Are Autologous Stem Cell Transplants Still Required to Treat Myeloma in the Era of Novel Therapies? A Review from the Chronic Malignancies Working Party of the EBMT

(1)

HAL Id: hal-02969044

https://hal.sorbonne-universite.fr/hal-02969044

Submitted on 16 Oct 2020

HAL is a multi-disciplinary open access archive for the deposit and dissemination of sci- entific research documents, whether they are pub- lished or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.

L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Distributed under a Creative Commons Attribution - NonCommercial - NoDerivatives| 4.0 International License

Are Autologous Stem Cell Transplants Still Required to Treat Myeloma in the Era of Novel Therapies? A Review from the Chronic Malignancies Working Party

of the EBMT

Laurent Garderet, Curly Morris, Meral Beksac, Gösta Gahrton, Stefan Schönland, Ibrahim Yakoub-Agha, Patrick Hayden

To cite this version:

Laurent Garderet, Curly Morris, Meral Beksac, Gösta Gahrton, Stefan Schönland, et al.. Are Au-

tologous Stem Cell Transplants Still Required to Treat Myeloma in the Era of Novel Therapies? A

Review from the Chronic Malignancies Working Party of the EBMT. Biology of Blood and Marrow

Transplantation, Elsevier, 2020, 26 (9), pp.1559-1566. �10.1016/j.bbmt.2020.04.016�. �hal-02969044�

(2)

Review

Are Autologous Stem Cell Transplants Still Required to Treat Myeloma in the Era of Novel Therapies? A Review from the Chronic Malignancies Working Party of the EBMT

Laurent Garderet

^1,

*, Curly Morris

²

, Meral Beksac

³

, G€ osta Gahrton

⁴

, Stefan Sch€ onland

⁵

, Ibrahim Yakoub-Agha

⁶

, Patrick J. Hayden

⁷

1Sorbonne Universite, INSERM, UMR_S 938, Centre de Recherche Saint-Antoine—Team Proliferation and Differentiation of Stem Cells, Assistance Publique-Hôpitaux de Paris, Hôpital Pitie Salpêtriere, Service d'Hematologie, Paris, France

2Haematology, Queen's University Belfast Faculty of Medicine Health and Life Sciences, Belfast, United Kingdom

3Ankara University, Ankara, Turkey

4Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden

5Amyloidosis Center, Division of Stem Cell Transplantation, Department Internal Medicine V, Hematology, Oncology, Rheumatology, Heidelberg University Hospital, Heidelberg, Germany

6CHU de Lille, LIRIC, INSERM U995, Universite de Lille, Lille, France

7Department of Haematology, Trinity College Dublin, St. James’s Hospital, Dublin, Ireland

Article history:

Received 21 January 2020 Accepted 7 April 2020

A B S T R A C T

Melphalan at a myeloablative dose followed by autologous stem cell transplantation (ASCT) remains the standard of care for transplant-eligible patients with myeloma. However, therapies such as new immunomodulatory drugs and proteasome inhibitors and, more recently, monoclonal antibodies and chimeric antigen receptor T cells are challenging the traditional role of ASCT. Which patients benefit from ASCT? Can its use be delayed untilfirst relapse? Thefield is moving rapidly as novel agents lead to new patient care strategies. The place of ASCT in this changing landscape will be reviewed and reassessed.

© 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/) Key Words:

Myeloma Autologous stem cell transplantation Immunotherapy CAR T cells

The treatment of multiple myeloma (MM) has changed beyond recognition over the past 50 years

[1-5]. The use of high-

dose intravenous melphalan to treat MM was

ﬁ

rst described by McElwain and Powles in 1983

[6]. As practice evolved, it was

given at a higher, myeloablative dose and was followed by autol- ogous stem cell transplantation (ASCT) [7,8]. Although only some of the original randomized clinical trials of ASCT in mye- loma reported an overall survival (OS) bene

ﬁ

t, there was a con- sistent improvement in progression-free survival (PFS), and the use of a single ASCT became the standard of care for younger patients, generally younger than 65 years, who could tolerate the procedure safely, so-called transplant-eligible patients

[9- 13]. More than 10,000 autologous transplants are currently per-

formed for MM in european society for blood and marrow trans- plantation (EBMT) centers each year, and it is the most common indication for ASCT, far exceeding lymphoma (Figure 1).

This prompted evaluation of the ef

ﬁ

cacy of tandem ASCT, 2 transplants given 3 to 6 months apart in the absence of disease progression after the

ﬁ

rst one. In a randomized trial, tandem transplantation was found to confer superior PFS compared to a single ASCT, especially in those patients who did not achieve a very good partial response after the

ﬁ

rst transplant

[9]. How-

ever, results for OS were inconsistent, and over time, the use of tandem ASCT declined.

In parallel, numerous new therapeutic options have been discovered, starting with the immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) (Figure 1). Thalido- mide, the original IMiD

[14], was replaced by lenalidomide

and pomalidomide, more potent agents that are less likely to cause neuropathy. The current focus is on agents such as iber- domide, which appears to have some ef

ﬁ

cacy in patients who are refractory to all other IMiDs.

Proteasome inhibitors have also improved both the response rates and the corresponding depths of response. The

ﬁ

rst mole- cule was bortezomib. This was followed by car

ﬁ

lzomib, which proved to be twice as effective as bortezomib in terms of the duration of response in 1 recent head-to-head study, and the third-generation oral proteasome inhibitor, ixazomib. All these

Financial disclosure: See Acknowledgments on page 1564.

*Correspondence and reprint requests: Laurent Garderet, MD, PhD, Service d’hematologie, Hôpital Pitie Salpêtriere, 45-83 boulevard de l’hôpital, 75013, Paris, France.

E-mail addresses:laurent.garderet@aphp.fr,laurent.garderet@sat.aphp.fr (P.J. Hayden).

https://doi.org/10.1016/j.bbmt.2020.04.016

(http://creativecommons.org/licenses/by-nc-nd/4.0/)

Biology of Blood and Marrow Transplantation

journal homepage: www.bbmt.org

(3)

new agents have been combined with corticosteroids and, more recently, with antibodies, generally resulting in greater ef

ﬁ

cacy and tolerable toxicity pro

ﬁ

les

[15].

With so many effective and well-tolerated new drugs avail- able to treat MM, is there still a role for ASCT? Should we con- tinue to perform ASCT upfront, or should it be delayed until

ﬁ

rst relapse? Conversely, do high-risk patients bene

ﬁ

t from tandem ASCT? What are the eligibility criteria for transplanta- tion? Should we still perform ASCT over the age of 65 years, even in

ﬁ

t patients? These are the questions that clinicians treating myeloma are currently debating, and each will be dis- cussed in turn below.

