2025++BSH／UKMS指南：复发性多发性骨髓瘤的管理

Correspondence

BSH Guidelines Administrator, British Society for Haematology, 100 White Lion Street, London N 91 P,UK Email: bshguidelines@b-s-h.org.uk

KEYWORDS

guidelines,management,relapsed multiple myeloma

SCOPE

The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with relapsed and refractory multiple myeloma who have disease progression after at least one prior ther-apy. These guidelines and recommendations do not re-place multidisciplinary discussion and the need to take account of clinical features, patient preference and the funding and reimbursement of treatments at any given point in time.

METHODOLOGY

This guideline was compiled according to the British Society for Haematology(BSH) process at www.b-s-h.org.uk/guide lines. The Grading of Recommendations Assessment,Development and Evaluation(GRADE) nomenclature was used to evaluate the levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradleworkinggroup.org and are summarised in appendix 3 of the guidance document linked above.

Abbreviations:Bela-PD,belanmatab pomalidimide dexamethasone;Bela-VD,belantamab bortezomiz bortezomiz dexamethasone;Benda VD,bendamustine veldale dexamethasone;CEVAD,cyclophosphamide,etoposide,vincristine,adriamycin,dexamethylasone;Cilta-cel,catlacambattageneueulteucel;CPD,cyclophosphamide,pomalidimide,dexamethasone;CRD,cyclophosphamide,nelalidenomide,dexamethasone;CTD,cyclophosphamide,vincristine,doxorubicin,dexamethasone;CVD,cyclophosphamide,bortezomid,dexamethasone;Dara,daratumumab;Dara-KD,daratumumab,carfilzomib,dexamethasone;Dara-PD,daratumumab,pomalidimide,dexamethasone;Dara-RD,daratumumab, lenalidomide,dexamethasone;Dara-VD,daratumumab, bortezomib,dexamethasone;DDEXamethasone,cyclophosphamide,etoposide,cisplatin;DT-PACE,dexamethasone,cisplatin,doxorubicin,dexamethasone;Elo-pD,Elotuzumab,pomalidimide,dexamethasone;Elo-RD,Elotuzumab,lenalidomide,dexamethasone;ESHAP,Etoposide,methylprednisolone,cytarabine and cisplatin;Idecel,Idecabtagene vicleucet;Iatsux-KD,Isatuximab,carfilzomib,dexamethasone;Isatuximab,polamidomide,dexamethasone;Ixa-CD,Ixazomib,dexamethasone;Ixa-CD,Ixazomib,dexamethasone;Ixa-CD,Ixazomib,dexamethasone;Ixa-CD,Ixazomib,dexamethasone;Fprilzomib, dexamethasone;KD,carfilzomib,dexamethasone;KRD,carfilzomib, lenalidomide,dexamethasone;MPT,melphalan,prednisolone,thalidomide;OPP-EBV-CAD,vincristine,procarbazine,prednisone,epidoxidirubicin,bleomycin,vinblastine, lomustine, dodorubicin, and vindesine; Pano-VD,panobinostat, bortezomib, dexamethasone; Pano-VTD,panobinostat bortezomib thalidomide dexamethasone;PD,pomalidomide,dexamethasone;PVD,pomalidomide,bortezomib,dexamethasone;RD,lenalidomide,dexamethasone;T or Thal,Thalidomide;TD,Thalidomide,dexamethasone;V, bortezomib;VD, bortezomib,dexamethasone;VMP, bortezomib,melpanolis, prednisolone; Vori-VD, voriconazole bortezomib dexamethasone;VTD,bortezomid,dexamethasone;VTD-PACE, bortezomib, thalidomide,dexamethasone; cisplatin, doxorubicin,cyclophosphamide,etoposide.

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# LITERATURE REVIEW DETAILS

Recommendations are based on a review of published lit-erature, performed by Niche Science and Technology, using Medline, PubMed, Embase, Central and Web of Science searches from the beginning of 2000 up to June 2020.Further updates took place in December 2023 and 2024.Consideration was predominantly given to phase II and III clinical trials with early phase studies or case series only considered where there was a paucity of higher grade evi-dence. Conference abstracts were excluded.

# REVIEW OF THE MANUSCRIPT

The manuscript was reviewed by the UK Myeloma Society Executive Committee, the British Society for Haematology(BSH) Guidelines Committee Haemato-Oncology Task Force, the BSH Guidelines Committee, the Haemato-Oncology sounding board of BSH and the UK Charity Myeloma UK. It was also on the members section of the BSH website for comment. These organisations do not necessarily approve or endorse the contents.

INTRODUCTION

This guideline aims to outline the optimal management of patients with relapsed and/or refractory myeloma. It in-cludes recommendations about evaluation and monitoring of patients with relapsed disease and their subsequent treat-ment. There are many factors that influence choice of treat-ment at each line of therapy, and therefore, it is not possible or desirable to generate a single algorithm to guide treat-ment. However, these guidelines aim to reflect the most ro-bust data available at the time of publication. These should complement multidisciplinary discussion, and patient-specific factors must always be taken into consideration.These guidelines focus on the United Kingdom, but include regimens that at the time of publication may not be reim-bursed in all regions of the United Kingdom, even though robust evidence for their use exists.

Definitions

Advances in front-line treatment have led to better outcomes in multiple myeloma(MM). However, almost all patients with MM progress, even those who achieve a prolonged and deep response after initial therapy.1 The definitions of relapsed myeloma(RMM) distinguish between serological progression, for which there are clear biochemical param-eters,2 and clinical progression defined by the development of new CRAB features(hypercalcaemia, renal dysfunction,anaemia, bone disease). Relapsed and refractory myeloma(RRMM) is defined as disease that progresses on therapy or progresses within 60 days of the last treatment in patients

who previously achieved at least a minimal response(MR).Primary refractory MM refers to failure to achieve an MR with first-line treatment and is discussed in the BSH guide-lines on newly diagnosed myeloma.2,3

For the purposes of this guideline, triple class refractory multiple myeloma(TCR-MM) is defined as disease refrac-tory to at least one immunomodulatory drug(IMiD), pro-teasome inhibitor(PI) and anti-CD38 monoclonal antibody(mAb). Penta-refractory myeloma is defined as being refrac-tory to two IMiDs, two PIs and an anti-CD38 mAb.

While meeting these criteria defines relapsed disease,they are most useful for ensuring consistency of reporting,interpretation and comparison of trial data. Progressive my-oma does not necessarily mean that treatment is indicated immediately, and this is discussed in detail below.

All progression-free survival(PFS) and overall survival(OS) data are median values.

Evaluation at progression

The aim of evaluation at progression is to identify evidence of actual or impending end organ damage and potential prognostic factors. In addition to the standard haematologi-cal and biochemical blood tests, it is good practice for a bone marrow aspirate and trephine(BMAT) examination to be performed. This may be more important at first and second relapse than later relapses. This investigation is particularly important in cases of non- or oligo-secretory disease or if unexplained cytopias coexist, for example, to exclude my-elodysplasia. When BMAT is undertaken, genetic analysis should be considered if there is the possibility of directed therapy based on the results. Testing for high-risk disease by fluorescence in situ hybridisation(FISH) and/or genomic analysis is important if a second autologous stem cell trans-plant(ASCT) is being considered, as outcomes of a second ASCT are less favourable in the presence of high-risk dis-ease.4 The value of testing is less clear if high-risk cytogenetic abnormalities were already identified at diagnosis; however,acquisition of additional adverse genetic abnormalities is well recognised at progression and may result in a patient moving from standard- to high-risk disease.6 In addition,the identification of t(11;14), if not previously tested for, is potentially important as this subgroup of MM patients may preferentially respond to specific therapies such as veneto-clax, as discussed later.

Functional cross-sectional imaging is important for re-assessing disease at progression, especially for new bony symptoms, and in non-secretory, oligo-secretory or extra-medullary disease. There is a rationale for considering this imaging in clinically asymptomatic serological progression to identify new focal lesions that may define clinical re-lapse that would otherwise be occult. Imaging modalities that enable bone marrow infiltration and disease activity evaluation, for example, whole body diffusion-weighted magnetic resonance imaging(MRI) and positron emission tomography-computerised tomography(PET-CT), have

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an important role in assessing treatment response and dis-ease relapse. Plain X-ray imaging is inadequate and is not recommended.

There is no clear basis for firm recommendations about the frequency of surveillance imaging where treatment is not immediately needed but annually until treatment is required would be reasonable.

Determining management strategy

Numerous factors need to be considered when determining the approach to the management of a patient with relapsed MM. These comprise characteristics of the patient's disease,previous therapy received and the patient's own prefer-ences. These determinants of therapy were reviewed by the International Myeloma Working Group(IMWG) in its rec-ommendations for the management of RMM5(outlined in Box 1).

Asymptomatic relapse

There is no evidence from randomised trials to indicate the optimum management strategy in this situation. However,it is recommended that treatment is commenced before the development of new end organ damage, hence the utility of functional imaging.

Serological progression alone does not necessarily warrant immediate treatment. Slow serological progression without CRAB criteria can be simply monitored, for example, initially at monthly intervals.8 However, a rapid trajectory of serolog-ical progression should prompt consideration of treatment,even without CRAB criteria. Treatment initiation should also be considered at asymptomatic relapse where high-risk fea-tures are present, for example, previous short treatment-free interval, previous light chain-induced renal impairment, ex-tramedullary disease or unfavourable cytogenetics.9

BOX 1 Factors influencing treatment strategy in relapsed or RRMM

Disease characteristics

High- versus low-risk cytogenetics

Destructive bone disease and renal impairment

Presence or absence of extramedullary disease

Trajectory of relapse

Characteristics of prior or ongoing therapy

Short versus long duration of response to previous therapy

Progression on current therapy

Toxicities associated with prior therapy

Patient characteristics

Performance status and frailty

Co-morbid conditions

Preference regarding mode of treatment administration

$$\text{Overall goals of care}$$

Principles underlying the treatment of relapsed multiple myeloma

Once the decision to commence treatment has been made,enrolment in clinical trials should be considered. Several phase 3 clinical trials have demonstrated improved PFS with the use of three drug regimens(triplets) compared with the use of two drugs(doublets).10 However, it should be remem-bered that these trials have tended to exclude frail patients and patients with severe renal impairment, and a less ag-gressive treatment approach might be more suitable for such patients, who may also prefer a wholly oral combination.Enrolment in clinical trials should not hinder access to future treatments. In the United Kingdom, it has been clarified by the National Institute for Health and Care Excellence(NICE)that if a patient's clinical condition falls within the recom-mendation of an NICE technology appraisal, they should be prescribed the medication as recommended in the guidance,regardless of any previous participation in a clinical trial in which they may have received medicines for their condi-tion(https://www.nice.org.uk/about/what-we-do/our-progr ammes/nice-guidance/nice-technology-appraisal-guidance).

Sequencing of treatment

It is preferable to use a different backbone agent from that used in the most recent regimen unless there has been a long treatment-free interval. This is particularly the case if disease progression has occurred while on a continuous or mainte-nance treatment when the disease will, by definition, be re-fractory. Exceptions to this principle do exist, for example, if a backbone agent is to be used in combination with one or more agents with a different mode of action or if, particularly in the late stages of disease, the patient was refractory to the chosen drug during an earlier line of therapy. The rationale for this is the demonstration of evolution of competing subclones in MM that may result in previously resistant disease becoming drug sensitive.8 Which therapy to use in a given situation is discussed in more detail at the end of these guidelines.

Decision-making in relapsed myeloma

There are well-established processes in the United Kingdom for multidisciplinary team working both within and be-tween hospitals. This is particularly important in relapsed disease where decision-making requires a detailed under-standing both of disease biology and of the likely benefit and toxicities of the increasing number of potential treatments,including access to clinical trials and new therapies. Where

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possible patients should be treated in specialist myeloma clinics with access to appropriate advice and support for all stages of the disease.

Supportive and palliative care

Good supportive care is an important component of the management of RMM. Best practice in this area is described in other guidelines(Myeloma: diagnosis and management[National Institute for Health and Care Excellence: NG35(updated 2018))].12 Bisphosphonate therapy should be re-started at the time of frank relapse if it has previously been stopped, as this significantly reduces skeletal events, with a trend towards an improvement in overall survival.13 The op-timal frequency and duration of bisphosphonate therapy at relapse is not established.

In multiply relapsed patients, a decision often needs to be made between offering further systemic treatment and pal-liative care. Such decisions are naturally individualised, but if further treatment is instigated, enrolment into appropriate clinical trials is recommended, bearing in mind the gener-ally improved outcomes produced compared with standard treatments. ${}^{14}$

COVID-19 pandemic

The COVID-19 pandemic of 2020 onwards has caused clini-cians to reappraise the way myeloma patients, including those with RMM, are investigated and managed. The emphasis has been on reducing hospital visits, increasing use of oral regimens with home delivery and self-administration of subcutaneous drugs at home where appropriate.15 Many of these changes in practice have been beneficial to provision of healthcare and have continued even as COVID-19 has become endemic.

