Wang TF, Zwicker JI,Ay C,et al.The use of direct oral anticoagulants for primary thromboprophylaxis in ambulatory cancer patients: Guidance from the SSC of the ISTH.J Thromb Haemost.2019;17:1772-1778.Note: The AVERT apixaban trial had only 2.6% myeloma patients, and myeloma patients were excluded from the CASSINI rivaroxaban trial.

Continued

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

MANAGEMENT OF VENOUS THROMBOEMBOLISM(VTE) IN MULTIPLE MYELOMA RECOMMENDATIONS FOR VTE PROPHYLAXIS

|VTE Prophylaxis Recommendations|| |---|---| |≤3 Points by IMPEDE Score or <2 Points by SAVED Score|≥4 Points by IMPEDE Score or ≥2 SAVED Scorea| |● Aspirin 81-325 mg once daily|● LMWH (equivalent to enoxaparin 40 mg daily) OR ● Rivoxaban 10 mg daily OR ● Rivoxaban 10 mg daily OR ● Apixaban 2.5 mg twice daily OR ● Fondaparinux 2.5 mg daily OR ● Warfarin (target INR, 2.0-3.0)|

Duration of VTE Prophylaxis

●Indefinite while on myeloma therapy

- 3-6 months followed by aspirin (longer periods of anticoagulation may be considered in the presence of additional patient, treatment-specific, or transient VTE risk factors)

aA less common choice of agent includes dalteparin 5000 units subcutaneously(SC) daily(category 2B).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

MANAGEMENT OF RENAL DISEASE IN MULTIPLE MYELOMAa

Testsb

Supportive Care

●Provide hydration to dilute tubular light chains; goal urine output is 100-150 cc/h

•Serum creatinine, electrolytes, and uric acid

●Urinalysis, electrolytes, and sediment

●Monitor fluid status

●24-hour urine collection for protein and UPEP/UIFE

●SPEP/SIFE and serum FLCs

●Treat hypercalcemia,hyperuricemia,and other metabolic abnormalities

●Consider renal ultrasound and renal biopsy.

●Discontinue nephrotoxic medications

Treatment Options

●Pulse dexamethasone

● Dialysis

Refractory electrolyte disturbances, uremia, and fluid overload

●Regimens containing bortezomib and/or daratumumab

•Can switch to other regimen once renal function has improved or stabilized

●Mechanical removal of serum FLCs with high cutoff dialysis filters or plasmapheresis may have a limited role. Systemic therapy should not be delayed if performing this procedure.

●See Response Criteria for Multiple Myeloma (MYEL-E)

●See Myeloma Therapy (MYEL-G)

●Renal dosing of all medications

Recommendations for Lenalidomide Dosing in Patients with Multiple Myeloma who Have Renal Impairment

|Category|Renal Function (Cockcroft-Gault CrCL)|Lenalidomide Dosing in Multiple Myeloma| |---|---|---| |Moderate renal impairment|CrCL≥30 mL/min to <60 mL/min|10 mg every 24 h| |Severe renal impairment|CrCL<30 mL/min (not requiring dialysis)|15 mg every 48 h| |End-stage renal disease|CrCL<30 mL/min (requiring dialysis)|5 mg once daily; on dialysis days, dose should be administered after dialysis|

Bone-Modifying Agent Dosing in Patients with Multiple Myeloma Who Have Renal Impairment

|Degree of Renal Impairment|Pamidronate (focal segmental glomerulosclerosis)|Zoledronic Acid (tubular cell toxicity)|Denosumab| |---|---|---|---| |None|90 mg IV every 3-4 wks|4 mg IV every 1-3 mo|120 mg SQ Q 4 wks| |Mild/moderate renal impairment|Use standard dose|Reduce dose|120 mg SQ Q 4 wks| |Severe renal impairment|60-90 mg|Not recommended|120 mg SQ Q 4 wksc|

a Defined as serum creatinine >2 mg/dL or established glomerular filtration rate(eGFR)<60 mL/min/1.73 sqm.

b Consider other diagnosis such as amyloid and light chain disease for patients with significant proteinuria. Dimopoulos MA, et al. Lancet Oncol 2023;24:e293-e311.

cPatients with creatinine clearance <30 cc/min can experience severe hypocalcemia and should be monitored.

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

MONOCLONAL GAMMOPATHY OF RENAL SIGNIFICANCE

![CLINICAL FINDINGS\nINITIAL WORKUP\n9455\nRenal biopsy. 2 recommended if: - Acute kidney injury - E.gFRC - 60 mL/min and - 2 mL/min per year decline\nAlbumin:creatinine>30 mg/mol\n● Pianconi: 经肉pland\n● Fanconi syndrome\n Consider renal biopsy if: - AKI stage 1 or 2 - eGFR < 60 mL/min and - 2 mL/min per year\n·Acute kidney injury\n established GFR (eGFR)● Urinalry is - Urinalry\n· Metabolic panel\n● Albumin: creatinine > 30 - OPEF 1(g/day) ● Albumin: creatinine > 30 - OPEF 1(g/td/0000000001888888888800000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000\n](2/aj0YEe4oUhYkBdfpda0fYP/figure52e5a81ea197438a97822dae42f0ca42_0_5.png) NCCN授权医脉通提供NCC指南全文下载。wmIsy2025/11/04,23:33在医脉通平台下载，仅供个人使用，严禁分发。2025美国国家综合癌症网络版权所有。

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

MONOCLONAL GAMMOPATHY OF RENAL SIGNIFICANCE

TREATMENT

●For plasma cell-related MGRS, use the management algorithm for MM (MYEL-4)

●For lymphoplasmacytic-related MGRS,see NCCN Guidelines for Waldenstrom Macroglobulinemia/Lymphoplasmacytic Lymphoma

●For any MGRS with monoclonal B-cell lymphocytosis (MBL) features, see NCCN Guidelines for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

RESPONSE ASSESSMENT

●For IgG- or IgA-associated MGRS, use the Response Criteria for MM (MYEL-E)

●For IgM-associated MGRS,use the response criteria for WM (See NCCN Guidelines for Waldenstrom Macroglobulinemia/Lymphoplasmacytic Lymphoma)

●For FLC-associated MGRS, use the response criteria for amyloidosis(See NCCN Guidelines for Systemic Light Chain Amyloidosis)

●For cases in which the causal monoclonal paraprotein is not detectable or is difficult to measure:

>evaluate renal function

evaluate bone marrow involvement or radiologic findings

Individualize treatment based on response and toxicity of prior therapy,patient's performance status, and renal function at the time of relapse

a Systemic agents associated with neurotoxicity should be used with caution.

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

MONOCLONAL IMMUNOGLUBIN DEPOSITION DISEASE

CLINICAL FINDINGS

![Monoclonal Immunoglobulin Deposition Diseases(MIDD) ● Light chain disease(LCDDD) or 90% are (MIDD) 80% (of which 80%-90% are Kappa LC) ● Heavy chain deposition disease(HCCDD) ~10% ● Light and heavy chain deposition chain deposition disease(LHCDD) ~10% ● Light and heavy chain deposition the(LHCDD) ~10% ● Peripheral blood flow cytometry for diagnosis of CLL/SLL or LPL (see NCCN Guidelines for Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma and NCCN Guidelines for Waldenstrom Macroglobulinemia/Lymphoplasmacytic Lymphoma) ● Organ involvement by frequency: kidney (~96%), heart (~21%), liver (~19%), peripheral nervous system (~8%). Note: All recommendations are category 2A unless otherwise indicated. ● Invol. All recommendations are category 2A a Nonlateral Energy at 2A A 2020A Sine CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN\n](2/aj0YEe4oUhYkBdfpda0fYP/figure0de9925ff5c14b02abe353e303845799_0_6.png) a Organ involvement by frequency: kidney(~96%), heart(~21%), liver(~19%), peripheral nervous system(~8%).

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

MONOCLONAL GAMMOPATHY OF NEUROLOGICAL SIGNIFICANCE

![IgMa MGNS (Monoclonal gammopathy of neurological has neurological(0-1)Gammopathy (0-1)Gamm2rel) of neurological localization of WM/LPL) 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 \n](2/aj0YEe4oUhYkBdfpda0fYP/figure122c44d6b15c418abed8db56df2de122_0_5.png) a In patients presenting with suspected disease related to peripheral/axonal neuropathy, rule out amyloidosis in patients presenting with nephrotic syndrome or unexplained cardiac problems.

b MYD88 wild-type occurs in<10% of patients and should not be used to exclude diagnosis of WM if other criteria are met.

NCCN

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

POLYNEUROPATHY,ORGANOMEGALY,ENDOCRINOPATHY,MONOCLONAL PROTEIN,SKIN CHANGES (POEMS)

INITIAL WORKUP

RECOMMENDED INITIAL TESTING

ADDITIONAL TESTING AS INDICATED

DIAGNOSIS

|● Complete H&P examination|●CT chest/abdomen/pelvis to document lymphena, pleural organomegaly, ascites, pleural effusion, edema|● Sural nerve biopsy|For management of POEMS syndrome, see POEMS-2| |---|---|---|---| |● Evaluate for organomegaly ●Fundoscopic exam ● Hyperhidrosis ● Diarrhea ● Weight loss ● Menstrual and sexual function ● Skin examination for hyperpigmentation, hypertrichosis, acrocyanosis, glomeruloid hemangiomata, plethora, flushing, clubbing, etc ● Detailed neurologic history(numbness,pain, weakness, balance, orthostasis) and exam (sensation and motor function)|●Testosterone, estradiol, fasting glucose, thyroid-stimulating hormone, parathyroid hormone, prolactin, serum cortisol, luteinizing hormone ●CBC, complete metabolic panel, serum immunoglobulins (IgG, IgA, IgM), electrophoresis and immunofixation, serum FLC, 24-h urine for total protein, UPEP, and UIFE, vascular endothelial growth factor (VEGF), and interleukin 6 (IL-6) Bone marrow aspirate and biopsy with FISH panel for myeloma . Echocardiography to assess right ventricular systolic and pulmonary artery pressures ●CT body bone windows and or FDG-PET/CT for sclerotic bone lesions|● For criteria for diagnosis, see POEMS-3 ● Sural nerve biopsy ●Follicle-stimulating hormone, adrenocorticotropin hormone, cosyntropin stimulation test ● Biopsy of bone lesion if needed ● Excisional lymph node biopsy, if Castleman disease or other B-cell lymphomas are suspected . FISH panel for myeloma myeloma . Evaluate for light chain amyloidosis, if appropriate (see NCCN Guidelines for Systemic Light Chain Amyloidosis)|If management of POEMS syndrome, see POEMS-2 ● For management of POEMS syndrome, see POEMS-2 ●Echnosis is MM, follow MM algorithm If diagnosis is WM, see NCCN Guidelines for WM/LPL If diagnosis is Castleman disease, see NCCN Guidelines and to FISH panel for Castleman Disease If diagnosis is Systemic Light Chain Amyloidosis, see Amyloidosis for Amyloidosis|

Adapted with permission: Dispenzieri A. Am J Hematol 2019;94:812-827.

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive NCCN Guidelines Version 3.2026 Cancer Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

POLYNEUROPATHY,ORGANOMEGALY,ENDOCRINOPATHY,MONOCLONAL PROTEIN,SKIN CHANGES (POEMS)

TREATMENT

RESPONSE ASSESSMENT

•RT alone to isolated bone lesion (<3 sites) in patients without clonal BMPC

•Autologous HCT in patients who are eligible as sole therapy or as consolidation after induction therapy

Induction therapy options include:

◆ Lenalidomide/Dexamethasone±Daratumumab

Bortezomiba,b/Dexamethasone

▶ Cyclophosphamide/Dexamethasone

Pomalidomide/Dexamethasone

•In patients who are not candidates for HCT,options include:

▶All regimen listed above

Melphalan/Dexamethasone

Useful in Certain Circumstances

●Myeloma systemic therapy options can be used in certain circumstances (MYEL-G)

See POEMS-4 for Response Criteria→ Progression

Individualize treatment based on response and toxicity of prior therapy and patient's performance status at the time of progression

a Bortezomib may cause exacerbation of neuropathy.

b Bortezomib may be replaced with carfilzombin in select patients.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

POLYNEUROPATHY,ORGANOMEGALY,ENDOCRINOPATHY,MONOCLONAL PROTEIN,SKIN CHANGES(POEMS)

|Table 1. Criteria for the Diagnosis of POEMS syndromea|| |---|---| |Mandatory major criteria|1. Polyneuropathy (typical demyelinating)| |Mandatory major criteria|2. Monoclonal plasma cell-proliferative disorder (almost always $\lambda$ )| |Other major criteria (one required)|3. Castleman diseaseb| |Other major criteria (one required)|4. Slerotic bone lesions| |Other major criteria (one required)|5. Vascular endothelial growth factor elevation| |Minor criteria|6. Organomegaly (splenomegaly, hepatomegaly, lymphadenopathy)| |Minor criteria|7. Extravascular volume overload (edema, pleural effusion, or ascites)| |Minor criteria|8. Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic)| |Minor criteria|9. Skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing, white nails)| |Minor criteria|10. Papilledema| |Minor criteria|11. Thrombocytosis/polycythemiai| |Other signs and symptoms|Clubbing,weight loss,hyperhidrosis,pulmonary hypertension,restrictive lung disease,thrombotic diatheses,diarrhea,low vitamin $B_{12}$ levels|

Reprinted with permission: Dispenzieri A. Am J Hematol 2019;94:812-827.

The diagnosis of POEMS syndrome is confirmed when both of the mandatory major criteria, one of the other three major criteria, and one of the six minor criteria are present.

a There is a Castleman disease variant of POEMS that occurs without evidence of a clonal plasma cell disorder that is not accounted for in this table. This entity should be considered separately.

b Because of the high prevalence of diabetes mellitus and thyroid abnormalities, this diagnosis alone is not sufficient to meet this minor criterion.

c Approximately 50% of patients will have bone marrow changes that distinguish it from a typical MGUS or myeloma bone marrow. Anemia and/or thrombocytopenia are distinctively unusual in this syndrome unless Castleman disease is present.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

POLYNEUROPATHY,ORGANOMEGALY,ENDOCRINOPATHY,MONOCLONAL PROTEIN,SKIN CHANGES (POEMS)

|Table 2. Response Criteria for POEMS Syndrome||||| |---|---|---|---|---| |Parameter|Evaluable|Complete Response|Improvement|Progressiona| |Plasma VEGF|2x ULN|Normalb|50% reduction from baseline|50% increase from lowest level| |Hematologic|M-spike 0.5 g/dL, c 1.0 g/dL,e|Negative serum and urine IFE and bone marrowb|50% reduction of M-spike from baselinef|25% increase from lowest level, which must be >0.5 g/dL| |PET/CT|At least one lesion with FDG SUV g|No FDG uptake|50% reduction in sum of SUV max g|30% increase in sum of SUV max g from lowest level which must be at least 4 SUV +9 OR appearance of new FDG avid lesion| |mNIS +7 POEMS|All patients|$$\begin{array}{l}\\ \\ \\ \\ \\ \\ \end{array}$$|15% decrease from baseline (a minimum of 10 points)|15% increase from lowest value (a minimum of 10 points)| |Ascites/effusion/edema|Present|Absent|Improved by 1 CTCAE grade from baseline|Worsened by 1 CTCAE grade from lowest grade| |ECHO RVSP|≥40 mm Hg|$$\begin{array}{l}\\ \\ \\ \end{array}$$|<40 mm Hg|| |Papilledema|Present||Absent|Worsening by 1 CTCAE grade| |DLCO|<70% predicted|≥70% predicted|$$\begin{array}{l}\\ \\ \\ \\ \end{array}$$|Worsening by 1 CTCAE grade|

Abbreviations:CTCAE,common terminology criteria for adverse events,IFE,immunofixation electrophoresis,ECHO RVSP,echocardiogram right ventricular systolic pressure,DLCO,diffusing capacity of carbon monoxide.

Reprinted with permission: Dispenzieri A. Am J Hematol 2019;94:812-827.

aAny progression event(VEGF, hematologic, or clinical will be considered progression, assuming change is attributable to disease and not an adverse event). To document progression, option exists for repeating value. If confirmed,progression date is first date of suspected progression.

d For PR evaluable.

e Quantitative IgA is acceptable surrogate for M-spike for proteins migrating in the beta region.

f VGPR is defined as no measurable monoclonal protein on serum or urine electrophoresis, but positive IFE.

b For VEGF, M-spike, and IFE response documentation, blood values need to be repeated for verification.

cFor VGPR evaluable.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

|ADL|activities of daily living| |---|---| |AKI|acute kidney injury| |ANC|absolute neutrophil count| |AS-PCR|allele-specific polymerase chain reaction| |BCMA|B-cell maturation antigen| |BMPC|bone marrow plasma cell| |BNP|b-type natriuretic peptide| |BUN|blood urea nitrogen| |BsAb|bispecific antibody| |CAR|chimeric antigen receptor| |CBC|complete blood count| |CLL|chronic lymphocytic leukemia| |CMV|cytomegalovirus| |CNS|central nervous system| |CrCl|creatinine clearance| |CRS|cytokine release syndromes| |CSF|cerebrospinal fluid| |CSI|cranospinal irradiation| |CTCAE|common terminology criteria for adverse events| |CTV|clinical target volume|

|DLCO|diffusing capacity of the lung for carbon monoxide| |---|---| |EBV|Epstein-Barr virus| |ECHO|echocardiogram| |eGFR|estimated glomerular filtration rate| |EMG|electromyogram| |ESA|erythropoiesis-stimulating agent| |BMCP|b-type natriuretic peptide| |BUN|blood urea nitrogen| |BsAb|bispecific antibody| |CAR|chimeric antigen receptor| |CBC|complete blood count| |CLL|chronic lymphocytic leukemia| |CMV|cytomegalovirus| |CNS|central nervous system| |CrCl|creatinine clearance| |CRS|cytokine release syndromes| |CSF|cerebrospinal fluid| |CSI|craniospinal irradiation| |CTCAE|common terminology criteria for adverse events| |CTV|clinical target volume|

|ICANS|immune effector cell-associated neurotoxicity syndrome| |---|---| |IFE|immunofixation electrophoresis| |Ig|immunoglobulin| |IHC|immunohistochemistry| |IL-6|interleukin-6| |IMiD|immunomodulatory drug| |IMPEDE|IMiD,BMI,Pathologic fracture,ESA (erythropoietin stimulating agent), Dexamethasone/Doxorubicin, Ethnicity| |IMRT|intensity-modulated radiation therapy| |IMS|International Myeloma Society| |IMWG|International Myeloma Working Group| |INR|international normalized ratio| |ISS|International Staging System| |ISRT|involved-site radiation therapy| |IT|intrathecal| |IVIG|itravenous immunoglobulin| |JCV|John Cunningham virus|

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

|BABBREVIATIONS|BABBREVIATIONS|BABBREVIATIONS|BABBREVIATIONS| |---|---|---|---| |LCDD|light chain deposition disease|PCR|polymerase chain reaction| |LDH|lactate dehydrogenase|PCV|pneumococcal conjugate vaccine| |LHCDD|light and heavy chain deposition disease|PI|proteasome inhibitor| ||disease|PPJ|pneumocystis jirovecii pneumonia| |LMWH|low-molecular-weight heparin|POEMS|polyneuropathy,organomegaly, endocrinopathy, monoclonal protein,| |LP|lumbar puncture||skin changes| |mb|monoclonal antibody|PR|partial response| |MBL|monoclonal B-cell lymphocytosis|PTV|planning target volume| |MFC|multicolor flow cytometry||| |MGNS|monoclonal gammopathy of neurological significance|R-ISS|Revised International Staging System| |MGRS|monoclonal gammopathy of renal significance|RSV|respiratory syncytial virus| |MGUS|monoclonal gammopathy of undetermined significance||RSV| |MIDD|monoclonal immunoglobulin deposition disease|CoV-2|severe acute respiratory syndrome| |MM|multiple myeloma|SAVED|Surgery within 90 days, Asian race,| |MRD|minimal residual disease||Venous thromboembolism history, age over Eighty (80), dexamethasone| |NCS|nerve conduction study|SIFE|serum immunofixation electrophoresis| |NGF|next-generation flow|SLL|small lymphocytic lymphoma| |NGS|next-generation sequencing|SNP|single nucleotide polymorphism| |NT-proBNP|N-terminal prohormone B-type natriuretic peptide|SPEP SUV|sum of product of greatest perpendicular diameters standardized uptake value| |OAR|organs at risk||| |OS|overall survival|||

TCR T-cell redirecting therapy

|UIFE|urine immunofixation electrophoresis| |---|---| |ULN|upper limit of normal| |UPEP|urine protein electrophoresis|

VEGF 5GPR very good partial response VMAT volumetric modulated arc therapy VTE venous thromboembolism

WBRT whole brain radiation therapy

WM/LPL Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

NCCN Guidelines Index Table of Contents Discussion

||NCCN Categories of Evidence and Consensus| |---|---| |Category 1|Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.| |Category 2A|Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.| |Category 2B|Based upon lower-level evidence, there is NCCN consensus (≥50%, but <85% support of the Panel) that the intervention is appropriate.| |Category 3|Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.|

All recommendations are category 2A unless otherwise indicated.

|NCCN Categories of Preference|| |---|---| |Preferred|Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.| |Other recommended|Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.| |Useful in certain circumstances|Other interventions that may be used for selected patient populations (defined with recommendation).|

All recommendations are considered appropriate.

![NCCN\n](2/aj0YEe4oUhYkBdfpda0fYP/figure6b6fbc9f26b948e7b4c8ed94589f3cb6_0_1.png) National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

Discussion

This discussion corresponds to the NCCN Guidelines for Multiple Myeloma. Last updated: 10/31/2023

Follow-Up After Hematopoietic Cell Transplantation.

Maintenance Therapy $\ldots$ MS-26

Therapy for Previously Treated Multiple Myeloma $\ldots$ N.30

Overview $\ldots$ MS-2

Supportive Care for Multiple Myeloma. .MS-45

Management of Renal Disease in Multiple Myeloma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Guidelines Update Methodology.2023

Monoclonal Gammopathy of Renal Significance (MGRS).MS-49

Literature Search Criteria...MS-2

Initial Workup MS-49

Sensitive/Inclusive Language .MS-2

Treatment. $\ldots$ MS-49

Diagnosis and Workup $\ldots$ MS-2

POEMS Syndrome 00S-51

Solitary Plasmacytoma .MS-6

Initial Workup MS-51

The response to RT should be assessed after at least 3 months of completion of RT....MS-8

Treatment.. MS-52

Surveillance/Follow-up Tests for Solitary Plasmacytoma $\ldots$ MS-8

References .MS-51

Smoldering (Asymptomatic) Myeloma $\longdots$MS-8

Primary Therapy for Smoldering (Asymptomatic) Myeloma $\ldots$ MS-8

Surveillance/Follow-up Tests for Smoldering(Asymptomatic) Myeloma $\ldots$ MS-9

Active (Symptomatic) Multiple Myeloma .MS-9

Primary Therapy for Active(Symptomatic) Multiple Myeloma......MS-10

Monitoring After Primary Myeloma Therapy of Both Transplant and Non-Transplant Candidates.

Hematopoietic Cell Transplantation..MS-22

References .MS-51

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

Overview

Multiple myeloma (MM) is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. MM is most frequently diagnosed among people aged 65 to 74 years, with the median age being 69 years.1 The American Cancer Society has estimated 35,730 new MM cases and an estimated 12,590 deaths in the United States in 2023.2

Guidelines Update Methodology

The complete details of the development and update of the NCCN Guidelines are available at www.NCCN.org.

Literature Search Criteria

Prior to the annual update of the NCCN Guidelines for Multiple Myeloma,an electronic search of the PubMed database was performed to obtain key literature published since the previous update, using the following search terms: Smoldering Multiple Myeloma, Solitary Plasmacytoma, Multiple Myeloma, Monoclonal Gammopathy of Undetermined Significance, and POEMS syndrome. The PubMed database was chosen because it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature.

The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types:Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV;Guideline; Practice Guideline; Randomized Controlled Trial;Meta-Analysis; Systematic Reviews; and Validation Studies.The data from key PubMed articles as well as articles from additional sources deemed as relevant to these guidelines as discussed by the panel have been included in this version of the Discussion section. Recommendations for which high-level evidence is lacking are based on the panel's review of lower-level evidence and expert opinion.

Sensitive/Inclusive Language

NCCN Guidelines strive to use language that advances the goals of equity,inclusion,and representation.NCCN Guidelines endeavor to use language that is person-first; not stigmatizing; anti-racist, anti-classist, anti-misogynist, anti-ageist, anti-ableist, and anti-weight-biased; and inclusive of individuals of all sexual orientations and gender identities. NCCN Guidelines incorporate non-gendered language, focusing on organ-specific recommendations. This language is accurate and inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms men, women, female, and male when citing statistics, recommendations,or data from organizations or sources that do not use inclusive terms.Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently. If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals.NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses.

Diagnosis and Workup

It is important to distinguish MM from other plasma cell neoplasms/dyscrasias to determine prognosis and provide appropriate treatment.

The initial diagnostic workup in all patients should include a history and physical examination. To differentiate symptomatic and asymptomatic MM the following baseline laboratory studies are needed: a complete blood count (CBC) with differential; examination of peripheral blood smear; blood urea nitrogen (BUN); serum creatinine; creatinine clearance (calculated or measured directly) and serum electrolytes; liver function tests; serum

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

calcium; serum uric acid; albumin; lactate dehydrogenase(LDH); and beta-2 microglobulin.

UPEP for monitoring patients with measurable urinary M protein and can also be affected by renal function Once individuals are found to have an M protein, light chain abnormalities, or both, the same studies should be used serially. Patients with a negative UPEP do not need this study repeated, except to confirm remission or if the clinical situation changes.

Peripheral smear may show abnormal distribution of red blood cells(RBCs) such as the Rouleaux formation(red cells taking on the appearance of a stack of coins) due to elevated serum proteins.3 Increased BUN and creatinine indicate decreased kidney function,whereas LDH and beta-2 microglobulin levels reflect tumor cell characteristics. NT-proBNP is also recommended, and if N-terminal prohormone of brain natriuretic peptide N-terminal prohormone of brain natriuretic peptide(NT-proBNP) is not available BNP can be performed.

Bone Marrow Evaluation: The percentage of clonal bone marrow plasma cells(BMPCs;≥10%) is a major criterion for the diagnosis of MM. The percentage of plasma cells in bone marrow is estimated by unilateral bone marrow aspiration and biopsy. Immunohistochemistry and/or flow cytometry can be used to confirm presence of monoclonal plasma cells,and to more accurately quantify plasma cell involvement. ${ }^{9}$ The cytoplasm of abnormal plasma cells contains either kappa or lambda light chains,and predominance of one or the other light chain expressing plasma cells indicates clonality. Specific immunophenotypic profiles of the myeloma cells may have prognostic implications. ${ }^{10}$

Serum and Urine Analysis: Serum analysis includes quantitative immunoglobulin levels(IgG, IgA, and IgM); serum protein electrophoresis(SPEP) for quantitation of M protein; and serum immunofunization electrophoresis(SIFE) to obtain more specific information about the type of M protein present. Assessing changes in levels of various proteins,particularly the M protein, helps track disease progression and response to treatment. Urine analysis as a part of the initial diagnostic workup includes evaluating 24-hour urine for total protein, urine protein electrophoresis(UPEP), and urine immunofixation electrophoresis(UIFE).

Cytogenetic Studies: Although MM may be morphologically similar,several subtypes of the disease have been identified at the genetic and molecular levels. Bone marrow studies at initial diagnosis should include chromosome analysis by fluorescence in situ hybridization(FISH)performed on the plasma cells obtained from bone marrow aspiration.Metaphase cytogenetics is not recommended unless myelodysplasia is suspected. Specific chromosomal abnormalities have been identified in patients with MM involving translocations, deletions, or amplifications.According to the NCCN Multiple Myeloma Panel members, the FISH panel for prognostic estimation of plasma cells should be examined for del(13),del(17p13),t(4;14),t(11;14),t(14;16),t(14;20),1q21 gain/amplification,and 1p deletion. The utility of this information is to determine biological subtype and for prognostic recommendations as well as candidacy for clinical trials.

Free Light Chain Assay: The serum free light chain (FLC) assay along with serum M protein analyses (SPEP and SIFE) yield high sensitivity while screening for MM and related plasma cell disorders.4-6 It is also helpful in prognostication of monoclonal gammopathy of undetermined significance(MGUS), smoldering myeloma, active MM, immunoglobulin light chain amyloidosis, and solitary plasmacytoma.6,7 The serum FLC assay also allows for quantitative monitoring of patients with light chain amyloidosis and light chain myeloma. In addition to all of the above, the FLC ratio(FLCr) is required for documenting stringent complete response (sCR)according to the International Myeloma Working Group (IMWG) Uniform Response Criteria.8 The serum FLC assay cannot replace the 24-hour

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

Deletion of 17p13 (the locus for the tumor-suppressor gene, p53) leads to loss of heterozygosity of TP53 and is considered a high-risk feature in MM.11-13

Several studies have confirmed that MM patients with t(4;14), t(14;16),and t(14;20) have a poor prognosis, while t(11;14) is believed to impart less risk.14-17

Abnormalities of chromosome 1 are also among the frequent chromosomal alterations in MM.°The short arm is most often associated with deletions and the long arm with amplifications.°Gains/amplification of 1q21 increases the risk of MM progression and incidence of the amplification is higher in relapsed than in newly diagnosed patients.°L8,20

Risk stratification based on the chromosomal markers is being utilized for prognostic counseling, selection, and sequencing of therapy. ${ }^{21-23}$

Imaging: A skeletal survey has been the standard for decades for assessing bone disease for any individual with suspected MM.24 However,this technique has significant limitations related to lower sensitivity compared to advanced imaging. CT alone or in combination with FDG-PET has been shown to be significantly superior regarding the sensitivity to detect osteolytic lesions in patients with monoclonal plasma cell disorders. A multicenter analysis by the IMWG compared conventional skeletal survey with whole-body CT scans from 212 patients with monoclonal plasma cell disorders. Whole-body CT was positive in 25.5%of patients with negative skeletal survey. The sensitivity of the skeletal survey and whole-body low-dose CT in the long bones is not significantly different; the difference is mainly in detection of abnormalities in the spine and pelvis.24 In a study of 29 patients, 5 (17%) showed osteolytic lesions in CT while skeletal survey results were negative.25 Furthermore, studies have shown whole-body low-dose CT is superior to skeletal survey

radiographs in areas that are difficult to visualize with skeletal surveys such as the skull and ribs. ${ }^{26}$

FDG-PET/CT too has been shown to identify more lesions than plain x-rays and detect lesions in patients with negative skeletal surveys.27-29 It is important to note that if FDG-PET/CT is chosen instead of whole-body low-dose CT, the imaging quality of the CT part of the FDG-PET/CT should be equivalent to a whole-body low-dose CT. Usually the CT part is used only for attenuation correction, which may not be sufficient to assess bone disease due to MM and stability of the spine. Whole-body PET/CT is useful in detecting extramedullary disease outside of the spine.

For initial diagnostic workup of patients suspected of having MM, the NCCN Panel recommends either whole-body low-dose CT or FDG-PET/CT. The panel has also noted that skeletal survey including long bones is acceptable where advanced imaging is not available (eg, in low-resource settings). CT contrast agents are not necessary for detection of myeloma bone disease and should generally be avoided in myeloma patients whenever possible.

Additional Diagnostic Tests

The NCCN Multiple Myeloma Panel recommends additional tests that may be useful in some circumstances. MRI and PET are useful for discerning smoldering myeloma from MM. Since the disease burden in patients with smoldering myeloma is lower than those with MM, imaging techniques with high sensitivity need to be used and MRI is a sensitive technique for detecting marrow infiltration by myeloma. ${}^{30,31}$ PET is used specifically to rule out lytic bone disease as well as extramedullary involvement.According to the NCCN Panel, if whole-body low-dose CT or FDG-PET/CT is negative, consider whole-body MRI without contrast to discern smoldering myeloma from MM.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

A tissue biopsy may also be necessary to confirm the diagnosis of suspected plasmacytomas, particularly extramedullary deposits. Also, if amyloidosis is suspected, the diagnosis is established by following the recommendations outlined in the NCCN Guidelines for Systemic Light Chain Amyloidosis.

