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Opinion

The Role of Autologous Stem Cell Transplantation in the Treatment of Newly Diagnosed Multiple Myeloma: Is It Time to Rethink the Paradigm in the Era of Targeted Therapy?

by
Paul G. Richardson
Department of Medical Oncology, Dana-Farber Cancer Institute, Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Boston, MA 02115, USA
Hemato 2024, 5(2), 144-156; https://doi.org/10.3390/hemato5020012
Submission received: 7 March 2024 / Revised: 22 March 2024 / Accepted: 1 April 2024 / Published: 9 April 2024

Abstract

:
High-dose melphalan (HDM) plus autologous stem cell transplant (ASCT) remains a standard-of-care treatment approach for eligible patients with newly diagnosed multiple myeloma (NDMM) based on demonstrated superiority in terms of progression-free survival (PFS) versus nontransplant approaches. Very high rates of minimal residual disease (MRD)-negative responses are also being seen with novel triplet and quadruplet induction regimens plus HDM-ASCT. However, recent clinical trials have shown no overall survival benefit with transplant versus nontransplant approaches. Furthermore, HDM is associated with several important downsides, including acute and long-term toxicities, transient decreases in quality of life, the need for hospitalization, an increased mutational burden at relapse, and an elevated risk of second primary malignancies. In this context, given the highly heterogeneous nature of MM in the NDMM patient population, as well as the continued emergence of novel agents and treatment approaches, there is an increasing rationale for considering deferred HDM-ASCT approaches in selected patients. Approaches under investigation include MRD-adapted therapy and the use of novel immune-based therapies as alternatives to HDM-ASCT. Ongoing developments in understanding the pathobiology and prognostic factors in NDMM, plus immune profiling and routine MRD evaluation, will result in novel, HDM-sparing treatment paradigms, enabling further improvement in patient outcomes.

1. Introduction

It has now been over 40 years since the first publication by Tim McElwain and Ray Powles on their pioneering work with high-dose melphalan (HDM) for patients with multiple myeloma (MM) [1]. The past four decades have witnessed an explosion of new treatments, such that the modern therapeutic armamentarium is barely recognizable from that of the 1980s. And yet, HDM not only endures but also retains its position as a standard-of-care approach, together with autologous stem cell transplantation (ASCT), for eligible patients with newly diagnosed MM (NDMM) [2,3,4,5]. Clearly, melphalan matters in MM. However, as the late, great Tim McElwain himself remarked to me when I was fortunate enough to be working for him at the Royal Marsden in Sutton, UK in 1990, “We will be doing our patients a real service if we can do better than melphalan in the years ahead”. So, the question now is can we do better? Can we build on the positive aspects of HDM while leaving behind the undesirable features that can be a burden—or potentially worse—for our patients? In the emerging era of highly efficacious immune-based therapies and minimal residual disease (MRD)-guided therapy, I believe that, in an increasing number of selected patients, we can.