Recommendations

● Consider bone marrow examination including genetic analysis and functional imaging at relapse(2C).

● A full reassessment should be made at relapse of the pa-tient's disease characteristics, previous treatment and preferences(1C).

● A rapid trajectory of serological relapse is an indication to consider systemic treatment, even in the absence of CRAB criteria(2C).

● Consider enrolling patients into clinical trials at every line of therapy, including multiply relapsed patients for whom palliative care is not indicated(2C).

TREATMENT OF RELAPSED MYELOMA

The following sections aim to give an overview of the data available to guide treatment decisions given the increase in

range of options for RMM. While many UK funding deci-sions are based on prior lines of therapy, we have not made reference to these except where the licence for that drug or combination of drugs is restricted to either a given line or prior treatment history. Key data are tabulated to summarise the salient features of each trial and key outcomes. However,it is not possible to provide a comprehensive critique of each trial, and it is important to be aware of the differences in trial inclusion criteria, not least prior treatments received, which are heavily influenced by the time period in which patients were recruited. Where possible, recruitment period is indi-cated in the tables.

PROTEASOME INHIBITORS(PIs)

Proteasome inhibition is an established treatment strategy for patients with MM.

Bortezomib, the first in class proteasome inhibitor showed activity as a single agent in patients with RMM.Based on the observed synergism with other agents, vari-ous combinations have been evaluated in phase 2/3 trials. In RMM, bortezomib in combination with pomalidomide,cyclophosphamide,18 anthracyclines,19 panobinostat,20 da-ratumumab21 and selinexor22,23 has demonstrated efficacy(see Table 1). Data from front-line protocols incorporat-ing bortezomib suggest that a weekly regimen is as effec-tive, and associated with less neuropathy, as twice weekly regimens.24

Carfilzombib is a second-generation PI resulting in sustained proteasomal inhibition and has been used at a range of doses in clinical trials(see Table 2). Carfilzombi(56 mg/m2 twice weekly) plus dexamethasone increased PFS and OS compared to bortezombi and dexamethasone,even among bortezombi-refractory patients,30 with less peripheral neuropathy, but higher rates of cardiovascu-lar complications. Aggressive hydration may contribute to fluid overload and congestive heart failure31; judicious intravenous fluid use is therefore recommended after the first cycle, especially in patients with cardiac compromise,hypertension or renal impairment. Hypertension should be controlled carefully.32 Once weekly carfilzombi has reduced cardiac toxicity and superior efficacy to twice weekly(27 mg/m2).33,34 A 56mg/m2 dose is preferred to balance efficacy and toxicity.

Carfilzomib has been evaluated in combination with cyclophosphamide and dexamethasone, resulting in re-sponse rates of 52% in triple class refractory myeloma.35 In the MUK five study, carfilzomib, cyclophosphamide and dexamethasone at second line improved overall response rates versus bortenzomib, cyclophosphamide and dexa-methasone, but without PFS benefit. However, carfilzomib maintenance improved PFS versus no maintenance, sup-porting the use of the drug in this setting.36 Carfilzomib(27mg/m2 twice weekly) combined with lenalidomide plus dexamethasone is also superior to lenalidomide and dexamethasone alone.33-37 Carfilzomib has also been

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TABLE 1 Bortezomib combinations in relapsed myeloma.

|Study, year|Recruitment period (total n)|Arms|Median prior lines (range)|CR ≥MR(%)|PFS(m)|OS(m)|Comments| |---|---|---|---|---|---|---|---| |APEX|Phase 3|V(iv, biw) vs.|2(1-4)|38 vs.18|6 vs.|29.8 vs.|In V arm:| |Richardson et al. NEJM,2005|2002-2003 (669)|High dose D|||<1|(HR,0.55, p<0.001)|Grade≥3 AE 75% (HR 0.57)| ||||||||30% Grade≥3 peripheral| ||||||||neuropathy 8% In D arm: Grade≥3 AE 60%| |SUMMIT Richardson et al. Cancer, 2006|Phase 2 2002-2003 (202)|VD(iv, biw)|6(2-15)|27|4|12.7|17| |Kropff et al. BJ Haem,200718|Phase 2 2004-2005 (54)|VCD(iv, biw)|1-6|90|16|12|22| ||||||||Prior ASCT in 43% Grade≥3 neuropathy 24% Grade≥3 thrombocytopenia 30% Grade≥3 peripheral neuropathy 8% In D arm: Grade≥3 AE 60%| |SUMMIT Richardson et al. Cancer, 200625|Phase 2 2002-2003 (202)|VD(iv, biw)|6(2-15)|27|4|12.7|17| |Kropff et al. BJ Haem,200718|Phase 2 2004-2005 (54)|VCD(iv, biw)|1-6|90|16|12|22| ||||||||Prior ASCT in 43% Grade≥3 neuropathy 24% Grade≥3 thrombocytopenia 33%| |CREST Jagannath et al. BJ Haem,2008|Phase 3 2001-2002 (54)|V 1mg/m2 VD 1mg/m2 VD 1.3mg/m2|1(1-3) 44 44 50|33 9 12.5 70 8 58|7(TTP) 11(TTP) 8|26.8 60|61% and 27% of patients completed eight cycles twice weekly bortezomib in the 1.0 and 1.3 mg/m2 respectively| |RETREIVE Petrucci et al. BJ Haem,2013|Phase 2 (130)|V or VD retreatment|2(1-4)|58|1|8.4|Not reported| |Moreau et al. Lancet Onc,2011|Phase 3 2008-2010 (222)|sc V vs.iv|1|ORR after 4 cycles 42 vs.42|6vs.8|10.2 vs.8.0 8|1 year OS 72.6% vs.76.7%| |Petrucci et al. Cancer, 2013|Phase 1/2 (42)|Weekly VMP in NTE RRMM|2 lines (26%) Prior ASCT 33.|ORR 57|NA|TTP 18|30|

Abbreviations:AE,adverse event;bi,biweekly;D/Dex,dexamethasone;iv,intravenous;NTE,non-transplant eligible;sc,subcutaneous;TTP,time to progression;V,bortezomib.

studied in randomised phase 3 trials in combination with other agents including dartumabum and isatuximab(see Tables 2, 3 and 4).

Iaxizom is an orally bioavailable proteasome inhibitor.In combination with lenalidomide and dexamethasone, it improves RR and PFS compared to those two agents alone, ${}^{58}$ including in patients with high-risk cytogenetic abnormali-ties.59 Other combinations including ixazomib, cyclophos-phamide and dexamethasone60,61 and ixazomib, thalidomide and dexamethasone have been reported.62 Ixasomib studies are summarised in Table 5.

Toxicities

$\text{Key toxicities are shown(Box 2)}$

IMMUNOMODULATORY DRUGS

General points

Immunomodulatory drugs(IMiDs) bind to the ubiqui-tously expressed E3 ligase protein cereblon(CRBN) re-sulting in direct and immune-mediated activity against myeloma.65 Thalidomide was available first, and the strongest evidence for its use is in the front-line setting;nonetheless, it has demonstrated efficacy in RMM, par-ticularly at second line.66-72 Lenalidomide and then poma-lidomide became available later and initially had their strongest evidence in RMM but are preferable to use over thalidomide in earlier lines where possible due to lower toxicity, with continuous therapy being the standard of care.39,40,73-74 All are orally administered.

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TABLE 2 Carfilzibomb combinations in relapsed myeloma.

|Study, year|Recruitment period (total n)|Arms|Median prior lines (range)|ORR(%)|CR(%)|PFS(m)|OS(m)|Comments| |---|---|---|---|---|---|---|---|---| |ASPIRE Stewart et al. NEJM,201438|Phase 3 2010-2012 (792)|KRD vs.RD K 27mg/m2 biw|2 (1-3)|87.1 vs. 66.7|31.8 vs. 9.3|26.3 vs.17.6 (HR 0.69)|48.3 vs. 40.4|HRQoL superior in KRD arm.≥Gr 3 AE,83.7% vs.80.7% in KRD vs.KD Signal for cardiovascular events in KRD arm| |ENDAVOR Darouso Lancet Oncol, 201630|Phase 3 2012-2014 (929)|KD vs.VD K 56mg/m2 biw|2 (1-3)|77 vs.63|NA|18.7 vs.9.4 (HR 0.53, p<0.0001)|NA|PFS was primary end-point Significantly more peripheral neuropathy in Vd arm| |A.R.R.O.W. Moreau et al. Lancet Oncol, 201833|Phase 3 2015-2018 (578)|KD 70mg/m2 ow vs.KD biw 27mg/m2|(2-3) ow vs.KD biw|62.9 vs. 40.8|7 vs.2 vs.11.2 vs.7.6 (HR 0.69, p=0.0029)|NA|≥Gr 3 AE 68% biw vs.62% ow 27mg/m2 is not standard dose in doublet regimen(56mg/m2)|| |MUK five Yong et al. Haematologica, 202136|Phase 2 2013-2016 (300)|KCD vs. VCD(2:1 randomisation) K 36mg/m2 biw|1 (all patients)|84.0 vs. 63.1|11.7 vs.10.2 (NS)|30.9 vs. 28.1|Similar overall PFS but superior activity(≥VGPR) with KCD in genetically high-risk disease and early relapse patients|| |Abbreviations: biw, biweekly; ow, once-weekly.|||||||||

Abbreviations:biw,biweekly;ow,once-weekly.

IMiDs in combinations

Although robust head-to-head comparisons are lacking,addition of corticosteroids appears to improve response rate(RR) and PFS. 41,68,69,75 The addition of alkylating agents may improve RR and be effective even in patients refractory to the IMiD as a single agent, 43,44,70-72,76-77 though randomised data exist only for pomalidomide. 78,79 Since clinicians are likely to be familiar with thalidomide and lenalidomide, those trials are not discussed in detail;key studies are tabulated(Tables 3,6 and 7). In an open-label phase III trial enrolling 559 lenalidomide-exposed patients, addition of pomalidomide to bortezomib and dexamethasone significantly improved ORR and PFS.17 Although robust comparisons of IMiD-alkylator against IMiD-PI have not been undertaken in RMM, data indi-cate efficacy for both. Some reports suggest that clarithro-mycin may also augment efficacy,80,81; however, caution is warranted as a randomised study in the up-front set-ting indicates that a deeper RR with the lenalidomide-clarithromycin-dexamethasone combination is offset by a higher rate of toxic deaths in the clarithromycin arm.82 Combinations of ImiDs with monoclonal antibodies are discussed in a subsequent section.

Toxicities

Many early thalidomide trials used high doses which are often difficult to deliver in practice. This class of drugs has problematic toxicities(see Box 3), and results have im-proved in parallel with increasing experience of toxicity management. Thalidomide in particular has a higher risk of neurotoxicity, both central and peripheral and is less well tolerated than other ImiDs. The thromboembolic risk appears highest early in treatment and when steroids are used and is lower during maintenance.93 Steroid-related side effects are common, and one option to minimise these is to reduce or discontinue steroids once maximum response has been achieved in order to maintain ongoing IMiD therapy.

Recommendations: IMiDs and PIs

● Triplet combinations are recommended over doublets,subject to patient tolerability(1A).

● Generally, a PI-IMiD-steroid combination is rec-ommended(e.g. carfilzomib-leinalidomide-dexa-methasone, iazomib-leinalidomide-dexamethasone,pomalidomide-bortezomib-dexamethasone)(1A).

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TABLE 3 Lenalidomide combinations in relapsed myeloma.

|Study, year|Recruitment period (total n)|Arms|Median prior lines (range)|ORR(%)|CR(%)|PFS(m)|OS(m)|Comments| |---|---|---|---|---|---|---|---|---| |MM-009|Phase 3|RD vs.|≥1|≥PR:61%|14.1%|11.1|29.6|≥Gr 3 neutropenia| |Weber et al.|2003-2005|Placebo+ Dex||≥PR:|0.6%|4.7|20.2|41.2% vs.4.6%| |N Engl J Med, 200759|(353)|||19.9%||(HR 0.35)|(HR 0.44)|≥Gr 3 infection:21.5% vs.12%| |MM-010|Phase 3|RD vs.|2(1-≥2)|≥PR:|15.9%|TTP:11.3|37.3|≥Gr 3 neutropenia| |Domopoulos et al.|2003-2004|Placebo+ Dex|2(1-≥2)|60.2%|3.4%|TTP:4.7|30.7|29.5% vs.2.3%| |N Engl J Med, 200740|(351)|||≥PR: 24.0%||(HR:0.66)|(HR:0.66)|≥Gr 3 thrombocytopenia: 11.4% vs.5.7% PN<10%| |Richardson et al.Blood, 200941|Phase 2 2003-2004 (222)|R|3(1-≥)|ORR: 44% ≥PR:26%|2%|4.9|23.2|R dose=30 mg OD. No steroid 80% had prior thal| |REVLite Quach et al. Br J Haematol, 201742|Phase 2 2007-2010 (149)|RD|2(1-≥3)|71%|15%|8.9|30.5|R 15mg,Dex 20mg No PFS/OS difference cf. MM-009/MM-010 but less toxic(e.g.≥Gr 3 neutropenia 29% vs.41%)| |Nijhof et al.|Phase 1/2 2011-2014 (67)|Cyclo R Pred|3(1-10)|83%|3%|12.1|29.0|N.B. All patients len refractory ≥Gr 3 neutropenia 22%, ≥Gr 3 thrombocytopenia 22%, ≥Gr 3 infection 21%| |Recec et al. Br J Haematol, 201544|Phase 1/2 2007-2009 (32)|Cyclo R Pred|2(1-5)|94%|19%|16.1|27.6|| |Palumbo et al. Leukemia,201045|Phase 2 2007-2008 (44)|R Mel Pred Thal|1(1-2)|75% (≥PR)|2%|1 years: 51.5%|1 year:72%|| |Knop et al. Blood,200946|Phase 1/2 2005-2007 (69)|R+Adriamycin+Dex|2(1 to>2)|73%|14.5%|40 weeks||≥Gr 3 neutropenia 48% ≥Gr 3 thrombocytopenia: 38%|

● When one of these combinations is unavailable or clini-cally inappropriate, a PI-alkylator-steroid or IMiD-al-kylator-steroid combination should be considered(2B).