Serum viscosity should be evaluated when clinical symptoms of hyperviscosity are suspected, particularly in those with high levels of M protein.

Hepatitis B and C testing and human immunodeficiency virus(HIV)screening should be done as required.

Single nucleotide polymorphism(SNP) array and/or next-generation sequencing (NGS) panel on bone marrow help provide a more detailed evaluation of MM genetics and allow for further risk categorization through the identification of additional abnormalities that may be of prognostic and/or therapeutic value.32 Therefore, the NCCN Multiple Myeloma Panel has included these tests as a useful adjunct in certain circumstances.

The panel also suggests baseline clone identification or storage of bone marrow aspirate sample for clone identification for future minimal residual disease(MRD) testing by NGS if required and assessment for circulating plasma cells in peripheral blood, as clinically indicated. Risk assessment by gene expression profiling can also be considered. ${ }^{33}$

Clinical Findings

Based on the results of the clinical and laboratory evaluation, patients are initially classified as either MGUS, solitary plasmacytoma, smoldering(asymptomatic) disease, or active(symptomatic) disease. More recently,patients with an MGUS who have organ dysfunction related to the monoclonal gammopathy have been variably classified as having monoclonal gammopathy of clinical significance(MGCS) or monoclonal

gammopathy of renal significance(MGRS), depending on the nature of organ involvement.

Staging and Risk Stratification Systems for MM

Definitions: The IMWG definition of MM includes biomarkers in addition to requirements of CRAB features. ${}^{34}$ The CRAB criteria that define MM include: increased calcium levels (>11.5 mg/dL), reenal insufficiency(creatinine $>2 mg/dL$ or creatinine clearance <40 mL/min), anemia(hemoglobin $<10 g/dL$ or $2 g/dL$ less than normal), and presence of bone lesions. The IMWG has also clarified that presence of one or more osteolytic lesions seen on skeletal radiography, whole-body MRI, or whole-body FDG-PET/CT fulfills the criteria for bone disease. ${}^{34}$ The MM-defining biomarkers identified by the IMWG SLiM features (SLiM stands for Sixty, Light chain ratio, MRI) include one or more of the following:greater than or equal to sixty percent clonal plasma cells in the bone marrow; involved/uninvolved free light chain ratio of 100 or more with the involved FLC being greater than or equal 100 mg/L; or MRI with more than one focal marrow (non-osteolytic) lesion. ${}^{34}$ All of these myeloma-defining events are referred to as SLiM-CRAB. Asymptomatic patients fulfilling these criteria should be treated as having active MM.

The criteria by the IMWG for patients with smoldering (asymptomatic) MM include serum M protein (IgG or IgA) greater than or equal to 30 g/L and/or clonal BMPCs 10% to 59% and absence of CRAB features, myeloma-defining events, or amyloidosis. ${ }^{34}$ The updated IMWG diagnostic criteria for MM allow initiation of therapy before end-organ damage on the basis of specific biomarkers, and also allow the use of sensitive imaging criteria to diagnose MM, including whole-body FDG-PET/CT and MRI.34 Recently, a study analyzed clinical and laboratory information from 421 patients with smoldering myeloma and identified M protein greater than 2 g/dL, FLCr of greater than 20, and plasma cells greater than 20% as important risk factors for progression. Patients with 2 or more of these features had a

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

median time to progression (TTP) of 29 months.35 Mateos et al in an analysis of 2004 patients found that the presence of t(4;14),t(14;16),1 q amp/gain, or del(13q) was a further risk factor and patients with one of these findings, along with all 3 of the 20/2/20 model had a risk of progression of 67% at 2 years.36

standard risk. The R-ISS also identifies three stages: 1) R-ISS I, which includes ISS I standard risk chromosomal abnormalities or evaluated LDH levels; 2) R-ISS III, which includes ISS III and either high-risk chromosomal abnormalities or elevated LDH levels; and 3) R-ISS II, which includes all the other possible combinations and is neither R-ISS I nor R-ISS II.

Risk Stratification: The NCCN Panel has provided a list of factors that put patients at high risk of disease progression and/or relapse. For patients with newly diagnosed MM, these factors include being diagnosed as R-ISS III, having extramedullary disease,$^{37}$ having circulating plasma cells,$^{38}$have certain cytogenetic abnormalities [eg, del(1p32), t(4;14), t(14;14), t(14;20), del(17p)/monosomy 17; 1 q21 gain/1 q21 amplification; MYC translocation$^{39}$; or high-risk gene expression profile.$^{33}$

The main limitation of the R-ISS is that most of the patients were classified as R-ISS II or the intermediate-risk group; it therefore included patients with large variations in risk of progression/death.

In the second revision of the R-ISS(R2-ISS), the intermediate-risk group has been further divided into low- and high-risk groups. ${ }^{23}$

The NCCN Panel has also listed factors for risk of disease progression in those with relapsed MM. These include disease relapse within 2 years of initial therapy with hematopoietic cell transplant(HCT) and maintenance regimens or with 6 months of primary induction therapy with HCT;acquisition of 1q gain and/or del(17p)39; or presence of extramedullary disease at relapse.37

Therefore, the R2-ISS identifies four risk groups by assigning a numerical value to each risk factor based on their influence on overall survival (OS):ISS-III is 1.5 points, ISS-II is 1 point, del(17p) is 1 point,t(4;14) is 1 point,1q+ is 0.5 points, and serum LDH > the upper limit of normal is 1 point.The low-risk group is 0 points, low-intermediate-risk group is 0.5-1 points;intermediate high-risk group is 1.5-2.5 points, and high-risk group is 3-5 points. ${ }^{23}$ The limitation of R2-ISS is that it has only been validated in newly diagnosed MM.

These factors are useful for counseling patients regarding prognosis and for selection and sequencing of subsequent therapy.

Solitary Plasmacytoma

Staging Systems: Those with active MM can be staged using the International Staging System(ISS).40 The ISS identifies three stages based on serum beta-2 microglobulin and serum albumin.

The diagnosis of solitary plasmacytoma or solitary plasmacytoma with minimal marrow involvement requires a thorough evaluation with advanced imaging studies to rule out the presence of additional lesions or systemic disease, because many patients presumed to have solitary plasmacytomas are found to have additional sites.42,43

The revised ISS (R-ISS) includes serum beta-2 microglobulin, serum albumin, and prognostic information from the LDH and high-risk chromosomal abnormalities [t(4;14), t(14;16), 17p13 deletion] detected by

FISH and is the preferred staging approach.41 Having del(17p) and/or translocation t(4;14) and/or translocation t(14;16) are considered as high risk. Those with no high-risk chromosomal abnormality are considered

Whole-body imaging with low-dose CT or FDG-PET/CT is recommended for initial diagnostic workup of patients suspected of having MM or solitary plasmacytoma. Skeletal survey is acceptable in certain circumstances.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

low-dose CT and FDG-PET/CT in detecting osteolytic lesions in patients with monoclonal plasma cell disorders.24

Whole-body imaging with MRI(or FDG-PET/CT, if MRI is not available) is the first choice for initial evaluation of solitary osseous plasmacytoma, and whole-body FDG-PET/CT is the first choice for initial evaluation of solitary extraosseous plasmacytoma. The sensitivity of FDG-PET/CT for areas of increased metabolism and the high soft-tissue resolution of MRI enable both techniques to provide information on the presence or absence of solitary plasmacytomas. While the sensitivity of both techniques for the detection of focal lesions is similar, MRI provides a higher sensitivity for a diffuse infiltration.44,45 No data exist on the comparison of FDG-PET/CT and MRI in solitary plasmacytoma. In retrospective analyses, the risk of progression to MM within 2 years of diagnosis has been shown to be higher with osseous plasmacytoma(35%) compared with extramedullary lesions(7%).46 This might, at least in part, be due to undetected diffuse infiltration reflecting systemic disease, which makes the superior sensitivity of MRI significant in this regard. Since the risk of progression of solitary plasmacytoma into MM or relapse is relatively high(14%-38% within the first 3 years of diagnosis), yearly follow-up with the same imaging technique used at first diagnosis should be performed for the first 5 years and subsequently only in case of clinical or laboratory signs or symptoms.47

Primary Therapy for Solitary Plasmacytoma

The treatment and follow-up options for solitary plasmacytoma or solitary plasmacytoma with minimal marrow involvement (<10% plasma cells in bone marrow) are similar. RT has been shown to provide excellent local control of solitary plasmacytomas.48-54 The largest retrospective study (N=258) included patients with solitary plasmacytoma (n= 206) or extramedullary plasmacytoma (n= 52).55 Treatments included RT alone (n=214),RT plus chemotherapy (n=34), and surgery alone (n=8). Five-

<EndOfPara>year OS was 74%, disease-free survival was 50%, and local control was 85%.55

Patients with solitary plasmacytoma (n = 206) who received localized RT(varying doses) had a lower rate of local relapse (12% in those who received between 40-50 Gy) than those who did not receive RT and were treated with surgery (80\%). ${ }^{54}$

According to the NCCN Panel, treatment planning of solitary plasmacytomas should be performed using modern treatment principles including imaging-based delineation (MRI, CT with contrast, and/or FDG-PET CT) of a gross tumor volume (GTV), clinical target volume (CTV), and planning target volume (PTV) and adjacent organs at risk (OARs). CTV expansions should generally include at least 0.5 cm of margin for microscopic extent, and up to 2 to 3 cm for involvement of long bones.PTV margins should be minimized using modern daily image guidance.Treatment of adjacent vertebral bodies for spine lesions is not required if there is no suspicion of clinical involvement. In addition, advanced technology (ie, intensity-modulated RT [IMRT], volumetric modulated arc therapy [VMAT], protons) should be used when feasible to limit radiation doses to surrounding OARs. Principles of involved-site RT (ISRT) should be used to avoid large radiation fields and inappropriately including uninvolved sites that would increase the risk of toxicity.

The dose used in most published papers ranges from 30 to 60 Gy.53,54,56

The recommended RT dose by the NCCN Panel is 40 to 50 Gy in 1.8 to 2.0 Gy fractions (20-25 total fractions) to the involved site. The panel also recommends treatment with 35 to 40 Gy as an alternative for solitary plasmacytomas less than 5 cm in size, due to the high rates of local control reported for smaller tumors. 51,57-59

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

The response to RT should be assessed after at least 3 months of completion of RT.

Surveillance/Follow-up Tests for Solitary Plasmacytoma

Follow-up and surveillance tests for solitary plasmacytoma consist of blood and urine tests and imaging. Serial measurements to check for re-emergence or appearance of M protein are required to confirm disease sensitivity to RT. The recommended follow-up interval for patients with plasmacytoma after RT is every 3 to 6 months. The imaging results may not be accurate if the scans are performed sooner than 3 months of RT.However, patients with soft tissue and head/neck plasmacytoma could be followed less frequently after an initial 3-month follow-up. All plasmacytomas should be imaged yearly, preferably with the same technique used at diagnosis, for at least 5 years.

The blood tests include CBC with differential and platelet count, serum chemistry for creatinine, and corrected calcium. Serum FLC assay, serum quantitative immunoglobulins, and SPEP with SIFE may be performed as needed.

The urine tests as needed include 24-hour urine assay for total protein,UPEP, and UIFE. Bone marrow aspirate and biopsy are recommended as clinically indicated.

If progression to MM occurs, then the patient should be re-evaluated as described in Diagnosis and Workup, and systemic therapy must be administered as clinically indicated.

Smoldering(Asymptomatic) Myeloma

Smoldering (asymptomatic) myeloma describes a stage of disease with no symptoms and no related organ or tissue impairment. ${ }^{60}$ Patients with

asymptomatic smoldering MM may have an indolent course for many years without therapy.

Primary Therapy for Smoldering (Asymptomatic) Myeloma

Smoldering myeloma is a precursor to MM. All patients with smoldering myeloma have a risk of progression to MM. ${}^{61}$ However, the rate of progression varies from months to several years based on certain risk features. ${}^{61}$

The historic approach for management of smoldering myeloma has been close observation. However, recently there has been mounting evidence that those with high-risk features may benefit from early intervention.

A relatively small, randomized, prospective, phase III study by the PETHEMA group investigated whether early treatment with lenalidomide and dexamethasone in patients (n= 119) with smoldering myeloma, at high risk of progression to active MM, prolongs the TTP. ${ }^{62}$ The high-risk group in the study was defined using the following criteria: plasma cell bone marrow infiltration of at least 10% and/or a monoclonal component(defined as an IgG level of ≥ 3 g/dL, an IgA level of ≥ 2 g/dL, or a urinary Bence Jones protein level of >1 g per 24 hours); and at least 95%phenotypically aberrant plasma cells in the bone marrow infiltrate. The OS reported in the trial at 3 years was higher in the group treated with the lenalidomide and dexamethasone arm (94% vs.80%; HR, 0.31;95% CI,0.10-0.91; P=.03).62 At a median follow-up of 75 months (range, 27-57 months), treatment with lenalidomide and dexamethasone delayed median TTP to symptomatic disease compared to no treatment (TTP was not reached in the treatment arm compared to 23 months in the observation arm; HR, 0.24;95% CI, 0.14-0.41).63 The high OS rate seen after 3 years was also maintained (HR, 0.43;95% CI, 0.20-0.90). According to the NCCN Panel, the flow cytometry-based high-risk criteria specified in the study is not uniformly available and participants did not receive advanced

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

imaging. Based on the criteria used in the trial, some patients with active myeloma were classified as having high-risk smoldering myeloma.

In a larger, multicenter, phase III, randomized trial, patients with smoldering myeloma (n = 182) were either treated with lenalidomide until progression or observed. The lenalidomide group experienced improved progression-free survival (PFS) and decreased end organ damage (eg,renal failure, bone lesions) when compared with those who were observed.64 Grade 3 or 4 adverse events were reported in 41% of patients treated with lenalidomide.64 On subgroup analysis, the PFS benefit was seen in those with high-risk smoldering myeloma but was less clear in those with low- or intermediate-risk disease.64

The Mayo 2018 20/2/20 criteria stratify patients based on risk. The criteria take into consideration the following risk factors: percentage of BMPCs greater than 20%, M protein greater than 2 g/dL, and FLCr greater than 20. Patients with two or more of the above risk factors are considered to have high risk. These risk factors were developed from a retrospective study of patients with smoldering myeloma (n = 417). In those with high risk (≥2 factors present), the estimated median TTP was 29 months, in those with intermediate risk (1 factor present), the estimated median TTP was 68 months, and for those with low risk (none of the risk factors present), the estimated median TTP was110 months.35

The Mayo 2018 20/2/20 criteria were validated in a large retrospective analysis of 2004 patients with smoldering myeloma.65 The estimated progression rates at 2 years among those with low-, intermediate-, and high-risk disease were 5%, 17%, and 46%, respectively.65

The NCCN Panel suggests using the Mayo 2018/IMWG 20/2/20 criteria to stratify patients based on risk. According to the NCCN Panel, the low-risk group should be enrolled in a clinical trial or observed at 3- to 6-month intervals(category 1). For the high-risk group, the NCCN Panel prefers

enrollment in an ongoing clinical trial (strongly recommended and preferred option) or observation at 3-month intervals, as clinically indicated or treatment with single-agent lenalidomide only in carefully selected patients (category 2B).62,64 Those with rising markers or high-risk factors must be monitored closely. It is important to note that patients can evolve from having low-risk to high-risk SMM over time, requiring recalibration of follow-up strategies.

Surveillance/Follow-up Tests for Smoldering(Asymptomatic)Myeloma

The surveillance/follow-up tests for smoldering myeloma include CBC with differential and platelet count; serum chemistry for creatinine, albumin,corrected calcium, serum quantitative immunoglobulins, SPEP, and SIFE;and serum FLC assay as clinically indicated. The urine tests include 24-hour urine assay for total protein, UPEP, and UIFE.

Bone marrow aspirate and biopsy with FISH, SNP array, NGS, or multiparameter flow cytometry may be used as clinically indicated.

Imaging studies with MRI without contrast, whole-body low-dose CT and/or CT, and/or whole-body FDG-PET/CT are recommended annually or as clinically indicated. The NCCN Panel recommends considering using the same imaging modality used during the initial workup for the follow-up assessments.

If the disease progresses to symptomatic myeloma, then patients should be treated according to the guidelines for symptomatic MM.

Active(Symptomatic) Multiple Myeloma

Newly diagnosed MM is typically sensitive to a variety of classes of drugs:immunomodulatory drugs(IMiDs),proteasome inhibitors(Pls), and monoclonal antibodies.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

Primary Therapy for Active (Symptomatic) Multiple Myeloma

Patients presenting with active (symptomatic) myeloma are initially treated with primary therapy and primary therapy is followed by high-dose chemotherapy with autologous HCT in transplant-eligible patients.

One of the first steps in evaluating newly diagnosed patients with MM is to determine whether they are candidates for high-dose therapy and transplant, based on age and comorbidities. However, it should be noted that advanced age and renal dysfunction are not absolute contraindications to transplant. Therefore, referral to an HCT center to assess whether a patient is eligible for HCT is important.

Stem cell toxins, such as nitrosoureas or alkylating agents, compromise stem cell reserve. Regimens with these agents(notably melphalan) should be avoided in patients who are potential candidates for HCT until stem cells are collected. If delaying HCT, then stem cells should be collected and stored. The panel recommends harvesting peripheral blood stem cells within the first 6 cycles of therapy initiation prior to prolonged exposure to lenalidomide and/or daratumumab if HCT is being considered.

The algorithm has a list of primary therapy regimens recommended by the NCCN Multiple Myeloma Panel members for transplant-eligible and non-transplant candidates and also lists drugs recommended for maintenance therapy in each setting. The list is selected and is not inclusive of all regimens.

The NCCN Multiple Myeloma Panel has categorized all myeloma therapy regimens as:“preferred,”“other recommended,” or“useful in certain circumstances.” The purpose of classifying regimens as such is to convey the sense of the panel regarding the relative efficacy and toxicity of the regimens. Factors considered by the panel include evidence, efficacy,toxicity, pre-existing comorbidities such as renal insufficiency, and in some cases access to certain agents.

The NCCN Panel prefers 3-drug regimens as the standard for primary treatment of all patients who are transplant eligible. This is based on improved response rates, depth of response, and rates of PFS or OS seen with 3-drug regimens in clinical trials. Frailty assessment should be performed in older adults, as well as consideration of dose modifications,particularly steroids, based on functional status and age.

The doublet regimens are no longer recommended for transplant candidates with the rationale that doublets would be recommended for patients who would not be considered for initial treatment with a 3-drug regimen, such as those not initially eligible for transplant. Patients with poor performance status or who are frail can be started on a 2-drug regimen, with a third drug added after performance status improves.

It is also important to consider supportive care for all patients at diagnosis.For example, 80% of patients have bone disease and up to 33% have renal compromise. In all patients, careful attention to supportive care is critical to avoid early complications that may compromise therapeutic outcome.

General Considerations for Dosage and Administration of Commonly Used Agents:

While weekly and twice-weekly dosing schemas of bortezomib are acceptable and supported by data, weekly dosing is preferred. Twice-weekly bortezomib can be associated with neuropathy that may limit efficacy due to treatment delays or discontinuation. Therefore, Reeder et al modified the CyBorD regimen to a once-weekly schedule of bortezomib. ${ }^{66}$ In the study, patients treated with weekly bortezomib achieved responses similar to the twice-weekly schedule(overall response rate[ORR], 93% vs.88%; very good partial response[VGPR], 60% vs.61%). In addition, they experienced fewer grade 3/4 adverse events(37%/3% vs. 48%/12%). Fewer dose reductions of

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

bortezomib/dexamethasone were required in the modified schedule and neuropathy rates were the same in both cohorts, even though the total bortezomib dose per cycle was higher in the weekly versus the twice-weekly schedule (6.0 mg/m2 vs.5.2 mg/m2).66

The NCCN Panel has noted that subcutaneous administration is the preferred route for bortezomib. This is based on the results of the MMY-3021 trial. The trial randomized patients (n = 222) to single-agent bortezomib administered either by the conventional IV route or by subcutaneous route. ${ }^{67}$ The findings from the study demonstrate non-inferior efficacy with subcutaneous versus IV bortezomib with regard to the primary endpoint (ORR after 4 cycles of single-agent bortezomib). The results showed no significant differences in terms of PFS or 1-year OS between groups. ${ }^{67,68}$ However, patients receiving bortezomib subcutaneously had a significant reduction in peripheral neuropathy.

Carfilzomib can potentially cause cardiac, renal, and pulmonary toxicities.Careful assessment before initiating treatment with carfilzomib and close monitoring during treatment is recommended. Regarding dosing and administration, the panel notes that carfilzomib may be used once or twice weekly and at different doses. Ixazomib may be substituted for carfilzomib in select patients.

A randomized trial has compared two formulations of daratumumab as monotherapy. The subcutaneous formulation of daratumumab and hyaluronidase-fihj resulted in a similar ORR, PFS, and safety profile and fewer infusion-related reactions compared with IV daratumumab.69 According to the NCCN Panel, daratumumab IV infusion or daratumumab and hyaluronidase-fihj, subcutaneous injection may be used in all daratumumab-containing regimens. Some patients may not be appropriate for subcutaneous treatment, for example those with significant thrombocytopenia.

Prolonged use of steroids can be detrimental in frail patients>60 years of age. Therefore, the NCCN Panel recommends a tailored approach of reducing the dose to 20 mg weekly and discontinuing with either treatment response plateau or toxicity.70,71

By binding to CD38 expressed on the surface of RBCs, daratumumab and isatuximab-irfc may result in false-positive indirect antiglobulin test(indirect Coombs test). The binding of these antibodies to RBCs masks detection of antibodies to minor antigens in the patient's serum and interferes with serologic testing. Therefore, type and screen should be performed before using daratumumab or isatuximab-irfc.

The monoclonal antibodies used for myeloma treatment can produce a false-positive serum immunofixation, if the M protein is IgG kappa. In such instances, special interference testing or mass spectrometry-based assessment may be used to differentiate between the two.

Bone disease, renal dysfunction, and other complications such as infections, hypercalcemia, hyperviscosity, and coagulation/thrombosis should be treated with appropriate adjunctive measures (see Supportive Care for Multiple Myeloma in this Discussion).

Preferred Primary Therapy Regimens for Newly Diagnosed Transplant Candidates

The preferred primary therapy options for patients who are HCT eligible include bortezomib/lenalidomide/dexamethasone(category 1) and carfilzomib/lenalidomide/dexamethasone(category 2A).

Bortezomib/Lenalidomide/Dexamethasone Phase II and III study results have shown that primary therapy with bortezomib/lenalidomide/dexamethasone is active and well tolerated in

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

newly diagnosed patients with MM, transplant eligible as well as transplant ineligible.

In the first phase l/Il prospective study of lenalidomide/bortezomib/dexamethasone in patients with newly diagnosed MM, the rate of partial response(PR) was 100%, with 74% VGPR or better and 52% complete response(CR)/near CR.72

The benefits of bortezomib/lenalidomide/dexamethasone as primary therapy were also seen in the results of the phase II IFM 2008 trial? and phase II EVOLUTION trial.74 In the phase II IFM 2008 trial, patients received bortezomib, lenalidomide, and dexamethasone as induction therapy followed by HCT.73 Patients subsequently received 2 cycles of bortezomib/lenalidomide/dexamethasone as consolidation cycles and 1-year lenalidomide maintenance. VGPR rate or better at the completion of induction was 58%.73 After transplantation and consolidation therapy the rate of VGPR or better was 70% and 87%, respectively.73

Bortezomib/lenalidomide/dexamethasone was compared to lenalidomide/dexamethasone in the multicenter phase III SWOG S077 trial.75 Patients (n = 525) with previously untreated MM were randomly assigned to receive 6 months of induction therapy with either bortezomib/lenalidomide/dexamethasone (N = 264) or lenalidomide/dexamethasone (N = 261), each followed by maintenance therapy with lenalidomide/dexamethasone until progression or unacceptable. The triple-drug regimen group had significantly longer PFS(43 months vs. 30 months; HR, 0.712; 96% CI, 0.56-0.906) and improved median OS (75 months vs. 64 months; HR, 0.709; 95% CI, 0.524-0.959).75 As expected, ≥ grade 3 neuropathy was more frequent in the bortezomib-containing arm (24% vs. 5%; P <.0001) as bortezomib was administered twice weekly and intravenously in this study.75

With longer-term follow-up(median 84 months), the benefits of adding bortezomib to lenalidomide and dexamethasone were seen to be maintained. ${ }^{76}$ The PFS with bortezomib/lenalidomide/dexamethasone was 41 months versus 29 months for lenalidomide/dexamethasone. ${ }^{76}$ The OS was not yet reached (>84 months) with the bortezomib regimen versus 69 months for lenalidomide/dexamethasone. ${ }^{76}$

A randomized multicenter phase III trial (ENDURANCE E1A11) studied newly diagnosed patients (n = 1053) with MM treated with either bortezomib/lenalidomide/dexamethasone or carfilzomib/lenalidomide/dexamethasone as induction therapy. Patients with high-risk features [with the exception of patients with t(4;14)] were not included in this trial. After a median follow-up of 9 months, median PFS was 34.4 months with the bortezomib-regimen versus 34.6 months with the carfilzomib regimen.77 A response of VGPR or better was seen in 65% of patients treated with bortezomib/lenalidomide/dexamethasone and 74% of patients treated with carfilzomib/lenalidomide/dexamethasone $(P=.0015).$ With respect to adverse events, the carfilzomib regimen was associated with less peripheral neuropathy but more cardiac, pulmonary, and renal toxicities. $^{77}$

carfilzomib/lenalidomide/dexamethasone(P=.0015). With respect to adverse events, the carfilzomib regimen was associated with less peripheral neuropathy but more cardiac, pulmonary, and renal toxicities. ${}^{77}$

In order to minimize the toxicities seen with the standard dose of bortezomib/lenalidomide/dexamethasone, a phase ll study evaluated the efficacy of dose-adjusted bortezomib/lenalidomide/dexamethasone(VRd-lite).78 The VRd-lite regimen included subcutaneous bortezomib(1.3 mg/m2) on days 1,8,15, and 22, and oral dexamethasone(20 mg)on the day of and the day after bortezomib administration. Lenalidomide was omitted on days 1,8, and 15, which are the days of bortezomib administration. The ORR after 4 cycles of VRd-lite was 83%, including a CR of 25%. The ORR and VGPR or better were further improved to 100% and 74%, in those who received autologous HCT.78

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

Based on the above results, the NCCN Panel included bortezomib/lenalidomide/dexamethasone as a category 1, preferred option for primary treatment of transplant-eligible patients with MM.

<EndOfPara>anemia(16%), leukopenia(13%), and thrombocytopenia(11%).10% This study also accessed MRD. The PFS was found to be longer in patients with negative MRD.81

Carfilzomib/Lenalidomide/Dexamethasone

Carfilzomib is a second-generation PI that binds highly selectively and irreversibly to the proteasome. It is administered intravenously.A multicenter phase I/II trial evaluated the combination of carfilzomib,lenalidomide, and dexamethasone in newly diagnosed patients with MM.79 In this trial, patients (n = 53) received carfilzomib with lenalidomide and low-dose dexamethasone. After 4 cycles, hematopoietic cells were collected from eligible patients. ${ }^{79}$ Out of 35 patients from whom hematopoietic cells were collected, 7 proceeded to transplantation, and the remainder continued with carfilzomib/lenalidomide/dexamethasone. ${ }^{79}$

Another phase II study examined patients (n = 76) with newly diagnosed MM who received carfilzomib/lenalidomide/dexamethasone primary therapy followed by HCT. The primary endpoint of sCR after 8 cycles of therapy was met, with a 60% sCR rate in the overall population. In a median follow-up of 56 months, median PFS and OS were not reached. The estimated 5-year PFS rate was 72%, and the estimated 5-year OS rate was 84% in the intention to treat population. Adverse events of grade 3 to 4 included neutropenia (34%), lymphopenia (32%), infection (22%),and cardiac events (3%). ${ }^{82}$

collected from eligible patients.79 Out of 35 patients from whom hematopoietic cells were collected, 7 proceeded to transplantation, and the remainder continued with carfilzibol/lenalidomide/dexamethasone.79

With a median follow-up of 13 months, 24-month PFS was estimated at 92%.The most common grade 3 and 4 toxicities in≥10% of patients included hyphoposphatemia (25%), hyperglycemia (23%), anemia (21%),thrombocytopenia (17%), and neutropenia (17%). Peripheral neuropathy was limited to grade 1/2 (23%).79

The results of the phase III ENDURANCE trial77 showed similar PFS with carfilzomib/lenalidomide/dexamethasone versus bortezomib/lenalidomide/dexamethasone. However, as mentioned previously, high-risk patients were not included.

Carfilzomib/lenalidomide/dexamethasone was associated with less neuropathy but more dyspnea, hypertension, heart failure, and acute kidney injury compared with bortezomib/lenalidomide/dexamethasone.77 Based on the data from the above studies, the NCCN Panel has included the carfilzomib/lenalidomide/dexamethasone regimen as a preferred option for primary treatment of transplant-eligible patients with MM.

Another phase II trial also evaluated the same regimen (carfilzomib in combination with lenalidomide and dexamethasone) in newly diagnosed patients (n = 45) with MM. After 8 cycles of treatment, patients with stable disease (SD) received up to 24 cycles of lenalidomide 10 mg/day on days 1 to 21.80 Thirty-eight patients were evaluable for response and toxicity. After a median follow-up of 10 months, PFS was 83.3%. Twenty-five patients completed 8 cycles of the carfilzomib, lenalidomide, and dexamethasone regimen, of which 24 continued to lenalidomide therapy and 1 patient opted to exit the study after initial therapy. The most common non-hematologic and hematologic toxicities (≥ grade 3) in >10% of patients included electrolyte disturbances (18%), liver function test elevation (13%), rash/pruritus (11%), fatigue (11%), lymphopenia (63%),

The NCCN Panel has included in a footnote that ixazomib may be substituted for carfilzomib in select patients receiving the carfilzomib/lenalidomide/dexamethasone regimen. The data from this comes from the phase III TOURMALINE-MM2 trial, which evaluated the addition of ixazomib to lenalidomide and dexamethasone versus lena-lidomide/dexamethasone plus placebo in newly diagnosed MM patients not eligible for autologous HCT.83 Higher rates of CR were reported with the addition of ixazomib to lenalidomide/dexamethasone(26% vs. 14%;

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

OR,2.10;P<.001). The median TTP was longer in the ixazomib arm(45.8 months vs. 26.8 months; HR, 0.738).83 The primary endpoint was PFS, and median PFS was increased by 13.5 months with the addition of ixazomib(35.3 months vs.21.8 months; HR,0.830; P=.073).83 This trial, however, did not meet its pre-specified primary endpoint of improved PFS as the data did not meet the threshold for statistical significance.84

Other Recommended Primary Therapy Regimens for Newly Diagnosed Transplant Candidates

Daratumumab/Lenalidomide/Bortezomib/Dexamethasone

The benefit of adding a fourth drug for the primary treatment of transplant-eligible patients is emerging. In the phase II GRIFFIN trial,transplant-eligible patients with MM (n = 207) were randomized to daratumumab/bortezomib/lenalidomide/dexamethasone or bortezomib/lenalidomide/dexamethasone followed by autologous HCT plus consolidation and maintenance.85 The sCR rate after autologous HCT and consolidation with the 4-drug regimen was 42% versus 32%with the 3-drug regimen.85 Follow-up after a median of 22 months showed further improved sCR rates for the daratumumab-containing 4-drug regimen(62.6% vs.45.4%; P=.0177).85 Although the hematologic toxicities were higher with the 4-drug regimen, no major safety concerns were reported in the study.85

Subsequent analysis showed that the benefit persisted after longer follow-up. After 24 months, the rate of sCR was 66% for the daratumumab-containing 4-drug regimen compared with 47% for bortezomib/lenalidomide/dexamethasone(P=.0096). In those who received the 4-drug regimen, the MRD-negative status for≥12 months was seen in 44% vs.12.6% with the 3-drug combination (P<.0001).86

The NCCN Panel has included

daratumumab/lenalidomide/bortezomib/dexamethasone as an option for primary treatment of transplant-eligible patients with MM.