IMPROVING THE CONDITIONING REGIMEN

In a pivotal early trial, the French Myeloma Group (Inter- groupe Fran

¸

cais du My elome) used melphalan in combination with radiotherapy as conditioning for autologous transplantation, although it became clear that there was increased toxicity with- out any increase in ef

ﬁ

cacy

[16]. Total marrow irradiation com-

bined with melphalan (200 mg/m2), however, may be more effective

[17]. Since then, a number of other conditioning regi-

mens have been evaluated in trials. The addition of busulfan to melphalan (140 mg/m2) was recently compared to single-agent melphalan (200 mg/m2) in a randomized clinical trial, and the median progression-free survival following the combination was signi

ﬁ

cantly better at 64.7 months as opposed to 43.5 months with melphalan alone [18,19]. The addition of bortezomib to melphalan, however, did not signi

ﬁ

cantly affect outcomes in another randomized phase III study

[20]. Another alkylating

agent, bendamustine, has been combined with melphalan with

encouraging results

[21]. Despite these interesting reports, the

standard of care remains melphalan at a dose of 200 mg/m2.

ASCT VERSUS NONTRANSPLANT APPROACHES

Given the availability of more potent combination chemo- therapy regimens, there has been an increasing trend to compare them directly with ASCT (Table 1). In general, these trials were designed to compare upfront ASCT with transplant at

ﬁ

rst relapse. In 2 recent Italian studies, patients received 4 cycles of lenalidomide and dexamethasone as induction and were then randomized between 1 of 2 different lenalidomide-based combi- nation chemotherapy regimens or high-dose melphalan (200 mg/m2) followed by ASCT. The

ﬁ

rst study compared 6 cycles of melphalan, prednisone, and lenalidomide with tandem ASCT and the second trial 6 cycles of cyclophosphamide, lenalidomide, and dexamethasone with tandem ASCT. Both approaches showed superior PFS in the ASCT arms [22,23]. Similarly, a European Myeloma Network trial (EMN02) demonstrated that upfront con- solidation with ASCT following induction with bortezomib (Vel- cade), cyclophosphamide, and dexamethasone was associated with a signi

ﬁ

cant improvement in both the depth of response and the median PFS compared to consolidation with bortezomib, melphalan, and prednisone (PFS not reached versus 44 months)

[24]. However, some reviewers have criticized these 3 trials for

having what they considered to be suboptimal induction regi- mens, which were either PI or IMiD based, and therefore lacked the ef

ﬁ

cacy of contemporary PI- and IMiD-based regimens. A more recent Intergroupe Fran

¸

cais du My elome study addressed this question and found that ASCT still remained superior to the triplet combination of bortezomib, lenalidomide, and

Figure 1.Transplantations as reported in the EBMT and major new therapies for myeloma in the past 20 years.

1560 L. Garderet et al. / Biol Blood Marrow Transplant 26 (2020) 1559 1566

(4)

dexamethasone (VRd), a more contemporary approach. ASCT consolidation and maintenance lenalidomide was compared to consolidation with VRd followed by maintenance lenalidomide, and the former approach was superior in inducing deeper hema- tologic responses, including a signi

ﬁ

cantly higher proportion of patients with no detectable minimal residual disease (MRD,

ﬁ

rst- generation

ﬂ

ow cytometry with a sensitivity of 10 4; 79% versus 65%,

P<

.001). After 4 years of follow-up, patients who under- went ASCT consolidation also had a superior PFS (50 versus 36 months), although there was no difference in 4-year OS (81% ver- sus 82%)

[25]. Other European groups likewise found ASCT to be

more effective while pooled and meta-analyses con

ﬁ

rmed the superiority of ASCT in improving PFS [26,27]. In 2018, Gay et al.

[28]

reported the results of the FORTE trial in which ASCT was compared with the KRd regimen consisting of car

ﬁ

lzomib (Kypr- olis), lenalidomide (Revlimid), and dexamethasone. The

ﬁ

rst reports revealed similar response and MRD negativity rates (8- color second-generation

ﬂ

ow cytometry [sensitivity 10 5]) in the ASCT and KRd arms. High-risk patients in both groups achieved MRD negativity rates of around 50%. In the most recent update, however, a PFS advantage has emerged for high-risk patients who proceeded to ASCT. Finally, it is important to point out that if ASCT improved PFS, OS was improved in some studies but not in others (Table 1).

SINGLE VERSUS TANDEM ASCT

Tandem transplantation was

ﬁ

rst compared to single ASCT

more than 10 years ago

[29-31], and there have been further trials

over the past decade. PFS was superior in the tandem transplant

arms in all studies, whereas the OS rates were superior in only a

few of them. In the absence of conclusive evidence of bene

ﬁ

t and

given the increased toxicity and resource requirements, enthusi-

asm for tandem ASCT waned. Long-term follow-up analysis of the

GMMG-HD2 trial comparing single versus tandem transplantation

following conditioning with melphalan (200 mg/m2) found that

OS and event-free survival did not differ signi

ﬁ

cantly between the

2 arms

[32]. On the contrary, in a preliminary analysis of the Euro-

pean EMN02/HO95 study, patients who underwent tandem ASCT

had a signi

ﬁ

cantly higher 3-year PFS (74% versus 62%,

P

= .005)

