1. Introduction
Multiple myeloma (MM) is the second most common individual hematologic malignancy [ 1 , 2 ], with an estimated global incidence of almost 180,000 new cases and 120,000 deaths in 2020, comprising approximately 1% of the global cancer burden [ 1 ]. The disease more commonly affects males (~56% of cases) and is generally a disease of the elderly, with the median age at diagnosis in the United States being 69 years [ 3 ]. MM exhibits substantial heterogeneity at diagnosis and throughout the disease course associated with multiple disease-related and patient-related characteristics including disease stage [ 4 , 5 ], cytogenetic abnormalities [ 6 ], age, and frailty [ 7 , 8 ], providing the context for the drive to develop personalized treatment approaches [ 9 , 10 , 11 ]. Overall survival (OS) has increased markedly over the past four decades, with the 5-year survival rate in the United States more than doubling to 59.8% [ 3 ] and the median OS in younger, fitter patients reaching approximately 10 years [ 12 ]. This is associated with the introduction and widespread adoption of high-dose melphalan plus autologous stem cell transplantation (HDM-ASCT) as a frontline therapy in eligible patients and, more importantly, the more recent development and use of numerous highly active novel agents and regimens throughout the disease course in multiple lines of therapy [ 13 , 14 ]. Such progress is rapid and ongoing, as evidenced by the recent approvals by the United States Food and Drug Administration (FDA) in 2021–2023 of the chimeric antigen receptor (CAR) T cell therapies idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) [ 15 , 16 ], and of the bispecific antibodies teclistamab, elranatamab, and talquetamab [ 17 , 18 , 19 ].
Current Treatment of Newly Diagnosed MM (NDMM) and the Role of HDM-ASCT
The current standards of care for the treatment of NDMM are based on three classes of agents: the proteasome inhibitors (PIs; bortezomib, carfilzomib, ixazomib), the immunomodulatory drugs (lenalidomide, pomalidomide, thalidomide), and the monoclonal antibodies (mAbs; anti-CD38 mAbs daratumumab, isatuximab; anti-SLAMF7 mAb elotuzumab) [ 13 , 20 ]. These agents are administered in combination—typically with dexamethasone—as triplet and, increasingly, quadruplet induction therapies, and as single-agent or doublet maintenance regimens as part of frontline therapy [ 13 , 20 ]. Post-induction consolidation therapy depends on a patient’s eligibility for HDM-ASCT, which remains the standard approach for patients aged ≤65–70 years without contraindicating comorbidities [ 13 , 20 ].
The use of HDM-ASCT as a standard in transplant-eligible patients was initially established based on randomized trials versus chemotherapy in the era prior to novel agents, in which transplant resulted in improved progression-free survival (PFS) and OS [ 21 , 22 ]. More recently, large phase 2 and phase 3 studies incorporating triplet novel-agent induction, with or without consolidation, and maintenance therapy have further demonstrated that the addition of HDM-ASCT confers a highly significant PFS benefit [ 23 , 24 , 25 , 26 , 27 , 28 ]. For example, the DETERMINATION phase 3 trial showed that the addition of HDM-ASCT to lenalidomide-bortezomib-dexamethasone (RVd) induction, plus lenalidomide maintenance to progression, resulted in a nearly 2-year median PFS benefit (67.5 vs. 46.2 months) and a 35% reduction in the risk of progression (RVd-alone vs. RVd + ASCT hazard ratio [HR] 1.53) [ 24 ]. The Intergroupe Francophone du Myélome (IFM) 2009 phase 3 trial, which had a similar design but administered lenalidomide maintenance for 1 year only, also showed a substantial PFS benefit with the addition of a transplant (median PFS 47.3 vs. 35.0 months, HR 1.43), although this was markedly less than the duration of disease control seen in both arms of DETERMINATION [ 23 ].