Regimens Useful In Certain Circumstances for Newly Diagnosed Transplant Candidates

Bortezomib/Cyclophosphamide/Dexamethasone

Data from three phase II studies involving newly diagnosed patients with MM have demonstrated high response rates with cyclophosphamide, bortezomib, and dexamethasone (CyBorD) as primary treatment. ${ }^{74,87,88}$ The trial by Reeder et al carried out in the United States and Canada demonstrated an ORR of 88%, including a VGPR or greater of 61% and 39% CR/near CR with CyBorD as the primary regimen. ${ }^{87}$ The depth of response seen after primary treatment was maintained after transplant in those who underwent transplantation (70% rates of CR/near CR; rate of at least VGPR or better was 74%). ${ }^{87}$ According to the long-term follow-up analysis, the 5-year PFS and OS rates were 42%(95% CI, 31-57) and 70%(95% CI, 59-82). ${ }^{89}$

Analysis of the German DSM Xla study also demonstrated high responses with CyBorD as primary treatment (ORR was 84%, with a 71.5% PR rate and 12.5% CR rate). High response rates were seen in patients with unfavorable cylogenetics. ${}^{88}$

In the updated results of the phase II EVOLUTION study, primary treatment with CyBorD demonstrated an ORR of 75% (22% CR and 41%≥VGPR), and the 1-year PFS rate was 93%.74

Based on data from these and other phase II studies, the NCCN Multiple Myeloma Panel has now included the combination of bortezomib/cyclophosphamide/dexamethasone to the list of primary treatment available for transplant candidates. This is designated as a regimen that may be useful in certain circumstances, including in patients

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

with acute renal insufficiency or those who do not have access to bortezomib/lenalidomide/dexamethasone. According to the NCCN Panel,one can consider switching to bortezomib/lenalidomide/dexamethasone after renal function improves.

Bortezomib/Doxorubicin/Dexamethasone

The updated results from the HOVON-65/GMMG-HD4 group phase III trial of newly diagnosed patients with stage II/III MM demonstrated high response rates after primary therapy with bortezomib/doxorubicin/dexamethasone versus vincristine/doxorubicin/dexamethasone(VAD), and this superior response rate (CR + near CR was 31% vs. 15%; P <.001) was maintained even after HCT with significantly higher ORR. ${ }^{90}$ No unexpected toxicities occurred, and del(13q) did not have a significant impact on response.Response rates improved with bortezomib maintenance (34% vs. 49% ; P<.001). ${ }^{90}$ After a median follow-up of 41 months, PFS in patients treated with bortezomib/doxorubicin/dexamethasone as primary therapy followed by HCT and bortezomib maintenance was 35 months versus 28 months in patients treated with VAD followed by HCT and maintenance with thalidomide. Patients treated with bortezomib/doxorubicin/dexamethasone had a significantly better PFS (HR, 0.75; 95% CI, 0.62-0.90; P=.002).90 The OS was also found to be better in the bortezomib, doxorubicin, and dexamethasone arm (HR, 0.77; 95% CI, 0.60-1.00; P=.049). In high-risk myeloma with increased creatinine more than 2 mg/dL, bortezomib significantly improved PFS from a median of 13 months to 30 months (HR,0.45; 95% CI, 0.26-0.78; P=.004) and OS from a median of 21 months to 54 months (HR, 0.33; 95% CI, 0.16-0.65; P<.001). A benefit in terms of increased PFS was also observed in patients with deletion of 17 p 13.90 The rate of grade 2 to 4 peripheral neuropathy was higher in those treated with the bortezomib-containing regimen versus VAD (40% vs. 18%). In addition, newly developed grade 3 to 4 peripheral neuropathy occurred in

8% of patients during thalidomide maintenance and 5% of patients during bortezomib maintenance.90

Based on data from the HOVON-65/GMMG-HD4 trial and the uniform consensus among the NCCN Multiple Myeloma Panel members,bortezomib/doxorubicin/dexamethasone is a regimen that may be useful in certain circumstances for primary therapy for transplant-eligible patients with MM.

Carfilzomib/Cyclophosphamide/Dexamethasone

The carfilzomib/cyclophosphamide/dexamethasone regimen has been studied in phase I/II trials of transplant-ineligible newly diagnosed patients with MM. Trials have investigated both once-weekly and twice-weekly carfilzomib dosing combined with fixed-dose cyclophosphamide and dexamethasone. 991,92 A pooled analysis of two phase I and II studies comparing two alternative schedules of carfilzomib, transplant-ineligible newly diagnosed patients with MM showed similar response rates in those treated with once-weekly carfilzomib at a dose of 70 mg/m2 compared to those treated with twice-weekly carfilzomib at a dose of 36 mg/m2. The PFS and OS were also similar. The median PFS was 35.7 months in the once-weekly group and 35.5 months in the twice-weekly group(HR,1.39; P=.26). The 3-year OS was 70% and 72%, respectively(HR,1.27; P=.5).93

Consistent with the above results, a phase lb study, CHAMPION-2,evaluated the safety and tolerability of twice-weekly carfilzombi(three different doses) in combination with cyclophosphamide and dexamethasone for the treatment of newly diagnosed MM patients. This study found that 56 mg/m2 carfilzombib combined with weekly cyclophosphamide and dexamethasone was effective and with manageable toxicity. ${}^{94}$

The NCCN Panel has included carfilzomib/cyclophosphamide/dexamethasone for both transplant and

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

non-transplant settings as an option useful in certain circumstances such as those with renal insufficiency and/or peripheral neuropathy. The panel notes carfilzomib may be substituted with ixazomib in select patients. A multicenter, phase II trial investigated the efficacy and toxicity of ixazomib,cyclophosphamide and low-dose dexamethasone as induction, followed by single-agent ixazomib maintenance, in older, transplant-ineligible,newly diagnosed patients.95 The ORR after initial therapy with ixazomib/cyclophosphamide/dexamethasone was 73%. After a median follow-up of 26.1 months, the PFS was 23.5 months.95

Daratumumab/Carfilzomib/Lenalidomide/Dexamethasone

A non-randomized clinical trial (n = 41) examined adding daratumumab to the 3-drug combination regimen of carfilzomib/lenalidomide/dexamethasone without HCT. The primary endpoint of MRD rate was achieved in 71% of patients, with a PFS rate of 98% and an OS rate of 100% at a median of 11 months follow-up. The most common grade 3/4 adverse events included neutropenia (27%), rash(9%), lung infection (7%), and increased alanine aminotransferase levels(4%).97

Daratumumab/Bortezomib/Thalidomide/Dexamethasone

In the CASSIOPEIA trial, patients with newly diagnosed MM (n = 1085)were first randomly assigned to receive induction with 4 cycles of bortezomib/thalidomide/dexamethasone with or without daratumumab,followed by autologous HCT plus 2 cycles of consolidation with the induction regimen. ${ }^{96}$ The primary endpoint of the first part of this trial was assessment of response 100 days after transplantation.

The phase II MASTER trial studied daratumumab, carfilzomib,lenalidomide, and dexamethasone in newly diagnosed MM and used MRD status by NGS to determine whether additional consolidation with the induction regimen after autologous HCT is needed, depending on whether the subject had two consecutive MRD-negative results at a level of 10${}^{5}$

At day 100 after transplantation, the daratumab arm reported deeper response rates(CR or better of 39% vs. 26%). The addition of daratumab increased neutropenia (28% vs. 15%) and lymphopenia(17% vs. 10%). Infusion reactions to daratumumab (mostly mild) were reported in 35% of patients.

At a median follow-up of 25 months, 80% of the overall population reached MRD negativity, with a PFS of 87%. The most common serious adverse events included pneumonia and venous thromboembolism.98

The NCCN Panel has included

daratumumab/carfilzomib/lenalidomide/dexamethasone as a primary therapy option for transplant-eligible patients with MM under the category useful in certain circumstances(category 2A) based on the above data.

The NCCN Panel has included

Daratumumab/Bortezomib/Cyclophosphamide/Dexamethasone

daratumumab/bortezomib/thalidomide/dexamethasone as a primary therapy option for transplant-eligible patients with MM under the category useful in certain circumstances(category 2A) based on the results of the CASSIOPEIA trial and FDA approval for this indication.

Patients with MM (n = 101) including newly diagnosed patients (n = 87)and patients with relapsed MM (n = 14) received daratumumab/bortezomib/cyclophosphamide/dexamethasone.99 In newly diagnosed patients, after 4 cycles of induction therapy, VGPR or better was seen in 44.2% and the ORR observed was 79.1%.99 The median PFS was not reached and the 12-month PFS rate was 87%. At the time

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

of clinical cut-off, the 12-month OS rate was 98.8%(95% CI, 92.0-99.8%).99Efficacy was also observed in patients with relapsed MM.

Based on the above results, NCCN Panel has included daratumumab/bortezomib/cyclophosphamide/dexamethasone for newly diagnosed patients with MM (transplant eligible and ineligible patients) as an option under useful in certain circumstances.

Bortezomib, Dexamethasone, Thalidomide, Cisplatin, Doxorubicin,Cyclophosphamide, and Etoposide (VTD-PACE)

The Total Therapy 3(TT3) trial evaluated induction therapy with the multi-agent regimen, VTD-PACE(bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide), prior to high-dose melphalan-based tandem auto-transplants and later as consolidation therapy.100 This regimen is a potent combination of newer agents as well as traditional chemotherapy agents.

This regimen is listed under the category useful in certain circumstances.According to the NCCN Panel, VTD-PACE could be an option for newly diagnosed patients presenting with high-risk and aggressive extramedullary disease or plasma cell leukemia.

Isatuximab/Bortezomib/Lenalidomide/Dexamethasone

The GMMG-HD7 evaluated the benefit of the addition of isatuximab to bortezomib/lenalidomide/dexamethasone. The study randomized patients(n= 662) to receive bortezomib/lenalidomide/dexamethasone or isatuximab/bortezomib/lenalidomide/dexamethasone. ${ }^{101}$ With respect to MRD negativity, the percentage of patients achieving the MRD-negative status at the end of induction was higher with the addition of isatuximab(50.1% vs.35.6%;OR,1.83;95% CI,1.34-2.51;P<.001).The rates of VGPR or better were also significantly higher with the addition of isatuximab(60.5% vs.77.3%; P<.001) and overall adverse events and serious adverse events reported were similar between the arms. ${ }^{101}$

Preferred Primary Therapy Regimens for Newly Diagnosed Non-Transplant Candidates

Many of the regimens described above for transplant candidates are also options for non-transplant candidates. As in transplant-eligible patients, 3-drug regimens are preferred by the NCCN Panel as these regimens have been shown to induce higher response rates and depth of response in clinical trials. The 2-drug regimens are reserved for older and/or frail patients. The list of preferred options for non-transplant candidates includes: bortezomib/lenalidomide/dexamethasone and daratumumab/lenalidomide/dexamethasone.

Bortezomib/Lenalidomide/Dexamethasone

Phase II study results (discussed in the transplant setting) have shown that primary therapy with bortezomib/lenalidomide/dexamethasone is active and well tolerated in all newly diagnosed patients with MM regardless of autologous HCT status. ${ }^{72}$

The randomized phase III SWOG S0777 trial, comparing bortezomib/lenalidomide/dexamethasone to lenalidomide/dexamethasone as induction therapy without an intent of immediate transplantation,reported superior results with the 3-drug regimen.75.76

In transplant-ineligible newly diagnosed patients with MM, a phase II study with the dose-adjusted VRd-lite regimen showed that the dose-adjusted regimen had comparable efficacy and better tolerability than the standard-dose regimen. The VRd-lite dosage included lenalidomide 15 mg orally on days 1-21; bortezomib 1.3 mg/m2 subcutaneously on days 1,8,15, and 22; and dexamethasone 20 mg orally on the day of and the day after bortezomib for 9 cycles followed by 6 cycles of consolidation with lenalidomide and bortezomib. The ORR after 4 cycles of VRd-lite was 86%, with 66% achieving a VGPR or better.102

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

The NCCN Panel included the bortezomib/lenalidomide/dexamethasone regimen as a category 1, preferred option for patients with MM not eligible for HCT, as well as the VRD-lite regimen as an option useful in certain circumstances for patients who are frail and not eligible for HCT.

(90.9% vs.73.9%), and PFS at 18 months was 72% versus 50%. With respect to toxicity, there was an increased rate of grade 3 or 4 infections(23% vs. 15%) and daratumumab-related infusion reactions were seen in 27.7% of patients.

Daratumumab/Lenalidomide/Dexamethasone

Based on the results of the ALCYCLONE trial, the NCCN Panel has included daratumumab/bortezomib/melphalan/prednisone as a category 1 option for treatment of patients with newly diagnosed MM not eligible for HCT. Since regimens containing melphalan are rarely used in North America, the regimen daratumumab in combination with bortezomib/lenalidomide/dexamethasone has now been listed under other recommended regimens in this setting.

In transplant-ineligible patients(n = 737) with newly diagnosed MM, a phase III trial (MAIA) compared daratumumab/lenalidomide/dexamethasone to lenalidomide/dexamethasone. The addition of daratumumab to lenalidomide/dexamethasone resulted in median PFS not being reached at a median follow-up of 56.2 months compared to a median PFS of 34.4 months in the control group (HR, 0.68; P<.0001). The rates of several adverse events were higher in the daratumumab group compared to the control group, including neutropenia (54% vs. 37%), pneumonia (19% vs.11%), and lymphopenia (16% vs. 11%). Treatment-related deaths occurred in 4% of patients in the daratumumab group and 3% of patients in the control group. Based on the results of this study the FDA has approved the use of daratumumab/lenalidomide/dexamethasone in this setting. $^{103}$

Carfilzomib/Lenalidomide/Dexamethasone

The results of a phase I/ll trial demonstrated that the combination of carfilzomib/lenalidomide/dexamethasone is well tolerated and is also effective in all newly diagnosed patients. ${ }^{79}$ An updated follow-up analysis of the subset of 23 older patients (aged $\geq$ 65 years) showed that use of the carfilzomib, lenalidomide, and low-dose dexamethasone regimen for an extended period of time resulted in deep and durable responses. All patients achieved at least a PR. With a median follow-up of 30.5 months,the reported PFS rate was $79.6 \%$ (95% CI, 53.5-92.0) and OS was $100 \%$ . 105

The NCCN Panel has also included

daratumumab/lenalidomide/dexamethasone as a category 1, preferred option for newly diagnosed patients who are transplant ineligible.

Other Recommended Primary Therapy Regimens for Newly Diagnosed Non-Transplant Candidates

The phase II trial by Korde et al81 also showed that treatment with the carfilzomib/lenalidomide/dexamethasone regimen results in high rates of deep remission. The results were very similar across age groups, with the oldest patient on the trial being 88 years of age, and the regimen was found to be effective in individuals with high-risk disease. ${ }^{81}$

Daratumumab/Bortezomib/Melphalan/Prednisone

In the randomized phase III trial (ALCYONE), randomized patients (n =706) with newly diagnosed MM ineligible for transplant were to receive bortezomib/melphalan/prendisone with or without daratumumab until disease progression.104 The addition of daratumumab increased the ORR

Based on the above phase II studies that did not exclude transplant-ineligible patients, the NCCN Panel has included carfilzomib/

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

lenalidomide/dexamethasone as an option for treatment of all patients with newly diagnosed MM, including those who are not eligible for HCT.

The panel has noted in a footnote that itazombis may be substituted for carfilzomib in select patients. The evidence for this comes from a phase I/II study (discussed in the previous section for HCT-eligible candidates)that evaluated the safety and efficacy of the all-oral combination of ixazomb with lenalidomide and dexamethasone in patients with newly diagnosed MM treated with combination lenalidomide and dexamethasone.106 Both tolerability and activity of this regimen in older patients (those ≥ 65 years of age) was similar to that in younger patients in this study.

Daratumumab/Bortezomib/Cyclophosphamide/Dexamethasone

Based on the results of the LYRA study(described above), and the NCCN Panel has included

daratumab@morbezomib/cyclophosphamide/dexamethasone as a treatment option for non-transplant settings.

Regimens Useful In Certain Circumstances for Newly Diagnosed Non-Transplant Candidates

Lenalidomide/Low-Dose Dexamethasone

The results of the SWOG SO232 trial107 that included transplant-ineligible patients and the ECOG E4A03 trial108 that included older patients with MM demonstrate that lenalidomide in combination with low-dose dexamethasone is a well-tolerated and effective regimen for these groups of patients. In the ECOG E4A03 trial the OS rate was significantly higher in the lenalidomide plus low-dose dexamethasone arm compared with the lenalidomide plus high-dose dexamethasone arm.108 The inferior survival outcome seen with high-dose dexamethasone was greatest in patients aged≥65 years. At 2 years, patients who did not proceed to transplant had an OS rate of 91% with lenalidomide and low-dose dexamethasone.108

The international, multicenter trial (FIRST trial) evaluated efficacy and safety of lenalidomide/dexamethasone given continuously for 72 weeks with melphalan/prednisone/thalidomide (MPT) in older (n = 1623)transplantation-ineligible patients with newly diagnosed MM. ${}^{109}$ The primary endpoint of this trial was PFS, and secondary endpoints were OS and adverse events, including the incidence of secondary malignancies.After a median of 37 months of follow-up, the risk of progression or death was reduced by 28% in patients receiving continuous lenalidomide/dexamethasone versus MPT (HR, 0.72; 95% CI, 0.61-0.85;P <.001). ${ }^{109}$ Continuous lenalidomide/dexamethasone also reduced the risk of progression or death compared with 18 cycles of lenalidomide/dexamethasone (HR, 0.70; 95% CI, 0.89-1.20; P = .70). In the interim analysis, an OS benefit was seen in the lenalidomide/dexamethasone arm versus MPT (HR, 0.78; CI, 0.64-0.96; P = .02). ${ }^{109}$

There are several reports showing higher incidences of secondary malignancies when lenalidomide is used as a maintenance therapy post-transplantation or in a melphalan-containing regimen. 110-113 In the FIRST trial, the overall incidence of secondary malignancies, including hematologic malignancies, was lower in the continuous lenalidomide/dexamethasone arm. The overall rates of second primary cancers were 3.0% in the continuous lenalidomide/dexamethasone arm,6.0% in the arm receiving 18 cycles of lenalidomide/dexamethasone, and 5.0% in the MPT arm. 109 In an analysis based on renal function of patients enrolled in the FIRST trial, continuous lenalidomide/low-dose dexamethasone compared with MPT reduced the risk of progression or death in patients with normal, mild, and moderate renal impairment by 33%,30%, and 35%, respectively. ${}^{114}$

Lenalidomide/low-dose dexamethasone is considered an option useful in certain circumstances(category 1) by the NCCN Multiple Myeloma Panel

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

for transplant-ineligible patients with MM. The panel recommends appropriate thromboprophylaxis for patients receiving this therapy. Based on the results of the FIRST trial, ${ }^{109,115}$ the NCCN Panel recommends considering treatment with continuous lenalidomide/dexamethasone until disease progression for patients who are not eligible for transplant.

Lenalidomide/Cyclophosphamide/Dsexamethasone

The efficacy and tolerability of

cyclophosphamide/lenalidomide/dexamethasone in newly diagnosed patients was demonstrated in a phase II study. Of the 53 patients enrolled in the trial, 85% had a PR or better including VGPR in 47%. The median PFS was 28 months (95% CI, 22.7-32.6) and at 2 years the OS was 87%(95% CI, 78-96).116

$^{117}$ The Myeloma XI trial compared responses to cyclophosphamide/lenalidomide/dexamethasone with cyclophosphamide/thalidomide/dexamethasone. $^{118}$ The results reported that the combination of cyclophosphamide/lenalidomide/dexamethasone was associated with significantly longer PFS(median 36 vs. 33 months, P=.0116) and OS at 3 years (82.9% vs. 77.0%, P=.0072). $^{118}$

The NCCN Panel included

lenalidomide/cyclophosphamide/dexamethasone as a primary therapy option for patients with MM who are not eligible for transplant under the category useful in certain circumstances(category 2A).

Bortezomib/Dexamethasone

A U.S.community-based, randomized, open-label, multicenter, phase IIIb upFRONT trial compared the safety and efficacy of three highly active bortezomib-based regimens in previously untreated older patients with MM ineligible for HCT.119 The patients with symptomatic, measurable MM were randomized (1:1:1) to one of the following regimens:

bortezomib/dexamethasone(n=168);

bortezomib/thalidomide/dexamethasone(n= 167); or melphalan/prednisone/bortezomib(n= 167) followed by maintenance therapy with bortezomib.The primary endpoint was PFS; secondary endpoints included ORR, CR/near CR and VGPR rates, OS, and safety.All three induction regimens exhibited substantial activity, with an ORR of 73%(bortezomib/dexamethasone), 80%(bortezomib/thalidomide/dexamethasone), and 70%(melphalan/prednisone/bortezomib) during the treatment period. ${ }^{120}$ After a median follow-up of 42.7 months, the median PFS and OS were not significantly different between the three treatment arms. ${ }^{119}$ Response rates, including CR and greater than or equal to VGPR, improved after bortezomib maintenance, with no concomitant increase in the incidence of peripheral neuropathy.

While the triple regimen with bortezomib/lenalidomide/dexamethasone is the preferred therapy for patients with newly diagnosed MM, older or frail patients may be treated with doublet regimens. The NCCN Multiple Myeloma Panel has included bortezomib/dexamethasone as a primary therapy as an option that is useful in certain circumstances for patients with MM who are ineligible for HCT.

Bortezomib/Cyclophosphamide/Dexamethasone

The role of bortezomib/cyclophosphamide/dexamethasone as initial therapy for patients with MM ineligible for HCT was studied in a small phase II trial (n=20).121 The median age of patients in this study was 76 years(range 66-90 years). After a median of 5 cycles, the ORR was 95%with 70% of patients achieving VGPR or better response. With respect to toxicity, 6 patients experienced non-hematologic grade 3/4 adverse events(20%), including muscle weakness, sepsis, and pneumonia. Neutropenia and thrombocytopenia were seen in 2 patients (10%).121

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

Based on the above and the results from the EVOLUTION trial74(described earlier) that had included transplant-ineligible patients and the above phase II trial results,121 the NCCN Panel has included bortezomib/cyclophosphamide/dexamethasone as an option useful in certain circumstances for non-transplant candidates. This option may be considered especially in patients with acute renal insufficiency or for patients who have no access to a PI in combination with lenalidomide/dexamethasone. According to the NCCN Panel, one can consider switching to Pl/lenalidomide/dexamethasone after renal function improves.

Monitoring After Primary Myeloma Therapy of Both Transplant and Non-Transplant Candidates

Response Criteria

Assessing the response to treatment is a key determinant of MM treatment. Patients on treatment should be monitored for response to therapy and for symptoms related to disease and/or treatment.

The updated IMWG response criteria definitions ${}^{8,122,123}$ for CR, sCR,immunophenotypic CR,molecular CR,VGPR,PR,minimal response(MR)for relapsed/refractory MM, SD, and progressive disease(PD) are outlined in Response Criteria for Multiple Myeloma in the algorithm. This has been updated to include measures of MRD assessments. It is recommended that the IMWG uniform response criteria should be used in all clinical trials. ${ }^{124}$ According to the NCCN Panel, response should be assessed using the IMWG criteria. ${ }^{8}$

Carfilzomib/Cyclophosphamide/Dexamethasone

A phase II study examined the safety and efficacy of$$\text{carfilzomib/cyclophosphamide/Dexamethasone in patients}\geq 65\text{ years of}$$age with newly diagnosed MM and ineligible for autologous HCT.91 Out of 55 patients, 52 (95%) had at least a PR, 39 of 55 (71%) patients had at least a VGPR, 27 of 55 (49%) patients had a near CR or CR, and 11 of 55 (20%) patients had an sCR. After a median follow-up of 18 months, the 2-year PFS and OS rates were 76% and 87%, respectively.91 Frequently reported grade 3 to 5 toxicities were neutropenia (20%), anemia (11%),and cardiopulmonary events (7%). Peripheral neuropathy was limited to grades 1 and 2 (9%).

The same imaging modality used during the initial workup should ideally be used for the follow-up assessments. Follow-up tests after primary MM therapy include those used for initial diagnosis: a CBC with differential and platelet counts, blood glucose, electrolytes, and metabolic panel.

Assessing changes in levels of various proteins, particularly the M protein,helps track disease progression and response to treatment. SPEP is used to track for quantitative immunoglobulins and 24-hour urine UPEP helps track total protein.

The NCCN Panel has included

carfilzomib/cyclophosphamide/dexamethasone as an option useful in certain circumstances for treatment of patients with newly diagnosed MM not eligible for HCT with renal insufficiency and/or peripheral neuropathy.

The FLCr is required for documenting sCR according to the IMWG Uniform Response Criteria.8 The serum FLC assay cannot replace the 24-hour UPEP for monitoring patients with measurable urinary M protein and can also be affected by renal function.

Bone marrow aspirate and biopsy with FISH should be performed as clinically indicated, especially at relapse.

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

Follow-up with advanced whole-body imaging (ie, FDG-PET/CT, low-dose CT, whole-body MRI without contrast) is recommended as needed.Residual focal lesions detected by either FDG-PET/CT or MRI have been shown to be of adverse prognostic significance.125-128 Zamagni et al reported PFS of 44 months in patients with residual focal lesions on FDG-PET/CT versus 84 months for those without residual focal lesions on FDG-PET/CT after systemic treatment (P=.0009).127 In the IMAJEM trial, both PFS and OS were significantly better in patients with negative FDG-PET/CT results before initiation of maintenance therapy (P=.011 and P=.033, respectively).128 An analysis by Walker et al showed that conventional MRI normalizes over a prolonged period of time making FDG-PET/CT superior in this regard.125 However, in small cohorts,functional imaging sequence for MRI called diffusion-weighted imaging was shown to have superior sensitivity to detect residual disease compared with FDG-PET/CT.129-131 Furthermore, unlike FDG-PET/CT, MRI does not expose the patient to radiation.

A meta-analysis of 14 studies has shown that MRD negativity predicts improved PFS and OS, including in those who achieved CR.132 Therefore,the NCCN Panel recommends consideration of MRD testing as indicated for prognostication after shared decision-making.

Hematopoietic Cell Transplantation

The NCCN Panel recommends considering harvesting peripheral blood hematopoietic stem cells prior to prolonged exposure to lenalidomide and/or daratumumab(ie, optimally 4 or fewer induction cycles) in patients for whom transplant is being considered. Collecting enough hematopoietic stem cells for two transplants (depending on the intended number of transplants and age) in anticipation of a tandem transplant, boost after cellular therapy, or a second transplant as subsequent therapy is recommended. Alternatively, all patients may consider continuation of primary therapy until the best response is reached. The optimal duration of primary therapy after achieving maximal response is unknown; hence,

maintenance therapy (see section on Maintenance Therapy) or observation can be considered beyond maximal response.

Transplant Eligibility

All patients are assessed to determine eligibility for HCT. The NCCN Panel recommends that all patients eligible for HCT should be referred for evaluation by HCT center and hematopoietic stem cells (for at least two transplants, in younger patients) should be harvested.

High-dose therapy with HCT support is a critical component in the treatment plan of eligible patients newly diagnosed with MM. The types of HCT may be single autologous HCT, a tandem HCT (a planned second course of high-dose therapy and HCT within 6 months of the first course),or an allogeneic HCT.

The NCCN Guidelines for Multiple Myeloma indicate that all types of HCT are appropriate in different clinical settings; these indications are discussed further below. In general, all candidates for high-dose chemotherapy must have sufficient hepatic, renal, pulmonary, and cardiac function. However, renal dysfunction is not an absolute contraindication to transplant.

Autologous Hematopoietic Cell Transplantation

Autologous HCT results in high response rates and remains the standard of care after primary therapy for eligible patients. In 1996, results of the first randomized trial were reported; this trial demonstrated that autologous HCT is associated with statistically significantly higher response rates and increased OS and event-free survival (EFS) when compared with the response of similar patients treated with conventional therapy.133 In 2003,results of a second trial comparing high-dose therapy to standard therapy showed an increase in the CR rate and an improvement in OS (54 months in the high-dose group compared to 42 months for standard therapy).134 Barlogie and colleagues reported on the results of an American trial that

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

randomized 510 patients to receive high-dose therapy with autologous HCT or standard therapy. ${ }^{135}$ With a median follow-up of 76 months, there were no differences in response rates, PFS, or OS between the two groups. The reason for the discrepant results is not clear but may be related to differences in the specific high-dose and conventional regimens between the American and French study. For example, the American study included total body irradiation (TBI) as part of the high-dose regimen; TBI has subsequently been found to be inferior to high-dose melphalan. ${ }^{136}$

Another trial included 190 patients 55 to 65 years of age randomized to standard or high-dose therapy. ${ }^{137}$ This study was specifically designed to include older patients, since the median age of the participants in other trials ranged from 54 to 57 years and the median age in this trial was 61 years. After 120 months of follow-up, there was no significant difference in OS, although there was a trend toward improved EFS in the high-dose group(P=.7).Additionally, the period of time without symptoms,treatment, or treatment toxicity was significantly longer in the high-dose group. The study concluded that the equivalent survival suggests that the treatment choice between high-dose and conventional-dose chemotherapy should be based on personal choice in older patients. For example, an early transplant may be favored because patients can enjoy a longer interval of symptom-free time.

A phase III study compared high-dose melphalan followed by autologous HCT with MPR (melphalan, prednisone, and lenalidomide) consolidation after induction. Patients (n= 402) were randomly assigned (in a 1:1:1:1 ratio) to one of the four groups: high-dose therapy and autologous HCT followed by maintenance with lenalidomide; high-dose therapy and HCT alone; primary therapy with MPR followed by lenalidomide; and primary therapy with lenalidomide alone. ${ }^{138}$ At a median follow-up of 51 months,HCT resulted in longer median PFS (43 vs. 22 months; HR 0.44; 95\% CI,

0.32-0.61) and OS (82% vs. 65% at 4 years; HR 0.55; 95% CI, 0.32-0.93).138

Results from the IFM 2005/01 study of patients with symptomatic MM receiving primary therapy with bortezomib and dexamethasone versus VAD showed a marked improvement in ORR with bortezomib and dexamethasone over VAD(see Preferred Primary Therapy Regimens for Newly Diagnosed Transplant Candidates).139 Responses were evaluated after primary treatment and post-autologous HCT. After the first autologous HCT, CR/near-CR rates were 35.0% in the bortezomib plus dexamethasone arm, compared with 18.4% in the VAD arm.139 The VGPR rates were 54.3% versus 37.2%. Median PFS was 36.0 months versus 29.7 months(P=.064) with bortezomib plus dexamethasone versus VAD after a median follow-up of 32.2 months.139 Also, PFS was also significantly longer in patients achieving greater than or equal to VGPR after primary treatment than in patients achieving less than VGPR (median 36 vs.29.7 months).139

In another study, 474 patients were randomized to primary therapy with bortezomib/dexamethasone/thalidomide(n= 236) or thalidomide/dexamethasone(n= 238) before double autologous HCT and as consolidation therapy after HCT. 140 The 3-drug regimen yielded high response rates compared with the 2-drug regimen, with a CR rate of 19%(vs.5%) and greater than or equal to VGPR of 62%(vs.31%). After HCT,improved incremental responses were still seen with bortezomib/dexamethasone/thalidomide compared with thalidomide plus dexamethasone.140 The IFM 2009 phase III trial compared the efficacy and safety of bortezomib/lenalidomide/dexamethasone alone versus bortezomib/lenalidomide/dexamethasone plus autologous HCT for the treatment of newly diagnosed MM in patients≤65 years.141 The reported CR rate was 48% in the group that received induction therapy alone versus 59% in the transplantation group(P=.03). No MRD was detected

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

in 65% of the patients who received received

The OS of patients in the IFM 2009 phase III trial was high in both groups,the one that received autologous HCT and the one that did not. ${ }^{141}$ Although autologous HCT improved PFS it did not improve OS,suggesting that delaying HCT is an option and is not associated with negative effects on OS.

negative effects on OS.

According to the NCCN Guidelines, for transplant-eligible patients autologous HCT is the preferred option after primary induction therapy while a delayed HCT after early stem cell collection and storage is appropriate as well(category 1). A repeat HCT can be considered for treatment of progressive/refractory disease after primary treatment in patients with prolonged response to initial HCT.