[33]. To directly address the role of consolidation therapy after a ﬁ

rst ASCT, the phase III STAMINA BMT-CTN trial randomized

patients with newly diagnosed MM who had previously under-

gone a

ﬁ

rst ASCT to 1 of 3 arms: a second transplant; bortezomib,

lenalidomide, and dexamethasone (RVd) consolidation; or no con-

solidation

[34]. All patients then received maintenance lenalido-

mide. At 38 months, the investigators found no differences

between the 3 groups in terms of either PFS (59% versus 58% ver-

sus 54%) or OS (82% versus 85% versus 84%). The toxicity pro

ﬁ

les

and the rates of second primary malignancies were similar across

the 3 treatment arms. Some of the discrepancies between the

European and North American studies have been attributed to var-

iations in both the types and duration of induction therapies. In

the European trial, patients were enrolled prior to starting induc-

tion therapy and had a predetermined number of induction cycles

that did not include an immunomodulatory drug. By contrast,

patients in the BMT-CTN trial were enrolled after starting therapy,

and as a group, they received signi

ﬁ

cantly more induction therapy

(up to 12 months). In addition, the 3 BMT-CTN treatment groups

were evenly balanced with respect to prior therapies: most

patients received an immunomodulatory agent, and most patients

were treated with the RVd regimen, the then standard-of-care

induction regimen. The use of this more effective induction ther-

apy in the BMT-CTN trial is likely to have been a factor in the fail-

ure of tandem ASCT or RVd consolidation post-transplant to have

improved survival. In summary, the best current evidence for the

Table1 SummaryofPhaseIIIClinicalTrialsEvaluatingtheEfficacyofASCTintheEraofNovelAgentInductionTherapy ClinicalTrialNo.InductionRandomizedArmsORREFS/PFSOSMRD() Palumboetal.[22]NDMMpatients <65yearsold402Rd£4cyclesMPR£6cycles!NomaintCR(postconsolidation):18%MedianPFS:22mo5-yearOS:59%NA MPR£6cycles!R-maintMedianPFS:34mo5-yearOS:70%NA Mel200mg/m2£2cycles!NomaintCR(postconsolidation):23%MedianPFS:37mo5-yearOS:67%NA Mel200mg/m2£2cycles!R-maintMedianPFS:55mo5-yearOS:78%NA Gayetal.[23]NDMMpatients 65yearsold389Rd£4cyclesCRd£6cycles!R-maintCR:27%MedianPFS:28mo4-yearOS:76%NA CRd£6cycles!Rp-maintCR:23%MedianPFS:24mo4-yearOS:68%NA Mel200mg/m2£2cycles!R-maintCR:33%MedianPFS:32mo4-yearOS:75%NA Mel200mg/m2£2cycles!Rp-maintCR:37%MedianPFS:38mo4-yearOS:77%NA Cavoetal.[24]NDMMpatients 65yearsold1503VCd£34cyclesVMP!+/VRd!R-maintVGPR:75%3-yearPFS:57%MedianOS:NR36%[10-5] Mel200mg/m2£1or2!+/VRd!R-maintVGPR:84%3-yearPFS:64%MedianOS:NR64%[10-5] Attaletal.[25]NDMMpatients 65yearsold700VRd£3cyclesVRd£5cycles!R-maintCR:48%MedianPFS:36mo4-yearOS:82%65%[10-4] Mel200mg/m2!VRd£2cycles!R-maintCR:59%MedianPFS:50mo4-yearOS:81%79%[10-4] ClinicaltrialNo.InductionRandomizedArmsVGPR%sCR%MRD()105 159KCD£4cyclesASCT+KCD£4cycles763242 Gayetal.[28]NDMMpatients 65yearsold158KRD£4cyclesASCT+KRD£4cycles894458 157KRD£4cyclesKRD£8cycles874354 InGayetal.[28]trial:Afterfirstrandomization,allpatientswererandomizedtolenalidomidemaintenancewithorwithoutcarfilzomib. ORRindicatesoverallresponserate;EFS,event-freesurvival;NDMM,XXX;MPR,melphalan,prednisone,andlenalidomide;CR,completeremission;NA,notavailable;R-maint,lenalidomidemaintenance;Mel,XXX;Rd,lenalidomide anddexamethasone;CRd,cyclophosphamide,lenalidomide,anddexamethasone;Rp-maint,lenalidomideandprednisonemaintenance;VCd,bortezomib,cyclophosphamide,anddexamethasone;VMP,bortezomib,melphalan,and prednisone;VGPR,verygoodpartialresponse;sCR,stringentcompleteremission;KCD,carfilzomib,cyclophosphamide,anddexamethasone;NDMM,newlydiagnosedmultiplemyeloma;Mel,melphalan.

(5)

use of tandem ASCT is for patients who have not achieved a very good partial response following the

ﬁ

rst ASCT or, as detailed below, for those with high-risk disease.

DELAYED ASCT

As upfront ASCT conferred no OS advantage in most random- ized clinical trials, some authors have advocated deferring ASCT until

ﬁ

rst relapse [35,36]. Two retrospective studies compared early ASCT (within 12 months of the diagnosis) and delayed ASCT (after 12 months)

[35]. In theﬁ

rst study of 290 patients treated with IMiD-based induction who subsequently underwent ASCT, there were similar median times to progression (TTPs) fol- lowing ASCT (20 versus 16 months;

P =

NS) and no difference in terms of 4-year OS (73% in both groups) in the early and delayed ASCT cohorts. Similar results were reported in an analysis of 167 patients undergoing early or delayed ASCT

[36]; despite a trend

toward a longer median TTP in the early ASCT group (28 versus 23 months;

P

= .055), no differences in OS were noted between the 2 groups at 3 (90% versus 82%) and 5 years (63% versus 63%).

However, one could argue that these trials were not powered to detect OS differences and that the median TTP was shorter than those seen in trials using modern maintenance approaches.

In support of its current early use, it was reported in a French study that upfront ASCT was associated with a longer treatment-free, symptom-free period when compared to delayed transplantation

[37]. However, this study could also

be considered less relevant in the setting of contemporary treatment approaches, as most patients currently receive maintenance therapy post-transplant. In addition, some patients are not suitable candidates for ASCT at

ﬁ

rst relapse for reasons such as progressive comorbidities or older age. None- theless, delayed ASCT remains an option for selected patients, especially those with standard risk disease, as suggested in the current Mayo Clinic guidelines (mSMART 2019)

[38].

ELIGIBILITY FOR ASCT

As ASCT has become the standard of care in MM with a reported transplant-related mortality rate of less than 1%, the eligibility criteria for ASCT have gradually expanded.

Initially, there was broad consensus that the upper age limit should be around 65 years. Over time, however, many retrospective and prospective studies have demonstrated that physiologic rather than chronologic age should be the key determinant of patient eligibility

[39-42]. High-dose melpha-

lan and ASCT have been reported to be safe and feasible in patients with multiple myeloma aged over 70 years, and age alone should not be an exclusion criterion

[43]. In addition, a

recent large retrospective CIBMTR study con

ﬁ

rmed the feasi- bility of ASCT in patients over this age threshold

[44]. How-

ever, the role of ASCT in older patients has once again been questioned following the excellent results achieved in the recent chemotherapy-based Maia trial

[45]. This study

enrolled patients older than 65 years, and 45% of them were older than 75 years. Newly diagnosed nontransplant-eligible patients were randomized to either lenalidomide and dexa- methasone or the combination of daratumumab, lenalidomide, and dexamethasone (DRd), with patients in both arms remain- ing on treatment until disease progression. The results obtained with the DRd triplet were clearly superior. The esti- mated percentage of patients alive without disease progres- sion at 30 months was 71% in the daratumumab arm and 56%

in the control arm (P

<

.001). The percentage of patients with a complete response or better was 48% in the daratumumab group and 25% in the control group (P

<

.001). A total of 24% of the patients in the daratumumab group, as compared to 7% of

the patients in the control group, had no evidence of MRD (at a threshold of 1 tumor cell per 105 white blood cells) (P

<

.001).

The expected median PFS with the DRd triplet was nearly 5 years, and the side effects were manageable. However, as almost all the randomized transplant trials performed in MM to date have reported that consolidation with ASCT following induction conferred a PFS bene

ﬁ

t and as some also reported an OS bene

ﬁ

t, it cannot be assumed that ASCT is no longer required; there will continue to be a need for well-designed randomized clinical trials to formally assess the bene

ﬁ

t of ASCT following potent novel regimens such as DRd.