However, the importance and feasibility of the personalization of therapy is growing [ 9 , 10 , 11 ]. In the context of increasingly active quadruplet induction regimens [ 29 , 30 , 31 , 32 ] and our growing understanding of the mutagenic effects of melphalan [ 24 , 33 , 34 , 35 , 36 ], as well as no OS benefit having been demonstrated with HDM-ASCT in recent studies [ 23 , 24 , 25 , 26 , 37 ], the role of HDM-ASCT as a standard approach for all-comers in transplant-eligible NDMM is being challenged. Indeed, several treatment guidelines and recommendations are including deferred HDM-ASCT as a possible option for select patients in the frontline setting ( Table 1 ). In this review, we explore the drivers behind the increasing use of deferred HDM-ASCT and a more tailored approach to therapy, as well as evaluating future treatment approaches for NDMM based on minimal residual disease (MRD) status and the incorporation of the next generation of novel immune-based therapies.
2. The Challenge of Comparing Upfront Versus Deferred HDM-ASCT
It is important to acknowledge that directly comparing outcomes with upfront or deferred HDM-ASCT is challenging due to multiple potential confounders. For example, there is an inherent immortal time bias towards patients who receive deferred HDM-ASCT as a second-line therapy, because these patients must have already received frontline therapy and must still be young and fit enough to undergo HDM-ASCT as part of their second-line treatment [ 42 ]. Early analyses suggested that there were no differences in OS between the two approaches, and this may have been due, in part, to such potential bias [ 42 , 43 , 44 ]. However, there is the potential for bias in the opposite direction too if the group receiving deferred ASCT largely includes patients with an earlier need for second-line therapy following failure of their front-line regimen, i.e., those with more aggressive relapses. Moreover, in the context of the rapidly expanding range of highly active treatment options for relapsed/refractory MM (RRMM), a PFS benefit with upfront HDM-ASCT versus a non-transplant approach could result in a delayed need for second-line therapy, during which time additional novel, active treatment options might be approved in this setting.
Furthermore, for such comparisons, trials with a lengthy follow-up are required in order to evaluate outcomes through both first- and second-line therapy, which may be substantial for transplant-eligible patients in the modern era [ 12 ]. The IFM 2009 and DETERMINATION trials provide valuable data in this regard, as both trials recommended HDM-ASCT as second-line therapy following RVd alone [ 24 , 25 ]. In IFM 2009, with a median follow-up of 7.5 years, 262/350 (74.9%) and 217/350 (62.0%) patients on the RVd-alone and RVd + ASCT arms, respectively, required second-line therapy, with 201/262 (76.7%) versus 49/217 (22.6%) of them having received ASCT as part of that treatment. As in earlier studies of early versus later transplant, no difference in OS (8-year rate: 60.2% vs. 62.2%) was seen between arms [ 23 ], suggesting that deferred ASCT as part of the second-line therapy represents a reasonable clinical option. This is supported by several studies demonstrating substantial efficacy with HDM-ASCT in the RRMM setting [ 14 , 45 , 46 ]. Interestingly, however, in DETERMINATION no difference in OS (5-year rate: 79.2% vs. 80.7%) was seen between RVd alone and RVd + ASCT after a median follow-up of almost 6.5 years [ 24 ], despite only 78/279 (28.0%) RVd-alone patients who had discontinued protocol therapy having received subsequent HDM-ASCT. These findings, in the context of the large PFS benefit with RVd + ASCT, suggest the possibility of competing risk impacting OS.
3. The Rationale for Deferring HDM-ASCT
In addition to the absence of an OS benefit to date with RVd + ASCT versus RVd-alone in the IFM 2009 and DETERMINATION trials, several other factors contribute to the rationale for deferring HDM-ASCT and the design of treatment protocols by which to do so.
3.1. Acute Adverse Impacts of High-Dose Melphalan
HDM-ASCT may be associated with an increased risk of certain acute toxicities, which are important to bear in mind when considering upfront or deferred HDM-ASCT approaches. While treatment-related mortality rates are now low [ 24 , 25 , 47 ], HDM nevertheless results in the prolonged suppression of bone marrow function and significantly higher rates of severe hematologic toxicities than induction therapy alone, notably neutropenia [ 48 ], along with an associated increased risk of infection. For example, in DETERMINATION, the overall rate of any hematologic adverse events (AEs) over the course of treatment was 89.9% on the RVd + ASCT arm compared with 60.5% with RVd alone, with rates of febrile neutropenia (9.0% vs. 4.2%) and pneumonia (9.0% vs. 5.0%) also higher with RVd + ASCT [ 24 ]. Similarly, the incidence of grade 3/4 neutropenia (92% vs. 47%) and grade 3/4 infections (20% vs. 9%) was higher with RVd + ASCT versus RVd alone in the IFM 2009 study [ 25 ].