Tandem Hematopoietic Cell Transplantation

Tandem HCT refers to a planned second course of high-dose therapy and HCT within 6 months of the first course. Planned tandem transplants have been studied in several randomized trials. The IFM94 trial reported by Attal et al randomized newly diagnosed patients with MM to single or tandem autologous transplants.142 A total of 78% of patients assigned to the tandem transplant group received the second transplant at a median time of 2.5 months after the first. A variety of options for therapy of relapsed disease were provided. For example, relapsing patients in either group underwent either no therapy, additional conventional therapy, or

another HCT. The probability of EFS for 7 years after the diagnosis was 10% in the single transplant group compared to 20% in the double transplant group. In a subset analysis, those patients who did not achieve a complete CR or VGPR within 3 months after the first transplant appeared to benefit the most from a second transplant. The investigators of the IFM94 study have suggested that the improvement in projected survival associated with tandem transplant is related not to improved response rates, but to longer durations of response. Four other randomized trials have compared single versus tandem transplant.137,143-145 None of these trials showed a significant improvement in OS. However,since the median follow-up in these trials ranged from 42 to 53 months,the lack of significant improvement is not surprising. The trial by Cavo et al143 found that patients not in CR or near CR after the first transplant benefited the most from a second transplant. This confirms the observations of the IFM94 trial using non-TBI-based high-dose regimens.In both the French and Italian trials, the benefit of a second autologous HCT was seen in patients who do not achieve a CR or VGPR(>90%reduction in M protein level) with the first procedure. These two studies were not adequately powered to evaluate the equivalence of one versus two transplants in patients achieving a CR or VGPR after the first transplantation

A review of long-term outcomes of several trials of autologous transplantation by Barlogie et al found that tandem transplantations were superior to both single transplantations and standard therapies. ${}^{146}$ Also,post-relapse survival was longer when EFS was sustained for at least 3.5 years after tandem transplantation. ${}^{146}$ -147 Results of the multicenter, phase III study(EMN02/HO95 MM trial) suggested that tandem autologous HCT for newly diagnosed MM may be superior in extending PFS compared with single autologous HCT after induction therapy with a bortezomib-based regimen. ${}^{148}$ In another more recent study, after initial HCT patients were randomly assigned to receive a second HCT followed

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

by lenalidomide maintenance; or 4 cycles of bortezomib, lenalidomide,and dexamethasone followed by lenalidomide maintenance; or lenalidomide maintenance alone. ${ }^{149}$ At 38 months, all three arms showed similar PFS and OS. ${ }^{149}$

The NCCN Multiple Myeloma Panel recommends collecting enough hematopoietic stem cells for at least one HCT in al/ eligible patients, and for two transplants in the younger patients if tandem, transplant or repeat transplant would be considered. According to the NCCN Multiple Myeloma Panel, a tandem transplant with or without maintenance therapy can be considered for all patients who are candidates for HCT and is an option for patients who do not achieve at least a VGPR after the first autologous HCT and those with high-risk features. The support for use of maintenance therapy after tandem transplant comes from the study by Palumbo et al,138 which addressed the role of maintenance therapy with lenalidomide after autologous transplantation.138 Although associated with more frequent grade 3 or 4 neutropenia and infections, maintenance therapy with lenalidomide was found to significantly reduce risk of disease progression or death(HR, 0.47) after both single and tandem transplantation compared with no maintenance.138

A second autologous HCT can be considered at the time of disease relapse. A retrospective case-matched control analysis was performed comparing patients who underwent a second autologous HCT to those treated with conventional chemotherapy for relapsed MM. 150 Similar to previously published smaller studies, 151-153 this retrospective analysis demonstrated that a second autologous HCT is associated with superior relapse-associated mortality compared with conventional chemotherapy(68% vs. 78%), along with improved OS(32% vs. 22%) at 4 years. In this analysis, factors associated with improved OS and PFS included younger age(<55 years), beta-2 microglobulin<2.5 mg/L at diagnosis, a remission duration of>9 months, and a greater than PR to their first autologous

HCT.This analysis indicates that a second autologous transplant, for relapsed or progressive MM, may be an option for carefully selected patients. Some of these patients can achieve durable complete or partial remission. 153,154

A multicenter, randomized phase III trial compared treatment with high-dose melphalan plus second autologous HCT with cyclophosphamide in patients with relapsed MM who had received autologous HCT as primary treatment. ${ }^{155}$ The patients included in the study were $>18$ years of age and needed treatment for progressive or relapsed disease at least 18 months after a previous autologous HCT. All patients first received bortezomib/doxorubicin/dexamethasone induction therapy. Patients with adequately harvested hematopoietic stem cells were then randomized to high-dose melphalan plus second autologous HCT(n $=89$ ) or oral cyclophosphamide(n $=85$ ). The primary endpoint was time to disease progression. ${ }^{155}$ After a median follow-up of 31 months, median TTP in patients who underwent second autologous HCT after induction therapy was 19 months versus 11 months for those treated with cyclophosphamide(HR, 0.36; 95% CI, 0.25-0.53; P<.0001). Grade 3-4 neutropenia(76% vs. 13%) and thrombocytopenia(51% vs. 5%) were higher in the group that underwent autologous HCT versus cyclophosphamide. ${ }^{155}$ Median OS in the HCT group was 67 months versus 52 months in the cyclophosphamide maintenance group. ${ }^{156}$

According to the NCCN Multiple Myeloma Panel, repeat autologous HCT for relapsed disease may be considered either on or off clinical trial depending on the time interval between the preceding HCT and documented progression.

The prognosis of patients who relapse after autologous HCT appears to differ depending on the timing of the relapse.157-161 Data from retrospective studies162-165 suggest 2 to 3 years as the minimum length of remission for consideration of second autologous HCT for relapsed disease.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

Allogeneic Hematopoietic Cell Transplantation

Allogeneic HCT includes either myeloablative or nonmyeloablative (ie,“mini” transplant) transplants. Allogeneic HCT has been investigated as an alternative to autologous HCT to avoid the contamination of reinfused autologous tumor cells, but also to take advantage of the beneficial graft-versus-tumor effect associated with allogeneic transplants. However, lack of a suitable donor and increased morbidity has limited this approach,particularly for the typical older MM population. Non-myeloablative transplants are designed to decrease the morbidity of the high-dose chemotherapy but preserve the beneficial graft-versus-tumor effect.Therefore, the principal difference between myeloablative and nonmyeloablative transplants relates to the chemotherapy regimen used.Specific preparatory regimens have not been a focus of the NCCN Guidelines, and therefore these guidelines do not make a distinction between these approaches.

Given the small candidate pool, it is not surprising that there have been no randomized clinical trials comparing myeloablative allogeneic to autologous HCT, but multiple case series have been published describing allogeneic HCT as an initial therapy or as therapy for relapsed/refractory MM. In a 1999 review, Kyle et al reported a mortality rate of 25\% within 100 days and overall transplant-related mortality of approximately 40%and few patients were cured. ${ }^{166}$ Other reviews have also reported increased morbidity without convincing proof of improved survival. ${ }^{167,168}$ However, there are intriguing data from the SWOG randomized trial of autologous transplant versus conventional chemotherapy. ${ }^{135}$ The original trial had an ablative, allogeneic transplant group consisting of patients with HLA identical siblings. Thirty-six patients received allografts, and due to the high 6-month mortality of 45%, the allogeneic arm was closed. After 7 years of follow-up the OS of the conventional chemotherapy, autologous,and allogeneic arms were all identical at 39%. The autologous and conventional chemotherapy arms do not demonstrate a plateau, whereas

the allogenic curve was flat at 39%. This suggests that a proportion of these patients are long-term survivors. Thus, there is ongoing interest in myeloablative allogeneic HCT, particularly given the lack of a significant cure rate for single or tandem autologous HCT.

Patients whose disease either does not respond to or relapses after allogeneic hematopoietic cell grafting may receive donor lymphocyte infusions to stimulate a beneficial graft-versus-myeloma effect169-176 or other myeloma therapies on or off a clinical trial.

Follow-Up After Hematopoietic Cell Transplantation

Follow-up tests after HCT are similar to those done after primary myeloma therapy. MRD assessment is indicated for prognostication. Studies have shown that MRD negativity after autologous HCT translates to significantly improved PFS and OS rates.177-179 Similar results have also been reported in the allogeneic HCT setting where the presence of MRD after allogeneic HCT has been associated with a significantly adverse PFS and OS.180 The NCCN Panel recommends assessing for MRD during follow-up as indicated prognostication after shared decision-making with patient.124

Maintenance Therapy

The NCCN Panel has clarified in the algorithm section the maintenance regimens appropriate for those who received autologous HCT versus those who did not and classified them as either preferred, other recommended, or useful in certain circumstances.

Maintenance Therapy: Preferred Regimen

Lenalidomide as Maintenance

Lenalidomide as maintenance therapy after autologous transplantation has been evaluated in two independent randomized phase III studies.110,111

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

In the CALGB 100104 trial, patients were randomized to maintenance therapy with lenalidomide(n=231) versus placebo(n=229)after autologous HCT.111 At a median follow-up of 34 months, 37% of the patients who received lenalidomide versus 58% who received placebo had disease progression or died. The median TTP in the lenalidomide group was 46 months versus 27 months in the placebo group(P<.001). Second primary cancers occurred in 18 patients who received lenalidomide(8%)and in 6 patients who received placebo(3%).111

Data from the international, randomized, double-blind phase III IFM 2005-02 trial(n = 614) show that patients treated with lenalidomide as consolidation therapy after an autologous HCT followed by lenalidomide as maintenance therapy had upgraded responses. Of the 614 patients enrolled in the trial, 307 were randomly assigned to lenalidomide maintenance therapy and 307 to placebo. Maintenance treatment was continued until the patient withdrew consent, the disease progressed, or unacceptable toxic effects occurred. The final analysis of the IFM 2005-02 trial was performed after a median follow-up of 30 months and 264 patients had disease progression (104 in the lenalidomide group and 160 in the placebo group). The median PFS was 41 months in the lenalidomide group, compared with 23 months in the placebo group (HR,0.50; $P < .001$; median follow-up period was 30 months). The probability of surviving without progression for 3 years after randomization was 59% in those treated with lenalidomide and 35% in those who received the placebo. The benefit of lenalidomide maintenance therapy, evidenced by rate of PFS at 3 years after randomization, was higher in all patients who received lenalidomide maintenance therapy compared with those who received placebo. This benefit was observed in patients who had a VGPR at randomization (64% vs. 49%, $P=.006$ ) and those who did not (51% vs.18%, $P<.001$ ).110 An increased incidence of second primary cancers was observed in the lenalidomide group (32 had second primary cancers in the lenalidomide group and 12 in the placebo group). ${ }^{110}$ The updated survival

analysis of the same study after 91 months for follow-up reported median TTP of 57.3 months (95% CI, 44.2-73.3) with lenalidomide and 28.9 months (23.0-36.3) with placebo(HR,0.57;95% CI,0.46-0.71;P<.0001). ${ }^{181}$ The most common grade 3-4 adverse events in the lenalidomide group compared to placebo were neutropenia (50% vs. 18%)and thrombocytopenia (15% vs. 5%). An increased rate of second primary malignancies (hematologic plus solid tumor) were diagnosed in the lenalidomide group compared with placebo (14% vs. 4%). ${ }^{181}$

The study by Palumbo et al ${}^{138}$ (discussed in Autologous Hematopoietic Cell Transplantation) showed that although maintenance therapy with lenalidomide is associated with more frequent grade 3 or 4 neutropenia and infections, it significantly reduced risk of disease progression or death(HR,0.47) compared with no maintenance. ${}^{138}$

The benefit of lenalidomide maintenance was studied in a meta-analysis of data from 1209 patients enrolled in the trials discussed above randomized to maintenance with lenalidomide or placebo.182 The study showed improved median PFS with lenalidomide maintenance(52.8 vs.23.5 months; HR 0.48;95% CI,0.42-0.55).At 7 years, the OS was 62% in the group receiving lenalidomide maintenance versus 50% in the group receiving placebo. In those with high-risk cytogenetics, a PFS benefit, but not an OS benefit was seen with lenalidomide maintenance versus placebo.

The lenalidomide group had higher rates of second primary malignancy occurring before progression, and the rates of PD were higher in the group receiving placebo.

A report from the HOVON 76 trial indicates that lenalidomide maintenance may not be a feasible option after mini-allogeneic HCT. ${}^{183}$ However,another recently reported study has shown the feasibility of maintenance

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

therapy with low-dose lenalidomide after allogneic HCT in patients with high-risk MM. ${}^{184}$

Data from the phase III MM-015 study show that lenalidomide maintenance after primary therapy with

melphalan/prednisone/lenalidomide (MPL) significantly reduced the risk of disease progression and also increased PFS.185 In this study, newly diagnosed patients with MM (n = 459) aged ≥65 years were randomized to receive MP followed by placebo, MPL, or MPL followed by lenalidomide until progression. Maintenance with lenalidomide significantly prolonged PFS. The PFS of patients treated with MPL followed by maintenance lenalidomide was significantly prolonged (n = 152; median, 31 months)compared with the other two arms: MPL (n = 153; median, 14 months; HR,0.49; P <.001) or MP (n = 154; median, 13 months; HR, 0.40;P<.001).Lenalidomide maintenance therapy improved PFS by 66\% compared with placebo, regardless of age.185 In the FIRST trial, use of lenalidomide indefinitely until progression was associated with a superior PFS compared with a fixed duration of 18 months.

The GMMG-MM5 trial (n = 502) examined maintenance therapy with lenalidomide following induction therapy and HCT in newly diagnosed MM patients. Patients received lenalidomide for a fixed duration of 2 years or until either CR. The primary endpoint was PFS, which was not significantly different between arms after a median follow-up of 60.1 months. Higher OS was seen with lenalidomide given for 2 years than for lenalidomide given until CR (HR, 1.42; 95% CI, 1.04-1.93; P=.03).Serious adverse events were more common in the group that received lenalidomide for 2 years versus until CR (77.6% vs. 58.2%) and included infections, cardiac disorders, neuropathy, and thromboembolic events.186

Based on the evidence from the phase III trials,110,111,185 the NCCN Multiple Myeloma Panel lists single-agent lenalidomide as one of the preferred maintenance regimens(category1) for both transplant-eligible and

transplant-ineligible patients. Lenalidomide lacks the neurologic toxicity seen with thalidomide. However, there seems to be an increased risk for secondary cancers, especially post-transplantation, ${}^{110-112}$ or after a melphalan-containing regimen. ${}^{113}$ According to the results of the FIRST trial, in the continuous lenalidomide/dexamethasone arm, the absence of the alkylator melphalan seems to be more effective in terms of improving PFS and lowering incidence of second malignancies. 109

A meta-analysis of randomized controlled trials examined patients treated with lenalidomide maintenance versus patients with no maintenance or placebo in the transplant setting. ${ }^{182}$ The analysis showed that patients treated with lenalidomide maintenance had significantly improved PFS(HR, 0.48; 95% CI, 0.41-0.55) and a trend toward OS with lenalidomide maintenance (HR, 0.75; 95% CI, 0.63-0.90; P=.001) versus no maintenance or placebo. ${ }^{182}$

The benefits of improved PFS with lenalidomide maintenance must be weighed against the increased rate of severe (grade 3 and 4) neutropenia,risk of second cancers, and other toxicities.187 The NCCN Panel notes that the benefits and risks of maintenance therapy with lenalidomide versus secondary cancers should be discussed with patients.

Other Recommended Regimen for Maintenance Therapy

Bortezomib as Maintenance Therapy

The results from the HOVON study show that maintenance with single-agent bortezomib after autologous HCT is well tolerated and is associated with improvement of ORR.90 Patients in the HOVON trial were randomly assigned to one of the two arms consisting of either primary treatment with VAD followed by autologous HCT and maintenance with thalidomide or with bortezomib/doxorubicin/dexamethasone followed by autologous HCT and bortezomib as maintenance therapy for 2 years. The study reported high near-CR/CR rates after primary treatment with the bortezomib-based

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

regimen. Bortezomib as maintenance therapy was well tolerated and associated with additional improvement of response rates90(see Preferred Primary Therapy Regimens for Newly Diagnosed Transplant Candidates).

A multicenter phase III trial in newly diagnosed patients with MM showed that consolidation with bortezomib after autologous HCT improved PFS only in patients not achieving at least VGPR after autologous HCT.188 There was no difference in PFS in patients with greater than or equal to VGPR after autologous HCT.

The results of the phase III UPFRONT study also show that maintenance with single-agent bortezomib is well tolerated when administered after treatment with bortezomib-based primary therapy.119 Newly diagnosed patients with MM ineligible for high-dose therapy and HCT enrolled in the UPFRONT trial were randomized (1:1:1) and treated with one of the following bortezomib-based primary regimens: bortezomib and dexamethasone; bortezomib in combination with thalidomide and dexamethasone; or bortezomib with melphalan and prednisone followed by maintenance treatment with bortezomib. The results show that the response rates, including CR and greater than or equal to VGPR,improved after bortezomib maintenance in all arms, with no concomitant increase in the incidence of peripheral neuropathy. ${ }^{119}$

The NCCN Multiple Myeloma Panel members have added bortezomib as a maintenance therapy option for transplant-eligible as well as transplant-ineligible patients.

Maintenance Regimens Useful in Certain Circumstances

Bortezomib/Lenalidomide

Patients with high-risk cytogenetics have been shown to benefit from a combination of PI and IMiD as maintenance therapy.189,190 The study by Joseph et al of patients (n=1000) with newly diagnosed MM treated with lenalidomide, bortezomib, and dexamethasone induction therapy and risk-adapted maintenance showed that early transplantation and maintenance with doublet therapy (lenalidomide plus bortezomib) improves outcomes for those with high-risk myeloma.190

Carfilzomib/Lenalidomide as Maintenance

Patients enrolled in the FORTE trial (described above) were randomized to receive carfilzomib/lenalidomide maintenance therapy or lenalidomide alone as maintenance therapy.191 After a median duration of follow-up of 37 months, 3-year PFS was 75% in the carfilzomib/lenalidomide group versus 65% in the lenalidomide alone group (HR, 0.64; 95% CI, 0.44-0.94; P=.023). Most common grade 3-4 adverse events in the carfilzomib/lenalidomide group versus the lenalidomide group included neutropenia (20 % vs. 23 %), infections (5 % vs. 7 %), and vascular events(7 % vs. 1%), with one treatment-related adverse event leading to death in the carfilzomib/lenalidomide group. ${ }^{191}$

The NCCN Panel has included carfilzomib/lenalidomide maintenance therapy as an option useful in certain circumstances for transplant-eligible candidates.

Daratumumab with or without Lenalidomide as Maintenance Therapy After Autologous HCT

The second randomization of the CASSIOPEIA trial(results of first randomization described above) compared daratumumab maintenance for up to 2 years with observation following primary therapy with bortezomib/thalidomide/dexamethasone in transplant-eligible patients with newly diagnosed MM.192 At a median follow-up of 35.4 months from the second randomization, the primary endpoint of PFS was not reached in the daratumumab versus 46.7 months in the observation-only group (HR

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

0.53; 95% CI, 0.42-0.68; P<.0001). The most common grade 3 or 4 adverse events in the daratumumab maintenance group included lymphopenia(4%), hypertension(3%), and neutropenia(2%). Serious adverse events were more common in the daratumumab group(23% vs.19%), with two treatment-related deaths in the daratumumab group. 192

In the randomized, phase II GRIFFIN study described in a section above, daratumumab in combination with lenalidomide, bortezomib, and dexamethasone, followed by maintenance therapy with daratumumab and lenalidomide was compared to lenalidomide, bortezomib, and dexamethasone followed by maintenance therapy with lenalidomide alone,in newly diagnosed, transplant-eligible patients with MM. The addition of daratumumab to primary therapy, followed by daratumumab/lenalidomide maintenance therapy, led to deep and durable responses including high rates of sCR and MRD negativity.86

The NCCN Panel has added daratumumab alone (based on the CASSIOPEIA trial data) and daratumumab with lenalidomide

maintenance therapy (based on the GRIFFIN trial data) as options useful in certain circumstances after autologous HCT.

Ixazomib as Maintenance Therapy After Autologous HCT

The TOURMALINE-MM3 trial studied 2 years of maintenance with ixazomib versus placebo in patients who had achieved at least a PR following induction therapy and a single autologous HCT. After a median follow-up of 31 months, a 28% reduction in median PFS was observed

with ixazomib versus placebo(median PFS was 26.5 months vs. 21.3 months; HR,0.72;95% CI,0.58-0.89;P=.0023).193 A subsequent analysis of the same study demonstrated a higher rate of deepening

prolonging PFS.194 The median PFS in patients with VGPR/PR was 26.2 with ixazomib maintenance versus 18.5 months with placebo(HR, 0.636;P<.001).194

P<.001).194

The TOURALINE-MM4 trial is similar to TOURMALINE-MM3, but examined patients who were not receiving transplant. The study randomized patients who were not undergoing transplant and had achieved at least a PR following standard induction therapy to receive either ixazomib maintenance therapy or placebo. The primary endpoint was PFS since time of randomization. The primary endpoint was met, with a median PFS of 17.4 months in the ixazomib group versus 9.4 months in the placebo group(HR, 0.659; 95% CI, 0.542-0.801; P<.001). Grade 3 treatment-related adverse events were more common with ixazomib(36.6%) than placebo(23.2%). The most common any grade adverse events included nausea, vomiting, and diarrhea.195 While both TOURMALINE-MM3 and TOURMALINE-MM4 have demonstrated statistically significant improvement in PFS, the OS data for MM3 and MM4 have not demonstrated a statistically significant difference. 196

Based on the above data, the NCCN Panel has included ixazomib as a category 2B recommendation useful in certain circumstances maintenance option for both transplant-eligible and transplant-ineligible patients.

Therapy for Previously Treated Multiple Myeloma

A variety of therapies are available for previously treated or relapsed/refractory MM. The choice of appropriate therapy for a specific patient depends on the context of clinical relapse such as prior treatment and duration of response.

The therapeutic options for previously treated MM include systemic therapy; autologous hematopoietic cell transplant (HCT) for eligible patients who did not receive HCT as part of their initial treatment; or clinical trial. For those who had autologous HCT as part of initial treatment and had a durable response or had stable disease, consideration may be

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

given to a second transplantation at the time of relapse/disease progression. As a general principle, if the relapse occurs at greater than 6 months after completion of the initial primary therapy, patients may be retreated with the same primary regimen. This however does not apply to HCT where a longer remission would be needed to justify another transplant.

versus 15.2 months in the carfilzomib alone group (Hazard ratio (HR) HR,0.59;95 CI, 0.45-0.78; P<.0001).199 Based on the above data and the FDA approval, the NCCN Panel has included this regimen as a category 1, preferred option for relapsed/refractory MM, for patients with relapsed or refractory MM.

Isutaximab-irfc/Carfilzomib/Dexamethasone

Preferred Regimens for Previously Treated Multiple Myeloma - After One to Three Prior Therapies

For patients that are still sensitive to bortezomib and/or lenalidomide, any of the regimens listed below may be appropriate. Since, however,bortezomib-containing or lenalidomide-containing regimens are often given as induction therapy, and it is likely that at relapse the disease is refractory to these agents, especially if relapse is well within 6 months of primary treatment completion other combinations are preferred.

A prospective, randomized, open label, phase 3 study(IKEMA) examined the utility of isatuximab/carfilzomib/dexamethasone vs carfilzomib/dexamethasone in 302 patients with relapsed/refractory MM who had received one to three prior lines of therapy (median two prior lines of therapy). Treatment was continued until disease progression or unacceptable toxicity, with the primary endpoint being PFS. Median PFS was 35.7 months in the isatuximab/carfilzomib/dexamethasone group vs a median PFS of 19.15 months in the carfilzomib/dexamethasone group (HR 0.53;99% CI, 0.32-0.89, P=.0007). Grade 3 or higher treatment related adverse events occurred in 77% of patients in the isatuximab group vs 67% of patients in the control group. 200 Based on this data, the NCCN Panel has included isatuximab-irfc/carfilzomib/dexamethasone as a category 1, preferred regimen option for relapsed or refractory MM.

The NCCN Panel has provided a list of regimens for bortezomib-refractory and lenalidomide-refractory disease after one to three prior therapies.

Preferred Regimens for Bortezomib or Lenalidomide-Refractory Disease

Daratumumab/Carfilzomib/Dexamethasone

Carfilzomib/Pomalidomide/Dexamethasone

A phase 1b, open-label, non-randomized, multicenter trial first studied this regimen in patients(n= 82) with relapsed or refractory MM. At a median follow-up of 16 months, the overall response rate(ORR) was 84%. In the overall treatment population, while the median progression free survival

A phase II trial investigated carfilzomib/pomalidomide/dexamethasone followed by continuous pomalidomide/dexamethasone as second line therapy for relapsed/refractory MM in patients who had progression during lenalidomide maintenance therapy. Patients who were eligible for transplant and had not received it previously received HCT. On this regimen,75% of patients had a VGPR, and 37% displayed CR. At 40-months of follow up, the median PFS was 26 months for patients who received received therapy with HCT, and 17 months for patients who received carfilzomib/pomalidomide/dexamethasone therapy without HCT.The median OS was 67 months, with the most common grade 3 and 4

dexamethasone showed deeper responses and improved PFS.198 This response has been shown to be maintained with longer follow up analyses

response has been shown to be maintained with longer follow up analyses of about 27 months. PFS was 28.6 months in the daratumumab group

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

adverse events related to treatment including hematologic toxicity(41%),cardiovascular(6%) and respiratory(3%) events, and infections(17%).201 Based on these data, the NCCN Panel has included carfilzomib/pomalidomide/dexamethasone as a preferred regimen option for relapsed or refractory MM.

median follow up of 17.2 months (median PFS was not reached at time of follow up).The most common adverse event of grade 3 or higher was infection, which developed in 31.3% of patients (13.4% with grade 3 or higher pneumonia).204

Daratumumab/Pomalidomide/Dexamethasone

Based on the above data, the NCCN Panel has included daratumumab/pomalidomide/dexamethasone as a treatment option for patients with relapsed/refractory MM who have received one prior therapy including an IMiD and a PI.

The combination of daratumumab/pomalidomide/dexamethasone was evaluated in an open-label, multicenter, phase 1b study(MMY1001). This study included patients (n = 103 patients) who had received at least two prior lines of therapy (excluding daratumumab or pomalidomide).202 At a median follow-up of 13.1 months, the ORR was 60%. The median PFS and OS were 8.8 and 17.5 months, respectively, and estimated survival at 1 year was 66%.202 Toxicities reported were similar to those seen in other trials of pomalidomide and daratumumab, except for increase in neutropenia.202

Isatuximab-irfc/pomalidomide/dexamethasone

In an open-label, multicenter, phase III trial (ICARIA-MM), patients (n=307) with MM who had received at least two lines of prior therapy,including lenalidomide and a PI were randomized to receive pomalidomide/dexamethasone with or without isatuximab-irfc.205 After a median follow-up of 12 months, a higher ORR (60% vs. 35%) and improved PFS (median 11.5 months vs. 6.5 months; HR, 0.6; 95% CI,0.44-0.81) were reported in the isatuximab-irfc/pomalidomide/dexamethasone arm. In a prespecified subgroup analysis of this study, the addition of isatuximab-irfc showed improved ORR and PFS in patients with renal impairment.206

The open label phase III APOLLO trial randomly assigned patients with relapsed/refractory disease and at least one previous line of therapy(n=304) to receive pomalidomide/dexamethasone or daratumumab/pomalidomide/dexamethasone. With a median follow up time of 16.9 months, there was a statistically significant improvement in the primary endpoint of PFS for the added daratumumab group (12.4 months vs 6.9 months, P=.0018). Serious adverse events occurred in 50% of patients in the daratumumab group compared to 39% of patients in the pomalidomide/dexamethasone group, the most common being pneumonia and lower respiratory tract infections.203

The NCCN Panel has included isatuximab-

irfc/pomalidomide/dexamethasone as a category 1, preferred option for the treatment of patients with relapsed/refractory MM after two prior therapies including lenalidomide and a PI.

Ixazomib/Pomalidomide/Dexamethasone

In the phase l/ll Alliance A061202 study (n=29), patients with lenalidomide/PI refractory MM were treated with ixazomib/pomalidomide/dexamethasone- with 51.7% of patients having a PR or better, a median PFS of 4.4 months, a median response duration

The MM-014 study evaluated 112 patients with relapsed/refractory MM who had previously been treated with lenalidomide and assigned them to a regimen containing daratumumab/pomalidomide/dexamethasone. The primary endpoint was ORR which was achieved in 77.7% of patients in a

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

of 16.8 months, and a median OS of 34.3 months. Common adverse events included hematologic toxicity, and gastrointestinal events.

Another phase l/II study studied the safety and efficacy of ixazomib/pomalidomide/dexamethasone in patients who had multiple prior therapies, were refractory to lenalidomide alone, or were refractory to lenalidomide and bortezomib, or lenalidomide, bortezomib, and carfilzomib.208 The ORR was 33% and 40% with two different doses of ixazomib.208

Considering promising preliminary response rates, especially in patients refractory to both lenalidomide and a PI, the NCCN Panel has included ixazomib/pomalidomide/dexamethasone as a treatment option for patients with relapsed/refractory MM who have received at least two prior therapies including an IMiD and a PI and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Additional Preferred Regimens for Bortezomib-Refractory Disease:

In addition to the regimens listed in the section above, the following two lenalidomide-containing regimens may be used for lenalidomide-sensitive or naive and bortezomib-refractory disease.

Daratumumab/Lenalidomide/Dexamethasone

In a multicenter, open-label phase 3 trial(POLLUX), patients(n= 569)with relapsed/refractory MM were randomized to receive lenalidomide/dexamethasone with or without daratumumab until disease progression or unacceptable toxicity.209

After a median follow-up of 13.5 months, daratumumab in combination with lenalidomide and dexamethasone was associated with better PFS and ORR compared with lenalidomide/dexamethasone alone. After a median follow-up of 25.4 months, a subsequent analysis reported that the higher ORR(92.9% vs.76.4%,P<.001), and PFS(83% vs.60% at 12

months; 68% vs.41% at 24 months; HR 0.41, 95% CI 0.31-0.53) was maintained in those who had received daratumumab.209

The most common adverse events of grade 3 or 4 in patients treated with the daratumumab regimen versus lenalidomide/dexamethasone were neutropenia(51.9 vs.37.0%), thrombocytopenia(12.7% vs.13.5%), and anemia(12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions(mostly grade 1 or 2) were reported in 47.7% of patients.

With an extended follow-up of 3.5 years, the improvements in PFS and ORR continued to be maintained in patients treated with the daratumumab regimen(PFS 16.7 vs. 7.1 months; HR, 0.31; 95%; CI, 0.25-0.40; P<.0001). In a subgroup of patients with one prior line of therapy,the median PFS was 27.0 months with daratumumab versus 7.9 months with daratumumab and lenalidomide(HR, 0.22; 95% CI, 0.15-0.32; P<.0001). The ORR rates for patients with one prior line of therapy for those receiving the daratumumab-regimen was 92% compared with 74% in those receiving daratumumab/dexamethasone.210

Based on the above data, the NCCN Panel has added daratumumab/lenalidomide/dexamethasone as a category 1, preferred option for the treatment of patients with relapsed/refractory MM

Carfilzomib/Lenalidomide/Dexamethasone

The randomized, multicenter, phase III ASPIRE trial, studied the combination of lenalidomide and dexamethasone with or without carfilzomib in patients(n=792) with relapsed/refractory MM who had received one to three prior lines of therapy. The primary endpoint of the study was PFS. The results showed that addition of carfilzomib to lenalidomide and dexamethasone significantly improved PFS by 8.7 months(26.3 months for the carfilzomib arm vs. 17.6 months for lenalidomide and low-dose dexamethasone; HR for progression or death,

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

0.69;95% CI,0.57-0.83;P=.0001).The median duration of treatment was longer in the carfilzomib group (88.0 weeks vs. 57 weeks). The incidence of peripheral neuropathy was nearly identical in both arms(17%). Non-hematologic adverse effects (≥ grade 3) that were higher in the carfilzomib group compared with lenalidomide and dexamethasone included dyspnea (2.8% vs. 1.8%), cardiac failure (3.8% vs. 1.8%), and hypertension (4.3% and 1.8%). There were fewer discontinuations due to side effects in the carfilzomib arm (15.3% vs. 17.7%). Patients in the carfilzomib arm reported superior health-related quality of life than those who received lenalidomide and dexamethasone alone.211

Based on the above data, the NCCN Multiple Myeloma Panel has included the combination of carfilzomib with lenalidomide and dexamethasone as a category 1, preferred option for patients with relapsed/refractory MM.