MONOCLONAL ANTIBODIES

Anti-CD38

● When a PI-based doublet is used, carfilzomib-dexamethasone is aseone is preferred to bortezomib-dexamethasone(1A).

Daratumumab is a monoclonal antibody targeting CD38. It has efficacy as monotherapy with a pooled analysis of the 16mg/kg dose in two phase 1/2 trials showing an ORR of 31% in heavily pretreated patients.47 Toxicity was minimal and long-term treatment was well tolerated.

● When an IMiD-based doublet is used, lenalidomide-dexamethasone and pomalidomide-dexamethasone are options(1B).

● Steroids may be tapered/stopped based on toxicity and response(2C).

Daratumumab has been combined with standard back-bone regimens. Daratumumab improved RR and PFS when combined with bortezomib and dexamethasone; the hazard ratio for PFS was 0.31 with a median PFS of 16.7 months. 21,94 The addition of daratumumab was well tolerated with few excess side effects. Similar incremental benefit was shown in the trial combining daratumumab with lenalidomide and dexamethasone. 49,95 The structure of these two trials

● When selecting a PI, consider their respective toxicities,routes of administration and patient preference(2C).

● When IMiDs are used, risk-adapted thrombrophy-laxis should be employed for all patients and reassessed regularly(1B).

● When using PIs, varicella zoster prophylaxis should be offered(1B).

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TABLE 4 Monoclonal antibodies in relapsed myeloma.

|Study, year|Recruitment period (total n)|Arms|Median prior lines (range)|ORR(%)|CR(%)|PFS(m)|OS(m)|Comments| |---|---|---|---|---|---|---|---|---| |SIRIUS(GEN501)|Phase 1-2|Dara-|5(2-14)|31.1|4.7|4.0|20.1|Combined analysis of the 16mg/kg dose in these two trials| |Usmani et al. Blood,201647|2008-2015 (148)|Methylpred||||||| |CASTOR Palumbo et al. NEJM,201621|Phase 3 2014-2015 (498)|Dara-VD vs. VD|2(1-10)|83.3 63.2|28.8 9.8|11.6 2.4|16.7 7.1(HR 0.31)|Immature Immature K 56mg/m2 twice weekly| |CANDOR Dimopoulos et al. Lancet,202048|Phase 3 2017-2018 (466)|Dara-KD vs. KD|2(1-2)|84 75|29 10|14 3|NR 15.8(HR 0.63)|Immature K 56mg/m2 twice weekly| |POLLUX Dimopoulos et al. NEJM,201649|Phase 3 2014-2015 (569)|Dara-RD vs. vs. RD|92.9 76.4|51.2 21.0|44.5 17.5(HR 0.44)|67.6 51.8(HR 0.73)|Extended follow-up for PFS and OS|| |Bahlis et al. Leukemia,202050 Dimopoulos et al. JCO,202351|Leukemia,202050 Dimopoulos et al. (103)|Dara-PD|4(1-13)|60 17|8.8|17.5|MRD neg 29% in patients who achieved CR|| |EQUULEUS Chari et al. Blood,201752|Phase 2 (103)|Dara-PD vs. PD|2(1-5)|69 46|25 4|9 2|12.4 6.9(HR 0.63)|| |APOLLO Dimopoulos et al. Lancet Haem,202153|Phase 3 2017-2019 (304)|Dara-PD vs. PD|2(1-5)|25 46|9 2|12.4 6.9(HR 0.63)|Immature Only trial of monoclonal|| |ELOQUENT-2 Lonial et al. NEJM,201554|Phase 3 2011-2012 (646)|Elo-RD vs. RD|2(1-4)|79 66|11 11|14.9(HR 0.70)|48 40|| |ELOQUENT-3 Dimopoulos et al. NEJM,201855|Phase 3 2016-2017 (117)|Elo-PD vs. PD|3(2-8)|53 26|8 2|10.3 4.7(HR 0.54)|Immature of|| |ICARIA Attal et al. Lancet,201956|Phase 3 2017-2018 (307)|Isatux-PD vs. vs. PD|3(2-4)|60 35|5 1|11.5 0|Immature 6.5(HR 0.60)|| |IKEMA Moreau et al. Loreau et al. Lancet 202157|Phase 3 2017-2019 (302)|Isatux-KD vs. KD|2(1-3) 83|87 28|30 13|NR 19.2(HR 0.53)|Immature K 56mg/m2 twice weekly||

differed: The control arm of lenalidomide and dexameth-asone was continuous, with the triplet continuous therapy combination of lenalidomide, daratumumab and dexameth-asone associated with the best outcomes of any relapsed study to date, with median PFS of 44.5 months and OS of 67.6 months.50,51 Importantly, this was in a non-lealidomide refractory population, so this benefit will not be the case for those who had have progressed on lenalidomide. Differences in patient population preclude direct comparison, but sur-vival outcomes of both daratumumab combinations exceed those of monotherapy.

Daratumumab has been combined with other IMiDs and PIs in multiple trials. The addition of daratumumab to pomalidomide and dexamethasone improved RR and PFS in RMM including 79% of patients in the study who were

lenalidomide refractory.53 Daratumumab with carfilzomib and dexamethasone shows the same incremental benefit in PFS as when daratumumab is added to pomalidomide. 48,96 These combinations are strong options for patients exposed to bortezomit at induction and relapsing on lenalidomide maintenance. Given the improved response rates and du-ration with daratumumab combinations, daratumumab should preferentially be used in combination where possible.

Although originally administered by intravenous(IV)infusion in the majority of these reported trials, subcuta-neous(SC) dosing appears equally effective, is more con-venient and is associated with fewer first dose reactions so is now the standard of care97; some risk remains with the first dose, so premedication and post-injection observation is required but may not be needed after multiple doses.

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TABLE 5 Ixazomib combinations in relapsed myeloma.

|Study, year|Recruitment period (total n)|Arms(n)|Median prior lines (range)|ORR %|CR%|PFS (m)|OS(m)|Comments| |---|---|---|---|---|---|---|---|---| |TOURMALINE-MM1 Moreau et al. NEJM,2016|Phase 3 (722)|Ixa-Rd vs. Placebo+ Rd|3(1-3)|78 vs. 72|Not reported|20.6 vs. vs. 14.7|53.6 vs.51.6|Main AEs thrombocytopenia,fatigue,nausea and diarrhoea Median PFS 21.4m vs.9.7m in patients with high-risk cytogenetics.Extended follow-up(median 85m):no new or additional safety concerns| |JCO,2021||||||||| |Ixa Cyclo dex for RRMM Kumar et al. BJ Haem,20196|Phase 2 (78)|Ixa-CD|2|48|Not reported|14.2|NA|Ixa-ICd was well tolerated| |MUK eight Auner et al. Blood Cancer J,2022|Phase 2 2016-2018 (112)|Ixa-CD vs. CD|4|42.1 vs. 39.6|1.8 vs.1.9 vs. 6.7|5.6 vs. 6.7|14.1 vs.19.1 (ns)|Study allowed crossover from CD to Ixa-CD arm| |Ixa-TD/Ixa Ludwig et al. Br J Cancer,201962|Phase 2 2015-2019 (90)|Ixa-TD|1(1-8)|51.1|8.9%|8.5|Not reached|Ixa-TD x8 cycles then maintenance Ixa for 12 months| |Ixa-TD|Phase 2|Ixa-TD|1(1-3)|56.4|3.0|13.8|Not reached|Ixa-TD until progression Grade≥3 non-haem AE 21%|

BOX 2 Proteasome inhibitors-Key toxicities

Class effect:

● Cytopenias,particularly thrombocytopenia

● Increased incidence of varicella zoster infection

Bortezomib:

● Sensory neuropathy, potentially painful in a stocking and glove distribution

•Autonomic neuropathy, causing postural hypo-tension and diarrhoea

Ixazomib:

• Rash

● Gastrointestinal toxicity

• Peripheral neuropathy

Carfilzomib:

● Cardiac toxicity, including heart failure and ischaemic heart disease

● Renal dysfunction

• Hypertension

● Thrombotic microangiopathy

Daratumumab causes a positive direct antiglobulin test so extended red cell phenotyping is recommended before the first dose.

Isatuximab is a monoclonal antibody which binds to a different epitope of CD38. It has significant efficacy as monotherapy or with dexamethasone in multiply relapsed myeloma. ${ }^{98}$ Isatuximab increases RR and PFS when com-bined with pomalidomide and dexamethasone. ${ }^{56}$ Currently,it is given by IV infusion until disease progression. Grade 4 neutropenia was common in the clinical trial (61%), so pro-phylactic granulocyte colony stimulating factor (GCSF) from initiation of treatment is a consideration. In another phase 3 study, addition of isatuximab to carfilzomib $(56 mg / m^{2}$ twice weekly) and dexamethasone demonstrated an improved PFS approaching 3 years, which compares favourably with dara-tumumab carfilzomib and dexamethasone. This effective treatment combination requires multiple IV infusions per cycle long term, so venous access is a consideration. ${ }^{57}$

There are no data directly comparing the two anti-CD38 mAbs and limited data using either drug in patients previ-ously refractory or exposed to CD38 mAb. Important clin-ical trials involving both mAbs are summarised in Table 4.

Recommendation s

● Daratumumab is recommended in combination with

o Lenalidomide and dexamethasone(1A)

○ Bortezomib and dexamethasone(1A)

o Pomalidomide and dexamethasone(1A)

○ Carfilzomib and dexamethasone(1A)

● Daratumumab monotherapy is recommended for the treatment of relapsed myeloma if combination therapy is unavailable or unsuitable(2B).

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TABLE 6 Thalidomide combinations in relapsed myeloma.

|Study, year|Recruitment period (total n)|Arms|Median prior lines (range)|≥MR (%)|CR(%)|PFS(m)|OS(m)|Comments| |---|---|---|---|---|---|---|---|---| |OPTIMUM Kropff et al. Haematologica, 201266|Phase 3 2006-2009 (499)|T 100(121) vs. T 200(122) vs. T 400(130) vs. Dex(126)|1(1-3) 1(1-3) 25%|21% 2% 25%|3% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2% 2%||||

● Daratumumab should be administered by subcutane-ous injection(1A).

● Isatuximab is recommended in combination with o Pomalidomide and dexamethasone(1A)o Carfilzomib and dexamethasone(1A)

Anti-SLAMF7

Elotuzumab is a monoclonal antibody against signalling lymphocytic activation molecule F7(SLAMF7). The

addition of elotuzumab to lenalidomide and dexamethasone was associated with a modest improvement in response rates which translated into an improvement in PFS and OS.54,99-101 Elotuzumab has also been combined with pomalidomide where it may have additional impact, with significant improvements in response rates and PFS.102 The PFS uplift of adding elotuzumab to pomalidomide is similar to adding isatuximab to pomalidomide. It is a consideration for patients previously exposed to lenalidomide and an anti-CD38 monoclonal antibody. Elotuzumab is well tolerated with few side effects.