2. The Benefits of HDM

Large, randomized trials have unequivocally demonstrated the superiority of HDM-ASCT-based versus non-HDM-ASCT-based approaches for NDMM in terms of progression-free survival (PFS), both prior to [6,7] and in the era of novel agents [3,8,9]. In the DETERMINATION phase 3 trial of lenalidomide–bortezomib–dexamethasone (RVd) ± HDM-ASCT, followed by lenalidomide maintenance to progression, median PFS with RVd + ASCT versus RVd-alone was 67.5 versus 46.2 months, a benefit of 21.3 months, and the risk of progression/death was 35% lower with RVd + ASCT [3].
Furthermore, modern triplet and quadruplet induction regimens coupled with ASCT and maintenance therapy are demonstrating ever higher rates of deep and durable responses, including MRD-negative rates of up to 94% [3,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31]. Importantly, in the MANHATTAN study, MRD negativity was seen in 71% of patients without ASCT as part of a prespecified analysis, using daratumumab–carfilzomib–lenalidomide–dexamethasone as induction remission therapy, supporting the efficacy of the quadruplet alone [31]. MRD negativity represents an increasingly important goal of MM therapy [32] given the high rates now achievable and the strong prognostic value of MRD elimination for improved outcomes [11,13,14,33,34]. Of note, the proportion of patients achieving MRD-negative status was higher in the RVd + ASCT versus RVd-alone arm in both DETERMINATION (54% vs. 40% at the start of maintenance) [3] and the IFM 2009 trial (29.8% vs. 20.4%, p = 0.01) [11], although the PFS benefit in those patients in DETERMINATION who achieved MRD-negative status was similar irrespective of treatment arm [11].
These deep responses may be associated, in part, with the profound effects of HDM on both tumor cells and the immunosuppressive tumor microenvironment [35,36]; not only is the “stemness” of the disease targeted but also cytokine secretion and other signaling processes in MM cells that result in the stimulation of immunosuppressive cells and the inhibition of cytotoxic effector T cells and others, contributing to the depth of responses seen. Myeloablative conditioning with HDM-ASCT “resets” elements of the tumor microenvironment, thereby engendering an improved antitumor immune microenvironment and tumor-specific immunity following cellular reconstitution [37,38]. The continued success of HDM may be due to these beneficial immune effects, as well as their potential impacts on MM stem-like cells in the bone marrow milieu [39].

3. The Downsides of HDM

Although some early trials demonstrated an overall survival (OS) benefit with the use of ASCT-based versus non-ASCT-based approaches for NDMM [6,7], more recent evidence indicates no OS benefit from upfront transplant approaches with the use of novel combination therapy as induction and maintenance treatment [3,8,9,11,40,41]. Both the DETERMINATION and IFM 2009 trials demonstrated highly significant improvements in PFS with RVd + ASCT but no OS improvement after a median follow-up of >6 and almost 7.5 years, respectively [3,11]. While this may have reflected the use of salvage transplant in 77% of RVd-alone patients in IFM 2009 [11], only 28% of RVd-alone patients in the DETERMINATION trial had received subsequent HDM-ASCT [3]. In the modern era, with numerous, highly active salvage options available, early PFS benefit may no longer translate into OS benefit, especially if there are competing risks [3,40,42].
It is therefore important to consider the disadvantages of HDM-ASCT. These include both acute toxicities and long-term adverse effects. There are significantly higher rates of grade ≥ 3 hematologic toxicities associated with myeloablative HDM compared with nontransplant approaches [3,8,11], plus increased risks of infections and gastrointestinal disorders [3,8]. While the rate of acute treatment-related mortality is now gratifyingly low at 2% or less [3,8,40], elevated rates of acute toxicities, coupled with the need for hospitalization and the burden associated with treatment, also result in a transient but clinically meaningful decrease in patients’ quality of life while undergoing transplant [3,8,43]. Patients may therefore prefer more convenient and tolerable treatment, based on these and other real-world factors [44].
The long-term effects of HDM are also important. In DETERMINATION, elevated rates of grade ≥ 3 hematologic toxicities and infections were seen during lenalidomide maintenance following RVd + ASCT versus RVd-alone, which impacted lenalidomide tolerability and dosing [3]. DETERMINATION also exemplified the well-known mutagenic effect of HDM [3,45], with a significantly higher rate of acute myeloid leukemia (AML) and/or myelodysplastic syndrome (MDS) seen with RVd + ASCT versus RVd alone (n = 10 vs. 0, p = 0.002), events that had resulted in death in four out of ten patients at data cut-off [46]. Additionally, an increasing risk of AML/MDS over time has been demonstrated in an analysis of the Center for International Blood and Marrow Transplant Research registry [47]. More broadly, and importantly, HDM has been shown to increase the mutational burden at relapse [48] compared with non-transplant-based therapy [49], with a four-fold increase observed in the IFM/DFCI 2019 trial, which may adversely impact not only the risk of secondary hematologic malignancies but also increase resistance and growth advantages and decrease disease sensitivity to subsequent treatment over time.