Additional Preferred Regimens for Lenalidomide refractory Disease

In addition to the regimens listed in the section for bortezomib- and lenalidomide refractory disease, the following bortezomib-containing regimens may be used for bortezomib-sensitive or naive and lenalidomide-refractory disease.

Daratumumab/Bortezomib/Dexamethasone

A phase III trial showed that adding daratumumab to bortezomib and dexamethasone markedly improved outcomes for patients with recurrent/refractory MM.212 Patients(n= 498) were randomized to receive daratumumab/bortezomib/dexamethasone or bortezomib/dexamethasone.The ORR in the daratumumab arm was 82.9% compared to 63.2% in the control arm(P<.001).212 The rates of VGPR and CR were double in the daratumumab arm compared to the control arm(59.2% vs.29.1%,P<.001 and 19.2% vs.9.0%,P=.001, respectively).The 12-month estimated rate of PFS was significantly higher in the daratumumab arm compared to the control arm(60.7% vs.26.9%).212 The most common grade 3 or 4 adverse events reported in the daratumumab and control groups were

thrombocytopenia (45.3% and 32.9%, respectively), anemia (14.4% and 16.0%, respectively), and neutropenia (12.8% and 4.2%, respectively).212 Grade 1 or 2 infusion-related reactions associated with daratumabum were reported in 45.3% of the patients in the daratumabum group and grade 3 in 8.6% of the patients. These infusion-related reaction rates are consistent with findings from previous trials of daratumabum.213,214

After a median follow-up of 40 months, patients receiving the daratumumab containing regimen demonstrated a 69% reduction in the risk of disease progression or death(median PFS, 16.7 months vs 7.1 months; HR, 0.31; 95% CI, 0.25-0.40; P<.0001); showed significantly better ORR (85% vs 63%; P<.0001).215 Patients who received one prior line of therapy demonstrated the greatest benefit with daratumumab(median PFS, 27.0 months vs 7.9 months; HR, 0.22; 95% CI, 0.15-0.32; P<.0001).

Based on the above phase III data, the NCCN Panel has added daratumumab/bortezomib/dexamethasone as a category 1, preferred option for the treatment of patients with relapsed/refractory MM.

Pomalidomide/Bortezomib/Dexamethasone

A phase 3 open-label, multicenter, randomized, trial (OPTIMISMM) evaluated pomalidomide/bortezomib/dexamethasone (n=281) versus bortezomib/dexamethasone in patients (n=278) with relapsed or refractory MM who previously received lenalidomide. ${ }^{216}$After a median follow-up of 15.9 months, a significantly improved PFS was seen in the pomalidomide arm (median 11.20 months vs. 7.10 months;HR, 0.61; 95 \% CI, 0.49-0.77; P<.0001). The most common grade 3/4 treatment-related adverse events in the pomalidomide arm reported in this trial were neutropenia, infections, and thrombocytopenia. ${ }^{216}$ A post-hoc subgroup analysis of the OPTIMISSM trial evaluated outcomes in 226 patients at first relapse that had only received one prior line of therapy.Analyses were conducted by lenalidomide-refractory status, prior

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

bortezomib exposure, and prior HCT. There were statistically significant improvements in PFS in both lenalidomide refractory (17.8 vs 9.5 months, P=.0276) and lenalidomide non-refractory (22.0 vs 12.0 months, P=.0491) patients. There were also statistically significant improvements in PFS in patients who had received prior bortezomib (17.8 vs. 12 months),and patients with (22 vs. 13.8 months) and without (16.5 vs 9.5 months)prior HCT.217

Based on the above data, the NCCN Panel has included pomalidomide/bortezomib/dexamethasone as a category 1, preferred option preferred option for the treatment of patients with relapsed/refractory MM.

Selinexor/Bortezomib/Dexamethasone

An ongoing phase 3, randomized open label trial (BOSTON) compared selinexor/bortezomib/dexamethasone with bortezomib/dexamethasone in patients with previously treated MM (one to three prior lines of therapy,including Pls). Four hundred two patients were randomized to the selinexor/bortezomib/dexamethasone and 206 to the bortezomib/dexamethasone group. After a median follow up duration of 13.2 months in the selinexor/bortezomib/dexamethasone group, the median PFS was 13.93 months compared to a median follow up duration of 16.5 months and median PFS of 9.46 months in the bortezomib/dexamethasone group (HR 0.70; 95% CI, 0.53 - 0.93;P=.0075). The most frequent adverse events of grade 3-4 that were more common in the selinexor/bortezomib/dexamethasone group were thrombocytopenia (39% vs. 17%), fatigue (13% vs 1%), and anemia (16%vs 10%).${}^{218}$

Based on the above data the NCCN Panel has included once weekly selinexor in combination with bortezomib and dexamethasone as a category 1, other recommended regimen option for previously treated MM

Elotuzumab/Pomalidomide/Dexamethasone

In a phase II study, patients(n=117) with refractory/relapsed MM and refractory to lenalidomide and a PI were randomized to receive pomalidomide/dexamethasone or elotuzumab/pomalidomide/dexamethasone. ${ }^{219}$ After a follow-up of 9.1 months, the median PFS and ORR were both more than double with elotuzumab(PFS, 10.3 months vs. 4.7; ORR, 53% vs. 26%). ${ }^{219}$ Median OS was also significantly improved with elotuzumab/pomalidomide/dexamethasone compared with pomalidomide/dexamethasone(29.8 months vs. 17.4 months; HR 0.59(95% CI, 0.37 to 0.93; $P=.0217).^{220}$

The NCCN Panel has included the combination of pomalidomide/dexamethasone/elotuzumab as an option for patients who have received at least two prior therapies including an IMiD and a PI.

Preferred CAR T-Cell Therapies for Relapse After One to Three Prior Therapies

Other Recommended Regimens for Relapse After One to Three Prior Therapies

Carfilzomib(twice weekly)/Dexamethasone

The results of the phase III ENDEAVOR trial in patients with relapsed/refractory MM treated with multiple prior lines of therapy showed a two-fold improvement in median PFS with carfilzomib/dexamethasone compared to bortezomib/dexamethasone(18.7 months vs. 9.4 months;HR, 0.53; $P<.0001$ ).221 ORR was 77% in the carfilzomib group versus 63% in the bortezomib group; rates of CR or better were 13% and 6% and rates of VGPR were 42% and 22%, respectively. The median duration of response was 21.3 months in the carfilzomib group and 10.4 months in the bortezomib group. Adverse events(grade 3 or higher) in the carfilzomib arm compared to the bortezomib arm included hypertension (6% vs. 3%),

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

anemia (12% vs.9%), thrombocytopenia (10% vs. 14%), and dyspnea (5% vs.2%). Rate of grade ≥2 peripheral neuropathy was 6% in the carfilzomib group and 32% in the bortezomib group.221

The OS analysis showed that those treated with carfilzomib/dexamethasone lived 7.6 months longer (median OS was 47.6 months in the carfilzomib group vs. 40 months in the bortezomib group; HR, 0.791[95°C, 0.648-0.964]; P = .010).222 The most frequent grade 3 or worse adverse events in the carfilzomib arm compared to the bortezomib arm included hypertension (15% vs. 3%), anemia (16 % vs. 10%), dyspnea(6 % vs. 2%), decreased lymphocyte count (6 % vs. 2%), diarrhea (4 % vs.9 %), and peripheral neuropathy (1 % vs. 6 %).222 Rates of thrombocytopenia, pneumonia, and fatigue were similar in both groups.222

Based on the above phase III data, the NCCN Multiple Myeloma Panel has included the combination of carfilzomib (twice weekly) and dexamethasone as a category 1, preferred option for patients with relapsed/refractory MM.

Elotuzumab/Lenalidomide/Dexamethasone

The FDA has approved elotuzumab in combination with lenalidomide and dexamethasone for the treatment of patients with MM who have received one to three prior therapies. This is based on the results of the phase III trial, ELOQUENT-2. The trial randomized 646 patients (1:1) to receive either elotuzumab in combination with lenalidomide and dexamethasone or lenalidomide and dexamethasone alone. 223

The rates of PFS at the end of 1 and 2 years were higher for those receiving the elotuzumab-containing regimen(68% at 1 year and 41% at 2 years) compared with those receiving lenalidomide and dexamethasone alone(57% at 1 year and 27% at 2 years).223 Median PFS in the group receiving the elotuzumab-containing regimen was 19.4 months versus 14.9 months in those receiving lenalidomide and dexamethasone alone

(HR for progression or death in the elotuzumab group, 0.70; 95% CI,0.57-0.85;P<.001) indicating a relative reduction of 30% in the risk of disease progression or death.223 Common grade 3 or 4 adverse events in both arms of the trial were lymphocytopenia, neutropenia, fatigue, and pneumonia. Infusion reactions occurred in 33 patients (10%) in the elotuzumab group and were grade 1 or 2 in 29 patients.223

Consistent with the above findings, a subset analysis of 3-year follow-up reported a reduced risk of progression by 27% with the elotuzumab/lenalidomide/dexamethasone combination compared with lenalidomide/dexamethasone.224

The final results of the ELOQUENT-2 study have demonstrated that the addition of elotuzumab to lenalidomide/dexamethasone improved OS in patients with MM who received one to three prior lines of therapy (48.3 months vs. 39.6 months). ${ }^{225}$

Based on the above data and FDA approval the NCCN Panel has included elotuzumab in combination with lenalidomide and dexamethasone as a category 1 option for previously treated MM.

Ixazomib/Lenalidomide/Dexamethasone

A double-blind, randomized, placebo-controlled, phase III TOURMALINE MM1 trial randomized 722 patients with relapsed and/or refractory MM to a combination of ixazomib plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone(control group). This trial was designed based on the promising results of a phase I/ll study(discussed under Other Recommended Primary Therapy Regimens for Transplant Candidates. See nccn.org).

The results of the TOURALINE MM1 trial show a significant improvement in PFS with the ixazomib-containing regimen. After a median follow-up of almost 15 months, a 35% improvement in PFS was seen in

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

the group treated with the ixazomib regimen compared with the control group(HR, 0.74; P=.01).226 Median PFS was 20.6 months in the ixazomib-treated group versus 14.7 months in the group receiving lenalidomide and dexamethasone alone. In the ixazomib-treated group versus the control group, the ORR (78% vs. 72%, P=.035) and CR(11.7% vs. 6.6%, P=.019) were also improved. Of note, patients with high-risk cytogenetics enrolled in the trial receiving ixazomib had a similar HR for PFS as the entire study population (HR, 0.596 and 0.543,respectively).226 Grade ≥3 adverse events were reported in 74% and 69%of patients in the ixazomib-treated and control groups, respectively. These included anemia (9% with ixazomib/lenalidomide/dexamethasone vs. 13%with lenalidomide/dexamethasone), thrombocytopenia (19% vs. 9%), and neutropenia (23% vs. 24%).226 The addition of the ixazomib/lenalidomide/dexamethasone group had a slightly higher rate of peripheral neuropathy compared to lenalidomide/dexamethasone (27% vs. 22%).

Based on the results of the phase III TOURMALINE MM1 trial226 the NCCN Panel has included ixazombile/lenalidomide/dexamethasone as a category 1, preferred regimen option for previously treated MM after one to three prior therapies.

Bortezomib/Cyclophosphamide/Dexamethasone

The effects of adding an alkylating agent (such as cyclophosphamide) and a novel agent (such as lenalidomide or bortezomib) to dexamethasone have been investigated for patients with relapsed/refractory MM. The combination of bortezomib, dexamethasone, and cyclophosphamide was found to be effective in patients with relapsed/refractory MM with an acceptable toxicity profile.227,228 The NCCN Multiple Myeloma Panel members have included bortezomib/cyclophosphamide/dexamethasone as an other recommended regimen for relapsed/refractory MM after one to three prior therapies.

Bortezomib/Lenalidomide/Dexamethasone

Data from preclinical studies showed lenalidomide sensitizes myeloma cells to bortezomib and dexamethasone. The results of phase I and phase ll studies show that bortezomib/lenalidomide/dexamethasone is well tolerated and active, with durable responses in heavily pretreated patients with relapsed and/or refractory MM, including patients who have had prior lenalidomide, bortezomib, thalidomide, and HCT. 229,230 After a median follow-up of 44 months, the median PFS was 9.5 months and median OS was 30 months (95% CI, 24-37). ${ }^{230}$ The NCCN Multiple Myeloma Panel members have included bortezomib/lenalidomide/dexamethasone as other recommended regimen for relapsed/refractory MM after one to three prior therapies.

Carfilzomib/Cyclophosphamide/dexamethasone

Carfilzomib/cyclophosphamide/dexamethasone has been shown to be well tolerated with the toxicity profile of carfilzomib being similar to that seen in other trials. ${ }^{231}$

A phase II trial (MUKfive) compared the safety and toxicity of carfilzomib/cyclophosphamide/dexamethasone with bortezomib/cyclophosphamide/dexamethasone in patients with relapsed/refractory MM, who had received one prior regimen.231 A higher proportion of patients receiving carfilzomib achieved VGPR or better and was non-inferior to bortezomib.

Carfilzomib/cyclophosphamide/dexamethasone was well tolerated with the toxicity profile of carfilzomib being similar to that seen in other trials. ${ }^{231}$ This study also included a maintenance phase and demonstrated a median PFS of 11.9 versus 5.6 months in favor of carfilzomib maintenance versus observation.

Another phase II trial compared treatment with cyclophosphamide plus carfilzomib and dexamethasone to treatment with carfilzomib and

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

dexamethasone in patients (n=197) with relapsed/refractory MM after one to three prior lines. ${ }^{232}$ After a median follow-up of 37 months, median PFS was 19.1 with the 3-drug regimen compared to 16.6 months with the 2-drug regimen $(P=.577) .^{232}$ The combination of cyclophosphamide with carfilzomib and dexamethasone did not improve outcomes significantly compared with carfilzomib and dexamethasone alone in the overall population. However, in a sub-group analysis of the lenalidomide-refractory population, the addition of cyclophosphamide to carfilzomib and dexamethasone resulted in a PFS benefit of 18.4 versus 11.3 months (HR, 1.7; 95% CI, 1.1-2.7; P=.043). ${ }^{232}$

The NCCN Panel has included

carflizomib/cyclophosphamide/dexamethasone as treatment as an other recommended regimen for relapsed/refractory MM after one to three prior therapies.

Daratumumab/Cyclophosphamide/Bortezomib/Dexamethasone

In the LYRA study, ${ }^{99}$ among the small cohort of patients with relapsed MM(n=14), after 4 cycles of induction therapy ORR was 12.3% and VGPR or better was seen in 57.1% of patients. ${ }^{99}$ The ORR after 4 induction cycles was 71.4%. The median PFS was 13.3 months (95% CI,6.8-13.3). At 12-months, the OS rate was 54.5% (95% CI,8.6%-86.1%). ${ }^{99}$

Based on this, the NCCN Panel has included daratumumab/bortezomib/cyclophosphamide/dexamethasone as treatment option for relapsed/refractory MM.

Elotuzumab/Bortezomib/Dexamethasone

Numerous randomized trials have shown that three-drug combinations are consistently more effective than 2-drug combinations for the treatment of

MM. A phase ll trial studied the effect of addition of elotuzumab to bortezomib/dexamethasone in patients with relapsed/refractory MM. $^{233}$

Interim analysis results demonstrated a 28% reduction in risk of disease progression or death for patients in the elotuzumab-containing triple-drug arm compared to patients treated with bortezomib/dexamethasone(HR,0.72; 70% CI, 0.59-0.88). Median PFS was significantly higher in the elotuzumab-containing arm(9.7 months vs. 6.9 months). After 2 years the addition of elotuzumab continued to show an efficacy benefit compared to bortezomib/dexamethasone alone with a 24% relative risk reduction in PFS(HR, 0.76; 70% CI, 0.63-0.91).233

Based on the above phase II trial data, the NCCN Panel has included elotuzumab/bortezomib/dexamethasone as an other recommended regimen for relapsed/refractory MM after one to three prior therapies.

Ixazomib/cyclophosphamide/dexamethasone

This regimen has been shown to be tolerable and efficacious in newly diagnosed patients.95,234 A phase II study evaluated this regimen in the relapsed/refractory setting in patients with a median age of 63.5 years and found that it is well tolerated. At a median follow-up of 15.2 months in the phase II study, median PFS was 14.2 months. The PFS trend with this regimen was better in patients aged 65 and older compared with those less than 65 years(median 18.7 months vs. 12.0 months; HR 0.62,P=.14).235 The NCCN Panel has included this all oral regimen under the list of“other recommended regimens” for relapsed/refractory MM.

Lenalidomide/Cyclophosphamide/Dexamethasone

A retrospective analysis to assess the efficacy of lenalidomide in combination with cyclophosphamide and dexamethasone showed that this regimen is effective in heavily pre-treated patients with manageable adverse effects. ${ }^{236}$ The NCCN Panel has included cyclophosphamide/lenalidomide/dexamethasone treatment as an other

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

recommended regimen for relapsed/refractory MM after one to three prior therapies.

Pomalidomide/Cyclophosphamide/Dexamethasone

A phase II study compared the combination of pomalidomide/cyclophosphamide/dexamethasone to pomalidomide/dexamethasone in patients (n = 70) with relapsed/refractory MM who had received more than two prior therapies.237

The triple-drug combination significantly improved the ORR(≥PR, 64.7% vs.38.9%;P=.0355).The median PFS reported was 9.5 months versus 4.4 months. There were no significant differences in adverse event reports between the treatment arms: grade 3 and 4 anemia, neutropenia, and thrombocytopenia, respectively, were reported in 11%, 31%, and 6% of patients treated with pomalidomide/dexamethasone and 24%, 52%, and 15% of patients treated with the triplet regimen.237 Similar results were reported by a single-center retrospective study of patients (n = 20) with relapsed/refractory MM who received pomalidomide/cyclophosphamide/dexamethasone until transplant or disease. ${ }^{238}$ Response to the triple-drug regimen was 63%, with nearly half of patients (42%) after 1 cycle with a median time to response of 3 cycles.One-year median PFS was 80.7% and 65% of patients were relapse-free. ${ }^{238}$

Based on the above phase II trial data, the NCCN Panel has included pomalidomide/cyclophosphamide/dexamethasone as other recommended treatment option for patients with relapsed/refractory MM who have received two prior therapies, including an IMiD and a PI and disease progression on/within 60 days of completion of last therapy.

Regimens Useful In Certain Circumstances for Previously Treated MM-Early Relapse(one to three prior therapies)

Bortezomib/Liposomal Doxorubicin/Dexamethasone

Bortezomib with liposomal doxorubicin (PLD) was approved by the FDA as a treatment option for patients with MM who have not previously received bortezomib and have received at least one prior therapy. The approval was based on a priority review of data from an international phase III trial(n= 646) showing that use of the combination significantly extended the median time to disease progression compared with bortezomib alone (9.3 vs.6.5 months).239 Median duration of response was increased from 7.0 months to 10.2 months with the combination therapy. Based on these results, the NCCN Multiple Myeloma Panel considers bortezomib with the PLD regimen as a category 1 option that is useful in certain circumstances for patients with relapsed/refractory MM.

Bortezomib/Dexamethasone

The addition of dexamethasone to bortezomib in patients with relapsed/refractory MM who had PD during bortezomib monotherapy resulted in improvement of response in 18% to 34% of patients.240-242 The NCCN Multiple Myeloma Panel members have included the bortezomib and dexamethasone regimen as an option that is useful in certain circumstances for patients with relapsed/refractory MM(category 1).

Lenalidomide/Dexamethasone

Lenalidomide combined with dexamethasone received approval from the FDA as a treatment option for patients with MM who had received at least one prior treatment. This was based on the results of two studies of a total of 692 patients randomized to receive dexamethasone either with or without lenalidomide. The primary efficacy endpoint in both studies was TTP.A pre-planned interim analysis of both studies reported that the median TTP was significantly longer in the lenalidomide arm compared to the control group.243,244 The updated clinical data from the pivotal North

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

American phase III trial (MM-009) in 353 previously treated patients with MM reported increased OS and median time to disease progression in patients receiving lenalidomide plus dexamethasone compared to patients receiving dexamethasone plus placebo.244 Similar results were seen in the international trial MM-010.243 Patients in both of these trials had been heavily treated before enrollment. Many had three or more prior lines of therapies with other agents and more than 50% of patients had undergone HCT.243,244 Most adverse events and grade 3/4 adverse events were more frequent in patients with MM who received the combination of lenalidomide/dexamethasone compared to placebo and dexamethasone.Thrombocytopenia (61.5%) and neutropenia (58.8%) were the most frequently reported adverse events observed. The NCCN Multiple Myeloma Panel now considers this regimen as a category 1 option that is useful in certain circumstances for patients with relapsed/refractory MM.

Carfilzomib/Cyclophosphamide/Thalidomide/Dexamethasone:The results of the phase I/II trial showed that this 4-drug regimen is efficacious with an ORR of 91%, with 59% achieving VGPR or greater after 4 cycles in patients with MM.245 The PFS and OS at 24 months(median 17.5 months) was 76% and 96%, respectively.245 This regimen has now been included under the list of regimens“useful in certain circumstances" for relapsed/refractory MM.

Carfilzomib(weekly)/dexamethasone

In the phase III A.R.R.O.W. trial, patients (n = 578) with relapsed and refractory MM previously treated with two or three treatments, including PI and IMiD were randomly assigned (1:1) to receive carfilzomib once a week(70 mg/m2) or twice a week (27 mg/m2). All patients received dexamethasone. The media PFS was higher in the once weekly (11.2 months) compared with those who received twice weekly carfilzomib (7.6 months; HR 0.69, 95% CI 0.54-0.83; P=.0029). The overall safety was comparable between the two groups. ${ }^{246}$ The NCCN panel has included

this combination on the list of regimens "useful in certain circumstances"for relapsed/refractory MM.

Selinexor/daratumumab/dexamethasone

A phase lb/ll trial assessed the safety and efficacy of adding daratumumab to selinxer.dexamethasone. Patients (n=34) enrolled in the trial had received three or more prior lines of therapy, including a PI and an IMiD. In daratumumab naive patients, the ORR was 73%, with 11 VGPR, and 11 PR. The median PFS was 12.5 months. This regimen has been included under the list of regimens useful in certain circumstances for relapsed/refractory MM.

Selinexor/Carfilzomib/Dexamethasone

In a study of 32 patients who had received a median of four prior therapies were assigned to receive once weekly selinexor, carfilzomib, and dexamethasone. The ORR was 78% with a median PFS of 15 months.The most common grade 3 or higher treatment-related adverse events were thrombocytopenia(47%), nausea(6%), anemia(19%), and fatigue(9%).247

Another analysis of a subset of this patient population that had triple class refractory MM also showed an ORR of 66.7% with a median PFS of 13.8 months, and median OS of 33 months. ${ }^{248}$

This regimen has now been included under the list of regimens“useful in certain circumstances” for relapsed/refractory MM.

Venetoclax/Dexamethasone with or without Daratumumab or PI for t(11;14) Patients

A phase I study of patients (n=66) with relapsed/refractory MM who received a median of 5 prior lines of therapy studied venetoclax monotherapy and reported an ORR in 21% of patients with the response rate being higher in patients (n=30) with t(11;14) compared with those

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

without t(11:14) (40% vs.6%).249 Similar higher response rates have been found in patients with t(11:14) in real-world experience as well.250 An open label phase l/Il study examined venetoclax/dexamethasone in heavily pretreated t(11;14) patients. In this phase ll part of the study, patients had received a median of 5 prior lines of therapy. At a median follow-up of 9.2 months, the ORR was 48%, with a median TTP of 10.8 months.251

Several prospective trials have reported on the efficacy and tolerability of venetoclax/dexamethasone containing combination regimens in relapsed t(11;14) MM. A phase I study found that venetoclax/dexamethasone in combination with daratumabum with or without borpezizomb produced high rates of durable responses in patients with relapsed or refractory MM with t(11;14) translocation.252

In patients with no prior treatment with carfilzomib,venetoclax/dexamethasone plus carfilzomib was found to be safe and efficacious especially in those with t(11;14) translocations.253 This finding has been supported by case studies.254

The NCCN Panel had included venetoclax/dexamethasone with or without daratumumab or a PI as options for patients with t(11:14) translocation.

Pomalidomide/Dexamethasone

Pomalidomide, like lenalidomide, is an analogue of thalidomide. It possesses potent immunomodulatory and significant anti-myeloma properties.255

A phase III, multicenter, randomized, open-label study(MM-003)

conducted in Europe compared the efficacy and safety of pomalidomide and low-dose dexamethasone(n= 302) versus high-dose dexamethasone(n= 153) in patients with relapsed MM who were refractory to both lenalidomide and bortezomib. ${}^{256}$ After a median follow-up of 10 months,PFS, the primary endpoint of the study, was significantly longer in patients

who received pomalidomide and low-dose dexamethasone compared with those who received high-dose dexamethasone(4 months vs. 1.9 months;HR,0.45;P<.0001).256 The mediari OS was significantly longer in the patients who received pomalidomide and low-dose dexamethasone as well(12.7 months vs.8.1 months; HR,0.74;P=.0285).256 The most common hematologic grade 3 and 4 adverse effects found to be higher with the low-dose dexamethasone compared with the high-dose dexamethasone were neutropenia and pneumonia.256 Other phase III studies of pomalidomide plus low-dose dexamethasone in combination with other agents(eg, bortezomib) are currently ongoing(Clinical Trial ID:NCT01734928). A European multicenter, single-arm, open-label, phase Illb trial evaluated the safety and efficacy of pomalidomide and low-dose dexamethasone in a large patient population(N= 604).257 The median PFS reported was 4.2 months and OS was 11.9 months. Whether the patients received prior lenalidomide or bortezomib, the PFS, OS, and ORR reported were similar.257 The results of this trial are consistent with those observed in the pivotal MM-003 trial.256

In addition, several complementary phase II studies have been published evaluating the use of pomalidomide and dexamethasone in patients with MM relapsed/refractory to lenalidomide and/or bortezomib. A phase II study investigated two different dose regimens of pomalidomide and dexamethasone in 84 patients with advanced MM. Pomalidomide(4 mg)was given orally on days 1 to 21 or continuously over a 28-day cycle, and dexamethasone(40 mg) was given orally once weekly. ${ }^{258}$ ORR was 35%and 34% for patients in the 21-day and 28-day groups, respectively. With a median follow-up of 23 months, median duration of response, PFS, and OS were 7.3, 4.6, and 14.9 months across both groups, respectively. All patients experienced similar adverse events in both groups. The adverse events were primarily due to myelosuppression. ${ }^{258}$ Another phase II trial evaluated two doses of pomalidomide 2 or 4 mg/day with dexamethasone 40 mg weekly in heavily pre-treated patients (n = 35). ${ }^{259}$ The ORR in the 2-

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

mg cohort was 49% versus 43% in the 4-mg cohort. OS at 6 months was 78% and 67% in the 2- and 4-mg cohort, respectively. Myelosuppression was the most common toxicity.259

The FDA has approved pomalidomide for patients with MM who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. The FDA-recommended dose and schedule of pomalidomide is 4 mg orally on days 1 to 21 of repeated 28-day cycles with cycles repeated until disease progression along with the recommendation to monitor patients for hematologic toxicities, especially neutropenia.

Based on the above data, the NCCN Panel has included pomalidomide plus dexamethasone as a therapeutic option in patients who have received at least two prior therapies, including an IMiD and a PI, and have demonstrated disease progression on or within 60 days of completion of the last therapy(category 1).

Selinexor/Pomalidomide/Dexamethasone

An abstract presented at the 2021 ASCO Annual Meeting presented data from an ongoing phase I/ll clinical trial that contains one arm evaluating the regimen of selinexor/pomalidomide/dexamethasone(NCT02343042).Sixty-five patients were enrolled initially in phase I with a median of three prior lines of therapy. After determining a recommended phase II dose, it was administered to 20 patients. Among these patients, the ORR was 65% and the median PFS was not reached in a median follow up of 3.9 months.260 Based on the above data, the NCCN Panel has included selinexor/pomalidomide/dexamethasone as a therapeutic option in patients who have received at least two prior therapies, including an IMiD and bortezomib, and have demonstrated disease progression on or within 60 days of completion of the last therapy(category 1).

Daratumumab

Daratumumab is a human IgG kappa monoclonal antibody that targets the CD38 surface protein on myeloma cells.213 In a phase I/II study, patients who had received more than three lines of therapy including an IMiD and a Pl or were double refractory to Pl and IMiD were randomized to two different doses of daratumumab(8 mg/kg vs.16 mg/kg).Findings from 106 patients who received 16 mg/kg noted an ORR of 29.2% in 31 patients (3 sCR, 10 VGPR, and 18 PR). The median duration of response was 7.4 months and median TTP was 3.7 months. The estimated 1-year OS rate was 65%.214 Adverse events reported were fatigue (39.6%),anemia (33.0%), nausea (29.2%), and thrombocytopenia (25.5%). Grade 1 and 2 infusion-related reactions were seen in 42.5% of patients, mainly during first infusion. No patients discontinued the study due to infusion-related reactions.214

Based on the above phase II results and FDA approval, the panel has added daratumumab as an option for the treatment of patients with MM who have received at least three prior lines of therapy including a PI and an IMiD or who are double refractory to a PI and IMiD.

DCEP and VTD-PACE for Aggressive MM

Patients with an aggressive relapse may need multi-drug combinations such as DCEP,261-263 TD-PACE (thalidomide,dexamethasone,cisplatin,doxorubicin, high-dose cyclophosphamide, and etoposide),264,265 and VTD-PACE (bortezomib, thalidomide,dexamethasone,cisplatin,doxorubicin,cyclophosphamide, and etoposide)266-268 for effective disease control.

Preferred Regimens for Relapse After Four Prior Therapies

Currently there are three bispecific antibodies (elranatamab-bcmm,talquetamab-tgvs, and teclistamab-cqyv) and two chimeric antigen receptor (CAR) T-cell therapies(idecabtagene vicleucel and ciltacabtagene autoleucel) approved by the FDA and included as preferred

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

options by the NCCN Panel for relapsed/refractory MM after at least four prior therapies including an anti-CD38 monoclonal antibody, a PI, and an IMiD.

the ORR was 63% and 39.4% of patients demonstrated a CR or better.The median PFS was 11.3 months, with a median response duration of 18.4 months. Common adverse events included cytokine release syndrome in 72.1% of patients(0.6% grade 3) and grade 3 or hematologic toxicity including neutropenia (64.2%), anemia (37%), and thrombocytopenia (21.2%). Infections were also common, with grade 3 or 4 infection occurring in 44.8% of patients.