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TABLE 7 Pomalidomide combinations in relapsed myeloma.

|Study, year|Recruitment period (total n)|Arms|Median prior lines (range)|≥MR (%)|CR(%)|PFS(m)|OS(m)|Comments| |---|---|---|---|---|---|---|---|---| |MM-002 Richardson et al. Blood,201475|Phase 2 2009-201 (211)|Pom-low dose Dex vs. Pom|5(1-13)|33%|3% vs.2%|4.6 2.6 (HR 0.64) p<0.001|14.4 13.7 (HR 0.85) p=0.449|| |MM-003 (NIMBUS) Miguel et al. Lancet Oncol 2013^{73.86}|Phase 3 Open label 2011-2012 (455)|Pom-low dose dex dose|5(2-14) dex vs. high dose|≥PR: 31% ≥PR: 10%|1% vs. none 1.9 (HR 0.48) p<0.0001|12.7 8.1 (HR 0.74) p=0.0285|95% vs.92% len refractory and 79% vs.79% bort refractory at entry HRQoL data show benefit for Pom-LD Dex arm 8,88 ≥Gr3 infections:34% vs.33% ≥Gr 3 anaemia 33% vs.37%≥Gr 3 thrombocytopenia 22% vs.26%|| |STRATUS (MM-010) Dimopoulos et al. Blood,2016^{74}|Phase 3 2012-2014 (682)|Pom-Dex|5(2-18)|32.6% (=PR)|0.6%|4.6|11.9|All‘failed’len and bort| |IFM 2009-02 Leleu et al. Blood,2013^{89}|Phase 2 2009-2010(84)|Pom D1-21 vs. Pom D1-28|5 34|35 34|2 vs. 5 3.7 (HR 1.28) p=0.29|14.9 14.8 (HR 1.23) p=0.45|89% len and 81% bort refractory at entry ≥Gr 3 AE mainly myelosuppression in both groups 93% vs.85% NS|| |IFM-2010-02 Leleu et al. Blood,20159|Phase 2 2012-2013(50)|Pom Dex|3(2 to>3)|22%||12|All patients had t(4;14) or del 17p TTP:7.3m in del17p,2.8m in t(4;14)|| |Larocca et al. Blood,201391|Phase 1/2 2010-2012(57)|Pom-Cyclo- Pred|3(1-3)|51%|5%|10.4|1 year:69%|Pomalidomide naive patients| |Baz et al. Blood,2016^{78}|Phase 2 2011-2014(70)|Pom-Cyclo- Dexv. Pom-Dex|4(2-9) 4(2-12)|65 39|3 4.4 p=NS|16.8 NR (HR 0.54 adj) p=NS|Pom-naive patients Myelosuppression was more in Pom Cyclo Dex arm but not statistically significant|| |MUK Seven Croft et al. Blood,201879|Phase 2 2016-2018 (102)|Cyclo Pom Dex vs. Pom Dex|3(2-8) ≥PR:47|≥PR:69 0|9.8 vs. 0|6.9 vs. 4.6 p=NS|Closed early due to approval of pomalidomide by NICE in the UK|| |Cohen A et al. Br J Haematol, 20189^{72}|Phase 2 2018 (57)|Liposomal Doxorubicin- Pom-Dex|4(1-22)|49|7|5.4|Liposomal Doxorubicin 5mg/m2 All len-refractory|| |OPTIMISMM Richardson et al. Lancet Oncol, 201917|Phase 3 2013-2017 (559)|Pom Vel Dex vs. Vel Dex|2 2|82 50|≥VGPR:53% ≥VGPR:18%|11.2 vs.7.1 (HR 0.61) p<0.0001|≥Gr 3 Neutropenia 42% vs.9% PFS 22.01 vs.11.96m(1 prior line)||

Recommendation

● Elotuzumab in combination with dexamethasone and either lenalidomide or pomalidomide is recommended for the treatment of relapsed myloma(2A).

HISTONE DEACETYLASE INHIBITORS

Histone deacetylase inhibitors(HDACi) are epigenetic regulators which impact protein transcription. Vorinostat has been assessed in combination with bortezomib with no clinically meaningful improvement in survival being dem-onstrated.103 Panobinostat plus bortezomib demonstrated

<EndOfPara>responses in 34.5% of a bortezomib-refractory population. ${ }^{20}$ A phase 3 study assessed the addition of panobinostat to bortezomib and dexamethasone in patients not refractory to bortezomib. ${ }^{104,105}$ Panobinostat deepened and improved PFS by 6.1 months but not OS. Despite the longer PFS, time on treatment was shorter in the panobinostat group with 34%of patients in this arm discontinuing treatment due to ad-verse events, and >50% of patients requiring dose reduction of either bortezomib or panobinostat. Diarrhoea, fatigue,thrombocytopenia and neuropathy were common adverse events. A different trial combined this triplet with thalido-mide in patients mainly at first relapse, where treatment was better tolerated. ${ }^{106}$ The side effect profile can make this combination difficult to deliver, especially in the multiply relapsed setting and toxicities require careful management

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BOX 3 Immunomodulatory drugs-Key

● Teratogenicity

● Thromboembolism

● Cytopenias

● Rash

● Bile acid malabsorption (responds to bile acid sequestrants)

● Second primary malignancy(especially in combi-nation with melphalan)

● Thalidomide:

● Peripheral neuropathy(usually sensory)

and judicious dose reductions. A recent large randomised phase 2 trial compared the standard panobinostat dose with attenuated panobinostat regimens and identified that toxic-ity was reduced with attenuated dosing but at the expense of response rates.107 Important HDACi studies are summarised in Table 8.

Recommendation

● Panobinostat in combination with bortezomib and dexamethasone is recommended for the treatment of relapsed myeloma if other bortezomib-based triplet combinations are unavailable or unsuitable(2A).

● Adding thalidomide to this combination is a consider-ation(2B).

ALKYLATORS AND COMBINATION CHEMOTHERAPY IN RELAPSED MYELOMA

Alkylators such as melphalan and cyclophosphamide have been used to treat myeloma for over 50 years, although newer agents already discussed have to a large extent replaced alkyla-tors in many recently approved regimens. Consequently, some patients will have relatively limited exposure to alkylators and other DNA damaging agents. Many are inexpensive but are unlicensed and have not been subject to NICE or other Health Technology Appraisal reviews. Alkylator-based combinations involving'novel' agent backbones are predominantly discussed in the relevant section above. Due to the significant advances in anti-myeloma therapy over the last 20 years, Tables 9-11 below only summarise studies published from 2000 onwards to ensure relevance to current treatment pathways.

Alkylator-based regimens

Low-dose oral melphalan or cyclophosphamide were origi-nally evaluated in the newly diagnosed setting but are now

possible backbone agents in the relapsed setting. Continuous low-dose cyclophosphamide with prednisolone was not only effective(ORR 59.2%, median PFS 6months) but also well tolerated in RMM patients with severe cardiac failure.111 Interestingly,carfilzombim monotherapy showed no OS or PFS benefit over low-dose oral cyclophosphamide(alternate day dosing) in a heavily pretreated RMM population.110 Low-dose oral melphalan is sometimes used although recent data are limited. Intermediate-dose intravenous melphalan(50-70 mg/m2) resulted in ORR of 50% in vincristine-adriamycin-dexa-methasone(VAD) refractory myeloma with the key toxicity being myelopression.134

Intravenous bendamustine has been evaluated both with ste-roids alone119 and with either IMiDs or PIs. Bendamustine and IMiD combinations offer ORR of 47%-88% and median PFS of 7-22months with deeper and longer responses in less heavily treated populations.112-118 Toxicities were excessive with ben-damustine doses of 100mg/m2, and therefore, lower doses are needed for the regime to be deliverable.112-117 ORRs of 48%-69%are seen with bendamustine and bortezomib combinations with median PFS between 8 and 11 months.121,122 Irradiated blood products are needed for patients treated with bendamustine.

Anthracycline-based regimens

Intravenous doxorubicin (Adriamycin) formed the basis of VAD induction chemotherapy in the 1990s. Idarubicin, an oral alternative, may be equivalent to doxorubicin at front-line, and there are limited reports of responses using ida-rubicin and dexamethasone(Z-dex) in RMM.135 Idarubicin has been combined with interferon136 or with vincristine and dexamethasone in relapsed myeloma.123 Pegylated li-posomal daunorubicin126 alone or in combination with vincristine and thalidomide has been investigated124 but there is minimal use of this in the United Kingdom. A ran-domised phase 3 study of pegylated liposomal doxorubicin plus bortezomb compared with bortezomib monotherapy in RRMM improved median time to progression from 6.5 to 9.3 months with the combination.19 All anthracyclines cause dose-dependent myelosuppression particularly in heavily pretreated patients and are associated with potential cardiac toxicity, so caution needs to be exercised including attention to cumulative anthracycline exposure. While novel combi-nations are generally preferred, there remains a cohort of patients who may have never been exposed to anthracyclines and in patients with a good performance status and bone marrow reserve, anthracyclines may be considered if other options are not suitable or available.

Combination chemotherapy

Multi-agent combination chemotherapy generally refers to combinations of alkylators with anthracyclines and other DNA damaging drugs, sometimes alongside‘novel’ agents.Etoposide, methylprednisolone, cytarabine and cisplatin

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TABLE 8 Histone deacetylase inhibitors in relapsed myeloma.

|Study,Year|Recruitment period (total n)|Arms|Median prior lines(range)|ORR (%)|CR(%)|PFS(m)|OS(m)|Comments| |---|---|---|---|---|---|---|---|---| |PANORAMA1|Phase 3|Pano-VD vs.|60.7|11|12.0|40.3|No statistically significant difference in OS|| |San Miguel et al. Lancet Oncol,2016|2010-2012 (768)|VD||54.6|6|8.1(HR|35.8|in OS time on treatment was shorter on pano due to AEs| |PANORAMA2|Phase 2|Pano-Vd|4(2-11)|34.5|0|5.4|NR|Bortezomib refractory| |Richardson et al. Blood,2013|2010-2011 (55)|||||||| |PANORAMA3|Randomised Phase 2|Pano-20(3/|2(1-2)|62.2|5|NR|NR|Subcutaneous V Higher response rates with 20 mg doses.| |Laubach et al. Lancet Oncol 202107|2016-2019 (248)|week)VD vs. Pano-20(2/ week)VD vs. Pano-10(3/ week)VD||65.4 50.6|6|||Fewer side effects with 10 mg dose.| |MUK6|Phase1/2|||||||| |Popat et al. Lancet Haem,2016|2013-2014 (67)|Pano-VTD|1|91.3|6.5|15.6||| |Kaufman et al. Blood Cancer J,2019|Phase 1/2 2012-2015 (32)|Pano-KD|4(1-8)|57|7|8|23|K36mg/m2| |Chari et al. Blood Adv,2017109|Phase 2 (27)|Pano-RD|3(1-10)|41|7|7|NR|| |VANTAGE 088 Dimopoulos et al. Lancet Oncol,2013103|Phase 3 2008-2009 (637)|Vori-V vs. Placebo-V|2(1-3)|56.2 40.6|7.9 5.3|7.63 6.83|NR 28.1|No clinically meaningful improvement in PFS No statistically significant difference in OS|

(ESHAP) was assessed in a retrospective single-centre study of 32 relapsed and refractory myeloma patients with a 67% ORR and successful ASCT in 38/42. OS at 4 years was 62%. Significant haematological and renal toxicity was seen. ${}^{127}$ Retrospective analysis of DCEP, VTD-PACE or CVAD in RMM favoured VTD-PACE for ORR, but CVAD for PFS. ${}^{128}$ This study included a high proportion of bortezomib- and lenalidomide-refractory patients. A greater proportion of VTD-PACE-treated patients had re-ceived prior infusional chemotherapy so were potentially a more refractory group.

Four studies using PACE-based regimens all demon-strated an improvement in PFS and OS in those who went on to receive ASCT or clinical trial compared with no con-solidation(Table 11). ${}^{129-131,133}$ Modified PACE-based regi-mens may need to be used depending on prior toxicities.For example, cisplatin may warrant omission or substi-tution with carboplatin in renal impairment, and doxo-rubicin can be omitted if cardiac dysfunction is present.Cisplatin, bortezomib and thalidomide may need dose re-duction or omission in those with pre-existent significant peripheral neuropathy as all are recognised to potential exacerbate this.

Other multiagent regimens(summarised in Table 11)have been used, but there is limited experience of these regimens or of comparability to current treatment approaches.

Conclusions

Alkylator and/or anthracycline combinations are deliver-able, inexpensive and offer another potential treatment option after established therapies. Multi-agent chemo-therapy also has a potential role with evidence of dura-ble treatment responses even in those refractory to newer agents. Toxicities(e.g. myelotoxicity) are high and careful patient selection and/or dose modification may help limit these. If consolidation is not an option, then less intensive regimens may be more suitable given the relatively short duration of responses with multiagent chemotherapy alone. There remains an evidence gap to assess many of these conventional therapies more formally against newer agents, and clinical trials to help establish the role for these agents would be invaluable.

Recommendations

● Consider alkylator-based chemotherapy(cyclophos-phamide, melphalan or bendamustine) in combination with corticosteroids and IMiDs or proteasome inhibi-tors with appropriate dose modifications for myelosup-pression(2B).

● Consider idarubicin-based combinations as an oral op-tion if other non-anthracycline combinations are not available or suitable(2C).