4. One Size Does Not Fit All—Personalized Treatment Decision Making

4.1. Patient and Disease Heterogeneity

Patients with NDMM are typically a diverse population, with differing preferences and needs [44,50]. Transplant-eligible patients’ ages can range from ~30 years to >70 years [3,8,17], and they may have a wide variety of real-world considerations in their treatment decision making. Real-world effectiveness depends not only on demonstrated clinical trial efficacy but also on factors including work requirements, disruption to activities of daily living, impact on quality of life, management of comorbidities, symptom burden, and treatment-related toxicity [44,50]. Strategic considerations and a long-term perspective are thus critical, as transplant-eligible patients can expect to survive for a median of ~10 years [51], warranting evaluation of potential long-term toxicities and sequelae [47,52]. Furthermore, our understanding of specific patient-related factors is evolving and may in turn help guide HDM use. In this context, data from DETERMINATION indicated possible differential PFS benefit from transplant-based versus non-transplant-based approaches according to factors such as race, performance status, and body mass index, warranting further exploration [3,53,54]. Also of interest is the potential impact of clonal hematopoiesis of indeterminate potential (CHIP) on patients’ susceptibility to developing therapy-related myeloid neoplasms post transplant [55]; the presence of CHIP is an adverse prognostic factor in MM [55] and may facilitate the evolution of myeloid neoplasms following ASCT [56,57,58], suggesting its role as a biomarker of increased genotoxic risk [59].
MM is intrinsically a highly heterogeneous disease, with multiple prognostic clinical features. Immune dysfunction is fundamental to disease pathobiology [37], and MM is also genetically unstable and carries a high mutational burden [60,61]. Specific disease-related factors such as disease stage, isotype, and cytogenetic abnormalities are associated with long-term outcomes as well as with sensitivity to specific treatment approaches, including HDM [61]. Ongoing studies will help confirm characteristics indicating the potential need for transplant-based therapy, such as specific high-risk cytogenetic abnormalities, as well as characteristics that could inform deferring HDM-ASCT for selected patients, and so avoid both toxicity and worse long-term outcomes.

4.2. MRD Evaluation for Adaptive Therapy

The utility of MRD assessment for guiding treatment decision making is increasing given the high rates of MRD-negative responses being achieved with novel therapeutic approaches [3,8,9,10,11,12,13,14,15,17]. MRD negativity is not only strongly associated with better long-term outcomes [33] but also a direct surrogate for PFS, independent of the treatment approach [34]. Preliminary data from DETERMINATION showed similar PFS from the start of lenalidomide maintenance among MRD-negative patients on the RVd + ASCT and RVd-alone arms [3]. MRD-adapted therapeutic approaches are now being investigated with the aim of using risk-adapted consolidation treatment and reserving ASCT in select patients, such as in the ongoing MIDAS and ADVANCE trials (Figure 1).
Additional studies will also inform the optimal duration of maintenance in patients achieving and sustaining MRD-negative status; indeed, it is sustained MRD negativity (two assessments ≥ 1 year apart) rather than simply achieving MRD-negative status that is more highly prognostic for PFS and OS [25,63] and a prerequisite for a functional “cure”. Continuous induction/maintenance until disease progression is the standard of care in some geographies [4,5]; however, for those achieving MRD negativity, with or without ASCT, it will be important to understand “how much is enough”—i.e., after what duration of sustained MRD negativity can treatment be stopped without adversely affecting outcome—in order to avoid toxicities from unnecessarily prolonged therapy. Furthermore, the threshold for MRD-negative status in treatment decision making—i.e., 10−5 or 10−6—is an area of ongoing study, with the more sensitive threshold offering greater prognostic value [33,64] and emerging as the gold standard in research and clinical trials.