Renal impairment can be a limiting factor, especially if the creatinine clearance is lower than 30 mL/min, an exclusion cri- terion in most clinical trials. However, when lower doses of melphalan (100 to 140 mg/m2) were used in patients with renal impairment, the toxicity was comparable and the expected improved outcomes similar to those in patients with normal renal function

[46-50].

ASCT IN PATIENTS WITH HIGH-RISK CYTOGENETIC FEATURES

There is evidence for the use of ASCT in high-risk patients.

Myeloma is a heterogenous disease, and patients with high-risk cytogenetics (del17p, t(4;14) and t(14;16)), generally do less well. Cavo et al.

[33]

reported on a randomized phase III trial that compared single ASCT, tandem ASCT, and a nontransplant approach in the upfront setting. This trial con

ﬁ

rmed the superi- ority of ASCT over a transplant-free approach and also found that tandem ASCT was able to overcome the poor prognosis associated with high-risk cytogenetics abnormalities: 3-year PFS (52% versus 30%) and 3-year OS (74% versus 61%, respec- tively). These positive results contrast with those of the pro- spective phase III BMT-CTN 0702 STAMINA study, which compared 3 different approaches to consolidation following upfront ASCT: (1) a second ASCT followed by lenalidomide maintenance, (2) 4 cycles of RVd followed by lenalidomide maintenance, and (3) lenalidomide maintenance alone. The investigators found no difference in outcome between the 3 arms

[34]. In this trial, the induction regimens were heteroge-

neous, and all patients received maintenance therapy until pro- gression. In a recent update of the results of the FORTE trial, there was a signi

ﬁ

cantly higher incidence of relapse in MRD- negative high-risk patients treated on the KRd nontransplant arm of that study, suggesting that patients with high-risk mye- loma continue to bene

ﬁ

t from ASCT in the era of highly potent triplet induction regimens

[51]. Although there is no interna-

tional consensus, it is now common practice in Europe to con- sider performing tandem ASCT in patients harboring the del17p abnormality. Of note, allogeneic stem cell transplantation may also be considered as an option in selected patients with high- risk MM based on the recent report of better OS in a random- ized trial that compared tandem autologous-allogeneic hemato- poietic stem cell transplantation with tandem ASCT

[52].

ASCT AT RELAPSE

ASCT remains a treatment option at relapse

[53]. Cook et al.

[54]

published the

ﬁ

rst randomized phase III trial comparing ASCT with chemotherapy at

ﬁ

rst relapse. Although ASCT proved to be superior, some considered the control arm of 12 weeks of single-agent cyclophosphamide to have been subop- timal. A second randomized study with a more current com- parator arm consisting of lenalidomide and dexamethasone was recently presented. It did not show any bene

ﬁ

t for the ASCT arm in the intention-to-treat population, although a landmark analysis of patients who had actually undergone

(6)

ASCT revealed a signi

ﬁ

cant improvement in both PFS and OS

[55]. If the relapse-free interval after an initial ASCT is sufﬁ

- ciently long, at least 18 months in the absence of lenalidomide maintenance or 36 months if on maintenance, salvage ASCT remains a reasonable option

[38].

Lenalidomide maintenance is currently the standard of care following upfront ASCT and is often administered until disease progression. In this context, it should be recognized that most of the randomized trials of novel regimens to treat relapsed MM have evaluated combination therapies based on a lenali- domide backbone. In addition, recently approved non-IMid combination therapies such as daratumumab, bortezomib, and dexamethasone are generally continued until disease progres- sion. This may in future complicate the clinical decision as to when to use the option of a second autologous transplant.

In the setting of upfront tandem ASCT, the EBMT chronic malignancies working party (CMWP) has reported favorable outcomes following a third autologous transplant if the relapse-free interval following the initial tandem ASCT exceeded 3 years

[56]. Finally, selected refractory patients

with limited residual hematopoiesis following multiple relap- ses might achieve a degree of hematopoietic recovery with improved bone marrow function following salvage ASCT.

OTHER CONSIDERATIONS WITH ASCT

While health-related quality-of-life (QoL) studies are now being incorporated into many randomized trials, there are rela- tively few relating to novel agents or ASCT in myeloma, and interpretation of the results can be dif

ﬁ

cult. The large MRC (Mye- loma IX) study found few differences between the transplant and nontransplant arms, although there was a short-term negative effect on both fatigue and physical functioning attributable to high-dose therapy and ASCT

[57]. In the more detailed data set

from the Myeloma X study where patients were randomized to a second transplant or conventional chemotherapy following

ﬁ

rst relapse and reinduction, the ASCT patients reported a lower QoL that lasted for 6 months (and up to 2 years for pain), after which the patients who had had a second ASCT reported better out- comes. Interestingly, patients who experienced fewer adverse effects had a longer PFS and OS

[58]. As regards the effect of tim-

ing of transplant on QoL, similar outcomes were observed in upfront and delayed ASCT groups following VRd induction

[59].

Second primary malignancies (SPMs) are a concern after ASCT, especially since it has become standard practice to con- tinue lenalidomide maintenance until disease progression.

Both alkylating agents and lenalidomide have been linked to the development of SPMs. A contemporary EBMT analysis in the era of novel agents found that the cumulative reported incidence of hematologic and solid malignancies 6 years post- transplant was 1.4% and 3.6%, respectively

[60]. Although vigi-

lance is required in monitoring for SPMs, current maintenance approaches have contributed to signi

ﬁ

cantly improved sur- vival and outweigh the relatively small increased risk of SPMs.

Stem cell mobilization using granulocyte-colony stimulating factor and/or plerixafor is standard in North America, whereas most European centers continue to use chemotherapy-based approaches, most commonly cyclophosphamide and granulo- cyte-colony stimulating factor. A recent concern with the intro- duction of novel therapies, especially monoclonal antibodies, has been any potential effect on stem cell mobilization. In the recent Grif

ﬁ

n study, a randomized study of RVd with or without daratu- mumab, there was a small but signi

ﬁ

cant reduction in the stem cell yield in daratumumab recipients (median stem cell yield of 8.1 versus 9.4

£

106 cells/kg, D-RVd versus RVd). However, there was no difference in the rates of hematopoietic recovery

[61].