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TABLE 9 Alkylator-based regimens in relapsed myeloma.

|Study, year|Recruitment period(total n)|Arms|Median prior lines (range)|ORR(%)|CR(%)|PFS(m)|OS(m)|Comments| |---|---|---|---|---|---|---|---|---| |FOCUS|Randomised|Carfilzomib vs.|5(3-17)|19.1|3.7|10.2|≥Gr 3 toxicities similar|| |Hajek et al. Leukemia,2017110|phase 3 (315)|Cyclophosphamide + prednisolone||11.4|3.3 (ns)|10.0 (ns)|except renal failure greater in carfilzomib group and pneumonia greater in cyclo pred group|| |Zhou et al. Leuk Lymph, 2014111|Retrospective (54)|Cyclophosphamide + prednisolone||59.2|6|8|Relapsed refractory with severe cardiac failure|| |Beck et al. J Cancer Res Clin Onc,2017112|Phase 2 single arm (25)|Benda Len vsPred|1(1-2)|88 (VGPR: 36.4,PR: 36.4)|sCR/ nCR 27.3|22|38|Dose reduction required in most due to haematological toxicity| |Mey et al. Brit J Haematol 2017113|Phase 2 single arm (50)|Benda Len Dex6 then len x12|1|88.9|VGPR/ CR 51.1|18.6 CR 51.1|1-year OS 89 2-year OS 76|Median age 68.5(46-83) ≥Gr 3 neutropenia 74% (despite Peg-GCSF) ≥Gr 3 thrombocytopenia 38% ≥Gr 3 anaemia 20%| |Pozzi et al. Leuk Lymph, 2017114|Phase 1/2 (38)|Benda Len Dex|RRMM|47|10|2-year OS 65|2-year OS 65|2Gr 3 anaemia 20%| |Kumar et al. Am J Haematol, 2015115|Phase 1/2 (71)|Benda Len Dex|4(1-4)|49|VGPR/ CR 29|11.8|1-year OS 72|≥Gr 3 toxicity seen in 96% ≥Gr 3 haem tox in 97% ≥Gr 3 non-haem 51%| |Ponisch et al. Br J Haematol 2013116|Phase 1|Benda Len Dex|2(1-2)|76||18m PFS 48%|18 mo OS 64|| |Schey et al. Br J Haematol, 2015117|Randomised phase 2 (94)|Benda 100 Td vs. benda 60 Td|3(1-5)|46.3|7.5|Not reported|Not reported|Bendamustine 100 mg/ m2 not deliverable because of toxicity| |Ponisch et al. Br J Haematol, 2008118|Phase 2 (28)|Benda Thal Pred|2(1-6)|86|14|11|18|OS 32m vs.16m if no prior ASCT vs. prior ASCT(p=0.03)| |Stohr et al. J Cancer Res Clin Oncol,2015119|Retrospective (58)|Bendamustine +/- steroids|4(1-10)|20|7|17||| |Ludwig et al. Blood 2014120|Phase 2|Benda Vd(79)|2(1-6)|60.8|9.6|25.6||| |Ponisch et al. J Cancer Res Clin Oncol 2013121|Phase 2|Benda Vel Dex(Dze) 78|2(1-9)|69|VGPR/ CR 43|11 vs. 3 with prior haem toxicities|50 vs. 5 with prior haem toxicities|Comparison made between those that had grade 3 or 4 thrombocytopenia and/or neutropenia at baseline or not| |Berenson et al. Br J Haematol 2013122|Phase 2|Bendamustine Vel (40)|1-3:25% 4-6:33% >6:43%|48|7.1|8.4|13.3|No dexamethasone| |OSHO-077 Beck et al. J Cancer Res Clin Oncol,2017112|Phase 2 2011-2013 (25)|R-Benda-Pred|1(1-2)|88|4|22|38|Most patients needed dose reduction| |Mey et al. Br J Haematol. 2017113|Phase 2 2012-2014 (50)|R-Benda-Dex|1(1)|93|7|18.6|NR. 2 years:76|≥Gr 3 neutropenia:74% (despite Peg-G-CSF), thrombocytopenia 38%,anaemia 20%| |Kumar et al. Am J Hematol, 2015115|Phase 2 2010-2012 (50)|R-Benda-Dex|3(1-4)|55|4|11.8|NR: 1 year:72|≥Gr 3 toxicity seen in 96% ≥Gr 3 haem tox in 97% ≥Gr 3 non-haem 51%|

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TABLE 10 Anthracycline-based regimens in relapsed myeloma.

|Study, year|Recruitment period (total n)|Arms|Median prior lines(range)|ORR(%)|PFS(m)|OS(m)|Comments| |---|---|---|---|---|---|---|---| |Glasmacher et al. Haematologica, 2004123|Phase 2 (46)|Vincristine, idarubicin, dexamethasone|Refractory|35|Not reported|21months|Gr 4 leucopenia 10.8%9/46 refractory to prior ASCT| |Hussein et al. Oncologist, 2003124|Pilot Aug 2001-Oct 2003 (35)|Pegylated liposomal Doxorubicin- Vincristiine-TD|74(CR:8.6, VGPR:37.1)|NR|NR|Gr 3 neutropenia: 90%|| |Hussein et al. Mayo Clin Proc, 2006125|Phase 2 (49)|Pegylated liposomal Doxorubicin- Vincristine-TD|90|14||Gr≥3 VTE 25% Gr≥3 PN 22% Gr≥3 neutropenia|| |Mohrbacher Cancer 2002126|Phase 2 (37)|Liposomal daunorubicin, dexamethasone|NR|17.1|NR|7.6|Gr≥3 neutropenia 26%| |Orlowski et al. JCO,200719|Randomised Phase 3 (646)|Pegylated liposomal doxorubicin- bortezomib vs. bortezomib|44 41|TTP: 9.3 6.5|NR|NR|GR3/4 AEs higher in combination group|

TABLE 11 Multi-agent combinations in relapsed myeloma.

|Study, year|Recruitment period (total n)|Arms|Median prior lines(range)|ORR(%)|CR(%)|PFS(m)|OS(m)|Comments| |---|---|---|---|---|---|---|---|---| |D'Sa et al. Br J Haem,2004127|Retrospective, single centre (42)|ESHAP(42)|1|67|Not reported|4 year OS 62%|4 year OS 38/42 proceeded to ASCT|38/42 proceeded to ASCT| |Griffin et al. Cancer,2015128|Retrospective, single centre (107)|DCEP(52) VTD-PACE (22) CVAD(33)|3|53 73 48|8 9 4 0|3.8 5.4 5.8 13.1*|8.9 8.5 8.2|77% bortezomib refractory 66% lenalidomide refractory * If followed by ASCT| |Gerrie et al. BJH,2013129|Retrospective dual centre (75)|D(T)PACE|3(1-12)|49 (VGPR: 16)|5.6 13.4*|14.0 20.5*|*If followed by ASCT or a clinical trial.|| |Lakshman et al. AJH,2017130|Retrospective single centre|VTd-PACE (95) Vd-PACE(20) VLPR(26)|4(1-14)|54 (VGPR: 10.3)|3.1|Overall:8.1 15.1*|Non-randomised 8.1 *If followed by ASCT|Non-randomised as:IF followed by ASCT| |Srikanth et al. Eu J Haem,2008131|Retrospective single centre (26)|DT-PACE|2(0-5) Blastoid and extramedullary|58|6 5|ASCT:10 No ASCT: 3|7 ASCT:10 No ASCT: 7|Non-randomised| |Giles et al. Am J Hematol, 2000132|Phase II (36)|CEVAD||42||Not reported|24 weeks|Not more effective than VAD| |Djebbari et al. Eur J Haematol, 2020133|Retrospective multi-centre (59)|D-PACE|2(1-4)|NR|NR|TTNT 14.2|15.1|Longer TTNT if followed by ASCT (12.8 vs.2.7m)|

Abbreviations:CEVAD,cyclophosphamide-etoposide-vincristine-doxorubicin-dexamethasone;CVAD,cyclophosphamide-doxorubicin-dexamethasone;DCEP,dexamethasone-cyclophosphamide-etoposide-cisplatin;ESHAP,etoposide-cytarabine-cisplatin-methylprednisolone; VLPR, VTD-PACE-like regimens; VTD-PACE, bortezomib-thalidomide-dexamethasone-cisplatin-doxorubicin-cyclophosphamide-etoposide.

● Consider multiagent infusional chemotherapy in pa-tients refractory to immunomodulatory drugs and pro-teasome inhibitors(2C).

● Response duration to multiagent infusional chemother-apy is likely to be short so aim to offer consolidation with ASCT or another form of therapy(2C).

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● Toxicity,especially haematological, is high with multia-gent chemotherapy and careful patient selection should take place to assess the suitability of different treatment approaches(2D).

THE ROLE OF AUTOLOGOUS STEM CELL TRANSPLANTATION IN RELAPSED MYELOMA

In relapsed myeloma, autologous stem cell transplant(ASCT) has two main roles-in those who elected not to have an up-front autologous stem cell transplant at first re-sponse(deferred ASCT) and those who have relapsed having had a prior ASCT(second ASCT or ASCT2).

Deferred ASCT was assessed in the IFM2009 trial. All patients received VRD induction and underwent autolo-gous stem cell harvest but were randomised to receive VRD consolidation or ASCT. Both arms received lenalidomide maintenance for 1 year. PFS was 50 months in the ASCT arm and 36 months in the VRD arm; however, overall survival at 4 years was 81% and 82% respectively. 136/172 patients(79%)in the VRD arm received salvage ASCT.137 This trial sug-gests that deferred ASCT at time of progression is feasible in most patients and does not impact on OS, although the shorter PFS warrants consideration.

Second autologous stem cell transplant(ASCT2) is defined here as ASCT delivered as a component of relapse therapy in those who previously received ASCT at first line. It does not include tandem ASCT. The majority of evidence to support ASCT2 derives from non-randomised single- or multicentre series or retrospective analyses of registry data138-140 except two randomised studies. Myeloma X demonstrated a clear benefit of ASCT2 compared with cyclophosphamide consol-idation in terms of both time to next treatment(TNTT) and OS.141,142 This study reported failure to mobilise sufficient stem cells in second remission in 30/110 patients, emphasis-ing the importance of stem cell collection sufficient for two transplants before the first ASCT.143 The GMMG phase III trial ReLAPSE evaluated the role of ASCT followed by lenalid-omide maintenance compared with continuous lenalidomide and dexamethasone. While the primary end-points were not met, multivariate landmark analysis from the time of ASCT2 showed superior PFS and OS in those who received ASCT2 in the primary analysis.144 However, an updated analysis with ex-tended follow-up failed to show a PFS or OS difference either in the intent to treat group or in a post hoc landmark analy-sis of those who actually received ASCT2. It is important to note, however, that this study was not powered for the land-mark analysis, and lenalidomide and dexamethasone are not a current standard of care reinduction regimen with or without ASCT2 consolidation.145

The UKMRA Myeloma XII trial evaluated the role of con-solidation with ixazomib, thalidomide and dexamethasone followed by ixazomib maintenance following ASCT2. While this study was not designed to evaluate the impact of the ASCT2, the study demonstrated a PFS in the consolidation/

maintenance arm of 20months from randomisation and 30 months from initiation of post-relapse therapy, indicating that with an effective post-transplant strategy, long dura-tions of response can be achieved.146

Conditioning regimens varied among reported studies spanning two decades with a preference towards melphalan 200 mg/m2. Melphalan 100 mg/m2 showed inferior out-comes.147,148 Standard practice is to offer melphalan 200 mg/m2 subject to performance status, renal function and other co-morbidities.

Reported transplant-related mortality at day 100(TRM),ORR, PFS and OS are all highly variable reflecting improve-ments in supportive measures and pre-transplant reinduc-tion over a wide time frame(see Table 12). The median PFS after first-line therapy in these studies was 6-64.6 months,indicating a highly heterogeneous pre-transplant popula-tion. In the only randomised study, PFS after ASCT2 was 24 months in patients whose median PFS at first line was≥24months compared with 13 months if median PFS at first line was 24 months or less.141

Positive predictors of outcome after ASCT2 were PFS1>18months or TTNT>18months post ASCT1, achievement of very good partial response or better(≥VGPR) after reinduc-tion, fewer prior therapies, low International Staging System(ISS) at stage relapse, younger age and lack of high-risk cyto-genetics at relapse.140,142,153,164 Importantly, these studies did not include patients who had relapsed on lenalidomide main-tenance post-ASCT1. Given that maintenance significantly improves PFS1, the decision on whether or not to proceed with ASCT2 based on duration of response in patients relapsing on lenalidomide maintenance following ASCT1 is not clear cut;however, the benefit is likely to be greater in those with a lon-ger duration of response following ASCT1. A multicentre ret-rospective study showed ASCT2 was superior to conventional and novel agents.140 However, both this study and Myeloma X were undertaken prior to the currently available relapse options which include continuous therapy at relapse without ASCT2. The impact of maintenance post-ASCT2 is currently unknown and is being addressed in a randomised study by Cook et al.(Myeloma XII).140,142

The evidence base for salvage ASCT2 beyond second line and ASCT1 beyond first remission is limited. A care-ful assessment of suitability based on performance status,co-morbidities, prior treatments and consideration of the alternative non-transplant options should be made prior to therapy.