HDM is also associated with gastrointestinal disorders, including high rates of diarrhea, nausea, and vomiting, as well as esophageal, gastric, and colonic mucosal injury [ 49 , 50 , 51 ]. Grade 3/4 gastrointestinal AEs were reported in 28% versus 7% of patients receiving RVd + ASCT versus RVd alone in IFM 2009 [ 25 ], and the rate of treatment-related gastrointestinal AEs was similarly higher (19% vs. 8%) in DETERMINATION [ 24 ]. Moreover, HDM is specifically also associated with oral mucositis [ 52 ], with no such AEs reported in the RVd-alone arm of DETERMINATION [ 24 ].
The acute toxicities and the treatment burden of HDM can have a marked adverse impact on patients’ quality of life (QoL) associated with the transplant procedure, although QoL measures subsequently recover and may further improve compared to a pretreatment baseline [ 53 ]. Transient but clinically meaningful decreases in QoL were seen in the RVd + ASCT arm in both DETERMINATION [ 24 ] and IFM 2009 [ 54 ], with subsequent recovery during medium-term follow-up. These included transient worsening of the Global Health Status, Physical Functioning, and Role Functioning domain scores of the European Organisation for Research and Treatment of Cancer (EORTC) QoL Questionnaire–Core 30 module (QLQ-C30) and of the Side Effects score of the EORTC-QLQ Myeloma-specific module (MY20) [ 24 , 54 ].
3.2. Long-Term Sequelae of HDM
The potential for long-term sequelae of HDM associated with the genotoxicity of melphalan [ 33 ] is an important consideration when potentially deferring transplant. MM evolution and progression has been shown to be characterized by a number of mutational processes, including the melphalan-specific single-base substitution (SBS)-MM1 mutational signature [ 35 , 55 , 56 , 57 ], and it has been demonstrated that HDM exposure results in a significantly increased overall mutational burden in residual MM at the time of relapse [ 34 ]. Consequently, there is an increased risk of second primary malignancies (SPMs) in MM patients following HDM-ASCT—data from the United States National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program showed that the risk of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) in MM patients is 5–10 times the background rate in the general population, while an analysis of data from the Center for International Blood and Marrow Transplant Research (CIBMTR) demonstrated relative risks of 10–50 for AML and ~100 for MDS in a cohort of MM patients who received HDM-ASCT [ 36 ]. This is supported by recent clinical trial data from DETERMINATION, which showed a significantly higher rate of secondary AML/MDS in the RVd + ASCT versus RVd-alone arm (2.7% vs. 0%, p = 0.002) in the context of continuous lenalidomide maintenance post-ASCT/induction [ 24 ].
As highlighted in a recently published analysis of CIBMTR registry data, the risk of SPMs is an important survivorship issue for MM patients who underwent HDM-ASCT followed by lenalidomide maintenance [ 58 ]. On multivariate analysis, the CIBMTR data showed that having any SPM was associated with significantly shorter PFS (HR 2.62) and OS (HR 5.01), an association that appeared stronger for hematologic SPMs (PFS HR 3.85, OS HR 8.13) [ 58 ]; thus, SPMs may be a competing risk contributing to the lack of OS benefit with transplant-based versus non-transplant-based front-line therapy [ 23 , 24 ]. Similar findings were reported from an analysis of MM patients in the Netherlands Cancer Registry, in which the development of an SPM was associated with a greater mortality risk [ 59 ]; notably, these data showed a significant increase in the risk of AML/MDS SPMs over time, from 1994–2000 to 2001–2007 and 2008–2013, coinciding with the increasing use of HDM-ASCT for MM [ 59 ].