5. Alternatives to HDM-ASCT and the Emerging Role of Quadruplet Therapy

The evolving therapeutic armamentarium for NDMM includes multiple active, immune-based agents and triplet/quadruplet combination regimens, such as those utilizing immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies, which provide very high rates of MRD negativity both in conjunction with HDM-ASCT as well as in ASCT-sparing approaches (Table 1), leading to very promising outcomes [3,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31]. Thus, an increasing proportion of transplant-eligible NDMM patients could potentially defer transplant based on achieving MRD negativity; however, for patients with high-risk and ultra-high-risk cytogenetics, ongoing studies are primarily investigating quadruplet therapies as induction and consolidation with HDM-ASCT and doublet or triplet maintenance [18,23,25,26,28]. Furthermore, the small percentage of patients who have primary refractory disease to triplet or quadruplet induction may achieve improved second-line outcomes by utilizing HDM-ASCT in this setting [65,66], although optimal therapy for this population remains an area of ongoing study and unmet need for innovative therapies.
In addition to quadruplet regimens, there are multiple novel immune therapy approaches approved or being studied, including cereblon E3 ligase modulators (CELMoDs®) [67,68], antibody–drug conjugates [69], bispecific antibodies/T cell engagers [69], and chimeric antigen receptor (CAR) T cell therapies [69]. Through the immune mechanisms of these agents, substantial levels of antimyeloma immune effects that may complement or obviate the need for those arising from HDM are being described, with these agents being studied in early-phase and phase 3 trials in NDMM (Table 2) and additional studies planned, including a next-generation trial following on from DETERMINATION, called DETERMINATION 2. The future treatment landscape will likely contain an increased number of immune-based options, challenging the standard use of HDM-ASCT for eligible patients. Furthermore, other novel agents have been developed, including melphalan flufenamide (melflufen), which is fully approved for relapsed/refractory MM in Europe and elsewhere, although its US approval was recently withdrawn by the Food and Drug Administration for complex and controversial regulatory reasons. This notwithstanding, melflufen is a novel targeted cytotoxic drug–peptide conjugate that delivers the alkylator warhead directly to plasma cells and may thereby retain melphalan’s cytotoxic activity, including against “stemness”, while potentially resulting in less toxicity and an improved therapeutic index [70,71]. Moreover, current data support the use of this novel, first-in-class, peptide–drug conjugate in the management of relapsed and refractory MM in additional combination approaches, such as those recently reported in the ANCHOR study [72] and LIGHTHOUSE trial [73], with promising results seen using either bortezomib or daratumumab in combination with melflufen and dexamethasone.

6. Conclusions

Therapeutic innovations for transplant-eligible NDMM have resulted in significant improvements in PFS and OS, and ongoing approvals will further augment this, with potent quadruplet regimens emerging as new standards of care. The role of HDM-ASCT has already evolved, through MRD-adapted approaches, and the next wave of immune therapies will further expand alternative combination therapy options. Ongoing refinement and understanding of prognostic factors, characteristics, and biomarkers for treatment decision making, coupled with immune profiling and routine MRD evaluation, will provide the necessary tools to “do better” than HDM for select subgroups, further improving outcomes for our patients.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

Steve Hill, of Ashfield MedComms, an Inizio company, for medical writing and editing support, funded by Dana-Farber Cancer Institute and the RJ Corman Multiple Myeloma Research Fund.

Conflicts of Interest

P.G.R. discloses service on advisory committees/consulting for Celgene/Bristol Myers Squibb, GSK, Karyopharm, Oncopeptides, Regeneron, Sanofi, and Takeda, and Research grants from Oncopeptides and Karyopharm.