There are now other potential roles for second or salvage autologous stem cell transplant in either heavily pretreated patients with poor marrow reserve or in conjunction with CAR-T cell therapy and poor blood count recovery. Data are limited to case series,170 but this may have a larger role to play in the future if CAR-T-cell therapy becomes more standard.

Recommendations

● Do not offer ASCT2 to patients with PFS1 of<12 months(1A).

JENNER ET AL.

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 18

TABLE 12 (Continued)

|T. Continued 12 (Continued)||||||||||||| |---|---|---|---|---|---|---|---|---|---|---|---|---| |First author, journal and year of publication|Study design recruitment|Arms(n)|PFS 1(m)|Re-induction|HDT|Maintenance|ORR (>VGPR) %|TRM % at m|PFS2(m)|OS(m)|Favourable prognostic factor for PFS|Favourable prognostic factor for OS| |Rondon BBMT poster 201258|Retrorespective Abstract 1995-2011|N=60|32|Chemo|MEL100 MEL200|47%|77(NR)|NR|11.2|24|None|| |Jimenez-Zepeda BBMT 2012159|Retroresive Single centre 1992-2009|All patients n=81 PFS1<24 m PFS1>24m PFS1<36m|39 N|Mixed|MEL200 MEL140|None|97(47.4)|2.6 (100 days)|16.4 9.8 (100 days)|53 28.5 (17.3 21.2|TTP post ASCT1>24m ≥VGPR post ASCT2|TTP post ASCT1 ≥VGPR post ASCT2| |Michaelis BBMT 2013138|Retrorespective IBMTR registry 1995-2008|All patients n=187 PFS1<36months(131) PFS1≥36m(36)|32|||None 70%|74(25)|4 (60m)|11.2 (60m)|30 25 48|PFS1>36m|PFS1>36m| |Yhim|Retrorespective 1998-2010|All patients (192) ASCT2(48)|12 (1.1-83.8)|73% novel|MEL200MEL140||90(55)|2|11.4 (100 days)|35.4 18|PFS>18m negative high risk|PFS1>18m ISS<3| |BMT 201360|Comparative High risk Vs Low risk|Chemotherapy (144) ASCT2 PFS1≤18m (32) ChemoPFS1<18m (110) ASCT2 PFS1>18m (16) Chemo PFS1>18m|ASCT2 PFS1≤18m ChemoPFS1<18m (16) Chemo PFS1>18m|(1.1-83.8)|||94(57)|9.1 (100 days)|13 6.4 (48.1 48.1 (100 days)|49.9 17.2 48.1 (100 days)||Received ASCT2| |Lemieux BBMT 201361|Retrorespective 1996-2009|N=81|47|Novel/ chemo|MEL220 MEL200 MEL140 MEL+BU|37%|93(67)|0 (100 days)|18 18|48|PFS1>24m ≥VGPR post re-induction Maintenance|Age<60years ≥VGPR post PFS1>24m| |Auner Leuk lymph 201362|Retrorespective Single centre 1994-2011|All patients n=83 PFS1<21.5m(36) PFS1>21.5m(42) >PR(16) PR(41) 35.4 Chemo/ novel MEL200 MEL<200 None 69(19) 7 (100 days) 15.5 RR1 RR0.51 RR1 RR0.83 RR2.65 31.5 PFS1>21.5m ≥PR post re-induction ≥PR post re-induction|35.4|Chemo/ novel|MEL200 MEL<200|None|69(19)|7 (100 days)|15.5 RR1 RR0.51 RR1 RR0.83 RR2.65|31.5|PFS1>21.5m ≥PR post re-induction|≥PR post re-induction| |Wirk J Clin Med Res 2013163|Retrorespective Single Centre 1995-2011|N=27 PFS1<12m(6) PFS1>12m(21)||Chemo|44%|40(NR)|3.7 (100 days)|5 Not reached|15 15|40 (100 days)|15 Not reached|| |Chow Internal Medicine 2013164|Retrorespective Single centre PFS1<36m(5) 1992-2011|All patients n=30 PFS1<36m(3) PFS1 18-36m(13) PFS1>36m(12)|31.2|Chemo/ novel|MEL200 MEL<200 MEL200+BOR MEL+BU|Novel 200+BOR MEL200+BOR MEL+BU|80(60)|3 (100 days)|22 4.2 (100 days)|45 10.7 13.8 49.1|PFS1>18m PFS1>36m|Low ISS PFS1>18m PFS1>36m| |Sellner Cancer 201365|Retrorespective Single centre 1995-2010|All patients N=200 PFS1<12m(19) PFS1 12-18m(34) PFS1>18m(147)|64.6|Novel|MEL200 MEL140 MEL100|36.5% 36.5%|80(22)|3 (100 days)|15.2 (100 days)|42.3 (7.2 15.8|PFS1>18m Novel reinduction Response to reinduction ISSI|PFS1>18m Novel reinduction Response to reinduction ISSI|

TABLE 12 (Continued)

|Tert.44|Tert.44|Tert.44|Tert.44|Tert.44|Tert.44|Tert.44|Tert.44|Tert.44|Tert.44|Tert.44||| |---|---|---|---|---|---|---|---|---|---|---|---|---| |First author, journal journal recruitment||||||||||||| ||Study design||||HDT|Maintenance|ORR (>VGPR)%|TRM% at m|PFS2(m)|OS(m)|Favourable prognostic factor for PFS|Favourable prognostic factor for OS| |gonsalves|Retrospective|All patients n=98|46|Novel|MEL200|20% novel|86(84)|4|10.3|33|TTP>12m|TTP post| |BMT 201366|Single centre 2001-2011|TTP post ASCT1<12m TTP post ASCT1≥12m PFS1<18m|||MEL140|MEL200|20% novel|86(84)|4 (100 days)|5 11.5 7.1|12.6 41.6 19.4|Prior lines of therapy DoR post ASCT2 PCLI| |Cook|Phase 3|ASCT2 PFS1>18m|||PAD|MEL200 vs.|None|83(60)|1|19|67|| |Lancet Oncol|Randomised PFS1=TTNT Comparative|(89) ASCT2 PFS1<24m (25)|||Oral cyclo||75(47)|(100 days)|13 13|35||ASCT1>18m and 24m| |Haematol 2016142|2008-2012 Myeloma X|ASCT2 PFS1>24m (64) No ASCT2 PFS1>18m (85) No ASCT2 PFS1<24m (21) No ASCT2 PFS1>24m (64)|||||||9 11|||| |Abbi|Retrospective|All patients n=75|7.5|Novel|MEL200|50%|82(32)|5.3|10.1|22.7|Chemosensitive relapse Low risk cytogenetics TTP post|Chemosensitive relapse Low risk cytogenetics TTP post| |New York (US)167|1995-2012|PFS1<18m PFS1≥18m|||MEL140|MEL100|||||ASCT1≥12m|ASCT1≥12m| |Tremblay|Retrospective|N=74|53||MEL100|24%|68(38)|4 (100 days)|6.1|19.3|Chemosensitive disease PFS1>24m Low molecular risk|MEL200 Low molecular risk| |BMT168|Single centre 1998-2016||||MEL140|||||||| |Groval|Comparative|Salvage ASCT(111)|28.8|Novel/CC|Not reported|92(NR)|Not|28.8|48|Note median||| |BMT 2015140|Retrospective Multicentre 2000-2013|Noveld drugs (362) Conventional chemo (91)|27.6 25.2|CC||62(NR) 28(NR)|reported|14.4|39.6 7.2|PFS1>24months in all groups|age,Higher Hb|| |Muta Acta|Retrospective/ Registry (TRUMP2) Comparative 2000-2014|All patients (466) sASCT(70) ASCT1 to relapse <12m(23) ASCT1 to relapse >12m<24m(47) ASCT1 to relapse >24m no sASCT(n=376)|7 (4.3-115.5)|MEL200 MEL140||75.7(NR) (100 days)|1.4 (100 days)|HR 0.66 HR 0.75 HR 0.62|36.9 41.1 HR 0.62|Relapse after ASCT1>12m|Good ECOG Normal Renal function Responsive disease PFS1>24m|HiBaem|

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Favourable favourable factor for OS Non-high-risk pyrognetics favourable factor for PS Non-high-risk cyogenetics favourable factor for PSS 57 NPR 67.1 Non-high-risk cyogenetics Non-high-risk cyogenetics for PS 57 NPR 67.1 Non-high-risk cyogenetics NPR 67.1 Non-high-risk cyogenetics PSS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(m)Non-high-risk PS(

● Consider ASCT2 in suitable patients who achieve≥PR and who had TTNT after ASCT1≥18months and have not had maintenance post-ASCT1(1A).

● The decision regarding ASCT2 for other groups should take into account PFS1, whether maintenance was given following ASCT1 and the availability of alternative therapies and post-transplant strategies(2D).

● Consider collecting sufficient stem cells for two trans-plants prior to ASCT1(1C).

● Melphalan 200 mg/m2 is recommended as standard conditioning regimen with dose reduction as indicated(e.g. for renal impairment)(1C).

THE ROLE OF ALLOGENEIC STEM CELL TRANSPLANT IN RELAPSED MYELOMA

Allogeneic stem cell transplant(Allo-SCT) has the potential for sustained immune-mediated disease control. High non-relapse mortality(NRM) with myeloablative conditioning led to the introduction of reduced intensity conditioning(RIC) in MM in the late 1990s. The studies of allo-SCT in relapsed MM encompass a wide time span(see Table 13), and the majority of patients included had not had access to novel agents. Most studies are single-centre retrospective analyses,and the majority are not randomised; many include a combi-nation of up-front and relapse cases. Patriarca et al.included a biological allocation based on donor availability and an in-tention to treat analysis.171

Reporting of outcomes after Allo-SCT(see Table 13) is less standardised than in other areas of the myeloma litera-ture. Reported non-relapse mortality(NRM) varies widely:100 days(11%-23%), 1 year(8.4%-43%) and 3 years(14%).Long-term morbidity also needs to be considered in the de-cision process, with reported≥grade 2 chronic graft versus host disease(cGvHD) ranging from 24% to 48%.

Long-term outcome data are conflicting. Despite NRM of 22% at 20 years, Patriarca et al. do show an advantage for allo-SCT in RMM versus ASCT2, with follow-up of 7 years.171 Conversely, non-randomised registry data of allo-SCT demonstrated higher NRM and lower survival than ASCT2.175 Patients with active disease at time of allo-SCT have worse outcomes,177 and cytoreduction with ASCT2 prior to Allo-SCT is used by some.178 There are no robust data to show superiority of Allo-SCT over alternative ther-apies in any cytogenetically defined risk group. European Blood and Marrow Transplant(EBMT) registry data suggest cytomegalovirus(CMV) seronegativity of both patient and donor,<2 prior ASCT, longer time from ASCT1 and patient-donor gender mismatch are associated with significantly better outcomes.174

Drawing robust conclusions from this heterogeneous dataset is not possible. All the above should be taken into account when discussing with the patient whether or not to consider allo-ASCT, as well as prior therapies received and the availability of non-transplant treatment options.