Bispecific Antibodies:

Elranatamab-bcmm: Elranatamab-bcmm is a bispecific T-cell engager(BiTE) that binds CD3 on T cells and to B-cell maturation antigen (BCMA)on myeloma cells. In the phase II, MagnetisMM-3 trial, patients with relapsed/refractory MM received subcutaneous elranatamab once weekly. ${ }^{269}$ The primary population in whom the efficacy was seen were patients (n= 123) without prior BCMA-directed therapy. The findings indicated an ORR of 61.0% (75/123) and 35.0% greater than or equal to CR. Fifty responders switched to biweekly dosing, and 40 of those (80.0%)improved or maintained their response for $\geq 6$ months. Common adverse events reported were infections, cytokine release syndrome, anemia, and neutropenia. With biweekly dosing, grade 3-4 adverse events decreased from 58.6% to 46.6%. ${ }^{269}$

CAR T-Cell Therapies:

Idecabtagene vicleucel: Idecabtagene vicleucel is a BCMA-directed CAR-T cell therapy. In a phase II study(n=128) patients with relapsed and refractory MM who had received at least three prior regimens(including a PI,an IMiD, and an anti-CD38 antibody) received idecabtagene vicleucel.Patients had received a median of 6 previous regimens for MM and 94%had received HCT. In this population of heavily pretreated patients, after a median 13 months follow up, 73% of patients demonstrated response, with 33% having a CR or better. The median time to response was 1 month and median time to a CR or better was 2.8 months. High response rates(> 50%) were found in several examined subgroups including older patients, patients with high-risk cytogenetic abnormalities, penta-refractory disease, and high tumor burden. Adverse events at grade 3 or 4 were common and included neutropenia(91%), anemia(70%), and thrombocytopenia(63%). Twenty eight patients were retreated with idecabtagene vicleucel following disease progression and 21%demonstrated a second response. Grade 3 or 4 adverse events were common and were reported in 99% of patients. The most common adverse events were related to hematologic toxicity such as neutropenia(89%),anemia(60%),and thrombocytopenia(52%).Infections(69%) and cytokine release syndrome(84%) were also common treatment related adverse events, although the incidence of grade 3 or higher cytokine release syndrome was lower(5%).272 The NCCN Panel has included idecabtagene vicleucel as an option for patients who have received at

Talquetamab-tgvs: Talquetamab is a T cell redirecting bispecific antibody targeting both GPRC5D and CD3 on T cells. In the single-arm, open-label,multicenter trial, MMY1001 (MonumenTAL-1) patients (n=187) who had previously received at least four prior systemic therapies received talquetamab-tgvs subcutaneously weekly or talquetamab-tgvs biweekly used in until disease progression or unacceptable toxicity.27The most common adverse reactions reported with weekly and biweekly dosing were cytokine release syndrome (in 77\% and 80\% of the patients, respectively),skin-related events (in 67\% and 70\%), and dysgeusia (in 63\% and 57\%).270

Teclistamab-cqyv: Teclistamab-cqyv, similar to elranatamab-bcmm, is a BiTE that binds to CD3 on T cells and BCMA on myeloma cells. A phase I/II study examined the T-cell-redirecting bispecific antibody teclistamab-cqyv in 165 patients who had triple class refractory disease, with a median of five prior lines of therapy.271 After a median follow up of 14.1 months,

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

least four prior therapies, including an anti-CD38 monoclonal antibody, a PI, and an IMiD.

Ciltacabtagene autoleucel: Ciltacabtaggene autoleucel is another BCMA directed CAR T-cell therapy. The CARTITUDE-1 trial(n=97) was an open label phase lb/II study that looked to assess the safety and efficacy of ciltacabtagene autoleucel in patients with relapsed or refractory MM who had received three or more previous lines of therapy (including an IMID,PI, and andti-CD38 antibody).273 The median amount of prior therapies was six. After a median 12.4 months of follow up, the ORR was 97%, with 67% of patients achieving sCR. The PFS rate was 77% with an 89% OS rate. Adverse events included neutropenia in 95% of patients and anemia in 68%. Other common adverse events included thrombocytopenia (60%),leukopenia (61%), and lymphopenia (50%). Cytokine release syndrome also occurred in 95% of patients. There were six deaths due to treatment related adverse events.273 A follow up analysis at 18 months showed that responses were durable; 18-month PFS and OS rates were 66.0 % and 80.9 % respectively, with no new observed safety signals.274

Other Recommended Regimens for Relapse After Three Prior Therapies

Bendamustine

In a trial by Knop and colleagues, 31 patients who had experienced relapse after autologous transplantation were enrolled to receive increasing doses of bendamustine.275 The ORR was 55%, with a median PFS of 26 weeks for all patients and 36 weeks for patients who received higher doses of bendamustine(90-100 mg/m2). The toxicity was mild and mainly hematologic. A retrospective analysis of 39 patients has reported that bendamustine is effective and tolerable in patients with advanced progressive MM, with an ORR of 36%.276

The ECOG studied treatment with high-dose cyclophosphamide in patients with poor-risk features who had disease that was refractory to prior chemotherapy.277 The ORR reported was $43\%$ ( $29\%$ response rate in patients refractory to prior therapy with cyclophosphamide).277 Bendamustine is currently a treatment option for relapsed/refractory MM.

Bendamustine/Bortezomib/Dexamethasone

A phase ll study evaluated bendamustine/bortezomib/dexamethasone administered over six 28-day cycles and then every 56 days for 6 more cycles in patients (n = 75; median age 68 years) with relapsed/refractory MM treated with multiple prior therapies and not refractory to bortezomib.The PR rate was 71.5% (16% CR, 18.5% VGPR, 37% partial remission).At 12-month follow-up, median TTP was 16.5 months, and 1-year OS was 78%.278

Bendamustine/carfilzomib/dexamethasone

A multicenter trial evaluated combination therapy with bendamustine/carfilzomib/and dexamethasone in 63 patients with relapsed/refractory MM (with at least two lines of prior therapy). Fifty two percent of patients achieved a PR or better and 32% achieved a VGPR or better. After a median follow up of 22 months, the median PFS was 11.6 months with a median OS of 30.4 months. The most common adverse events of grade 3 or higher included lymphopenia (29%), neutropenia(25%), and thrombocytopenia (22%).279 The NCCN Panel has included carbilzomib in combination with bendamustine and dexamethasone as a treatment option for relapsed/refractory MM.

Bendamustine/Lenalidomide/Dexamethasone

A multicenter phase l/II trial investigated the combination of bendamustine,lenalidomide, and dexamethasone as treatment for patients (n=29) with relapsed/refractory MM. ${ }^{280}$ PR was seen in 52% (n=13) of patients, with VGPR in 24\%(n=6) of patients. The median PFS in the trial was 6.1

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

months (95% CI, 3.7-9.4 months), and the one-year PFS rate was 20%(95% CI, 6%-41%).280 The NCCN Panel has included lenalidomide in combination with bendamustine and dexamethasone as a treatment option for relapsed/refractory MM.

High Dose or Fractionated Cyclophosphamide

Studies have reported that high-dose cyclophosphamide or hyperfractionated cyclophosphamide is efficacious particularly in patients needing immediate disease control who have received multiple prior treatments.281,282 Therefore the NCCN Panel has included high dose or fractionated cyclophosphamide as an option for relapsed/refractory MM.

Selinexor/Dexamethasone:

Selinexor in combination with dexamethasone was studied in a phase llb trial (STORM) in patients with relapsed/refractory MM. ${ }^{283}$ The patients in the trial had multiple prior therapies and were refractory to IMIDs(lenalidomide and pomalidomide), Pls (bortezomib and carfilzomib), and the CD38 antibody daratumabum. A total of 122 patients were included in the intent-to-treat population. PR or better was observed in 26% of patients (95% CI, 19-35 with sCR in 2%, VGPR in 5%, and PR in 20% of the patients.

The most common adverse events reported during treatment were thrombocytopenia in 73% of the patients, fatigue in 73%, nausea in 72%,and anemia in 67%.

Based on the above results, the NCCN Panel has included selinexor/dexamethasone under other recommended options for patients with relapsed/refractory MM who have received at least four prior therapies and whose disease is refractory to at least two Pl, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.247

Regimens Useful in Certain Circumstances for Relapse After Four Prior Therapies

Belantamab Mafodotin-blmf

Belantamab mafodotin-blmf is a BCMA antibody, conjugated to a microtubule disrupting agent- monomethyl auristatin-via a stable,protease resistant linker. It is the first in its class. In the open-label phase II trial(DREAMM-2), belantamab mafodotin was evaluated in patients whose MM was refractory to multiple agents. Responses were seen in approximately one-third of patients.284 The most common grade 3/4 adverse events in the safety population were keratopathy,thrombocytopenia, and anemia.284

In November 2022, it was announced that belantamab mafodotin-blmf is being withdrawn as it did not meet the primary end point of having a superior PFS compared to pomalidomide/dexamethasone in the DREAMM-3 trial (HR 1.03; 95% CI, 0.72-1.47). The PFS with belantamab mafodotin-blmf was 11.2 months compared with 7 months for pomalidomide plus dexamethasone, however this was not statistically significant. Since, patients already receiving belantamab mafodotin-blmf and those enrolled on the FDA Risk Evaluation and Mitigation Strategy(REMS) program have been able to continue to receive the drug through a compassionate use program. There are other ongoing trials with belantamab mafodotin-blmf, the NCCN Panel has included this as an option useful in certain circumstance for those after 4 prior therapies(including a Pl , an IMiD, and an anti-CD38 monoclonal antibody).

Supportive Care for Multiple Myeloma

Important advances have been made in adjunctive treatment/supportive care of patients with MM. This involves careful patient education about the probable side effects of each drug, the drug combinations being used, and the supportive care measures required. Supportive care can be

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

categorized into those measures required for all patients and those that address specific drugs.

A recent meta-analysis of 20 randomized controlled trials comparing bisphosphonates with either placebo or a different bisphosphonate as a comparator concluded that adding bisphosphonates to the treatment of MM reduces vertebral fractures and probably reduces pain.292 It did not find a particular bisphosphonate to be superior to another.292 In a multicenter trial (CALGB 70604), patients with MM or bone metastases from a solid malignancy were randomly assigned to zoledronic acid either monthly or every 3 months for 2 years.293 The rates of skeletal-related events (SRE) were similar in both arms. Among the 278 patients with MM, rates of SRE were 26% in those receiving monthly versus 21% in those receiving treatment every 3 months.293

Bony manifestations in the form of diffuse osteopenia and/or osteolytic lesions develop in 85% of patients with MM. Related complications are the major cause of limitations in quality of life and performance status in patients with MM. A large, double-blind, randomized trial has shown that monthly use of IV pamidronate(a bisphosphonate) can decrease pain and bone-related complications, improve performance status, and, importantly,preserve quality of life in patients with Durie-Salmon stage III MM and at least one lytic lesion.285,286 Zoledronic acid has equivalent benefits.287 Results from the study conducted by Zervas et al288 show a 9.5-fold greater risk for the development of osteonecrosis of the jaw(ONJ) with zoledronic acid compared to pamidronate. Patients who are on bisphosphonates should have their renal function monitored. They should have a dental exam prior to the start of bisphosphonate therapy and should be monitored for ONJ.

A large, placebo-controlled, randomized trial compared denosumab with zoledronic acid in patients(n = 1718) with newly diagnosed MM with bone lesions. Time to first SRE and OS were similar in both arms. The denosumab arm had lower rates of renal toxicity and higher rates of hypocalcemia. ONJ was slightly higher in the denosumab arm(3% vs. 2%)but not statistically significant.294

The Medical Research Council(MRC) Myeloma IX study examined effects of zoledronic acid versus clodronate (a bisphosphonate not currently FDA approved) in patients with MM initiating chemotherapy regardless of bone disease. The patients were randomized to receive zoedronic acid (n=981) or clodronic acid (n = 979). Zoledronic acid was reported to reduce mortality and significantly improve PFS.289 Patients on clodronate and zoledronic acid had similar occurrence of acute renal failure and treatment-related serious adverse events. Zoledronic acid was associated with higher rates of ONJ than was clodronic acid.290 An extended follow-up(median, 5.9 years) of the MRC Myeloma IX showed significant improvement in OS (52 vs. 46 months; HR, 0.86; P=.01) compared with clodronic acid.291 The long-term rates of ONJ were also observed to be higher with zoledronic acid compared with clodronate (3.7% vs. 0.5%; P=.0001).291

The NCCN Guidelines for Multiple Myeloma recommend bisphosphonates(category 1) or denosumab for all patients receiving therapy for symptomatic MM regardless of documented bone disease. Denosumab is preferred by the NCCN Panel in patients with renal disease. The NCCN Panel recommends a baseline dental exam and monitoring for ONJ in all patients receiving a bone-modifying agent and monitoring for renal dysfunction with use of bisphosphonate therapy. With respect to duration of therapy, the panel also recommends continuing bone-targeting treatment(bisphosphonates or denosumab) for up to 2 years and continuing beyond 2 years would be based on clinical judgement. The frequency of dosing(monthly vs. every 3 months) would depend on the individual patient criteria and response to therapy.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

Excess bone resorption from bone disease can lead to excessive release of calcium into the blood, contributing to hypercalcemia. Symptoms include polyuria and gastrointestinal disturbances, with progressive dehydration and decreases in glomerular filtration rate. Hypercalcemia should be treated with hydration, bisphosphonates, denosumab,294 steroids,and/or calcitonin. Among the bisphosphonates(zoledronic acid, pamidronate, and ibandronate), the NCCN Multiple Myeloma Panel members prefer zeroledronic acid for treatment of hypercalcemia.287,295,296

The NCCN Panel has provided general principles of palliative RT for patients with MM. Careful planning of the radiation field and radiation technique is important to minimize toxicity to the spinal cord, brain, bone marrow, and adjacent organs at risk (OAR) as patients with MM may be treated multiple times during their disease course. The panel has noted that initiation of systemic therapy should not be delayed for RT and can often be given concurrently and that patients should be carefully monitored for toxicities.297,298 Low-dose RT (8 Gy x 1 fraction) or 20-30 Gy in 5-10 total fractions can be used as palliative treatment for uncontrolled pain, for impending pathologic fracture, or for impending cord compression. Moderately fractionated courses of 20-25 Gy in 8-10 fractions are generally preferred over higher doses (30 Gy) absent extenuating circumstances (e.g., severe symptomatic cord compression)to limit unnecessary toxicity and reduce risk of future treatment of adjacent or overlapping OAR (e.g., spinal cord).299 For RT dose constraint suggestions regarding bone marrow and other OAR, see NCCN Guidelines for Hodgkin Lymphoma.

Plasmapheresis should be used as adjunctive therapy for symptomatic hyperviscosity.300 Institutions differ in their use of plasmapheresis for adjunctive treatment of renal dysfunction.

Erythropoietin therapy may be considered for anemic patients, especially those with renal failure. Measuring endogenous erythropoietin levels may

also be helpful in treatment planning301,302 (see NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections). Daratumumab can interfere with cross-matching and RBC antibody screening.The NCCN Panel recommends performing type and screen prior to receiving daratumumab to inform future matching.

The highest risk for venous thromboembolism (VTE) is in the first 6 months following new diagnosis of MM. The NCCN Panel has outlined management of VTE, risk stratification, and VTE prophylaxis in a separate section in the NCCN Guidelines for Multiple Myeloma (see nccn.org) and VTE prophylaxis is administered to all patients, assuming there are no contraindications to anticoagulation agents or anti-platelets (see NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease).

To prevent infections in patients with MM, the panel recommends referring to the NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections, the CDC recommendations for CDC for Use of COVID-19 Vaccines in the US, and in the most recent update, the panel has outlined recommendations for prophylaxis and management of infections in patients undergoing treatment with CAR T-cell and bispecific antibody.

Management of Renal Disease in Multiple Myeloma

In patients with MM and monoclonal gammopathies, renal disease usually results from the production of monoclonal immunoglobulin or light/heavy chains by a clonal proliferation of plasma cells or B cells. Renal disease is seen in 20% to 50% of patients with MM and has been observed to negatively affect outcomes.303-305 The NCCN Panel has added a new page outlining management of renal disease in MM.

Renal insufficiency defined as elevated serum creatinine greater than 2 mg/dL or established glomerular filtration rate (eGFR) less than 60

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

mL/min/1.73 m2 in patients with MM is usually due to light chain cast nephropathy, but other etiologies need to be considered including hypercalcemia, volume depletion, and hyperuricemia as well as nephrotoxic medications or IV contrast. In addition, concomitant amyloidosis and monoclonal immunoglobulin deposition should be suspected when renal insufficiency or albuminuria is present without high levels of light chains.

recommended by the IMWG.311 A retrospective study evaluated lenalidomide and dexamethasone based on two phase III trials of lenalidomide/low-dose dexamethasone in patients with relapsed/refactory MM with a serum creatinine of<2.5 mg/dL. Patients grouped by creatinine clearance>60 mL/min(n=243),30-60 mL/min(n=82),and<30 mL/min(n=16) showed no difference in response rates to lenalidomide/low-dose dexamethasone.312 Patients with renal insufficiency had higher rates of thrombocytopenia and lenalidomide discontinuation than seen in patients without renal insufficiency. The NCCN Panel has outlined recommendations for lenalidomide dosing based on the degree of renal function in patients with MM and renal impairment. While prospective data to define optimal dosing are often lacking, pomalidomide has been studied in patients with relapsed MM in three different categories of renal insufficiency(eGFR 30-40 mL/min/1.73 sqm, eGFR<30 mL/min/1.73 sqm, and those requiring dialysis) and full-dose pomalidomide of 4 mg daily was found to be safe in all three groups.313

Diagnostic Tests

According to the NCCN Panel, diagnostic workup of patients with symptomatic MM should include serum creatinine, electrolyte measurements, eGFR, electrophoresis of a sample from a 24-hour urine collection, serum electrophoresis, and serum FLC measurement. If proteinuria predominantly consists of light chains with high serum levels of FLC, and the cause of renal insufficiency can be attributed to MM, a renal biopsy may not be necessary. However, patients without a clear and complete explanation for their renal insufficiency should undergo renal biopsy to look for other pathophysiology such as monoclonal immunoglobulin deposition disease(MIDD) or membranproliferative glomerulonephritis (MPGN).

Supportive Care: IV fluids should be started promptly to decrease the renal tubular light chain concentration with a goal urine output of 100 to 150 cc per hour. Careful assessment of the fluid status is critical to avoid hypervolemia, especially in patients with oliguria renal failure.

Treatment Options

The initial treatment of cast nephropathy includes initiating appropriate MM therapy and providing adequate supportive care.

In addition, nephrotoxic medications should be discontinued and other metabolic abnormalities such as hypercalcemia and hyperuricemia should be corrected. Hydration, bisphosphonates or denosumab, and calcitonin are recommended to reduce calcium levels in the case of hypercalcemia.In patients with renal disease, pamidronate and zoledronic acid should be used with caution. The NCCN Panel has provided the recommended dosing of these agents in those who have renal impairment.

Myeloma Therapy: Bortezomib and/or a daratumumab-containing regimen can be administered in patients with severe renal impairment and also those on dialysis and does not require renal dose adjustment.306-310 Once the renal function improves or stabilizes, one can switch to other regimens.

regimens.

Agents used in myeloma therapy should be used with caution and with dose adjustments based on the degree of renal function impairment as

Dialysis may be required in selected patients in addition to prompt institution of anti-myeloma therapy. Mechanical removal of light chains may be considered on a case-by-case basis. While the benefit of

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

mechanical removal of FLCs has not been established, there is limited evidence for the use of plasmapheresis or high-cutoff dialysis to reduce pathogenic light chains.

Monoclonal Gammopathy of Clinical Significance (MGCS)

Monoclonal gammopathy of undetermined significance(MGUS) is defined by the absence of MM-defining events, presence of monoclonal gammopathy of <3 g/dL, and clonal population of BMPCs less than 10%.The prevalence of MGUS in the general population is about 0.7%, and it increases with age.

MGCS refers to the potentially organ-toxic properties of M protein.Typically, the M protein in MGCS does not meet the diagnostic criteria for MM and Waldenstrom macroglobulinemia (WM). Previously MGCS were all grouped under MGUS. Monoclonal gammopathy affects the renal function, and it is referred to as MGRS. Peripheral neuropathy mediated by a M protein in the serum and urine without any evidence of MM or WM is now defined as monoclonal gammopathy of neurological significance(MGNS).

Monoclonal Gammopathy of Renal Significance (MGRS)

The term "MGRS" was proposed by the International Kidney and Monoclonal Gammopathy Research Group to collectively describe patients who meet the criteria for MGUS but demonstrate renal injury attributable to the underlying M protein.314

When the presence of monoclonal gammopathy affects the renal function,it is referred to as MGRS. Renal damage in the setting of symptomatic MM is not considered MGRS.

Initial Workup

In patients suspected of having MGRS, kidney biopsy is performed. A kidney biopsy is essential in demonstrating the nephrotoxicity of the M protein. The biopsy may be deferred if the eGFR is stable, the urinalysis is normal, or there is no evidence of proteinuria(it is not always light chain proteinuria).

The presence of monoclonal immunoglobulin deposits in the kidney indicates the existence of a plasma cell, B cell, or lymphoplasmytic clone that is responsible for the production of the M protein.

M protein must be detected by electrophoresis and immunofixation in the urine and serum and must be correlated with the one found in biopsy. Immunofluorescence staining should be performed with the biopsy sample for IgG subclasses, IgA and IgM, and kappa and lambda.

Imaging by PET/CT, low-dose CT, or whole-body MRI should be performed as clinically indicated. Bone marrow biopsy is carried out if suspected to have MM or WM.

Additional workup for appropriate diagnosis of suspected WM, CLL/SLL,or systemic light chain amyloidosis maybe carried out as outlined in the respective NCCN Guidelines(see NCCN Guidelines for Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma, NCCN Guidelines for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, and NCCN Guidelines for Systemic Light Chain Amyloidosis).

Treatment

The treatment of MGRS is directed at the underlying plasma cell or B-cell clones to improve or prevent further kidney damage in these patients. For IgG, IgA, and FLC MGRS, use the management algorithms for MM; for IgM MGRS, see NCCN Guidelines for Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma. For any MGRS with

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

monoclonal B-cell lymphocytosis (MBL) features, see NCCN Guidelines for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.

The response assessment in patients with MGRS who are being actively treated is as per the NCCN Guidelines listed above and includes SPEP and immunofixation; 24-hour urine collection for total protein, protein electrophoresis, and immunofixation; serum FLC assay; and serum creatinine.

Monoclonal Gammopathy of Neurological Significance (MGNS)

MGNS is a subset of MGCS that is predominantly characterized by neurologic symptoms (such as peripheral neuropathy) and the presence of M protein without evidence of active MM or WM.

Patients with MGNS may have varying electrophysiologic features. A single-center retrospective analysis suggests that approximately 69% of patients with MGNS showed demyelinating features while 26% showed axonal features.315 As a precursor state to numerous B-cell disorders,suspected MGNS does not always necessitate pharmacotherapy, but does warrant additional workup and evaluation to rule out other causes of neuropathy and inform clinical decision-making.

Initial Workup

MGNS may be the result of other comorbidities or conditions such as diabetes, cobalamin deficiency, thyroid dysfunction, Lyme disease, HIV infection, syphilis, autoimmune disease, or cryoglobulinemia. A comprehensive assessment of other causes of neuropathy is needed,including an evaluation for light chain amyloidosis, WM, or POEMS(Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes) syndrome. Additional components of an initial workup include anti-MAG antibodies, ganglioside antibody panel, nerve conduction study(NCS) or electromyogram(EMG), neurology consult,and chest/abdominal/pelvic CT with contrast(if possible). Sural nerve

biopsy may be considered in certain circumstances. A nerve biopsy is a less desirable diagnostic method due to the association with pain and potential permanent sensory or motor deficits.316

MYD88 L265P allele-specific PCR testing of bone marrow is included in the initial workup of a patient with suspected MGNS. A study analyzed the correlation of MYD88 L265P mutation in a large number of tumor samples across a variety of B-cell disorders and reported higher levels of IgM(P<.0001) and higher frequency of proteinuria(P=.002) in patients with the mutation compared to patients with wild-type MYD88. The incidence of MYD88 L265P mutation was reported in 100% of patients with WM, 47%of patients with MGUS, 6% with splenic marginal zone lymphoma, and 4%of patients with B-cell chronic lymphoproliferative disorders.317 Subsequent studies have also reported the strong correlation of MYD88 mutation status in MGNS and WM.318-320 It should be noted that wild-type MYD88 occurs in less than 10% of patients and should not be used to exclude diagnosis of WM if other criteria are met.

CXCR4 gene mutation testing may be considered in certain circumstances due to its prevalence in MGNS. Several studies reported CXCR4 gene mutation as a common somatic mutation that has been linked with the MYD88 L265P mutation.319-323 Notably, however, a study reported that CXCR4 mutation status had no impact on risk of death. ${}^{320}$ Therefore,CXCR4 gene mutation testing may be included in the initial workup of a patient with suspected MGNS but should be interpreted in the context of other clinical findings to confirm diagnosis.

Clinical Findings

If there is either low suspicion or intermediate suspicion of MGNS that does not affect activities of daily living(ADLs), observation and follow-up as clinically indicated is appropriate. A low suspicion of MGNS may be determined if the following clinical findings are present: motor/pain predominant,non-length dependent,rapid progression(weeks to months),

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

unilateral or asymmetrical, antibodies not present, and no demyelination confirmed by EMG/NCS.

If there is either intermediate suspicion that affects ADLs or high suspicion of MGNS, please refer to the NCCN Guidelines for Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma. A high suspicion of MGNS may be determined if the following clinical findings are present:sensory predominant, length dependent, slow progression(years),bilateral and symmetrical, antibodies present, and demyelination confirmed by EMG/NCS. Presence of the MYD88 L265P and/or CXCR4 mutations should also be considered in the further diagnosis of WM.

POEMS Syndrome

POEMS syndrome is a rare plasma cell disorder that is characterized by the dominant presence of demyelinating peripheral neuropathy and confirmed clonal plasma cell proliferation. The etiology is not well understood, but it is believed to be correlated with inflammatory cytokines,such as vascular endothelial growth factor(VEGF). Despite the individual components of the acronym, not all of the features are necessary to make a diagnosis of POEMS syndrome. There are also other important features that are not included in the acronym. Because of its rarity, POEMS syndrome may be underdiagnosed and mistaken for other chronic inflammatory syndromes.324-326

The diagnosis of POEMS syndrome is confirmed when both mandatory major criteria, one of the other three major criteria, and one of the six minor criteria are present. The mandatory major criteria for diagnosis of POEMS syndrome include the presence of polyneuropathy(typical demyelinating) and monoclonal plasma cell proliferative disorder [almost always $\lambda$ (lambda)]. Additionally, at least one of the following major criteria is required: Castleman disease, sclerotic bone lesions, and/or VEGF elevation. Minor criteria for diagnosis that may be present include organomegaly(ie, splenomegaly, hepatomegaly, lymphadenopathy),

extravascular volume overload (eg, edema, pleural effusion, ascites),endocrinopathy (ie, adrenal, thyroid, pituitary, gonadal, parathyroid,pancreatic), skin changes (ie,hyperpigmentation, hypertrichosis,glomeruloid hemangiomata, plethora, acrocyanosis,flushing, white nails),papilledema, and/or thrombocytosis/polycythemia. Other signs and symptoms may include clubbing, weight loss, hyperhidrosis, pulmonary hypertension, restrictive lung disease, thrombotic diatheses, diarrhea,and/or low vitamin B12 levels.325

Initial Workup

If POEMS syndrome is suspected, a complete history and physical examination is warranted. Clinical findings should be evaluated for potential correlation to organomegaly(including splenomegaly,hepatomegaly, and lymphadenopathy). Presentation of symptoms such as hyperhidrosis, diarrhea, weight loss, and menstrual/sexual dysfunction should be accounted for in the initial workup. Fundoscopic, skin, and neurologic examinations may be performed to identify abnormalities.325

Recommended initial testing beyond the initial workup includes electrophysiologic (nerve conduction) studies, CT of the chest/abdomen/pelvis(for lymphadenopathy, organomegaly,ascites,pleural effusion, and/or edema), echocardiography (for right ventricular systolic and pulmonary artery pressures), and CT body bone windows and/or FDG-PET/CT (for sclerotic bone lesions). Laboratory testing should include a CBC, complete metabolic panel, fasting glucose, serum immunoglobulins (ie, IgG, IgA, IgM), electrophoresis and immunofixation,serum FLC, 24-hour urine total protein, VEGF, interleukin-6 (IL-6), and numerous hormones (ie, testosterone, estradiol, thyroid-stimulating hormone, parathyroid hormone, prolactin, serum cortisol, luteinizing hormone). A bone marrow aspirate and biopsy, FISH panel, and PCR should be done to assess for MM. 325

Additional testing may be considered, if indicated. These additional tests include sural nerve biopsy, follicle-stimulating hormone,

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

adrenocorticotropin hormone, cosytropin stimulation test, biopsy of bone lesion(if needed), and excisional lymph node biopsy (if Castleman disease or other B-cell lymphomas suspected).325

Treatment

For a confirmed diagnosis of POEMS syndrome, treatment options may include RT, autologous transplant, and/or systemic therapy. RT alone is recommended for isolated bone lesions (defined as <3 sites) in patients without clonal BMPCs.

Autologous transplant is recommended in patients who are eligible as sole therapy or as consolidation after induction therapy. Patients who are not eligible for transplant should receive induction therapy as treatment.

melpalan/dexamethasone, cyclophosphamide/dexamethasone, or pomalidomide/dexamethasone.

Patients who progress after initial therapy should receive individualized treatment based on response and toxicity of prior therapy, with consideration of the patient's performance status at the time of progress.

National Comprehensive Cancer Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

References

1. SEER Stat Fact Sheets: Myeloma. Available at:http://seer.cancer.gov/statfacts/html/mulmy.html.

2. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin 2023;73:17-48. Available at:https://www.ncbi.nlm.nih.gov/pubmed/36633525.

3. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003;78:21-33. Available at:https://www.ncbi.nlm.nih.gov/pubmed/12528874.

4. Dispenzieri A, Kyle RA, Katzmann JA, et al. Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering(asymptomatic) multiple myeloma. Blood 2008;111:785-789. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17942755.

5. Dispenzieri A, Zhang L, Katzmann JA, et al. Appraisal of immunoglobulin free light chain as a marker of response. Blood 2008;111:4908-4915. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18364469.

6. Dispenzieri A, Kyle R, Merlini G, et al. International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia 2009;23:215-224. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19020545.

7. Kuhnemund A, Liebisch P, Bauchmuller K, et al. 'Light-chain escape-multiple myeloma'an escape phenomenon from plateau phase: report of the largest patient series using LC-monitoring. J Cancer Res Clin Oncol 2009;135:477-484. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/18802723.

8. Durie BG,Harousseau JL,Miguel JS,et al. International uniform response criteria for multiple myeloma. Leukemia 2006;20:1467-1473.Available at:https://www.ncbi.nlm.nih.gov/pubmed/16855634.

9. Craig FE, Foon KA. Flow cytometric immunophenotyping for hematologic neoplasms. Blood 2008;111:3941-3967. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18198345.

10. Paiva B, Vidriales MB, Perez JJ, et al. Multiparameter flow cytometry quantification of bone marrow plasma cells at diagnosis provides more prognostic information than morphological assessment in myeloma patients. Haematologica 2009;94:1599-1602. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19880781.

11. Xiong W, Wu X, Starnes S, et al. An analysis of the clinical and biologic significance of TP53 loss and the identification of potential novel transcriptional targets of TP53 in multiple myeloma. Blood 2008;112:4235-4246. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18337559.

12. Drach J, Ackermann J, Fritz E, et al. Presence of a p53 gene deletion in patients with multiple myeloma predicts for short survival after conventional-dose chemotherapy. Blood 1998;92:802-809. Available at:https://www.ncbi.nlm.nih.gov/pubmed/9680348.

13. Avet-Loiseau H, Attal M, Moreau P, et al. Genetic abnormalities and survival in multiple myeloma; the experience of the Intergroupe Francophone du Myelome. Blood 2007;109:3489-3495. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17209057.

14. Gertz MA, Lacy MQ, Dispenzieri A, et al. Clinical implications of t(11;14)(q13;q32),t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy. Blood 2005;106:2837-2840. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15976175.

15. Gutierrez NC, Castellanos MV, Martin ML, et al. Prognostic and biological implications of genetic abnormalities in multiple myeloma undergoing autologous stem cell transplantation: t(4;14) is the most relevant adverse prognostic factor, whereas RB deletion as a unique abnormality is not associated with adverse prognosis. Leukemia 2007;21:143-150. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/16855634.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

16. Ross FM, Chiecchio L, Dagrada G, et al. The t(14;20) is a poor prognostic factor in myeloma but is associated with long-term stable disease in monoclonal gamopathies of undetermined significance.Haematologica 2010;95:1221-1225. Available at:https://www.ncbi.nlm.nih.gov/pubmed/20410185.

23. D'Agostino M, Cairns DA, Lahuerta JJ, et al. Second Revision of the International Staging System(R2-ISS) for Overall Survival in Multiple Myeloma: A European Myeloma Network(EMN) Report Within the HARMONY Project. J Clin Oncol 2022;40:3406-3418. Available at:https://www.ncbi.nlm.nih.gov/pubmed/35605179.