Other long-term survivorship issues post-HDM may include an increased risk of hematologic complications with subsequent therapies—an analysis reported at the 2022 Annual Meeting of the American Society of Hematology (ASH) showed that a prior history of ≥1 HDM-ASCT was correlated with poor hematologic recovery after CAR T cell therapy, which, in turn, showed a possible association with subsequent MDS [ 60 ]. Furthermore, an analysis of 630 MM patients who had survived for >2 years following HDM-ASCT showed that, compared with sibling controls, MM patients treated with HDM-ASCT had 40% greater odds of developing severe and/or life-threatening chronic health conditions (CHCs), with a 10-year cumulative incidence of 58% [ 61 ]; these included venous thromboembolism, subsequent neoplasms, and, cataracts. A recent analysis of long-term survivors at a median of 4 years post-transplant also found that around a third of patients had clinically significant distress (per the Cancer- and Treatment-Related Distress [CTXD] instrument), most notably in the domain of ‘Health Burden’ [ 62 ]. These findings indicate the need for long-term monitoring to help manage subsequent morbidity and complications post-transplantation.
3.3. Personalization of Treatment and Patient Preferences
The current treatment armamentarium for MM contains a large number of highly active salvage therapy options and so, in the modern era and in regions with access to these multiple options, an upfront PFS benefit may no longer translate into an OS benefit due to the activity of subsequent lines of treatment [ 24 , 47 , 63 ]. In this context, real-world aspects of care, including patients’ preferences for treatment and their personal circumstances, are important when considering frontline therapy choices. For example, HDM-ASCT represents an intensive treatment approach that can place a substantial burden on patients in terms of the need for a period of hospitalization and recovery that will typically last a number of weeks—this may not be feasible for some patients, depending on their circumstances (e.g., dependents, work), and so they may prefer to select a more convenient and tolerable non-transplant option with less impact on their daily lives [ 11 ].
Furthermore, given the range of different options, and the goal of the personalization of treatment, it is important to explore the benefit of treatment modalities in patients with specific demographic, biologic, or disease-related characteristics. Indeed, subgroup data from the DETERMINATION trial support the idea that ‘one size does not fit all’—with RVd alone versus RVd + ASCT, HRs for PFS ranging from 0.96 to 3.40 were seen across patient subgroups defined by race, body mass index (BMI), disease stage, and cytogenetics [ 24 ]. Preliminary analyses have shown that there may be a differential impact of prognostic factors between the non-transplant RVd-alone and RVd + ASCT treatment approaches [ 64 ], suggesting that some factors, such as race, BMI, disease stage, and cytogenetics, may be associated with a greater or lesser benefit from these therapies. For example, with RVd alone versus RVd + ASCT in DETERMINATION, median PFS was 44.3 versus 67.2 months (HR 1.67) in white patients but was not reached versus 61.4 months (HR 1.07) in African American patients [ 24 ]. Similarly, in patients with a BMI of <25, median PFS was 33.6 months versus not reached (HR 2.60) with RVd alone versus RVd + ASCT, but the magnitude of benefit was notably lower in patients with a BMI of 25 to <30 (median PFS 52.3 versus 64.3 months, HR 1.24) or ≥30 (median PFS 45.8 versus 64.4 months, HR 1.41) [ 24 ]. PFS and OS benefits with RVd + ASCT also varied according to cytogenetics. Among patients with high-risk cytogenetic abnormalities [del17p, t (4;14), t (14;16)] receiving RVd alone versus RVd + ASCT, median PFS was 17.1 versus 55.5 months (HR 1.99) and 5-year OS was 54.3% versus 63.4% (HR 1.25), suggesting an emerging OS benefit; these benefits appeared particularly pronounced in patients with t (4;14), with PFS and OS HRs of 2.72 and 1.39, respectively, but less so in patients with del17p (PFS and OS HRs of 1.44 and 1.03, respectively). By contrast, in patients with standard-risk cytogenetics, median PFS was 53.2 versus 82.3 months (HR 1.38) and 5-year OS was almost identical at 86.2% versus 86.0% (HR 0.99) [ 24 ]. Further research into patient and disease characteristics and other biomarkers with an association with outcome is warranted to inform tailored treatment approaches in the future.