THE ROLE OF IMMUNOTHERAPY

The most recent advance in the

ﬁ

eld of MM has been the development of immunotherapy

[62]. In contrast to B cell lym-

phoma, monoclonal antibodies have only lately been added to the MM treatment armamentarium

[63]. Theﬁ

rst-in-human anti- SLAMF7 (CS1) antibody (elotuzumab) was found to induce signi

ﬁ

- cant responses when used to treat relapsed MM in combination with either bortezomib or lenalidomide in combination with dexamethasone. The newer antibodies target CD38, and those furthest in development, daratumumab and isatuximab, have been shown to be effective as single agents in the settings of advanced, relapsed, and relapsed/refractory disease. Many ran- domized phase III trials, in both the relapsed and front-line set- tings, have found that the addition of a monoclonal antibody to current triplets increases the overall response rate, the depth of response, and the proportion of patients who achieve MRD nega- tivity, as well as leading to superior PFS [45,64-68]. A consensus is emerging that the next generation of standard

ﬁ

rst-line regimens will most likely consist of proteasome inhibitors, immunomodu- latory drugs, and corticosteroids in combination with monoclonal antibodies. Since KRd appears to be one of the most potent drug combinations to date with response rates that rival ASCT, it is rea- sonable to expect even better results with the addition of daratu- mumab; this is the rationale of an ongoing phase II trial

[69].

Similarly, another trial is evaluating KRd in combination with isa- tuximab as front-line treatment of high-risk MM

[70]. Theﬁ

eld of immunotherapy is rapidly evolving, and an important advance has been the so-called T cell engagers, which simultaneously tar- get a tumor antigen and effector T cells, an example being AMG420. Also promising are antibody-drug conjugates.

The chimeric antigen receptor (CAR) T cell approach is a par- adigm shift in the treatment of hematologic malignancies. The results are particularly encouraging for B-ALL, diffuse large B cell lymphoma, and chronic lymphocytic leukemia, in which a subset of patients may be cured

[71-73]. CAR T cell therapies

targeting

k

immunoglobulin light chain

[74], CD19 [75,76], and

B cell maturation antigen (BCMA)

[77-82]

have been used to treat patients with relapsed or refractory multiple myeloma, with anti-BCMA therapy producing the best responses to date (Table 2). An early population within MM clones is believed to express CD19, and these cells may represent less differentiated MM stem cells. Supporting this hypothesis, anti-CD19 CAR T cell therapy combined with melphalan chemotherapy resulted in a median PFS of more than 6 months in over 50% of patients with relapsed or refractory MM, indicating that anti-CD19 CAR T cells may have antimyeloma effects

[76]. Targeting BCMA

yielded even better responses. Moreover, preliminary results show promising rates of MRD negativity in high-risk patients following CAR T cell infusions

[79]. Ongoing phase II studies in

high-risk myeloma are testing anti-BCMA CAR T cells in relapse and as

ﬁ

rst-line treatment following tandem ASCT

[83].

However, despite these conceptual advances, the duration

of responses following anti-BCMA CAR T cell therapies in MM

has so far been limited with a median PFS of around 9 months,

and the CAR T cells were no longer detectable in the peripheral

blood of most patients 1 year later. These patients, however,

had been heavily pretreated, and in this context, the overall

response rates of around 80% are impressive and are likely to

be better still when the CAR T cells are used at earlier stages of

the disease. These studies also appear to indicate that the

lower the tumor burden, especially following ASCT, the better

the results with CAR T cells. There is signi

ﬁ

cant toxicity, princi-

pally cytokine release syndrome, neurotoxicity, pancytopenia,

and hypogammaglobulinemia, although these adverse effects

were less severe in MM trials as compared to DLBCL CAR T cell

(7)

trials

[84]. More potent, less toxic agents are likely to become

available over the coming decade. In a recent phase II trial combining anti-CD19 and anti-BCMA CAR T cells, 17 of 21 patients achieved MRD negativity. The follow-up, however, remained short at 6 months

[85]. Other CAR T cells targeting

new tumor antigens such as SLAMF7, CD44v, and GPRC5D are under way in patients with MM [86,87], as well as CD38 and BCMA-bispeci

ﬁ

c CAR T

[88]. The current areas of research in

CAR T cell therapy include the use of gene editing to enhance their effectiveness and safety, combining CAR T cells with other approaches such as immunomodulatory drugs and checkpoint inhibitors, and the development of CAR T cells tar- geting multiple antigens

[89]. Of note, other cell therapy

approaches using natural killer cells are also in development

[90]. In terms of cost, these new cellular strategies are much

more expensive than ASCT.

Is there still a role for ASCT in the era of these potent novel immunotherapies? For the time being, the anti-BCMA thera- pies, including CAR T, T cell engagers, and antibody drug con- jugates, are being used in patients with advanced, often refractory, myeloma, although they will no doubt soon be assessed in earlier disease settings. However, in contrast to the CAR T experience in B cell lymphoma, there is, as yet, no evi- dence of a plateau in the rate of post-treatment relapse in patients with myeloma and no suggestion that CAR T therapy represents an alternative to upfront ASCT. Monoclonal anti- bodies, however, clearly increase the rate and depth of response and are likely to be rapidly integrated into the cur- rent transplant-based treatment algorithms.

CONCLUSIONS

MM patient outcomes have improved dramatically over the past 2 decades with a doubling of the median PFS. Myeloma is becoming a chronic disease, especially for standard-risk patients, some of whom may achieve what amounts to an operational cure. This has been made possible by the combined use of new types of drugs and ASCT. The induction regimens administered prior to ASCT have gradually improved, moving from a chemo- therapy-only approach, like the VAD protocol, to current regi- mens consisting of proteasome inhibitors, IMiDs, and corticosteroids, with monoclonal antibodies likely to be added in the near future. The use of consolidation and maintenance thera- pies post-transplant has increased the depth of response and pro- longed the duration of remissions. At present, ASCT remains the standard of care for newly diagnosed transplant-eligible patients

[67]. Chronologic age is less important than generalﬁ

tness, and renal impairment is not a contraindication. The Mayo Clinic con- sensus guidelines on the use of ASCT in MM

[38]

and the Euro- pean Myeloma Network guidelines

[91]

both endorse the use of upfront ASCT with high-dose melphalan in all eligible patients with MM, followed by PI- and/or IMiD-based maintenance ther- apy. In EBMT centers,

ﬁ

rst-line ASCT is still performed in most newly diagnosed patients with MM

[92]. In the United Kingdom,

NICE recommends ASCT following induction therapy and also after successful reinduction following

ﬁ

rst relapse for transplant- eligible patients

[93]. Tandem transplantation should be consid-

ered for patients with cytogenetically high-risk features, espe- cially those harboring del17p. Immunotherapy, including CAR T cells, will undoubtedly be incorporated into this algorithm in the near future. The evaluation of minimal residual disease is also likely to actively guide treatment strategies in the coming years.

ACKNOWLEDGMENTS

Financial disclosure:

The authors have nothing to disclose.