17. Ross FM, Avet-Loiseau H, Ameye G, et al. Report from the European Myeloma Network on interphase FISH in multiple myeloma and related disorders. Haematologica 2012;97:1272-1277. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22371180.

24. Hillengass J, Moulopoulos LA, Delorme S, et al. Findings of Whole Body Computed Tomography Compared to Conventional Skeletal Survey in Patients with Monoclonal Plasma Cell Disorders- a Study of the International Myeloma Working Group [Abstract]. Blood 2016;128:4468. Available at:http://www.bloodjournal.org/content/128/22/4468.

18. Hanamura I, Stewart JP, Huang Y, et al. Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation. Blood 2006:108:1724-1732.Available at:https://www.ncbi.nlm.nih.gov/pubmed/16705089.

25. Kropil P, Fenk R, Fritz LB, et al. Comparison of whole-body 64-slice multidetector computed tomography and conventional radiography in staging of multiple myeloma. Eur Radiol 2008;18:51-58. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16705089.

19. Carrasco DR, Tonon G, Huang Y, et al. High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell 2006;9:313-325. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16616336.

26. Princewill K, Kyere S, Awan O, Mulligan M. Multiple myeloma lesion detection with whole body CT versus radiographic skeletal survey.Cancer Invest 2013;31:206-211. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23406213.

20. Rosinol L, Carrio A, Blade J, et al. Comparative genomic hybridisation identifies two variants of smoldering multiple myeloma. Br J Haematol 2005;130:729-732. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16115129.https://www.ncbi.nlm.nih.gov/pubmed/16115129.

27. Nanni C, Zamagni E, Farsad M, et al. Role of 18F-FDG PET/CT in the assessment of bone involvement in newly diagnosed multiple myeloma: preliminary results. Eur J Nucl Med Mol Imaging 2006;33:525-531. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16453155.

21. Dispenzieri A, Rajkumar SV, Gertz MA, et al. Treatment of newly diagnosed multiple myeloma based on Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART): consensus statement. Mayo Clin Proc 2007;82:323-341. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17352369.

28. Siontis B, Kumar S, Dispenzieri A,et al. Positron emission tomography-computed tomography in the diagnostic evaluation of smoldering multiple myeloma: identification of patients needing therapy.Blood Cancer J 2015;5:e364. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26495861.

29. Zamagni E, Nanni C, Gay F, et al. 18F-FDG PET/CT focal, but not osteolytic, lesions predict the progression of smoldering myeloma to active disease. Leukemia 2016;30:417-422. Available at:

22. Kumar SK, Mikhail JR, Buadi FK, et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines.Mayo Clin Proc 2009;84:1095-1110. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19955246.

https://www.ncbi.nlm.nih.gov/pubmed/26490489.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

30. Hillenglass J, Fechtner K, Weber MA, et al. Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol 2010;28:1606-1610.Available at:https://www.ncbi.nlm.nih.gov/pubmed/20177023.

31. Merz M, Hielscher T, Wagner B, et al. Predictive value of longitudinal whole-body magnetic resonance imaging in patients with smoldering multiple myeloma. Leukemia 2014;28:1902-1908. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24535407.

32. Kumar SK, Rajkumar SV. The multiple myelomas- current concepts in cytogenetic classification and therapy. Nat Rev Clin Oncol 2018;15:409-421. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/29686421.

33. van Beers EH, van Vliet MH, Kuiper R, et al. Prognostic Validation of SKY92 and Its Combination With ISS in an Independent Cohort of Patients With Multiple Myeloma. Clin Lymphoma Myeloma Leuk 2017;17:555-562. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28735890.

34. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014;15:e538-548. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25439698.

35. Lakshman A, Rajkumar SV, Buadi FK, et al. Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J 2018;8:59. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29895887.

36. Mateos MV, Kumar S, Dimopoulos MA, et al. International Myeloma Working Group risk stratification model for smoldering multiple myeloma(SMM). Blood Cancer J 2020;10:102. Available at:https://www.ncbi.nlm.nih.gov/pubmed/33067414.

37. Touzeau C, Moreau P. How I treat extramedullary myeloma. Blood 2016;127:971-976. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26679866.

https://www.ncbi.nlm.nih.gov/pubmed/26679866.

38. Granell M, Calvo X, Garcia-Guinon A, et al. Prognostic impact of circulating plasma cells in patients with multiple myeloma: implications for plasma cell leukemia definition. Haematologica 2017;102:1099-1104.Available at: https://www.ncbi.nlm.nih.gov/pubmed/28255016.

39. Schavgoulidze A, Talbot A, Perrot A, et al. Biallelic deletion of 1p32 defines ultra-high-risk myeloma, but monoallelic del(1p32) remains a strong prognostic factor. Blood 2023;141:1308-1315. Available at:https://www.ncbi.nlm.nih.gov/pubmed/36375118.

40. Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol 2005;23:3412-3420. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15809451.

41. Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J Clin Oncol 2015;33:2863-2869. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26240224.

42. Knowling MA, Harwood AR, Bergsagel DE. Comparison of extramedullary plasmacytomas with solitary and multiple plasma cell tumors of bone. J Clin Oncol 1983;1:255-262. Available at:https://www.ncbi.nlm.nih.gov/pubmed/2668499.

43. Dores GM, Landgren O, McGlynn KA, et al. Plasmacytoma of bone,extramedullary plasmacytoma, and multiple myeloma: incidence and survival in the United States, 1992-2004. Br J Haematol 2009;144:86-94.Available at:https://www.ncbi.nlm.nih.gov/pubmed/19016727.

44.Zamagni E, Nanni C, Patriarca F,et al.A prospective comparison of 18F-fluorodeoxyglucose positron emission tomography-computed tomography, magnetic resonance imaging and whole-body planar radiographs in the assessment of bone disease in newly diagnosed multiple myeloma. Haematologica 2007;92:50-55. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17229635.

45. Fonti R, Salvatore B, Quarantelli M, et al. 18F-FDG PET/CT, 99mTc-MIBI, and MRI in evaluation of patients with multiple myeloma. J Nucl

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

Med 2008;49:195-200. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18199607.

46. Nahi H, Genell A, Walinder G, et al. Incidence, characteristics, and outcome of solitary plasmacytoma and plasma cell leukemia. Population-based data from the Swedish Myeloma Register. Eur J Haematol 2017;99:216-222. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28544116.

47. Paiva B, Chandia M, Vidriales MB, et al. Multiparameter flow cytometry for staging of solitary bone plasmacytoma: new criteria for risk of progression to myeloma. Blood 2014;124:1300-1303. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24876564.

48. Dimopoulos MA, Goldstein J, Fuller L, et al. Curability of solitary bone plasmacytoma. J Clin Oncol 1992;10:587-590. Available at:https://www.ncbi.nlm.nih.gov/pubmed/1548521.

49. Hu K, Yahalom J. Radiotherapy in the management of plasma cell tumors. Oncology (Williston Park) 2000;14:101-108, 111; discussion 111-102, 115. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/10680152.

50. Creach KM, Foote RL, Neben-Wittich MA, Kyle RA. Radiotherapy for extramedullary plasmacytoma of the head and neck. Int J Radiat Oncol Biol Phys 2009;73:789-794. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18707826.

51. Tournier-Rangeard L, Lapeyre M, Graff-Caillaud P, et al.Radiotherapy for solitary extramedullary plasmacytoma in the head-and-neck region: A dose greater than 45 Gy to the target volume improves the local control. Int J Radiat Oncol Biol Phys 2006;64:1013-1017.Available at: http://www.ncbi.nlm.nih.gov/pubmed/16343803.

52. Reed V, Shah J, Medeiros LJ, et al. Solitary plasmacytomas:outcome and prognostic factors after definitive radiation therapy. Cancer 2011;117:4468-4474. Available for defaulting

https://www.ncbi.nlm.nih.gov/pubmed/21437886.

53.Frassica DA, Frassica FJ, Schray MF, et al. Solitary plasmacytoma of bone: Mayo Clinic experience. Int J Radiat Oncol Biol Phys 1989;16:43-48. Available at:https://www.ncbi.nlm.nih.gov/pubmed/2912957.

https://www.ncbi.nlm.nih.gov/pubmed/2912957.

54. Ozsahin M, Tsang RW, Poortmans P, et al. Outcomes and patterns of failure in solitary plasmacytoma: a multicenter Rare Cancer Network study of 258 patients. Int J Radiat Oncol Biol Phys 2006;64:210-217.Available at:https://www.ncbi.nlm.nih.gov/pubmed/16229966.

55. Knobel D, Zouhair A, Tsang RW,et al. Prognostic factors in solitary plasmacytoma of the bone: a multicenter Rare Cancer Network study.BMC Cancer 2006;6:118. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/16677383.

56. Sasaki R, Yasuda K, Abe E, et al. Multi-institutional analysis of solitary extramedullary plasmacytoma of the head and neck treated with curative radiotherapy. Int J Radiat Oncol Biol Phys 2012;82:626-634.Available at:https://www.ncbi.nlm.nih.gov/pubmed/21277117.

57. Tsang RW, Gospodarowicz MK, Pintilie M, et al. Solitary plasmacytoma treated with radiotherapy: impact of tumor size on outcome. Int J Radiat Oncol Biol Phys 2001;501:113-120. Available at:https://www.ncbi.nlm.nih.gov/pubmed/11316553.

58. Tsang RW,Campbell BA,Goda JS,et al.Radiation Therapy for Solitary Plasmacytoma and Multiple Myeloma: Guidelines From the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys 2018;101:794-808. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29976492.

59. Gerry D, Lentsch EJ. Epidemiologic evidence of superior outcomes for extramedullary plasmacytoma of the head and neck. Otolaryngol Head Neck Surg 2013;148:974-981. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23482476.

60. Group TIMW. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. British Journal of Haematology

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

2003;121:749-757. Available at: http://dx.doi.org/10.1046/j.1365-2141.2003.04355.x.

61. Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of smoldering(asymptomatic) multiple myeloma. N Engl J Med 2007;356:2582-2590. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17582068.

62. Mateos MV, Hernandez MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med 2013;369:438-447. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23902483.

63. Mateos MV, Hernandez MT, Giraldo P,et al. Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial. Lancet Oncol 2016;17:1127-1136.Available at:https://www.ncbi.nlm.nih.gov/pubmed/27402145.

64. Lonial S, Jacobus S, Fonseca R, et al. Randomized Trial of Lenalidomide Versus Observation in Smolding Multiple Myeloma. J Clin Oncol 2020;38:1126-1137. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31652094.

65. San Miguel J, Mateos M-V, Gonzalez V, et al. Updated risk stratification model for smoldering multiple myeloma (SMM) incorporating the revised IMWG diagnostic criteria. Journal of Clinical Oncology 2019;37:8000-8000. Available at:https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.15 suppl.8000.

https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.15 @suppl.8000.

66. Reeder CB, Reece DE, Kukreti V,et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood 2010;115:3416-3417. Available at:https://www.ncbi.nlm.nih.gov/pubmed/20413666.

https://www.ncbi.nlm.nih.gov/pubmed/20413666.

67. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet

Oncol 2011;12:431-440. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21507715.

68. Arnulf B, Pylypenko H, Grosicki S, et al. Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma. Haematologica 2012;97:1925-1928. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22689676.

https://www.ncbi.nlm.nih.gov/pubmed/22689676.

69. Mateos MV, Nahhi H, Legiec W, et al. Subcutaneous versus intravenous myeloma(COLUMBA): a multicentre, open-label, non-inferiority,randomised, phase 3 trial. Lancet Haematol 2020;7:e370-e380. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32213342.

70. Nair V, Mohammed H, Mahmood S, et al. Assessing Steroid Toxicity in the Elderly with Multiple Myeloma. Blood 2019; 134(Supplement_1):5557. Available at: https://doi.org/10.1182/blood-2019-125442.

71. Larocca A, Bonello F, Gaidano G, et al. Dose/schedule-adjusted Rd-R vs continuous Rd for elderly, intermediate-fit patients with newly diagnosed multiple myeloma. Blood 2021;137:3027-3036. Available at:https://www.ncbi.nlm.nih.gov/pubmed/33739404.

72. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib,and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 2010;116:679-686. Available at:https://www.ncbi.nlm.nih.gov/pubmed/20385792.

73. Roussel M, Lauwers-Cances V, Robillard N, et al.Front-line transplantation program with lenalidomide, bortezomib,and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myelome. J Clin Oncol 2014;32:2712-2717. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25024076.

74. Kumar S, Flinn I, Richardson PG, et al. Randomized, multicenter,phase 2 study(EVOLUTION) of combinations of bortezomib,

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood 2012;119:4375-4382. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22422823.

80. Korde N, Zingone A, Kwok M, et al. Phase II clinical and correlative study of carfilzomib, lenalidomide, and dexamethasone(CRd) in newly diagnosed multiple myeloma (MM) patients [abstract]. j Clin Oncol 2012;30:e18568. Available at:

75. Durie BGM, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet 2017;389:519-527. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28017406.

http://meeting.ascopubs.org/cgi/content/abstract/30/15_suppl/e18568.

81. Korde N, Roschewski M, Zingone A, et al. Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma.JAMA Oncol 2015;1:746-754. Available at:https://www.ncbi.nlm.nih.gov/pubmed/280161891.

82.Jasielec JK, Kubicki T, Raje N, et al. Carfilzomib, lenalidomide, and dexamethasone plus transplant in newly diagnosed multiple myeloma.Blood 2020;136:2513-2523. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32735641.

76. Durie BGM, Hoering A, Sexton R,et al. Longer term follow-up of the randomized phase III SWOG S0777: bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (Pts)with previously untreated multiple myeloma without an intent for immediate immediate autologous stem cell transplant (ASCT). Blood Cancer J 2020;10:53. Available at:

83. Facon T, Venner, CP. Bahlis, NJ. et al Ixazomib Plus LenalidomideDexamethasone(IRd) vs. PlaceboRd for Newly Diagnosed Multiple Myeloma(NDMM) Patients Not Eligible for Autologous Stem Cell Transplant: The Double-Blind, Placebo-Controlled, Phase 3 TOURMALINE-MM2 Trial [Abstract]. Abstract MM-347 presented at Society of Hema-to-logic Oncology (SOHO) Eighth Annual Meeting 2020.Available at: https://clml-soho2020.elsevieridietalition.com/306/index.html#zoom=z.

https://www.ncbi.nlm.nih.gov/pubmed/32393732.

77. Kumar SK, Jacobus SJ, Cohen AD, et al. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem cell transplantation (ENDURANCE): a multicentre,open-label, phase 3, randomised, controlled trial. Lancet Oncol 2020;21:1317-1330. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32866432.

84. Facon T, Venner CP, Bahlis NJ, et al. Oral izaxomib, lenalidomide,and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma. Blood 2021;137:3616-3628. Available at:https://www.ncbi.nlm.nih.gov/pubmed/33763699.

78.Okazuka K, Ishida T, Nashimoto J, et al. The efficacy and safety of modified bortezomib-lenalidomide-dexamethasone in transplant-eligible patients with newly diagnosed multiple myeloma. Eur J Haematol 2020;104:110-115. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31733155.

85. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab,lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood 2020;136:936-945. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32325490.

https://www.ncbi.nlm.nih.gov/pubmed/31733155.

79. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzombij in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 2012;120:1801-1809.Available at:

2012;120:1801-1809. Available at:

86. Laubach JP, Kaufman JL, Sborov DW, et al. Daratumumab(DARA)plus lenalidomide, bortezomib, and dexamethasone(RVd) in patients

https://www.ncbi.nlm.nih.gov/pubmed/22665938.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

(Pts) with transplant-eligible newly diagnosed multiple myeloma(NDMM): Updated analysis of Griffin after 24 months of maintenance.Blood 2021;138:79-79. Available at:

https://www.sciencedirect.com/science/article/pii/S0006497121020693.

87. Reeder CB, Reece DE, Kukreti V,et al. Cyclophosphamide,bortezomb and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia 2009;23:1337-1341. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19225538.

88. Knop S, Liebisch P, Wandt H, et al. Bortezomib, IV cyclophosphamide, and dexamethasone(VelCD) as induction therapy in newly diagnosed multiple myeloma: Results of an interim analysis of the German DSMX Xia trial. 2009;27:8516-8516. Available at:https://ascopubs.org/doi/abs/10.1200/jco.2009.27.15s.8516.

89. Reeder CB, Reece DE, Kukreti V,et al. Long-term survival with cyclophosphamide, bortezomb and dexamethasone induction therapy in patients with newly diagnosed multiple myeloma. Br J Haematol 2014;167:563-565. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24974945.

90. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol 2012;30:2946-2955. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22802322.

91. Bringhen S, Petrucci MT, Larocca A, et al. Carfilzomib,cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood 2014;124:63-69. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24855212.

https://www.ncbi.nlm.nih.gov/pubmed/24855212.

92. Bringhen S,D'Agostino M,De Paoli L,et al.Phase 1/2 study of weekly carfilzomib, cyclophosphamide, dexamethasone in newly diagnosed transplant-ineligible myeloma. Leukemia 2018;32:979-985.

Available at: https://www.ncbi.nlm.nih.gov/pubmed/29263440.

93. Bringhen S, Mina R, Petrucci MT, et al. Once-weekly versus twice-weekly carfilzombin in patients with newly diagnosed multiple myeloma: a pooled analysis of two phase l/ll studies. Haematologica 2019;104:1640-1647. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30733270.

94. Boccia RV, Bessudo A, Agajanian R, et al. A Multicenter, Open-Label, Phase 1b Study of Carfilzomib, Cyclophosphamide, and Dexamethasone in Newly Diagnosed Multiple Myeloma Patients(CHAMPION-2). Clin Lymphoma Myeloma Leuk 2017;17:433-437.Available at:https://www.ncbi.nlm.nih.gov/pubmed/28576443.

95. Dimopoulos MA, Grosicki S, Jedrzejczak WW, et al. All-oral ixazomib, cyclophosphamide, and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma. Eur J Cancer 2019;106:89-98. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30471652.

96. Moreau P,Attal M,Hulin C,et al.Bortezomib,thalidomide,and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma(CASSIOPEIA): a randomised, open-label, phase 3 study.Lancet 2019;394:29-38. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29263440.

97. Landgren O, Hultcrantz M, Diamond B, et al. Safety and Effectiveness of Weekly Carfilzomib, Lenalidomide, Dexamethasone,and Daratumumab Combination Therapy for Patients With Newly Diagnosed Multiple Myeloma: The MANHATTAN Nonrandomized Clinical Trial. JAMA Oncol 2021;7:862-868. Available at:https://www.ncbi.nlm.nih.gov/pubmed/33856405.

98. Costa LJ,Chhabra S, Medvedova E,et al. Daratumumab,Carfilzomib, Lenalidomide, and Dexamethasone With Minimal Residual Disease Response-Adapted Therapy in Newly Diagnosed Multiple Myeloma. J Clin Oncol 2022;40:2901-2912. Available at:https://www.ncbi.nlm.nih.gov/pubmed/34898239.

99. Yimer H, Melear J, Faber E, et al. Daratumumab, bortezomib,cyclophosphamide and dexamethasone in newly diagnosed and

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

relapsed multiple myeloma: LYRA study. Br J Haematol 2019;185:492-502.Available at:https://www.ncbi.nlm.nih.gov/pubmed/30828799.

100.Barlogie B,Anaissie E,van Rhee F,et al.Incorporating bortezomiz into upfront treatment for multiple myema: early results of total therapy 3. Br J Haematol 2007;138:176-185. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17593024.

101. Goldschmidt H, Mai EK, Bertsch U, et al. Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone as induction therapy for newly diagnosed, transplantation-eligible patients with multiple myeloma(GMMG-HD7): part 1 of an open-label, multicentre, randomised, active-controlled, phase 3 trial. Lancet Haematol 2022;9:e810-e821. Available at:https://www.ncbi.nlm.nih.gov/pubmed/36328040.

102. O'Donnell EK, Laubach JP, Yee AJ, et al. A phase 2 study of modified lenalidomide, bortezomib and dexamethasone in transplant-ineligible multiple myeloma. Br J Haematol 2018;182:222-230. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29740809.

103. Facon T, Kumar SK, Plesner T,et al. Daratumumab, lenalidomide,and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol 2021;22:1582-1596. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34655533.

104. Mateos MV,Dimopoulos MA, Cavo M,et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med 2018;378:518-528. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29231133.

105.Dytfeld D,Jasielec J,Griffith KA,et al.Carfilzomib,lenalidomide,and low-dose dexamethasone in elderly patients with newly diagnosed multiple myeloma. Haematologica 2014;99:e162-164. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24972772.

106. Kumar SK, Berdeja JG, Niesvizky R, et al. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple

myeloma: an open-label phase 1/2 study. Lancet Oncol 2014;15:1503-1512. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25456369.

107.Zonder JA, Crowley J, Hussein MA, et al. Superiority of lenalidomide(Len) plus high-dose dexamethasone(HD) compared to HD alone as treatment of newly-diagnosed multiple myeloma(NDMM):Results of the randomized, double-blinded, placebo-controlled SWOG Trial S0232[abstract]. Blood 2007;110:Abstract 77. Available at:http://abstracts.hematologylibrary.org/cgi/content/abstract/110/11/77.

108. Rajkarum SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma:an open-label randomised controlled trial. Lancet Oncol 2010;11:29-37.Available at:https://www.ncbi.nlm.nih.gov/pubmed/19853510.

109. Benboubker L, Dimopoulos MA, Dispenzieri A, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med 2014;371:906-917. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25184863.

110. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366:1782-1791. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22571202.

111. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366:1770-1781. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22571201.

https://www.ncbi.nlm.nih.gov/pubmed/22571201.

112. Usmani SZ, Sexton R, Hoering A, et al. Second malignancies in total therapy 2 and 3 for newly diagnosed multiple myeloma: influence of thalidomide and lenalidomide during maintenance. Blood 2012;120:1597-1600. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22674807.

113. Palumbo A, Bringhen S, Kumar SK,et al. Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma: a

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2026 Multiple Myeloma

meta-analysis of individual patient data. Lancet Oncol 2014;15:333-342.Available at:https://www.ncbi.nlm.nih.gov/pubmed/24525202.

114. Dimopoulos MA, Cheung MC, Roussel M, et al. Impact of renal impairment on outcomes with lenalidomide and dexamethasone treatment in the FIRST trial, a randomized, open-label phase 3 trial in transplant-ineligible patients with multiple myeloma. Haematologica 2016;101:363-370. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26659916.

115. Hulin C, Belch A, Shustik C, et al. Updated Outcomes and Impact of Age With Lenalidomide and Low-Dose Dexamethasone or Melphalan,Predisone, and Thalidomide in the Randomized, Phase III FIRST Trial.

J Clin Oncol 2016;34:3609-3617. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27325857.

116. Kumar SK, Lacy MQ, Hayman SR,et al. Lenalidomide,cyclophosphamide and dexamethasone(CRd) for newly diagnosed multiple myeloma: results from a phase 2 trial. Am J Hematol 2011;86:640-645. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21630308.

117. Pawlyn X, Brioli A, Gregory W, et al. Lenalidomide Combined With Cyclophosphamide and Dexamethasone Is Effective and Well Tolerated Induction Treatment For Newly Diagnosed Myeloma Patients Of All Ages. Blood 2013;122:540-540. Available at:https://doi.org/10.1182/blood.V122.21.540.540.

118. Jackson GH, Davies FE, Pawlyn C, et al. Lenalidomide before and after autologous stem cell transplantation for transplant-eligible patients of all ages in the randomized, phase III, Myeloma XI trial. Haematologica 2021;106:1957-1967. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32499244.

https://www.ncbi.nlm.nih.gov/pubmed/32499244.

119. Niesvizky R, Flinn IW, Rifkin R,et al. Community-Based Phase IIIB Trial of Three UPFRONT Bortezomib-Based Myeloma Regimens. J Clin Oncol 2015;33:3921-3929. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/26056177.

120. Niesvizky R, Flinn IW, Rifkin R,et al. Efficacy and safety of three bortezomib-based combinations in elderly, newly diagnosed multiple myeloma patients: Results from all randomized patients in the community-based, phase 3b UPFRONT study[abstract]. Blood 2011;118:Abstract 478. Available at:http://abstracts.hematologylibrary.org/cgi/content/abstract/118/21/478.

121.Zepeda J,H.V,Duggan P,et al.Cyclophosphamide, bortezomib and dexamethasone(CyBORD) is a feasible and active regimen for non-transplant eligible multiple myeloma patients[Abstract]. Blood 2014;124:5751-5751. Available at:http://www.bloodjournal.org/content/124/21/5751.

122. Rajkumar SV. Multiple myeloma: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol 2011;86:57-65. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21181954.

123. Palumbo A, Rajkumar SV, San Miguel JF,et al. International Myeloma Working Group consensus statement for the management,treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation. J Clin Oncol 2014;32:587-600. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24419113.

124. Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol 2016;17:e328-e346. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27511158.

125. Walker R, Barlogie B, Haessler J, et al. Magnetic resonance imaging in multiple myeloma: diagnostic and clinical implications.J Clin Oncol 2007;25:1121-1128. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17296972.

126. Bartel TB, Haessler J, Brown TL, et al. F18-fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma. Blood 2009;114:2068-2076.Available at:https://www.ncbi.nlm.nih.gov/pubmed/19443657.

References

320. Treon SP, Cao Y, Xu L, et al. Somatic mutations in MYD88 and

CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia. Blood 2014;123:2791-2796. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24553177.

321. Bagratuni T, Ntanasis-Stathopoulos I, Gavriatopoulou M, et al.

Detection of MYD88 and CXCR4 mutations in cell-free DNA of patients with IgM monoclonal gammopathies. Leukemia 2018;32:2617-2625.

Available at: https://www.ncbi.nlm.nih.gov/pubmed/30026568.

322. Xu L, Hunter ZR, Tsakmaklis N, et al. Clonal architecture of CXCR4 WHIM-like mutations in Waldenstrom Macroglobulinaemia. Br J

Haematol 2016;172:735-744. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/26659815.

323. Ballester LY, Loghavi S, Kanagal-Shamanna R, et al. Clinical

Validation of a CXCR4 Mutation Screening Assay for Waldenstrom

Macroglobulinemia. Clin Lymphoma Myeloma Leuk 2016;16:395-403

e391. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27268124.

324. Bardwick PA, Zvaifler NJ, Gill GN, et al. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin

changes: the POEMS syndrome. Report on two cases and a review of

the literature. Medicine (Baltimore) 1980;59:311-322. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/6248720.

325. Dispenzieri A. POEMS Syndrome: 2019 Update on diagnosis, riskstratification, and management. Am J Hematol 2019;94:812-827.

Available at: https://www.ncbi.nlm.nih.gov/pubmed/31012139.

326. Khouri J, Nakashima M, Wong S. Update on the Diagnosis and

Treatment of POEMS (Polyneuropathy, Organomegaly, Endocrinopathy,Monoclonal Gammopathy, and Skin Changes) Syndrome: A Review.

JAMA Oncol 2021;7:1383-1391. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/34081097.

表 1
Disease	Definition
Smoldering Myeloma a,b (Asymptomatic)	●Serum monoclonal protein ≥ 3 g/dL or ●Bence-Jones protein ≥ 500 mg/24 h and ●Clonal bone marrow plasma cells (BMPCs) 10%-59% and ●Absence of myeloma-defining events or amyloidosis
Multiple Myeloma a,c (Symptomatic)	●Clonal BMPCs≥10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma- defining events: ● Myeloma-defining events: Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: $\diamond$ Hypercalcaemia: serum calcium>0.25 mmol/L(>1 mg/dL) higher than the upper limit of normal or $>2.75 mmol/L(>11 mg/dL) \diamond$ Renal insufficiency: creatinine clearance <40 mL per min or serum creatinine >177 μmol/L (>2 mg/dL) \diamond Anaemia: haemoglobin value of >20 g/L below the lower limit of normal, or a haemoglobin value <100 g/L \diamond Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT Anyone or more of the following biomarkers of malignancy: Clonal bone marrow plasma cell percentage ≥ 60% $\diamond$ Involved:uninvolved serum free light chain ratio ≥ 100 >1 focal lesions on MRI studies
Solitary Plasmacytoma ${}^{a}$	●Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells ●Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion) ●Absence of myeloma defining events
Solitary Plasmacytoma with minimal marrow involvement ${}^{a}$	$\bullet$ Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells ●Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion) ●Absence of myeloma defining events ●Clonal bone marrow plasma cells <10%
Plasma Cell Leukemia	$\bullet$ Presence of $\geq 5\%$ of plasma cells in circulation

表 2
International Staging System (ISS)	Revised-ISS (R-ISS)1	R2-ISS2,a	IMS-IMWG3
ISS Stage I ·Serum beta-2 microglobulin <3.5 mg/L ·Serum albumin ≥3.5 g/dL	R-ISS Stage l ●ISS stage l and standard risk chromosomal l risk abnormalities by FISH ●Serum LDH ≤ the ULN ●Serum LDH ≤ the ULN ●Serum LDH ≤ the ULN	Low-risk:0 pointsb ●Not ISS stage Il or II ● Serum LDH ≤ the ULN ● del(17p),t(4;14),1q+:Not detected	Standard Risk ● All patients not meeting criteria for HR
ISS Stage II ·Not ISS stage l or III	R-ISS Stage l ● Not R-ISS stage l or III	Low-intermediate risk: 0.5-1 pointsb ●ISS stage Il or ● Serum LDH > the ULN ● or ●del(17p) or t(4;14) or 1q+:Detected	Standard Risk ● All patients not meeting criteria for HR
ISS Stage III ·Serum beta-2 microglobulin ≥5.5 mg/L	R-ISS Stage l ●.SS stage III ●And either high-risk chromosomal abnormalities [del(17p) or translocation (4;14) or translocation (14;16)] by FISH or Serum (14;16)] by FISH or serum LDH >the ULN	Intermediate-high risk: 1.5-2.5 pointsb ●Any combination of high-risk features that equals a score of 1.5-2.5	High-Risk IMS-IMWG ·Del(17p)(>20% of plasma cells) and/or TP53 mutation ● One of these translocations co- occurring with 1q+ and/or del(1p32): t(14;16) t(14;10) t(14;20) ● Monoallelic del(1p32) along with 1q+ or biallelic del(1p32) ●High $\beta$ 2M(>5.5 mg/dL) with normal creatinine(<1.2 mg/dL)
		High-risk:3-5 pointsb ●Any combination of high-risk features that equals a score of 3-5	High-Risk IMS-IMWG ·Del(17p)(>20% of plasma cells) and/or TP53 mutation ● One of these translocations co- occurring with 1q+ and/or del(1p32): t(14;16) t(14;10) t(14;20) ● Monoallelic del(1p32) along with 1q+ or biallelic del(1p32) ●High $\beta$ 2M(>5.5 mg/dL) with normal creatinine(<1.2 mg/dL)

表 3
Factors Considered as High Risk for Progression/Relapse
For Those with Newly Diagnosed MM	For Those with Relapsed MM
●R-ISS III (MYEL-B 1 of 2) ● Extramedullary disease ●Circulating plasma cells ●Cytogenetic abnormalitiesc Del(1p32) t(4;14) t(14;16) t(14;20) Del(17p)/monosomy 17/TP53 mutation 1q21 gain/1q21 amplification,4 MYC translocation5 ●High-risk gene expression profile ●Markers of high proliferation rate	●Disease relapse within 2 years of initial therapy when transplant and maintenance are used. ●Relapse within 18 months in case of non-transplant-based treatment. ●Acquisition of 1q gain/amplification and/or del(17p)/TP53 mutation ●Extramedullary disease at relapse and/or circulating plasma cells

表 4
IMWG criteria for response assessment including criteria for minimal residual disease (MRD)
Response Category	Response Criteria
IMWG MRD criteria (requires a complete response as defined below)
Sustained MRD-negative	MRD negativity in the marrow (next-generation flow [NGF],next-generation sequencing [NGS],or both) and by imaging as defined below, confirmed minimum of 1 year apart. Subsequent evaluations can be used to further specify the duration of negativity (eg, MRD-negative at 5 years).
Flow MRD-negative	Absence of phenotypically aberrant clonal plasma cells by NGFc on bone marrow aspirates using the EuroFlow standard operation procedure for MRD detection in multiple myeloma (or validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells or higher.
Sequencing MRD-negative	Absence of clonal plasma cells by NGS on bone marrow aspirate in which presence of a clone is defined as less than two identical sequencing reads obtained after DNA sequencing of bone marrow aspirates using a validated equivalent method with a minimum sensitivity of 1 in 105 nucleated cells or higher.
Imaging plus MRD-negative	MRD negativity as defined by NGF or NGS plus disappearance of every area of increased tracer uptake found at baseline or a preceding FGP-TCT or decrease to less mediastinal blood pool standardized uptake value (SUV) or decrease to less than that of surrounding normal tissue.e
Standard IMWG response criteria
Stringent complete response	Complete response as defined below plus normal FLC ratio ${}^{9}$ and absence of clonal cells in bone marrow biopsy by immunohistochemistry (k/A ratio≤4:1 or ≥1:2 for k and /x patients, respectively, after counting ≥ 100 plasma cells).
Complete response	Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow aspirates.
Very good partial response	Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 h.
Partial response	≥50% reduction of serum M-protein plus reduction in 24-h urinary M-protein by ≥90% or to <200 mg per 24 h. If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference between involved and uninvolved flC levels is required in place of the M-protein criteria. If serum and urine M-protein are unmeasurable, and serum-free light assay is also unmeasurable, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma-cell percentage was ≥30%. In addition to these criteria, if present at baseline, a ≥50% reduction in the size (sum of the products of the maximal perpendicular diameters [SPD] of measured lesions) of soft tissue plasmacytomas is also required.
Minimal response	≥25% but ≤49% reduction of serum M-protein and reduction in 24-h urine M-protein by 50%-89%. In addition to the above listed criteria, if present at baseline, a 25%-49% reduction in SPD of soft tissue plasmacytomas is also required.