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Figure 1. Examples of MRD-adapted therapeutic approach—top, the MIDAS trial (IFM 2020-02; NCT04934475); bottom, the ADVANCE trial (NCT04268498) [62]. Red shadow indicates the HDM-ASCT-sparing treatment pathway for patients achieving MRD-negative status. ASCT, autologous stem cell transplantation; Dara, daratumumab; HDM, high-dose melphalan; IFM, Intergroupe Francophone du Myelome; KRd, carfilzomib, lenalidomide, dexamethasone; MRD, minimal residual disease; NDMM, newly diagnosed multiple myeloma; neg, negative; pos, positive.
Figure 1. Examples of MRD-adapted therapeutic approach—top, the MIDAS trial (IFM 2020-02; NCT04934475); bottom, the ADVANCE trial (NCT04268498) [62]. Red shadow indicates the HDM-ASCT-sparing treatment pathway for patients achieving MRD-negative status. ASCT, autologous stem cell transplantation; Dara, daratumumab; HDM, high-dose melphalan; IFM, Intergroupe Francophone du Myelome; KRd, carfilzomib, lenalidomide, dexamethasone; MRD, minimal residual disease; NDMM, newly diagnosed multiple myeloma; neg, negative; pos, positive.
Hemato 05 00012 g001
Table 1. MRD negativity rates with modern triplet and quadruplet induction therapies, with or without high-dose melphalan plus ASCT, followed by immune-therapy-based maintenance.
Table 1. MRD negativity rates with modern triplet and quadruplet induction therapies, with or without high-dose melphalan plus ASCT, followed by immune-therapy-based maintenance.
StudyInduction TherapyASCTConsolidation TherapyMaintenance TherapyMRD-Negativity Rate
IFM 2009 [8,11]RVd × 3 3-week cyclesNoRVd × 5 3-week cyclesR, 1 year20%
IFM 2009 [8,11]RVd × 3 3-week cyclesYesRVd × 2 3-week cyclesR, 1 year30%
GRIFFIN [12,29]RVd × 4 3-week cyclesYesRVd × 2 3-week cyclesR30%
DSMM XVII [24]KRd × 6 4-week cyclesYesKRd × 4 4-week cyclesR35% post induction
GMMG-HD7 [22]RVd × 3 6-week cyclesNoR + Isa vs. R36% post induction
DETERMINATION [3]RVd × 3 3-week cyclesNoRVd × 5 3-week cyclesR until progression40% *
FORTE [9]KCd × 4 4-week cyclesYesKCd × 4 4-week cyclesKR vs. R43%
CASSIOPEIA [10]VTd × 4 4-week cyclesYesVTd × 2 4-week cyclesDara vs. observation44%
PERSEUS [27]RVd × 4 4-week cyclesYesRVd × 2 4-week cyclesR until progression48%
GEM2012MENOS65 [14]RVd × 6 3-week cyclesYesRVd × 2 3-week cyclesIRd or Rd49% (SR); 37% (HR)
DETERMINATION [3]RVd × 3 3-week cyclesYesRVd × 2 3-week cyclesR until progression54% *
FORTE [9]KRd × 12 4-week cyclesNoKR vs. R56%
FORTE [9]KRd × 4 4-week cyclesYesKRd × 4 4-week cyclesKR vs. R62%
Myeloma XI [13]CTD/CRD/KCRD × 4 cyclesYesR vs. none63% (3 months post-ASCT)
IsKia [21]KRd × 4 4-week cyclesYesKRd × 4, KRd-light × 12R67% post consolidation
CASSIOPEIA [10]Dara-VTd × 4 4-week cyclesYesVTd × 2 4-week cyclesDara vs. observation44%
DSMM XVII [24]Elo-KRd × 6 4-week cyclesYesElo-KRd × 4 4-week cyclesElo-R50% post induction
GMMG-HD7 [22]Isa-RVd × 3 6-week cyclesNoR + Isa vs. R50% post induction
IFM 2018-01 [30]Dara-IRd × 6 3-week cyclesYesDara-IRd × 4 4-week cyclesR, 2 years51% (SR, after 1 year of maintenance)