Table2 ResponsestoCARTCells ReferenceNo.TargetORR,%PR,%VGPR,%CR,%sCR,%MRD(),%MedianPFSFollow-upComments Garfalletal.[76]10CD1970204010FIHanti-CD19 Alietal.[77]12BCMA33161patientFIHanti-BCMA Brudnoetal.[78]16BCMA8163VGPR100ifPR31wkEFS81%ORRatoptimaldose Rajeetal.[79]33BCMA8545100ifPR11.8mo90%ORRatoptimaldose Cohenetal.[80]25BCMA48(PR)20208DOR=4mo64%ORRatoptimaldose Xuetal.[81]17Bi-BCMA88127653%at12mo417d Zhaoetal.[82]57Bi-BCMA88145686315mo8mo Yanetal.[85]21CD19andBCMA951424144381243d(ifVGPR)179d PRindicatespartialresponse;FIH,ﬁrstinhuman;DOR,durationofresponse.

(8)

Conﬂict of interest statement:

L.G.: advisory board: Amgen, Cel- gene, Takeda, and Amgen. P.H.: advisory board: Celgene, Janssen, and Alnylam; honoraria: Takeda and Amgen. G.G.: none. C.M.:

none. I.Y.-A.: honoraria: Celgene, Janssen, Novartis, and Kite/

Gilead. M.B.: advisory board: Celgene, Janssen, Takeda, Sano

ﬁ

, Deva, and Amgen; speakers bureau: Janssen, Celgene, Deva, Takeda, and Amgen. S.S.: research support: Janssen and Sano

ﬁ

; advisory board: Janssen and Prothena; honoraria: Janssen, Takeda, and Prothena.

Authorship statement: L.G., C.M., and P.H. wrote the

ﬁ

rst draft of the manuscript, and all authors approved the

ﬁ

nal ver- sion of the manuscript.

REFERENCES

1. Palumbo A, Anderson K. Multiple myeloma.N Engl J Med. 2011;364:

1046–1060.

2. Rajkumar SV. Treatment of multiple myeloma. Nat Rev Clin Oncol.

2011;8:479–491.

3. Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients.Leukemia. 2014;28:1122–1128.

4. Goldschmidt H, Ashcroft J, Szabo Z, Garderet L. Navigating the treatment landscape in multiple myeloma: which combinations to use and when?

Ann Hematol.. 2019;98:1–18.

5. Chim CS, Kumar SK, Orlowski RZ, et al. Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond.Leukemia. 2018;32:252–262.

6. McElwain TJ, Powles RL. High-dose intravenous melphalan for plasma-cell leukaemia and myeloma.Lancet. 1983;2:822–824.

7. Barlogie B, Hall R, Zander A, Dicke K, Alexanian R. High-dose melphalan with autologous bone marrow transplantation for multiple myeloma.

Blood. 1986;67:1298–1301.

8. Barlogie B, Alexanian R, Dicke KA, et al. High-dose chemoradiotherapy and autologous bone marrow transplantation for resistant multiple myeloma.

Blood. 1987;70:869–872.

9. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome.N Engl J Med. 1996;335:91–97.

10. Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med.

2003;348:1875–1883.

11. Fermand JP, Katsahian S, Divine M, et al. High-dose therapy and autologous blood stem cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol. 2005;23:9227–9233.

12. Barlogie B, Kyle RA, Anderson KC, et al. Standard chemotherapy compared with high dose chemoradiotherapy for multiple myeloma:ﬁnal results of phase III US Intergroup Trial S9321.J Clin Oncol. 2006;24:929–936.

13. Blade J, Rosinol L, Sureda A, et al. High-dose therapy intensiﬁcation compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA.Blood. 2005;106:3755–3759.

14. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma.N Engl J Med. 1999;341:1565–1571.

15. Landgren O, Sonneveld P, Jakubowiak A, et al. Carﬁlzomib with immunomodulatory drugs for the treatment of newly diagnosed multiple myeloma.Leukemia. 2019;33(9):2127–2143.

16. Moreau P, Facon T, Attal M, et al. Comparison of 200 mg/m²melphalan and 8 Gy total body irradiation plus 140 mg/m²melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma:ﬁnal analysis of the Intergroupe Franco- phone du Myelome 9502 randomized trial.Blood. 2002;99:731–735.

17. Patel P, Oh AL, Koshy M, et al. A phase 1 trial of autologous stem cell transplantation conditioned with melphalan 200 mg/m²and total marrow irradiation (TMI) in patients with relapsed/refractory multiple myeloma.Leuk Lymphoma. 2018;59:1666–1671.

18. Lahuerta JJ, Mateos MV, Martinez-Lopez J, et al. Busulfan 12 mg/kg plus melphalan 140 mg/m²versus melphalan 200 mg/m²as conditioning regimens for autologous transplantation in newly diagnosed multiple myeloma patients included in the PETHEMA/GEM2000 study.Haematologica.

2010;95:1913–1920.

19. Bashir Q, Thall PF, Milton DR, et al. Conditioning with busulfan plus melphalan versus melphalan alone before autologous haemopoietic cell transplantation for multiple myeloma: an open-label, randomised, phase 3 trial.Lancet Haematol. 2019;6:E266–E275.

20. Roussel M, Hebraud B, Lauwers-Cances V, et al. Bortezomib and high-dose melphalan vs. high-dose melphalan as conditioning regimen before

autologous stem cell transplantation in de novo multiple myeloma patients: a phase 3 study of the Intergroupe Francophone Du Myelome (IFM 2014-02).Blood. 2017;130(suppl 1):398.

21. Gomez-Arteaga A, Mark TM, Guarneri D, et al. High-dose bendamustine and melphalan conditioning for autologous stem cell transplantation for patients with multiple myeloma.Bone Marrow Transplant. 2019;54:2027–2038.

22. Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance therapy in multiple myeloma.N Engl J Med. 2014;371:895–905.

23. Gay F, Oliva S, Petrucci MT, et al. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial.Lancet Oncol. 2015;16:1617–1629.

24. Cavo M, Hajek R, Pantani L, et al. Autologous stem cell transplantation versus bortezomib melphalan-prednisone for newly diagnosed multiple myeloma second interim analysis of the phase 3 EMN02/HO95 study.

Blood. 2017;130:397.

25. Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med.

2017;376:1311–1320.

26. Gay F, Oliva S, Petrucci MT, et al. Autologous transplant vs oral chemotherapy and lenalidomide in newly diagnosed young myeloma patients: a pooled analysis.Leukemia. 2017;31:1727–1734.

27. Dhakal B, Szabo A, Chhabra S, et al. Autologous transplantation for newly diagnosed multiple myeloma in the era of novel agent induction: a systematic review and meta-analysis.JAMA Oncol. 2018;4:343–350.

28. Gay F, Cerrato C, Rota Scalabrini D, et al. Carﬁlzomib-lenalidomide-dexamethasone (KRd) induction-autologous transplant (ASCT)-Krd consolidation vs KRd 12 cycles vs carﬁlzomib-cyclophosphamide-dexamethasone (KCd) induction-ASCT-KCd consolidation: analysis of the randomized Forte trial in newly diagnosed multiple myeloma (NDMM).Blood. 2018;132:121.