表 5
Standard IMWG response criteriaf (continued from previous page)
Stable disease	●Not recommended for use as an indicator of response; stability of disease is best described by providing the time-to-progression estimates. Not meeting criteria for complete response, very good partial response, partial response, minimal response, or progressive disease.
Progressive diseasekI	Any one or more of the following criteria: ●Increase of 25% from lowest confirmed response value in one or more of the following criteria: ●Serum M-protein (absolute increase must be≥0.5 g/dL); ●Serum M-protein increase ≥1 g/dL, if the lowest M component was ≥5 g/dL; ●Urine M-protein (absolute increase must be ≥200 mg/24 h); ●In patients without measurable serum and urine M-protein levels, the difference between involved and uninvolved FLC levels (absolute increase must be >10 mg/dL); ●In patients without measurable serum and urine M-protein levels and without measurable involved FLC levels, bone marrow plasma-cell percentage irrespective of baseline status (absolute increase must be ≥10%); ●Appearance of a new lesion(s), ≥50% increase from nadir in SPD of >1 lesion, or ≥50% increase in the longest diameter of a previous lesion >1 cm in short axis; ●≥50% increase in circulating plasma cells (minimum of 200 cells per $\mu$ L) if this is the only measure of disease.
Clinical relapse	Clinical relapse requires one or more of the following criteria: ●Direct indicators of increasing disease and/or end organ dysfunction(calcium elevation, renal failure, anemia, lytic bone lesions [CRAB features]) related to the underlying clonal plasma cell proliferative disorder. It is not used in calculation of time to progression or progression-free survival but is listed as something that can be reported optionally or for use in clinical practice; ●Development of new soft tissue plasmacytomas or bone lesions (osteoporotic fractures do not constitute progression); ●Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a 50% (and ≥1 cm) increase as measured serially by the SPD of the measurable lesion; ●Hypercalcemia (>11 mg/dL); ●Decrease in hemoglobin of≥2 g/dL not related to therapy or other non-myeloma-related conditions; ●Rise in serum creatinine by 2 mg/dL or more from the start of the therapy and attributable to myeloma; ●Hyperviscosity related to serum paraprotein.
Relapse from complete response (to be used only if the endpoint is disease-free survival)	Any one or more of the following criteria: ●Reappearance of serum or urine M-protein by immunofixation or electrophoresis; ●Development of≥5% plasma cells in the bone marrow; ●Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or hypercalcemia) (see above).
Relapse from MRD negative (to be used only if the endpoint is disease-free survival)	Any one or more of the following criteria: ●Loss of MRD negative state (evidence of clonal plasma cells on NGF or NGS, or positive imaging study for recurrence of myeloma); ●Reappearance of serum or urine M-protein by immunofixation or electrophoresis; ●Development of ≥5% clonal plasma cells in the bone marrow; ●Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or hypercalcemia).

表 6
THERAPY FOR PREVIOUSLY TREATED MULTIPLE MYELOMA${}^{a\text{-}d\text{-}l\text{-}o}$ Relapsed/Refractory Disease After 1-3 Prior Therapies
Preferred* Order of regimens does not indicate comparative efficacy
Anti-CD38 Refractory	Bortezom-Refractory	Lenalidomide-Refractory
●Carfilzomib/Lenalidomide/Dexamethasone (category 1)	●Carfilzomib/Lenalidomide/Dexamethasone(category 1)	●Daratumumab/Bortezomib/Dexamethasone(category 1)
●Carfilzomib/Pomalidomide/Dexamethasone	●Daratumumab/Lenalidomide/Dexamethasone(category 1)	●Isatuximab-irfc/Carfilzomib/Dexamethasone(category 1)
●Pomalidomide/Bortezomib/Dexamethasone (category 1)	●Isatuximab-irfc/Carfilzomib/Dexamethasone(category 1)	●Pomalidomide/Bortezomib/Dexamethasone(category 1)
(category 1)	●Carfilzomib/Pomalidomide/Dexamethasone	●Carfilzomib/Pomalidomide/Dexamethasone
After two prior therapies including	After one prior therapy including Lenalidomide and a PI	After one prior therapy including Lenalidomide and a PI
Lenalidomide and a proteasome inhibitor(PI) Elotuzumab/Pomalidomide/Dexamethasone	●Daratumumab/Pomalidomide/Dexamethasone(category 1)	Daratumumab/Pomalidomide/Dexamethasone(category 1)
After two prior therapies including an IMiD and a PI and with disease progression on/ within 60 days of completion of last therapy Ixazomib/Pomalidomide/Dexamethasone	After two prior therapies including Lenalidomide and a PI Isatuximab-irfc/Pomalidomide/Dexamethasone(category 1)	Itotuximab-irfc/Pomalidomide/Dexamethasone therapy
△Ixazomib/Pomalidomide/Dexamethasone	After two prior therapy including IMiD and a PI, and refractory to lenalidomide Ciltacabtagene autoleuc(category 1)	Ixazomib/Pomalidomide/Dexamethasone

表 7
THERAPY FOR PREVIOUSLY TREATED MULTIPLE MYELOMaa-d,l-p Relapsed/Refractory Disease After 1-3 Prior Therapies
Other Recommended	Other Recommended
- Elotuzumab/Lenalidomide/Dexamethasone(category 1)	After two prior therapies including an IMiD and a PI
- Ixazomib/Lenalidomide/Dexamethasone(category 1)	Belantamab mafodot-blmf/Bortezomib/Dexamethasone(category 1)
- Selinexor/Bortezomib/Dexamethasone(category 1)	After two prior therapies including an IMiD and a PI
- Bortezomib/Cyclophosphamide/Dexamethasone	progression on/within 60 days of completion of last therapy
- Carfilzomib/Cyclophosphamide/Dexamethasone	Pomalidomide/Cyclophosphamide/Dexamethasone(category 1)
- Daratumumab/Cyclophosphamide/Bortezomib/Dexamethasone	Doxamethasone
- Daratumumab/Carfilzomib/Pomalidomide/Dexamethasone
- Elotuzumab/Bortezomib/Dexamethasone
- Ixazomib/Cyclophosphamide/Dexamethasone
●Lenalidomide/Cyclophosphamide/Dexamethasone
Useful in Certain Circumstances
-	Bortezomib/Dexamethasone(category 1)
-	Pomalidomide/Dexamethasone(category 1)
●Carfilzomib/Cyclophosphamide/Thalidomide/Dexamethasone	Selinexor/Pomalidomide/Dexamethasone
●Selinexor/Carfilzomib/Dexamethasone	For treatment of aggressive MM
●Selinexor/Daratumumab/Dexamethasone	Dexamethasone/Cyclophosphamide/Etoposide/Cisplatin(DCEP)
●Venetoclax/Dexamethasone± Daratumumab or PI only for t(11;14)	Dexamethasone/Thalidomide/Cisplatin/Doxorubicin/Cyclophosphamide/ patients(Etoposide(DT-PACE)±Bortezomib(VTD-PACE)
	After at least three prior therapies including a PI and an IMiD or are double-refractory to a PI and an IMiD

表 8
THERAPY FOR PREVIOUSLY TREATED MULTIPLE MYELOMA a-d,l-o Relapsed/Refractory Disease After 3 Prior Lines of Therapy
Preferred
CAR T-cell Therapy:
Ciltacabtagene autoleucel
Idecabtagene vicleucel
After at least four prior therapies, including an anti-CD38 monoclonal antibody, a Pl, and an IMiD
Bispecific Antibodies(BsAb)r:
Elranatamab-bcmm
Linvoseltamab-gcpt
Talquetamab-tgvs
Teclistamab-cqyv
Other Recommendeded	Other Recommendeded
●High-Dose or Fractionated Cyclophosphamide
After at least four prior therapies and whose disease is refractory to at least two Pls, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody
●Selinexor/Dexamethasone
Useful in Certain Circumstances
●Belantamab mafodotin-blmf
●Bendamustine
●Bendamustine/Carfilzomib/Dexamethasone
●Bendamustine/Lenalidomide/Dexamethasone
●Talquetamab+ Teclistamab

表 9
Infection Risk	Increased Device Infection Risk	Increased Bacterial Infection Risk	Increased Viral Infection Risk	Increased Fungal Infection Risk
Contributing Factors	● Autologous HCT ● BsAb therapy ● CAR T-cell therapy ●CD38 antibodies ● Cytotoxic chemotherapy	● Diagnosis of MM ● BsAb therapy ● CAR T-cell therapy	● Proteasome inhibitors ● Monoclonal antibodies ●BsAb therapy ● CAR T-cell therapy	● High-dose steroids ● Prolonged Neutropenia ●BsAb therapy ● CAR T-cell therapy

表 10
Common Bacterial Infections	Indication & Duration
Interventions & Prophylaxis	Indication & Duration
Interventions & Prophylaxis	CAR-T	BsAb	AutoHCT	Other Indications
Levofloxacin: 500 mg PO daily Alternatives: Cefdinir 300 mg PO twice a day or augmentin 875 mg PO twice a day	Start when ANC < 500 or per clinician discretion and continue until neutrophil recovery.	Start when ANC < 500 or per clinician discretion and continue until neutrophil recovery.		Newly diagnosed MM: Consider levofloxacin for 12 weeks after diagnosis. ${}^{2}$
Immunoglobulin replacement	After CAR T-cell therapy, regular IVIG infusions based on clinical context.	Consider for the duration of BsAb therapy		For IgG <400 mg/dL and/ or recurrent life-threatening infections. ${}^{a}$
Pneumococcal vaccination	Revaccination starting 3-6 months after treatment.	Update vaccination status prior to starting BsAb treatment.	Revaccination starting 3-6 months after treatment.	The CDC recommends1 dose of PCV20 or 1 dose of PCV15 followed by 1 dose of PPSV23 at least 1 year later.

表 11
Common Viral and Fungal Infections
Interventions & Prophylaxis	Indication & Duration
Interventions & Prophylaxis	CAR-Tb	BsAbb	AutoHCT	Other Indications
Herpes simplex virus or Varicella-zoster virus: Acyclovir 400-800 mg PO twice/day or valacyclovir 500 mg PO once or twice/ day.	A minimum of 1 year; indefinite (preferred), irrespective of uncertainty status.	Indefinite, irrespective of vaccination status.	For 1 year post-HCT or as clinically indicated.	While receiving a regimen with Pls or monoclonal antibody and for at least 3 months beyond end of therapy or per institutional practice.
Hepatitis B virus and HIV: Screening	● HBsAg-positive ● HBsAg-negative ● HBcAb-IgG positive ● See NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections for HBV and HIV treatment	See NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections for HBV and HIV treatment
Pneumocystis jirovcell pneumonia (PJP): Trimethoprim-sulfamethoxazole (TP-SMX) therapy or pentamidine or atovaquone	Start with therapy and continue for at least 6 months after the infusion or until CD4 ≥200/mm3 (whichever is longer).	When equivalent dexamethasone dosing is >40 mg/day for 4 days per week or as clinically indicated per institutional practice.
SARS-CoV-2: COVID-19 vaccination	See The CDC's Staying Up to Date with COVD-19 Vaccines for specific guidance and see NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections for treatment.
Influenza virus: Vaccination	Per CDC for patients who are immunosuppressed.
RSV: Bivalent vaccine	●Single dose of bivalent vaccine for patients with MM aged ≥60 years. ● See CDC guidance for all other patient populations.
CMV: Prophylaxis	●Monitor viral load (by PCR) only in patients with suspected CMV-related disease (eg, colitis, pneumonitis, hepatitis) or otherwise unexplained fever and/or cytopenias or in patients with high risk of infections.b ● See NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections for Treatment of Cancer-Related Infections for treatment indication and treatment duration.
Adenovirus, EBV,JCV, parvovirus: No prophylaxis	Routine monitoring of viral load is not recommended.
Yeast: Fluconazole 400 mg PO daily	Start when ANC < 500 or per clinician discretion and continue until neutrophil recovery.
Mold: Azole	In patients with high risk of infectionsb: Consider ongoing prophylaxis with anti-mold azole.

表 12
IMPEDE Score1 for Risk Stratification (points assigned)
Individual Risk Factors	Points	Myeloma Risk Factors	Points
Positive Factors	Positive Factors	Positive Factors	Positive Factors
Central venous catheter/Tunneled central line	+2	Immunomodulatory drug(IMiD)	+4
Pelvic, hip, or femur fracture	+4	Erythropoiesis-stimulating agent	+1
Obesity (body mass index ≥25)	+1	Dexamethasone ≤160 mg/month	+2
Previous VTE	+5	Dexamethasone >160 mg/month	+4
		Doxorubicin or multiagent chemotherapy	+3
Negative Factors	Negative Factors	Negative Factors	Negative Factors
Ethnicity/Race = Asian/Pacific Islander	-3
Existing thromboprophylaxis: prophylactic LMWH (low-molecular-weight heparin) or aspirin	-3
Existing thromboprophylaxis: therapeutic LMWH or warfarin	-4

表 13
SAVED Score2 for Risk Stratification
Variable
Surgery within 90 days
Asian race
VTE history
Age≥80 years
Dexamethasone(regimen dose) ●Standard dose(120-160 mg/cycle) ●High dose(>160 mg/cycle)

表 14
VTE Prophylaxis Recommendations
≤3 Points by IMPEDE Score or <2 Points by SAVED Score	≥4 Points by IMPEDE Score or ≥2 SAVED Scorea
● Aspirin 81-325 mg once daily	● LMWH (equivalent to enoxaparin 40 mg daily) OR ● Rivoxaban 10 mg daily OR ● Rivoxaban 10 mg daily OR ● Apixaban 2.5 mg twice daily OR ● Fondaparinux 2.5 mg daily OR ● Warfarin (target INR, 2.0-3.0)

表 15
Category	Renal Function (Cockcroft-Gault CrCL)	Lenalidomide Dosing in Multiple Myeloma
Moderate renal impairment	CrCL≥30 mL/min to <60 mL/min	10 mg every 24 h
Severe renal impairment	CrCL<30 mL/min (not requiring dialysis)	15 mg every 48 h
End-stage renal disease	CrCL<30 mL/min (requiring dialysis)	5 mg once daily; on dialysis days, dose should be administered after dialysis

表 16
Degree of Renal Impairment	Pamidronate (focal segmental glomerulosclerosis)	Zoledronic Acid (tubular cell toxicity)	Denosumab
None	90 mg IV every 3-4 wks	4 mg IV every 1-3 mo	120 mg SQ Q 4 wks
Mild/moderate renal impairment	Use standard dose	Reduce dose	120 mg SQ Q 4 wks
Severe renal impairment	60-90 mg	Not recommended	120 mg SQ Q 4 wksc

表 17
● Complete H&P examination	●CT chest/abdomen/pelvis to document lymphena, pleural organomegaly, ascites, pleural effusion, edema	● Sural nerve biopsy	For management of POEMS syndrome, see POEMS-2
● Evaluate for organomegaly ●Fundoscopic exam ● Hyperhidrosis ● Diarrhea ● Weight loss ● Menstrual and sexual function ● Skin examination for hyperpigmentation, hypertrichosis, acrocyanosis, glomeruloid hemangiomata, plethora, flushing, clubbing, etc ● Detailed neurologic history(numbness,pain, weakness, balance, orthostasis) and exam (sensation and motor function)	●Testosterone, estradiol, fasting glucose, thyroid-stimulating hormone, parathyroid hormone, prolactin, serum cortisol, luteinizing hormone ●CBC, complete metabolic panel, serum immunoglobulins (IgG, IgA, IgM), electrophoresis and immunofixation, serum FLC, 24-h urine for total protein, UPEP, and UIFE, vascular endothelial growth factor (VEGF), and interleukin 6 (IL-6) Bone marrow aspirate and biopsy with FISH panel for myeloma . Echocardiography to assess right ventricular systolic and pulmonary artery pressures ●CT body bone windows and or FDG-PET/CT for sclerotic bone lesions	● For criteria for diagnosis, see POEMS-3 ● Sural nerve biopsy ●Follicle-stimulating hormone, adrenocorticotropin hormone, cosyntropin stimulation test ● Biopsy of bone lesion if needed ● Excisional lymph node biopsy, if Castleman disease or other B-cell lymphomas are suspected . FISH panel for myeloma myeloma . Evaluate for light chain amyloidosis, if appropriate (see NCCN Guidelines for Systemic Light Chain Amyloidosis)	If management of POEMS syndrome, see POEMS-2 ● For management of POEMS syndrome, see POEMS-2 ●Echnosis is MM, follow MM algorithm If diagnosis is WM, see NCCN Guidelines for WM/LPL If diagnosis is Castleman disease, see NCCN Guidelines and to FISH panel for Castleman Disease If diagnosis is Systemic Light Chain Amyloidosis, see Amyloidosis for Amyloidosis

表 18
Table 1. Criteria for the Diagnosis of POEMS syndromea
Mandatory major criteria	1. Polyneuropathy (typical demyelinating)
Mandatory major criteria	2. Monoclonal plasma cell-proliferative disorder (almost always $\lambda$ )
Other major criteria (one required)	3. Castleman diseaseb
Other major criteria (one required)	4. Slerotic bone lesions
Other major criteria (one required)	5. Vascular endothelial growth factor elevation
Minor criteria	6. Organomegaly (splenomegaly, hepatomegaly, lymphadenopathy)
Minor criteria	7. Extravascular volume overload (edema, pleural effusion, or ascites)
Minor criteria	8. Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic)
Minor criteria	9. Skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing, white nails)
Minor criteria	10. Papilledema
Minor criteria	11. Thrombocytosis/polycythemiai
Other signs and symptoms	Clubbing,weight loss,hyperhidrosis,pulmonary hypertension,restrictive lung disease,thrombotic diatheses,diarrhea,low vitamin $B_{12}$ levels

表 19
Table 2. Response Criteria for POEMS Syndrome
Parameter	Evaluable	Complete Response	Improvement	Progressiona
Plasma VEGF	2x ULN	Normalb	50% reduction from baseline	50% increase from lowest level
Hematologic	M-spike 0.5 g/dL, c 1.0 g/dL,e	Negative serum and urine IFE and bone marrowb	50% reduction of M-spike from baselinef	25% increase from lowest level, which must be >0.5 g/dL
PET/CT	At least one lesion with FDG SUV g	No FDG uptake	50% reduction in sum of SUV max g	30% increase in sum of SUV max g from lowest level which must be at least 4 SUV +9 OR appearance of new FDG avid lesion
mNIS +7 POEMS	All patients	$$\begin{array}{l}\\ \\ \\ \\ \\ \\ \end{array}$$	15% decrease from baseline (a minimum of 10 points)	15% increase from lowest value (a minimum of 10 points)
Ascites/effusion/edema	Present	Absent	Improved by 1 CTCAE grade from baseline	Worsened by 1 CTCAE grade from lowest grade
ECHO RVSP	≥40 mm Hg	$$\begin{array}{l}\\ \\ \\ \end{array}$$	<40 mm Hg
Papilledema	Present		Absent	Worsening by 1 CTCAE grade
DLCO	<70% predicted	≥70% predicted	$$\begin{array}{l}\\ \\ \\ \\ \end{array}$$	Worsening by 1 CTCAE grade

表 20
ADL	activities of daily living
AKI	acute kidney injury
ANC	absolute neutrophil count
AS-PCR	allele-specific polymerase chain reaction
BCMA	B-cell maturation antigen
BMPC	bone marrow plasma cell
BNP	b-type natriuretic peptide
BUN	blood urea nitrogen
BsAb	bispecific antibody
CAR	chimeric antigen receptor
CBC	complete blood count
CLL	chronic lymphocytic leukemia
CMV	cytomegalovirus
CNS	central nervous system
CrCl	creatinine clearance
CRS	cytokine release syndromes
CSF	cerebrospinal fluid
CSI	cranospinal irradiation
CTCAE	common terminology criteria for adverse events
CTV	clinical target volume

表 21
DLCO	diffusing capacity of the lung for carbon monoxide
EBV	Epstein-Barr virus
ECHO	echocardiogram
eGFR	estimated glomerular filtration rate
EMG	electromyogram
ESA	erythropoiesis-stimulating agent
BMCP	b-type natriuretic peptide
BUN	blood urea nitrogen
BsAb	bispecific antibody
CAR	chimeric antigen receptor
CBC	complete blood count
CLL	chronic lymphocytic leukemia
CMV	cytomegalovirus
CNS	central nervous system
CrCl	creatinine clearance
CRS	cytokine release syndromes
CSF	cerebrospinal fluid
CSI	craniospinal irradiation
CTCAE	common terminology criteria for adverse events
CTV	clinical target volume

表 22
ICANS	immune effector cell-associated neurotoxicity syndrome
IFE	immunofixation electrophoresis
Ig	immunoglobulin
IHC	immunohistochemistry
IL-6	interleukin-6
IMiD	immunomodulatory drug
IMPEDE	IMiD,BMI,Pathologic fracture,ESA (erythropoietin stimulating agent), Dexamethasone/Doxorubicin, Ethnicity
IMRT	intensity-modulated radiation therapy
IMS	International Myeloma Society
IMWG	International Myeloma Working Group
INR	international normalized ratio
ISS	International Staging System
ISRT	involved-site radiation therapy
IT	intrathecal
IVIG	itravenous immunoglobulin
JCV	John Cunningham virus

表 23
BABBREVIATIONS	BABBREVIATIONS	BABBREVIATIONS	BABBREVIATIONS
LCDD	light chain deposition disease	PCR	polymerase chain reaction
LDH	lactate dehydrogenase	PCV	pneumococcal conjugate vaccine
LHCDD	light and heavy chain deposition disease	PI	proteasome inhibitor
	disease	PPJ	pneumocystis jirovecii pneumonia
LMWH	low-molecular-weight heparin	POEMS	polyneuropathy,organomegaly, endocrinopathy, monoclonal protein,
LP	lumbar puncture		skin changes
mb	monoclonal antibody	PR	partial response
MBL	monoclonal B-cell lymphocytosis	PTV	planning target volume
MFC	multicolor flow cytometry
MGNS	monoclonal gammopathy of neurological significance	R-ISS	Revised International Staging System
MGRS	monoclonal gammopathy of renal significance	RSV	respiratory syncytial virus
MGUS	monoclonal gammopathy of undetermined significance		RSV
MIDD	monoclonal immunoglobulin deposition disease	CoV-2	severe acute respiratory syndrome
MM	multiple myeloma	SAVED	Surgery within 90 days, Asian race,
MRD	minimal residual disease		Venous thromboembolism history, age over Eighty (80), dexamethasone
NCS	nerve conduction study	SIFE	serum immunofixation electrophoresis
NGF	next-generation flow	SLL	small lymphocytic lymphoma
NGS	next-generation sequencing	SNP	single nucleotide polymorphism
NT-proBNP	N-terminal prohormone B-type natriuretic peptide	SPEP SUV	sum of product of greatest perpendicular diameters standardized uptake value
OAR	organs at risk
OS	overall survival

表 24
UIFE	urine immunofixation electrophoresis
ULN	upper limit of normal
UPEP	urine protein electrophoresis

表 25
	NCCN Categories of Evidence and Consensus
Category 1	Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.
Category 2A	Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.
Category 2B	Based upon lower-level evidence, there is NCCN consensus (≥50%, but <85% support of the Panel) that the intervention is appropriate.
Category 3	Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

表 26
NCCN Categories of Preference
Preferred	Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.
Other recommended	Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.
Useful in certain circumstances	Other interventions that may be used for selected patient populations (defined with recommendation).

图示：Solitary plasmacytoma or 8 Rt'±surgery^{m,n} RT^{l}±surgery^{m,n} 8 Rt'sly 1±s Serum quantum tunioglobulins, SPEP, with SIFE 8 Multiple Myeloma Seral 8 Rt'sly 1±s yery 2 8 Rt'sly 1±s Serum quantum tunioglobulins, SPEP, with SIFE 8 Rt'sly 1±s yery 2 8 00 Correne 0 4 8 Solitary plasmacytoma with minimal marrow involvement1,k Consider clinical trial Follow-up interval, 6 2-6 months: 0 CBC, differential, and platelet count Serum chemistry for creatinine and corrected calcium Serum quantitative immunoglobulins, SPEP, with SIFE Multiple SIFE Serum FLC assay ●Serum quantitative immunoglobulins, SPEP, with SIFE Sife Progressive Disease or or Progressive with UPEP with UIFE, as needed or Response followed by workup Response of Myeloma workup (MYEL-4) Multiple (MYEL-4) Response Progressive with myeloma (symptomatic) (MYEL-4) Multiple (MYEL-4) workup Response followed by progression^{q}

图示：Smoldering myeloma (asymptomatic)is High riskrs. Low risk Risk or Observe at 3- to 6-month intervals (category 1) Low risk or Observe at 3-month intervals (expected 1) Clinical trial'the preferred 4-month and 2013 intervals for 3-month intervals as clinically indicated s Check patients: Daratumab (category 1) Daratumumab (loaded: Lenalidomide (category 2B)" Every 3-6 months: CBC, differential, platelet count Creatinine, corrected calcium Serum quantitative immunoglobulins, SPEP, SIFE Serum FLC assay 24-hour urine for total protein, UPEP, and UIFE as clinically indicated Bone marrow aspirate and biopsy with FISH, NGS, or multi-parameter flow cytometry as clinically indicated sERum of TFE. UEE of DNA-MODE to contrast, whole-body MRI without contrast, low-dose CT, FDG-PET/CT annually or as needed, ideally with the same technique used at diagnosisd See NCCN Guidelines for Survivorship Multiple Myeloma (symptomatic)Myeloma (symptomatic) (MYEL-4)

图示：## Initiate myeloma therapy w,x and bone-targeting treatmenty + Supportive care treatment as indicated for symptom managementc,y (also see NCCN Guidelines for Supportive Care) Laboratory assessments appropriate for monitoring treatmentactivities may include: complete blood count (CBC) with differential and metabolic panel - Serum quantitative immunoglobulins, SPEP, and SIFEbb 24 - hour urine for total protein, UPEP, and UIFEbb as clinically indicated System eq, y (also also clinically for SACE) - Serum FLC assay - Whole-body MRI without contrast, low-dose CT, FDG-PET/CT annually or as clinically indicated, ideally with the same technique used at diagnosisd - Bone marrow aspirate and biopsy at relapse with FISH as clinically indicated - Bone marrow aspirate and biopsy at relapse with FISH as clinically indicated - Bone marrow aspirate, SPEP, and SIFEbb 24 - hour urine for total protein, UPEP, and UIFEbb as clinically indicated Response^ Response^ - Response After primary therapy (MYEL-5) $ (MYEL-6) 4 - System FLC assay

图示：Response after primary therapy Autologous z, aa, cc,dd,ee HCT(category 1) Maintenance therapy stable disease^q (category 1)^{w,x,dd,ff Response Continuous myeloma therapy or maintenance therapyw,x,dd,ff primary therapyq,cc Useful in Certain Circumstances for patients with high risk of progression/relapse: Tandem autologous or allogeneic HCTdd,ee Continuous myeloma therapy stable disease^q Maintenance therapy (category 1)^{w,x,dd,ff 0 nc}$$\|W(x, x, dd, ff progressive therapy Performance OKY-6.4 NCCN General dysfunction and advanced age are not contraindications to transplant. ${cc}$ Patients with stable disease can be considered for autologous HCT. dd Follow up with the tests listed on \`\`MYEL-4 under Follow-up/Surveillance. ee Whole-body FDG-PET/CT is recommended around day 100 after autologous HCT. ff The length of therapy should be balanced with toxicity and depth of response and disease status. MYEL-5 MYEL-6

图示：Relapse^ or · Discuss the patient's preferences and goals of care -Chinese the patient's preferences and goals of care -Chimeric antigen receptor (CAR) T-cell therapy specialist Chimeric antigen receptor (Palliative care specialist and supportive care' for symptom management (See NCCN Guidelines for Palliative Care) AND NCCN Guidelines for Supportive Care) Or Autologeneic HCTdd,gg Allogeneic HCTdd,gg/hh

图示：####Confusion,headache,visual visual symptoms,weakness,cranial nervebalsies palsies Essential - Brain and spine MRI with and without contrast.●Lumbar puncture with flow cytometry,cytopathology,cell count, total protein infections for use ####Useful in Certain Circumstances Biopsy of affected tissue if above test results are negative and suspicion is high ####High Useful in Certain Circumstances Biopsy of affected tissue if above test results are negative and suspicion is high Multimodality therapy (CNSM-2) and ####Multimodality therapy CNSM-2) ● Multimodality therapy (CNSM-2) with flow cytometry,cytopathology,cell enhancement or enhancement or parenchymal lesions on MRI without definitive clonal plasma cells demonstrated For example Diagnosis of skull or spinal plasmacytoma without meningeal infiltration and neurologic disease is not considered central nervous system (CNS) disease and should be treated per treatment guidelines for MM (MYEL-G)

图示：CLINICAL FINDINGS INITIAL WORKUP 9455 Renal biopsy. 2 recommended if: - Acute kidney injury - E.gFRC - 60 mL/min and - 2 mL/min per year decline Albumin:creatinine>30 mg/mol ● Pianconi: 经肉pland ● Fanconi syndrome Consider renal biopsy if: - AKI stage 1 or 2 - eGFR < 60 mL/min and - 2 mL/min per year ·Acute kidney injury established GFR (eGFR)● Urinalry is - Urinalry · Metabolic panel ● Albumin: creatinine > 30 - OPEF 1(g/day) ● Albumin: creatinine > 30 - OPEF 1(g/td/0000000001888888888800000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000

图示：Monoclonal Immunoglobulin Deposition Diseases(MIDD) ● Light chain disease(LCDDD) or 90% are (MIDD) 80% (of which 80%-90% are Kappa LC) ● Heavy chain deposition disease(HCCDD) ~10% ● Light and heavy chain deposition chain deposition disease(LHCDD) ~10% ● Light and heavy chain deposition the(LHCDD) ~10% ● Peripheral blood flow cytometry for diagnosis of CLL/SLL or LPL (see NCCN Guidelines for Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma and NCCN Guidelines for Waldenstrom Macroglobulinemia/Lymphoplasmacytic Lymphoma) ● Organ involvement by frequency: kidney (~96%), heart (~21%), liver (~19%), peripheral nervous system (~8%). Note: All recommendations are category 2A unless otherwise indicated. ● Invol. All recommendations are category 2A a Nonlateral Energy at 2A A 2020A Sine CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN. CnN

图示：IgMa MGNS (Monoclonal gammopathy of neurological has neurological(0-1)Gammopathy (0-1)Gamm2rel) of neurological localization of WM/LPL) 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1 Gmm 0-1

图示：NCCN

引用 / 出处

（2026.V3）NCCN临床实践指南：多发性骨髓瘤. 2026.