TABLE 13 Allogeneic stem cell transplant in relapsed myeloma.

|First author, journal year of publication|Study design recruitment period|Arms(n)|PFS1 m|Conditioning|ORR% (>VGPR%)(period)|RM or TRM % (period)|Acute GvHD gr 2-4|Chronic GvHD grade Relapse Comm: Favourable risk||||||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---| |First author, journal year of publication|Study design recruitment period|Arms(n)|PFS1 m|Conditioning|ORR% (>VGPR%)(period)|RM or TRM % (period)|Acute GvHD gr 2-4|ORR%|NRM or TRM % (period)|Acute GvHD gr 2-4|PFS2|OS||| |Lee BMT 2002149|Retrospective 1992-96|sASCT(42) sAlloSCT(42)|6m 7m|MEL20 MEL+CY|81(33)|10(12m) 43(12m)|NA|NA|12.5m|32m|72%|||| |Qazilbash Cancer 2006151|Retrospective 1992-2004|sASCT(14) RIC Allo SCT(26)|25m 17m|MEL20 MEL140+BTI FLU MEL ATG|64(21) 69(31)|7(100days) 11(100days)|NA 31%|NA 42%(23%)|6.8m 7.3m|29m 13m||PFS1>12m|favourable|| |de Lavallade BMT 200872|Retrospective 2002-2004|sAllo SCT (19) No donor(13)|FLU BU ATG, FLU low dose TBI (sibling)|61(NR)|33(100days)|33%|57%|46% at 36m 8% at 36m|50% at 36m 49% at 36m|||||| |Kroger BJ Haem 2010173|Prospective Multicentre 2002-2007|RIC Allo SCT (49)|FLU MEL ATG|54(46)|25%(12m)|25%|35%|10.6m|22.6m|27% at 12m 55% at 36m|Achievement CR|||| |Wirk J Clin Med Res 2013163|Retrospective Single centre 1995-2011|sASCT(27) Allo SCT (3) RIC Allo(16)|30m 21m|MEL200 BU-CY BU CY Eltoposide FLU+CY+TBI FLU+BU/ MEL+ATG|82(56) 58(37)|3.7%(36m) 5.3%(36m)|NA 36%|NA 26%|19m 6m|23m 19m|88% at 36m 91% at 36m|PFS1>12m Maintenance after sASCT2||| |Auner BMT 2013174|Retrospective EBMBTR 1999-2008|RIC Allo SCT (413)|31.2m|FLU-based RIC regime|63.3(NR)|21.5%(12m)|33%|26.7%|9.6m|24.7m|CMV status, longer PFS1, gender mismatch|||| |Freytes BMT 2014175|Retrospective CIBMT R 1995-2008|sASCT(137) RIC Allo SCT (152)|17m 12m|MEL200 FLU-based RIC Low-dose TBI/ MEL|NR 13%|2%(12m) 13%|NA 35%|NA 44%|12% at 36m 44%|46% at 36m 20% at 36m|ECOG and longer PFS1|||| |Patriarca BBMT 2012176|Retrospective Multicentre 2002-2008|No donor(94) RIC Allo SCT (68)|MEL200/novel agents FLU-based regime ATG in MUD|61(29) 80(33)|1%(24m) 22%(24m)|NA 41%|NA 39%|18% at 42% at 24m|53% at 24m 54% at 24m|||||| |Patriarca BBMT 2018171|Retrospective Multicentre 2002-2008|No donor(90) RIC AlloSCT (72)|16m 16m|As above|59(26) 81(38)|NR 27%(60m)|NA 33%|NA 65%|0% at 7years 18% at 7 years|9% at 7 years 31% at 7 years||||| |Greil Haematologica 2019177|Retrospective Single centre 2000-2016|RIC Allo SCT (63)|17.3m|FLU-based RIC regime|70(26) 12.4(120m)|8.4(12m) 12.4(120m)|25%|24%|14.2m|39.2% 72m 26.1% 120m|33.6% 12m 67.6120m|Responsive disease|||

Abbreviations:GvHD,graft-versus-host disease;NA,not applicable;NR,not reported;NRM,non-relapse mortality;TRM,transplant-related mortality.

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Recommendations

● There is insufficient evidence to routinely recommend allogeneic stem cell transplant at relapse or to define the patient population in which it should be considered(2C).

IMMUNOTHERAPIES

There is an increasing range of technologies used to treat my-elioma. It is not possible to discuss these exhaustively, rather we focus on those approaches for which there is significant published data, and which have or are soon likely to receive licences. These immunotherapies harness the immune sys-tem in novel ways, either using antibody-drug conjugates to directly deliver a cytotoxic drug to the plasma cell, or with the use of genetically reprogrammed or unmanipulated T cells, the latter being actively harnessed using bispecific an-tibodies. In all cases, targets on the surface of the myeloma plasma cell are utilised. We consider these treatments by mode of action in the section below.

BCMA targeted therapy

Many new therapies target B-cell maturation antigen(BCMA), a member of the tumour necrosis factor(TNF) re-ceptor superfamily expressed on plasma cells and myeloma cells.

Antibody-drug conjugate

Belantamab mafodotin is a monoclonal antibody-drug conjugate which binds to BCMA on the surface of plasma cells and internalises a cytotoxic drug. A phase 2 study,carried out on patients refractory to an IMiD, PI and anti-CD38 therapy at a median of eight lines of therapy, showed a 32% response rate at the dose of 2.5 mg/kg that has been taken forwards into phase 3 studies.179,180 Median PFS was 2.8 months with a median duration of response of 11 months and OS 13.7 months.

Belantabam was initially licensed as monotherapy at this dosing schedule for multiply relapsed patients based on these phase 2 trial results. However, it was withdrawn when the phase 3 randomised trial, while proving significant efficacy,failed to show superiority of PFS when comparing belan-tamab monotherapy to the pomalidomide/dexamethasone combination. 181

Studies combining belantamab with other standard therapies have shown favourable results. Belantamab in combination with bortezomb and dexamethasone has shown superiority when compared to daratumumab, bor-tezombib and dexamethasone(median PFS 36.6months vs. 13.4 months at a median follow-up of 28.2 months).

Similarly positive results were seen in a phase 3 trial com-bining belantamab with pomalidomide and dexamethasone compared with pomalidomide and dexamethasone alone(median PFS not reached vs. 12.7 months at a median fol-low-up of 21.8 months, HR 0.52 p<0.001).183 It is notable that the dosing strategy with belantamab differed in these trials,being 2.5 mg/kg every 21 days in combination with bortezo-mib and 2.5 mg/kg every 28 days, reducing to 1.9 mg/kg from cycle 2, when combined with pomalidomide. The main side effect identified in these trials is ocular toxicity, specifically punctate keratopathy. Despite the reduced dosing strategy in the pomalidomide combination trial, ocular toxicity was experienced by 89% of patients receiving belantamab, in-cluding 43% grade>3 events. This side effect requires care-ful monitoring and management with reductions in dose or frequency.184 Ocular toxicities usually fully resolve over the course of weeks. Other trials are evaluating alternative dos-ing strategies with dosing up to every 8 weeks.

T-cell engagers

T-cell engagers(TCEs) are antibodies that bind to a tumour antigen and CD3 to engage T cells. They have the advantage over chimeric antigen receptor T-cell(CAR-T) therapy of being available without the delay of a manufacturing pro-cess, which can be important in RMM where relapse kinet-ics are often faster. In a phase 1-2 study of 165 patients who had received a median of five prior lines of therapy, the anti-BCMA TCE teclistamab, administered on a weekly basis by subcutaneous injection, produced an ORR of 63% and MRD-negative rate of 26.7%. Cytokine release syndrome(CRS) was manageable, being mainly Grade 1-2, occurred in 72.1% but was very rarely high grade(grade 3 0.6%).Similarly, immune effector cell-associated neurotoxicity syndrome(ICANS) was only reported in 14.5% of patients and was all grade 1 or 2.185

Elranatamab is another BCMA-targeted TCE that was initially evaluated in a phase 1 trial in which 88 RRMM patients with a median of five prior regimens were treated.ORR was 63.6% with 38.2% achieving CR. For 55 patients at efficacious doses, median PFS was 11.8months and OS 21.2 months.186 The phase 2 study evaluated 123 patients with an ORR of 61.0% including 35% CR. Median PFS was 17.2 months with median OS not reached. Responses in re-sponding patients are extremely durable in the context of this patient population, with 67% of responding patients maintaining their response at 24 months.187 CRS rate was 57.7%(zero grade 3/4) and neutropenia 48.8%. Similar to te-clistamab, dosing is initially weekly then reducing to an al-ternate week dosing schedule for responders after six cycles,which is the basis for the licensed schedule.188

Linvoseltamab was the third anti-BCMA TCE to be devel-oped. The phase 2 study trialled this TCE at 50 and 200 mg doses in patients progressing after≥3 lines of therapy, with a median of five prior lines. The dosing schedule was less intensive than Teclistamab or Elranatamab, a 200 mg dose

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weekly for the first 14 weeks then reducing to every 2 weeks until 14 weeks when responding patients reduced further to once every 4 weeks. The ORR was 71% with 50% achiev-ing≥CR. The median DOR for responding patients at the 200 mg dose was 29.4 months. The overall side effect profile was similar to the other BCMA TCEs with virtually no high grade CRS or ICANS.189

Anti-BCMA TCEs cause profound hypogammaglobu-linaemia with IgG levels usually measured at<1g/L after several months of treatment, due to targeting of the poly-clonal plasma cell population. Long-term follow-up of Elranatamab-treated patients reports a grade 3/4 infection rate of 42.3% but importantly a 6.5% rate of grade 5 events. 187 These trials were undertaken during the early stages of the COVID-19 pandemic and deaths due to COVID-19 were not uncommon. Teclistamab is associated with a similar rate of severe infections(grade 3/4 44.8%). 185 Instigation of intrave-nous immunoglobulin therapy to counteract this immuno-paresis significantly reduces the risk of infection and severe infection.190

Talquetamab is a bispecific antibody targeting GPRC5D and has been evaluated in a phase 1 study of RRMM given in patients treated with a median of six prior lines of ther-apy. Several dosing strategies were trialled in this study, with the most attractive being subcutaneous dosing every 2 weeks after the initial step up dosing. Response rates associated with the various dosing regimens were between 64% and 72%. As with the anti-BCMA TCEs, responses are often du-rable. CRS rates and severity are similar to the anti-BCMA TCEs, but the different target is associated with a different side effect profile. GPRC5D is expressed on filiform papil-lae of the tongue and also in nail beds. Dysgeusia was seen in between 37% and 63% of patients depending on dose and was associated with weight loss in up to 32% of patients.Nail changes and rash are also common, but low grade. In comparison to the anti-BCMA TCEs, infection rates are low with, for example, no COVID-19-related deaths reported in the trial which was carried out at a similar time to the phase 1 and 2 Teclistamab and Elranatamab trials that reported multiple COVID-19-related deaths.191

Randomised studies of these and other TCEs, some of which engage other antigens, are ongoing.

Chimeric antigen receptor T-cell(CAR-T) therapy

CAR-T-cell therapy involves the genetic manipulation of autologous T cells which are reinfreed into the patient to induce anti-tumour response. The first published stud-ies of the BCMA-targeting iecabtaggene vicleucide(ide-cel)demonstrated ORR of 73% and MRD negativity of 26% in multiply relapsed patients and a PFS of 8.8 months.192,193 The randomised phase 3 KarMMa-3 study compared Ide-cel with standard regimens in patients relapsing after two to four prior regimens. The trial demonstrated an improve-ment in median progression-free survival of 13.3 months

with ide-cel versus 4.4 months with standard of care in RRMM.194 The trial allowed crossover after progression on standard therapies which may confound OS advantage, and interim analysis did not show an advantage, with median OS of 41.4 months with Ide-cel versus 37.9 months with standard regimens.

Ciltacabtagene autoleucel(cilta-cel), another BCMA CAR-T studied in triple class exposed myeloma, showed an ORR of 97% with 67% achieving stringent complete re-mission(sCR).12-month PFS was 77% and OS was 89%.195 Extended follow-up indicated a 27-month PFS of 54.9% and OS of 70.4%.196 In the phase 3 CARTITUDE-4 randomised study of calit-cel versus standard therapies in lenalidomide-refractory MM in patients receiving one to three prior ther-apies,419 patients were randomised with 12-month PFS of 75.9% in the clita-cel group and 48.6% in standard of care group and ORR was 84.6% vs. 67.3% respectively. In the clita-cel group, CRS occurred in 76.1%(1.1% grade 3/4) with 4.5% neurotoxicity(no grade 3/4).197 In a detailed analysis of neurotoxicity in the CARTITUDE-1 study, 12.4% had non-ICANS neurotoxicity with a range of symptoms including movement disorder, cognitive and personality changes and cranial nerve palsy. A range of possible risk factors iden-tified included high tumour burden and prior grade 2 or greater CRS.198

It is not possible to fully evaluate the comparative efficacy of ide-cel and cleta-cel due to differences in study design,including crossover and differing standard of care regi-mens in the ide-cel comparator arm. A detailed comparison is beyond the scope of these guidelines but is reviewed in more detail elsewhere.199 CAR-T-cell therapy can result in life-threatening complications such as CRS and neurotoxic-ity and must only be undertaken in approved centres where there is access to urgent management of toxicities. The deci-sion to treat with CAR-T-cell therapy should be made by my-eloma specialists and take account of the other treatments outlined in this guidance. Nonetheless, there are clear dif-ferences with CAR-T-cell therapy compared with most other therapies for RRMM, not least the single administration as opposed to continuous long-term therapy.

Both TCE and CAR-T-cell therapy can cause profound immune paresis and supportive therapies including antimi-crobial prophylaxis and intravenous immunoglobulin war-rant strong consideration. International consensus groups have made recommendations about the supportive manage-ment of those receiving TCE therapy.200 Important trials in-volving T-cell directed therapy are summarised in Table 14.

Recommendations

● In RRMM consider belantamab mafodotin with appro-priate ocular monitoring in combination with either:o Bortezom and dexamethasone(1A)o Pomalidomide and dexamethasone(1A)

● In triple class exposed RRMM consider:

o Elranatamab with appropriate supportive manage-ment(1B)

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o Teclistamab with appropriate supportive manage-ment(1B)

o Talquetamab with appropriate supportive manage-ment(1B)

O Ide-cel(idecabtagene vicleucel) with careful patient selection(1B)

o Citael-ccelactabagene autoleucel) with careful pa-tient selection(1B)

● When using T-cell-directed therapies in RRMM consider:

o The use of infection prophylaxis, including intrave-nous immunoglobulin, and other supportive mea-sures (2B)

o Access to the infrastructure to treat potentially life-threatening toxicities(2C)

Venetoclax

Venetoclax is an oral inhibitor of the anti-apoptotic pro-tein, BCL2, which is overexpressed particularly in my-eloma with the t(11;14) translocation. In a phase 1 study,patients with RMM received venetoclax monotherapy following a median of five prior therapies. ORR was 21%overall, but was 40% in t(11;14) patients, with 27% achiev-ing VGPR or greater.201 In a phase 1b trial of 66 relapsed patients, daily venetoclax was evaluated in combination with bortezombid and dexamethasone. The ORR was 67%with 42% VGPR or greater. Responses were seen in 78% of t(11;14) patients.202

When combined with bortezomib and dexametha-sone in a randomised phase 3 study, venetoclax increased PFS from 11.5 to 22.4 months. However, infections and infection-related deaths were greater in the venetoclax arm, which impacted OS. 203 Further studies are evaluat-ing the role of venetoclax in combinations in t(11;14) my-eloma, and therefore, testing for t(11;14) may guide patient selection.