29. Barlogie B, Jagannath S, Desikan KR, et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma.Blood. 1999;93:55–65.

30. Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem- cell transplantation for multiple myeloma.N Engl J Med. 2003;349:2495–2502.

31. Cavo M, Tosi P, Zamagni E, et al. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study.J Clin Oncol. 2007;25:2434–2441.

32. Mai EK, Benner A, Bertsch U, et al. Single versus tandem high-dose melphalan followed by autologous blood stem cell transplantation in multiple myeloma: long-term results from the phase III GMMG-HD2 trial.Br J Hae- matol. 2016;173:731–741.

33. Cavo M, Gay FM, Patriarca F, et al. Double autologous stem cell transplantation signiﬁcantly prolongs progression-free survival and overall survival in comparison with single autotransplantation in newly diagnosed multiple myeloma: an analysis of Phase 3 EMN02/HO95 Study.Blood. 2017;130 (suppl 1):401.

34. Stadtmauer EA, Pasquini MC, Blackwell B, et al. Autologous transplantation, consolidation, and maintenance therapy in multiple myeloma:

results of the BMT CTN 0702 Trial.J Clin Oncol. 2019;37:589–597.

35. Kumar SK, Lacy MQ, Dispenzieri A, et al. Early versus delayed autologous transplantation after immunomodulatory agents-based induction therapy in patients with newly diagnosed multiple myeloma.

Cancer. 2012;118:1585–1592.

36. Dunavin NC, Wei L, Elder P, et al. Early versus delayed autologous stem cell transplant in patients receiving novel therapies for multiple myeloma.

Leuk Lymphoma. 2013;54:1658–1664.

37. Fermand JP, Ravaud P, Chevret S, et al. High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial.Blood. 1998;92:3131–3136.

38. Gonsalves WI, Buadi FK, Ailawadhi S, et al. Utilization of hematopoietic stem cell transplantation for the treatment of multiple myeloma: a Mayo Stratiﬁcation of Myeloma and Risk-Adapted Therapy (mSMART) consensus statement.Bone Marrow Transplant. 2019;54:353–367.

39. Garderet L, Beohou E, Caillot D, et al. Upfront autologous stem cell transplantation for newly diagnosed elderly multiple myeloma patients: a prospective multicenter study.Haematologica. 2016;101:1390–1397.

40. Muchtar E, Dingli D, Kumar S, et al. Autologous stem cell transplant for multiple myeloma patients 70 years or older.Bone Marrow Transplant.

2016;51:1449–1455.

41. Sharma M, Zhang MJ, Zhong X, et al. Older patients with myeloma derive similar beneﬁt from autologous transplantation.Biol Blood Marrow Trans- plant. 2014;20:1796–1803.

42. Auner HW, Szydlo R, Hoek J, et al. Trends in autologous hematopoietic cell transplantation for multiple myeloma in Europe: increased use and improved outcomes in elderly patients in recent years.Bone Marrow Transplant. 2015;50:209–215.

43. Bashir Q, Shah N, Parmar S, et al. Feasibility of autologous hematopoietic stem cell transplant in patients aged70 years with multiple myeloma.

Leuk Lymphoma. 2012;53:118–122.

44. Munshi PN, Hari P, Vesole DH, et al. Breaking the glass ceiling of age in transplant in multiple myeloma.Blood. 2019;134(suppl 1). Abst 782.

45. Facon T, Kumar S, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma.N Engl J Med. 2019;380:2104–2115.

(9)

46. Auner HW, Iacobelli S, Sbianchi G, et al. Melphalan 140 mg/m²or 200 mg/

m²for autologous transplantation in myeloma: results from the Collabo- ration to Collect Autologous Transplant Outcomes in Lymphoma and Mye- loma (CALM) study. A report by the EBMT Chronic Malignancies Working Party.Haematologica.. 2018;103:514–521.

47. Augeul-Meunier K, Caillot D, Stoppa AM, et al. Extending autologous hematopoietic stem cell transplantation asﬁrst line treatment in multiple myeloma patients with severe renal impairment: a retrospective study of the Francophone Society of Stem Cell Transplantation and Cellular Ther- apy (SFGM-TC).Blood.. 2016;128(22). Abst 4637.

48. Mahindra A, Parameswaran H, Fraser R, et al. Patients (pts) with renal insufﬁciency (RI) and multiple myeloma (MM) have similar outcomes after autologous hematopoietic cell transplantation (AHCT) as those without.Blood.. 2016;128(22). Abst 994.

49. Dimopoulos MA, Sonneveld P, Leung N, et al. International Myeloma Working Group recommendations for the diagnosis and management of myeloma-related renal impairment.J Clin Oncol. 2016;34:1544–1557.

50. Li AY, Atenafu EG, St. Bernard R, et al. Toxicity and survival outcomes of autologous stem cell transplant in multiple myeloma patients with renal insufﬁciency: an institutional comparison between two eras.Bone Marrow Transplant.. 2020;55:578–585.

51. Gay F, Cerrato C, Petrucci MR, et al. Efﬁcacy of carﬁlzomib lenalidomide dexamethasone (KRD) with or without transplantation in newly diagnosed myeloma according to risk status: results from the FORTE trial.J Clin Oncol ASCO.. 2019;37. Abst 8002.

52. Giralt S, Costa LJ, Maloney D, et al. Tandem autologous-autologous versus autologous-allogeneic hematopoietic stem cell transplant for patients with multiple myeloma: long-term follow-up results from the Blood and Marrow Transplant Clinical Trials Network 0102 Trial.Biol Blood Marrow Transplant. 2020;26:798–804.

53. Auner HW, Szydlo R, Rone A, et al. Salvage autologous stem cell transplantation for multiple myeloma relapsing or progressing after up-front autologous transplantation.Leuk Lymphoma. 2013;54:2200–2204.

54. Cook G, Williams C, Brown JM, et al. High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open- label, phase 3 trial.Lancet Oncol. 2014;15:874–885.

55. Goldschmidt H, Baertsch MA, Schlenzka J, et al. Salvage autologous transplant and lenalidomide maintenance versus continuous lenalidomide/

dexamethasone for relapsed multiple myeloma: results of the randomized GMMG Phase III Multicenter Trial Relapse.Blood. 2018;132(suppl 1):253.

56. Garderet L, Iacobelli S, Koster L, et al. Outcome of a salvage third autologous stem cell transplantation in multiple myeloma.Biol Blood Marrow Transplant. 2018;24:1372–1378.

57. Cook G, Royle KL, Pawlyn C, et al. Quality of life during and following sequential treatment of previously untreated patients with multiple myeloma:ﬁndings of the Medical Research Council Myeloma IX randomised study.Br J Haematol. 2018;182:816–829.