NCT04113018 [16]Dara-KRd × 8 4-week cyclesNo/Yes/No–/Dara-KRd × 12 4-week cycles/Dara-KRd × 12 4-week cyclesR62% post induction
Derman et al. [19]Dara-KRd × 24 4-week cyclesNo63% (post 8 cycles)
GRIFFIN [12,29]Dara-RVd × 4 3-week cyclesYesDara-RVd × 2 3-week cyclesDara-R64%
SKylaRk [26]Isa-KRd × 4 4-week cyclesYes/NoIsa-KRd × 2/4 4-week cyclesIsa-KR (HR), R (SR)66% (post 6 cycles)
GMMG-CONCEPT [25]Isa-KRd × 6 4-week cyclesYes/NoIsa-KRd × 4 4-week cyclesIsa-KR, 26 cycles68%/54%
IRB16-1138 [20]Elo-KRd × 12 4-week cyclesNoElo-KRd × 0–12 4-week cyclesElo-Rd70%
MANHATTAN [31]Dara-KRd × 8 4-week cyclesNo71%
PERSEUS [27]Dara-RVd × 4 4-week cyclesYesDara-RVd × 2 4-week cyclesDara-R/R until progression75%
IsKia [21]Isa-KRd × 4 4-week cyclesYesIsa-KRd × 4, Isa-KRd-light × 12R77% post consolidation
MASTER [17,18]Dara-KRd × 4 4-week cyclesYesDara-KRd × 0–8 4-week cyclesR38% (post induction)
81% (post MRD-directed consolidation)
IFM2018-04 [28]Dara-KRd × 6 4-week cyclesYesDara-KRd × 4 4-week cyclesDara-R, 2 years94%
OPTIMUM/MUKnine (UHR NDMM) [23]Dara-CRVd × 6 cyclesYesDara-RVd × 6 cycles, Dara-RV × 12 cyclesDara-R until progression64% post ASCT
* Subset of patients at start of maintenance therapy. ASCT, autologous stem cell transplantation; CRD, cyclophosphamide, lenalidomide, dexamethasone; CTD, cyclophosphamide, thalidomide, dexamethasone; Dara, daratumumab; DSMM, Deutsche Studiengruppe Multiples Myelom; Elo, elotuzumab; GEM, Grupo Español de Mieloma; GMMG, German-Speaking Myeloma Multicenter Group; HR, high-risk cytogenetics; IFM, Intergroupe Francophone du Myelome; IRd, ixazomib, lenalidomide, dexamethasone; Isa, isatuximab; KCd, carfilzomib, cyclophosphamide, dexamethasone; KCRD, carfilzomib, cyclophosphamide, lenalidomide, dexamethasone; KR(d), carfilzomib, lenalidomide, (dexamethasone); MRD, minimal residual disease; NDMM, newly diagnosed multiple myeloma; R(d), lenalidomide (plus dexamethasone); RVd, lenalidomide, bortezomib, dexamethasone; SR, standard-risk cytogenetics; UHR, ultra high-risk; VTd, bortezomib, thalidomide, dexamethasone.
Table 2. Novel immune-based therapies under investigation in the setting of NDMM (ongoing trials per ClinicalTrials.gov, accessed on 20 March 2024).
Table 2. Novel immune-based therapies under investigation in the setting of NDMM (ongoing trials per ClinicalTrials.gov, accessed on 20 March 2024).
AgentStudyPhaseClinicalTrials.gov IDSettingPrimary EndpointInitial Completion Date
CAR T cell therapies
Ide-celKarMMa-2 [74]2NCT03601078Inadequate response to ASCT in 1st lineORR
CR rate
July 2025
KarMMa-93NCT06045806Ide-cel + R vs. R maintenance for sub-optimal response post ASCTPFSMarch 2031
BMTCTN19022NCT05032820Sub-optimal response post ASCT and R maintenancesCR/CR rate at 6 monthsJanuary 2025
Cilta-celCARTITUDE-6 [75]3NCT05257083
-
NDMM
-
Dara-RVd, cilta-cel, R maintenance; vs. Dara-RVd, ASCT, Dara-RVd, R maintenance
PFS
Sustained MRD-neg CR
June 2033
CARTITUDE-22NCT04133636
-
Cohort D: <CR post ASCT for NDMM
-
Cohort E: High-risk NDMM; Dara-RVd, cilta-cel, R maintenance
-
Cohort F: Standard-risk NDMM
MRD-negMay 2025
CARTITUDE-53NCT04923893