Recommendation

● Venetoclax is an option for the treatment of RMM with t(11;14) and with appropriate infection prophylaxis(2B).

Selinexor

Selinexor is an oral inhibitor of the nuclear export protein,exportin 1, which is overexpressed in multiple myeloma.In a phase 1b/2 study, 42 patients received selinexor plus bortezomib and dexamethasone. Patients had a median of three prior lines of therapy, and 50% were refractory to a PI. ORR was 63%; 84% for PI non-refractory; and 43% for PI-refractory patients. The PFS for all patients was 9.0 months; 17.8 months for PI non-refractory; and 6.1 months for PI refractory.23

A phase 3 study combined Selinexor with bortezomib and dexamethasone in comparison with bortezomib and dexa-methasone. Median PFS was 13.9 months with selinexor,bortezomib and dexamethasone and 9.5 months with borte-zomib and dexamethasone.22

In a phase 2b study, selinexor plus dexamethasone was given to 122 triple-refractory myeloma patients(median of 7 prior lines) including a subgroup of 68% who were penta-refractory. PR or better was observed in 26%. PFS was 3.7 months and OS was 8.6 months.204

Selinexor has some specific side effects, including signifi-cant nausea and cytopenias(see Box 4).

Recommendation

● Selinexor in combination with bortezomib and dexa-methasone is an option in relapsed myeloma(2B).

● Selinexor with dexamethasone is an option for the treat-ment of penta-refractory myeloma(2B).

SUBSEQUENT THERAPY BASED ON PRIOR TREATMENTS

As discussed in the opening section of these guidelines,there are several factors to consider when choosing a treat-ment regimen for a patient with RMM. Of these, the most important are prior therapies and the response to them.205 In a retrospective review of 1439 second-line and 1104 third-line patients in a tertiary referral centre treated between 2003 and 2021, the impact of newer therapies and combinations is clearly apparent. Over time proportionally more patients

BOX 4 Key toxicities of new therapies

Belantamab mafodotin

● Infusion-related reactions-suggest premedication with initial doses

● Keratopathy-requires ophthalmology review

TCE and CAR-T

● Cytokine release syndrome

● Neurotoxicity(central and peripheral)

● Cytopenias

● Atypical infections-consider IVIg, pneumocys-tis, zoster and antifungal prophylaxis

● Dysgeusia, weight loss, skin and nail changes(talquetamab)

Selinexor

● Nausea-consider use of NK1 antagonists or olanzapine

● Anorexia

● Cytopenias-consider dose reduction

TABLE 14 T-cell-directed therapy.

|Study, year of publication|Recruitment period (total n)|Arms|Median prior lines(range)|ORR (%)|CR (%)|MRD-(%)|PFS(m)|OS(m)|Comments| |---|---|---|---|---|---|---|---|---|---| |CARTITUDE-1 Berdeja Lancet 2021 Martin JCO 2022^195.196|Phase 1b/2 2018-2019 (113)|Cilta-cel|6(4-8)|97.9|82.5|NR|NR (27/12 PFS 54.9%)|NR (27/12 OS 70.4%)|14% of IIT population did not receive Ciltacel Figures quoted are for treated patients| |CARTITUDE-4 San Migel NEJM 2023^197|Phase 3|Cilta-cel(208) vs. Standard of care(211)|84.6 67.3|73.1 21.8|60.6 15.6|NR 11.8|NR|CRS 76.1% ICANS 4.5%|| |Munshi NEJM 2021^93|Phase 2 2017-2018 (140)|Ide-cel|6(3-16)|73|33|26|8.8|19.4|Dose escalation studies Figures quoted are for all patients treated at any dose| |KarMMa-3 Rodriguez-Otero NEJM 2023^194|Phase 3 (386)|Ide-cel(254) vs. Standard regimen(132)||71 42|39 5|13.3 4.4|NR|66% triple class refractory 95% daratumumab refractory Ide-cel: CRS 88%,≥Gr 3 5%|66% triple class refractory 95% daratumumab refractory Ide-cel: CRS 88%,≥Gr 3 5%| |MajesTEC-1 Moreau et al. NEJM 2022^185|Phase 1-2 2020-2021 (165)|Teclistamab|5(2-14)|63.0|39.4|26.7|11.3|18.3|CRS G1-2 72.1% ICANS G1-2 14.5%| |MonumenTAL-1 Chari NEJM 2022^191|Phase 1 (232)|Talquetamab IV(102) SC(130)|6|64-70|NR|NR|DOR 7.8-10.2|NR|Results for subcutaneous dosing CRS 77%-80% Skin toxicity 67%-70%| |MagnetisMM-1 Bahlis Nat Med 2023^186|Phase 1 (88,55 efficacious)|Elranatamab SC|5(2-14)|63.6|38.2|13/13 evalable|11.8|21.2|CRS 87.3% ICANS 16.4% Infections 74.5%| |MagnetisMM-3 Lesokhin Nat Med 2023^188|Phase 2 (123)|Elranatamab SC|5(2-22)|61.0|35.0|60.5% of CR|NR (15/12 PFS 50%)|NR NR (15/12 OS 56.7%)|CRS 57.7% Neutropenia 48.8%| |LINKER-MM1 Bumma JCO 2024^189|Phase 1/2 (117)|Linvoseltamab 200mg IV|5(2-16)|70.9|49.6|90.5% of evaluable and CR|NR(12/12 PFS 70%)|31.4|CRS 46.2% ICANS 7.7%|

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TABLE 15 Treatment options for relapsed myeloma based on prior treatment exposure and refractoriness.

||Lenalidomide naive/ borient bortezomib naive/sensitive|Lenalidomide refractory bortezomib naive/sensitive|Bortezomib refractory lenalidomide naive or sensitive|Len and bort refractory|Triple class exposed|| |---|---|---|---|---|---|---| |Preferred|Dara-RD|Bela-PD|Bela-PD|Bela-PD|Bela-PD|| ||Dara-VD|Bela-VD|Dara-RD|Dara-PD|Cilta-cel|| ||Elo-RD|Dara-VD|Elo-RD|Isatux-PD|Elranatamab|| ||Ixa-RD|Dara-PD|Isatux-PD|Isatux-KD|Ide-cel|| ||KRD|Dara-KD|KRD|Isatux-PD|Talquetamab|| |||Isatux-PD||Teclistamab||| |Alternatives|CRD|CVD|CRD|Alkylators± thal|Alkylators± thal|| ||CVD|Elo-PD|Ixa-RD|CPD|Dara-KD|| ||KCD|KD|RD|Dara|Elo-PD|| ||KD|PVD|Elo-PD|Elo-PD|Pano-VD|| ||RD|Selinexor-Vd||KD|Selinexor-D|| ||VD|VD|Pano-VD||||

Note: Consider PACE-based regimen if rapidly progressive disease and fit enough to consider intensive treatment. Consider ASCT2 as consolidation depending on treatment line and fitness. Consider clinical trials at every line.

were treated with novel agents, more with triplets rather than doublets and median OS from the first relapse increased from 30.9 months(95% CI: 26.8-183.0) to 65.8 months(95%CI: 50.7-72.8;p<0.001). Choice of subsequent therapy was strongly influenced by prior therapy received, and therefore,no conclusions can be drawn regarding the most efficacious combinations to use, but the authors hypothesise that use of novel agents and triplets is responsible for the improved outcomes.206

At every line of therapy, the option that is likely to be most efficacious should be offered as soon as permissible within the treatment pathway. In patients who have only received one previous line of therapy, the most important question is whether they received a lenalidomide- or bortezomib-containing regimen, or a regimen containing both drugs.In some situations, it may be difficult to ascertain to which drug(s) the patient is refractory, though in the future many will be lenalidomide-refractory, having received it to pro-gression, either as maintenance therapy after an ASCT207 or as part of first-line therapy.208

Table 15 summarises treatment recommendations for various clinical scenarios; supporting data are summarised in earlier sections of these guidelines. In lenalidomide-refractory patients, our recommendation is to switch to a regimen based on a PI, preferably with an additional mAb or antibody-drug conjugate. An alternative would be a reg-imen containing an alternative IMId(e. pomalidomide),combined with a PI and/or a mAb or antibody-drug conju-gate. It is difficult to extract clear data about lenalidomide-refractory patients from subgroup analyses of the phase 3 studies underpinning the recommended regimens, but in general, the PFS with these regimens is shorter for lenalidomide-refractory patients than in the whole group who received the treatment. ${}^{17,21,30}$

Patients who did not receive lenalidomide as first-line treatment should receive lenalidomide and dexamethasone-based regimens as second-line therapy. Of the suggested

regimens, DRd may offer the best PFS, but to date only KRd has demonstrated an OS benefit in patients who have received one previous line of therapy. Patients treated with a fixed duration of lenalidomide who progressed more than 6 months after stopping therapy could also be consid-ered for lenalidomide-based combinations if other backbone agents are not available.

The treatment of patients who have received two or more lines of therapy has become increasingly challenging ing in recent times, as these individuals are now likely to have received IMid, PI and mAb therapy. Pomalidomide and dexamethasone(Pom-dex), with either an anti-CD38 mAb or, if not available, with elotuzumab, an antibody-drug conjugate or cyclophosphamide are options in this group.56,78,102

For triple-refractory patients, median OS remains just 5.6 months.210 One option for the management for such a patient is to be entered into a clinical trial. Where this is un-available, BCMA-targeted therapy is a strong consideration.Elranamatab and teclistamab are available for treatment of triple refractory disease. Talquetamab is an alternative to BCMA-directed therapy(Table 15). Anti-BCMA CAR-T therapy is likely to be available soon for patients with tri-ple- refractory disease relapsing after three previous lines of treatment.179 CAR-T-cell therapy shows much promise in this patient group and has the potential to transform the management of triple-refractory disease.193

CONCLUSIONS

The treatment options for myeloma have expanded hugely in the last decade, providing clinicians with greater oppor-tunities and patients with improved outcomes. However,clinical decision-making has consequently become increas-ingly challenging. While there are numerous randomised controlled trials available, there are few large randomised

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studies comparing the different multi-agent treatment ap-proaches with one another.

From a UK perspective, funded treatments differ be-tween England, Wales, Scotland and Northern Ireland. A guideline of this nature is not able to take account of these variations and changes in funding over time. The focus of these guidelines has therefore been to describe the evidence base behind the currently available treatment options and make recommendations based on current best available clinical evidence. It has attempted to highlight the scenar-ios in which different options may be preferred over oth-ers. However, it is neither possible nor desirable to map out a single sequential treatment pathway for all myeloma patients as this would fail to recognise the importance of taking a personalised approach to management of relapsed myeloma. Undertaking a comprehensive assessment of dis-ease factors, patient factors and response to and toxicity of prior treatments in planning an individualised treatment plan for patients with relapsed myeloma patient provides the best prospect of continuing to improve patient outcomes.

AUTHOR CONTRIBUTIONS

MJ chaired the writing group. All the authors contributed to the writing and revising of guidelines.

CONFLICT OF INTEREST STATEMENT

MJ: Consultancy and Honoraria: J&J, BMS, Pfizer, Sanofi,Menarini Stemline and GSK. KB: Honoraria: Sanofi and J&J; SC: None declared. CP: Consultancy and Honoraria:BMS,Sanofi, Abbvie,J&J, Jazz, Sanofi, Amgen, Alnylam,Novartis, Gilead and Takeda. MG: Consultancy and Honoraria:Amgen,Sanofi,BMS, Menarini Stemline, J&J,Novartis, Takeda SS: Honoraria: Takeda, Binding Site,Sanofi and J&J.

ORCID

Mamta Garg https://orcid.org/0000-0002-3560-0132 Simon Stern https://orcid.org/0000-0003-1831-9549

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SUPPORTING INFORMATION

Additional supporting information can be found online in the Supporting Information section at the end of this article.

How to cite this article: Jenner M, Boyd K, Choudhuri S,Parrish C,Garg M,Stern S. Management of relapsed multiple myeloma: A British Society of Haematology and UK Myeloma Society guideline. Br J Haematol.2025;00:1-33.https://doi.org/10.1111/bjh.70149

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