58. Ahmedzai SH, Snowden JA, Ashcroft AJ, et al. Patient-reported outcome results from the open-label, randomized phase III Myeloma X trial evaluating salvage autologous stem-cell transplantation in relapsed multiple myeloma.J Clin Oncol.. 2019;37:1617–1628.

59. Roussel M, Hebraud B, Hulin C, et al. Health-related quality of life results from the IFM 2009 trial: treatment with lenalidomide, bortezomib, and dexamethasone in transplant-eligible patients with newly diagnosed multiple myeloma.Leuk Lymphoma. 2020;22:1–11.https://doi.org/10.1080/

10428194.2020.1719091. Online ahead of print.PMID: 32090636.

60. Sahebi F, Iacobelli S, Sbianchi G, et al. Incidence of second primary malignancies after autologous transplantation for multiple myeloma in the era of novel agents.Biol Blood Marrow Transplant. 2018;24:930–936.

61. Voorhees PM, Kaufman JL, Laubach JP, et al. Depth of response to daratumumab (DARA), lenalidomide, bortezomib, and dexamethasone (RVd) improves over time in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): Grifﬁn study update.Blood. 2019;134 (supp1)). Abst 691.

62. Franssen LE, Mutis, Lokhorst T, van de Donk NWCJ HM. Immunotherapy in myeloma: how far have we come? Ther Adv Hematol.. 2019;10.

2040620718822660.

63. Iftikhar A, Hassan H, Iftikhar N, et al. Investigational monoclonal antibodies in the treatment of multiple myeloma: a systematic review of agents under clinical development.Antibodies (Basel). 2019(2). 8.

64. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma.N Engl J Med. 2016;375:754–766.

65. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma.N Engl J Med. 2016;375:1319–1331.

66. Mikhael J, Richardson P, Usmani SZ, et al. A phase 1b study of isatuximab plus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma.Blood. 2019;134:123–133.

67. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem- cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA):

a randomised, open-label, phase 3 study. Lancet. 2019;394(10192):

29–38.

68. Mateos MV, Dimopoulos MA, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma.N Engl J Med.

2018;378:518–528.

69. Landgren O, Thoren K, Hultcrantz M, et al. Bone marrow-based and longitu- dinal blood based MRD tracking in newly diagnosed multiple myeloma patients treated with daratumumab, carﬁlzomib, lenalidomide and dexamethasone (DKRd): a correlative and clinical phase II study. Blood.

2018;132:3281.

70. Weisel K, Asemissen AM, Schieferdecker A, et al. Isatuximab, carﬁlzomib, lenalidomide and dexamethasone (I-KRd) in front-line treatment of high- risk multiple myeloma: results of the safety run-in cohort in the phase II, multicenter GMMG-CONCEPT trial.Paper presented at: Abstracts 17th International Myeloma Workshop, Boston. September 12-15, 2019.

71. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma.N Engl J Med. 2017;377:2531–

2544.

72. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med.

2018;378:439–448.

73. Turtle CJ, Hay KA, HanafiLA, et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor- modified T cells after failure of ibrutinib.J Clin Oncol. 2017;35:3010–3020.

74. Ramos CA, Savoldo B, Torrano V, et al. Clinical responses with T lympho- cytes targeting malignancy-associated kappa light chains.J Clin Invest.

2016;126:2588–2596.

75. Garfall AL, Maus MV, Hwang WT, et al. Chimeric antigen receptor T cells against CD19 for multiple myeloma.N Engl J Med. 2015;373:1040–1047.

76. Garfall AL, Stadtmauer EA, Hwang WT, et al. Anti-CD19 CAR T cells with high-dose melphalan and autologous stem cell transplantation for refractory multiple myeloma.JCI Insight. 2018;3: e120505.

77. Ali SA, Shi V, Maric I, et al. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma.

Blood. 2016;128:1688–1700.

78. Brudno JN, Maric I, Hartman SD, et al. T cells genetically modiﬁed to express an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma.J Clin Oncol.

2018;36:2267–2280.

79. Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma.N Engl J Med. 2019;380:1726–1737.

80. Cohen AD, Garfall AL, Stadtmauer EA, et al. B cell maturation antigen-spe- ciﬁc CAR T cells are clinically active in multiple myeloma.J Clin Invest.

2019;129:2210–2221.

81. Xu J, Chen LJ, Yang SS, et al. Exploratory trial of biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma.Proc Natl Acad Sci U S A. 2019;116:9543–9551.

82. Zhao WH, et al. A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma.J Hematol Oncol..

2018;11:141.

83. Shi X, Yan L, Shang J, et al. Tandem autologous transplantation and combined infusion of CD19 and BCMA-speciﬁc chimeric antigen receptor T cells for high risk MM: initial safety and efﬁcacy report from a clinical pilot study.Blood. 2018;132(suppl 1). Abst 1009.

84. Gauthier J, Turtle CJ. Insights into cytokine release syndrome and neurotoxicity after CD19-speciﬁc CAR-T cell therapy.Curr Res Transl Med.

2018;66:50–52.

85. Yan Z, Cao Jiang, Cheng Hai, et al. A combination of humanised anti-CD19 and anti- BCMA CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, phase 2 trial.Lancet Hematol. 2019;6:e521–e529.

86. Prommersberger S, Jetani H, Danhof S, et al. Novel targets and technolo- gies for CAR-T cells in multiple myeloma and acute myeloid leukemia.

Curr Res Transl Med. 2018;66:37–38.

87. Smith EL, Harrington K, Staehr M, et al. GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells.Sci Transl Med. 2019;27:11.. pii: eaau7746.

88. Li C, Mei H, Hu Y, et al. A bispeciﬁc CAR-T cell therapy targeting BCMA and CD38 for relapsed/refractory multiple myeloma: updated results from a phase 1 dose-climbing trial.Blood. 2019;134(supp 1). Abst 930.

89. Maus MV, June CH. Making better chimeric antigen receptors for adoptive T-cell therapy.Clin Cancer Res. 2016;22:1875–1884.

90. Bjordahl R, Gaidarova S, Woan K, et al. FT538: preclinical development of an off-the-shelf adoptive NK cell immunotherapy with targeted disrup- tion of CD38 to prevent anti-CD38 antibody-mediated fratricide and enhance ADCC in multiple myeloma when combined with daratumumab.

Blood. 2019;134(suppl 1)). Abst 133.

91. Gay F, Engelhardt M, Terpos E, et al. From transplant to novel cellular therapies in multiple myeloma: European Myeloma Network guidelines and future perspectives.Haematologica. 2018;103:197–211.

92. Duarte RF, Labopin M, Bader P, et al. Indications for haematopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2019.Bone Marrow Trans- plant.. 2019;54:1525–1552.

93. Pratt G, Morris TC. Review of the NICE guidelines for multiple myeloma.

Int J Lab Hematol. 2017;39:3–13.