-
Non-transplant NDMM
-
RVd–cilta-cel vs. RVd-Rd
PFSJune 2026
Antibody–drug conjugates
Belantamab mafodotinGEM-BELA-RVd2NCT04802356
-
Belantamab mafodotin + RVd induction/consolidation
-
ASCT
-
Belantamab mafodotin + R maintenance
Safety, AEsJuly 2025
LCI-HEM-NDMYE-KRDB-0011/2NCT04822337
-
Belantamab mafodotin + KRd
-
High-risk NDMM
CR rateOctober 2024
Winship5382-212NCT05208307Belantamab mafodotin plus Pom-dex as post-ASCT maintenance in high-risk patientsCR rateOctober 2024
I 7977202NCT04876248Belantamab mafodotin plus R as post-ASCT maintenance in MRD-pos patientsMRD-neg rateSeptember 2026
MDACC 2021-02012NCT05091372Belantamab mafodotin plus R as MRD-guided post-ASCT maintenanceMRD-pos to MRD-neg rateMarch 2025
UPCC 374202NCT04680468Belantamab mafodotin prior to ASCT and with R as maintenanceMRD-neg rateJuly 2026
DREAMM-91NCT04091126Belantamab mafodotin + RVd or Rd, nontransplant settingSafety, AEsApril 2025
MC19891/2NCT04892264Belantamab mafodotin + Dara-Rd, nontransplant settingCR rateMarch 2025
EAE1201/2NCT05280275Belantamab mafodotin + Dara-Rd, nontransplant settingSafety, AEs
ORR
March 2026
EAE1281/2NCT05573802Belantamab mafodotin + Rd + nirogacestat, nontransplant settingSafety, DLTs, AEs
ORR
October 2026
EAE-20201/2NCT04808037Belantamab mafodotin + Rd, nontransplant settingSafety, AEs
ORR
September 2028
Bispecific antibodies/T cell engagers
Teclistamab (BCMA × CD3)MASTER-22NCT05231629
-
MRD-pos post ASCT
-
Dara-R vs. Dara-teclistamab as consolidation and maintenance
Sustained MRD-neg rateDecember 2026
IFM 2021-012NCT05572229
-
Elderly NDMM
-
Teclistamab + Dara-R
VGPR rateMay 2025
MajesTEC-21NCT04722146
-
Teclistamab + Dara-RV
-
Teclistamab + Dara-R
Safety, DLTsOctober 2024
MajesTEC-4 [76]3NCT05243797Teclistamab-R vs. R as post-ASCT maintenancePFSApril 2028
MajesTEC-5/GMMG-HD102NCT05695508
-
Teclistamab-Dara-R(V)d + ASCT
-
Teclistamab-Dara-R maintenance
SafetyOctober 2026
MajesTEC-7 [77]3NCT05552222
-
Nontransplant NDMM
-
Teclistamab-Dara-R vs. Dara-Rd
PFS
MRD-neg CR
May 2029
GEM-TECTAL2NCT05849610
-
High-risk NDMM
-
Dara-RVd Teclistamab-Dara Teclistamab-Dara or Talquetamab-Dara
MRD-neg CRJanuary 2025
Elranatamab (BCMA × CD3)MagnetisMM-7 [78]3NCT05317416
-
MRD-positive post ASCT
-
Elranatamab vs. R
PFSAugust 2027
MagnetisMM-6 [79]3NCT05623020
-
Nontransplant NDMM
-
Elranatamab + Dara-R vs. Dara-Rd
PFS
MRD-neg rate
March 2028
NCI-2024-001102NCT06207799Pre-ASCT purging/post-ASCT maintenanceSafetyDecember 2029
Talquetamab (GPRC5D × CD3)MonumenTAL-21NCT05050097
-
MM—setting not specified
-
Talquetamab plus Dara-K/K/Dara-R/R/Pom
Safety
DLTs
December 2024
Cevostamab (FcRH5 × CD3)PLYCOM1/2NCT05583617
-
Post-transplant maintenance in high-risk cytogenetics NDMM
-
Cevostamab + R + tocilizumab
Safety,
Response rates
PFS, OS
March 2026
CELMoDs
IberdomideMIDAS
IFM 2020-02
3NCT04934475Iberdomide + Isa vs. R + Isa as post-ASCT maintenanceMRD-neg rateDecember 2024
EXCALIBER-Maintenance3NCT05827016Iberdomide vs. R maintenance post ASCTPFSMarch 2029
GMMG-HD9/DSMM XVIII3NCT06216158Iberdomide + Isa vs. iberdomide maintenance post ASCT2-year MRD-neg rateDecember 2028
GEM21menos653NCT05558319Iberdomide + Isa-Vd vs. RVd vs. Isa-RVdMRD-neg rateApril 2027
CC-220-MM-0011/2NCT02773030
-
Iberdomide + Vd in NDMM
-
Iberdomide + Dara-dex in transplant-ineligible NDMM
Safety
ORR
July 2026
BOREALIS2NCT05272826
-
Iberdomide +Vd in transplant-ineligible NDMM
sCR rateMarch 2028
EMN26 [80]2NCT04564703
-
Single-agent iberdomide maintenance post ASCT
Improved efficacy
Tolerability
December 2027
IBEX2NCT06107738Iberdomide + SC Dara as post-ASCT maintenance12-month MRD-neg rateDecember 2025
KID1/2NCT05199311
-
Transplant-eligible NDMM
-
Iberdomide + Kd
AEs
CR/sCR rate
November 2025
MSKCC 22-0402NCT05354557
-
Single-agent iberdomide maintenance after suboptimal post-ASCT response
CR rateApril 2025
University of Nebraska 852-212NCT05177536
-
Single-agent iberdomide maintenance post ASCT
1-year tolerabilityMarch 2025
IDEAL1/2NCT05392946
-
Iberdomide + Dara-Vd in NDMM
MTD
CR rate
May 2027
COMMANDER1b/2NCT05434689
-
Iberdomide + Dara-dex
-
Iberdomide + Dara-Kd
-
MRD-pos patients post-ASCT
DLT
MRD conversion rate
December 2025
GEM-IBERDARAX2NCT05527340
-
Iberdomide + Dex
-
Iberdomide + Dara-dex
ORR
CR rate
December 2029
AE, adverse event; ASCT, autologous stem cell transplantation; BCMA, B cell maturation antigen; CAR, chimeric antigen receptor; CELMoD, cereblon E3 ligase modulator; cilta-cel, ciltacabtagene autoleucel; (s)CR, (stringent) complete response; Dara, daratumumab; dex, dexamethasone; DLT, dose-limiting toxicity; FcRH5, Fc receptor homolog 5; G protein–coupled receptor, class C, group 5, member D; GMMG, German-Speaking Myeloma Multicenter Group; Ide-cel, idecabtagene vicleucel; IFM, Intergroupe Francophone du Myelome; Isa, isatuximab; K(d), carfilzomib, (dexamethasone); KRd, carfilzomib, lenalidomide, dexamethasone; MM, multiple myeloma; MRD, minimal residual disease; MTD, maximum tolerated dose; NDMM, newly diagnosed multiple myeloma; neg, negative; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; Pom-(dex), pomalidomide, (dexamethasone); pos, positive; R(d), lenalidomide, (dexamethasone); RV(d), lenalidomide, bortezomib, (dexamethasone); SC, subcutaneous; Vd, bortezomib, dexamethasone.
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MDPI and ACS Style

Richardson, P.G. The Role of Autologous Stem Cell Transplantation in the Treatment of Newly Diagnosed Multiple Myeloma: Is It Time to Rethink the Paradigm in the Era of Targeted Therapy? Hemato 2024, 5, 144-156. https://doi.org/10.3390/hemato5020012

AMA Style

Richardson PG. The Role of Autologous Stem Cell Transplantation in the Treatment of Newly Diagnosed Multiple Myeloma: Is It Time to Rethink the Paradigm in the Era of Targeted Therapy? Hemato. 2024; 5(2):144-156. https://doi.org/10.3390/hemato5020012

Chicago/Turabian Style

Richardson, Paul G. 2024. "The Role of Autologous Stem Cell Transplantation in the Treatment of Newly Diagnosed Multiple Myeloma: Is It Time to Rethink the Paradigm in the Era of Targeted Therapy?" Hemato 5, no. 2: 144-156. https://doi.org/10.3390/hemato5020012

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