3.4. Depth of Response and Rate of MRD Negativity with Quadruplet Induction
One prognostic marker that is already emerging as a potentially important way of guiding treatment escalation or de-escalation, including the use of deferred HDM-ASCT, is MRD status. Achieving MRD negativity has been demonstrated to be one of the key prognostic factors for long-term PFS and OS in patients with NDMM and a potential surrogate for outcomes [ 65 , 66 , 67 , 68 , 69 ]. Moreover, achieving sustained MRD negativity is highly correlated with prolonged PFS and OS [ 70 , 71 , 72 , 73 , 74 ] and is associated with better prognosis than simply achieving MRD-negative status; for example, an analysis of 23 patients with NDMM who were receiving lenalidomide maintenance following HDM-ASCT (n = 10) or induction therapy (n = 13) showed that patients who lost or were unable to obtain an MRD-negative status during the first year of maintenance were 14 times more likely to have disease progression than those with a sustained MRD-negative status for 1 year [ 70 ]. Notably, the immune milieu in patients with a sustained MRD-negative status who did not undergo HDM-ASCT was correlated with that in the bone marrow from healthy (non-MM) individuals [ 70 ]. The threshold for defining MRD-negative status (e.g., 10 −5 or 10 −6 ) also impacts its prognostic value, with MRD negativity resulting from more sensitive evaluation (i.e., 10 −6 vs. 10 −5 ) having greater prognostic value [ 67 , 75 ]; therefore, achieving MRD negativity at 10 −5 sensitivity may not be optimal compared with 10 −6 .
Importantly, the prognostic value of MRD-negative status is independent of treatment [ 65 , 66 , 67 , 68 ], with a similar PFS seen in MRD-negative patients receiving transplant or non-transplant approaches [ 24 , 28 ]. For example, in preliminary data from DETERMINATION, among the 39.8% and 54.4% of patients in the RVd-alone and RVd + ASCT arms who were evaluated for MRD status at the start of maintenance and were MRD-negative, the 5-year PFS rates were 59.2% and 53.5%, respectively [ 24 ]. Thus, patients who achieve an MRD-negative response to treatment prior to planned transplant may be appropriate for a deferred HDM-ASCT approach.
Rates of MRD negativity have been increasing substantially with the use of modern triplet and, notably, quadruplet induction and consolidation regimens, either in conjunction with HDM-ASCT or alone. As shown in Table 2 , MRD rates of up to 81% have been achieved with frontline treatment comprising quadruplet regimens plus HDM-ASCT [ 76 ], with MRD rates increasing throughout the course of frontline therapy from induction to transplant to consolidation to maintenance [ 77 ]. However, similarly high rates have also been seen with non-transplant approaches, with an MRD-negative response rate of 71% reported in the MANHATTAN trial of daratumumab plus carfilzomib-lenalidomide-dexamethasone [ 30 ]. Collectively, these data suggest that a substantial proportion of transplant-eligible patients may be able to defer HDM-ASCT if they achieve sustained MRD negativity with their induction therapy.
4. Discussion and Future Perspectives
In the context of the ongoing development of highly active quadruplet frontline regimens, and the increasingly high rates of MRD negativity being achieved, prospective clinical trials incorporating MRD-adapted therapeutic approaches for NDMM are underway to evaluate the feasibility of deferred HDM-ASCT in patients who achieve MRD-negative status following induction therapy. For example, the phase 3 MIDAS trial ( NCT04934475 ; IFM 2020-02) is evaluating MRD status in patients following six cycles of quadruplet induction therapy with isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd); those who achieve MRD negativity at a sensitivity of 10 −5 are then randomized to receive either a further six cycles of Isa-KRd or another two cycles of Isa-KRd plus HDM-ASCT, both followed by lenalidomide maintenance for 3 years. The primary objective of the study is to compare the rates of MRD negativity at 10 −6 sensitivity achieved with these two approaches at various time-points during treatment.
Similarly, in the phase 2 ADVANCE study ( NCT04268498 ), patients are being randomized to receive daratumumab plus KRd (Dara-KRd) or KRd alone for eight cycles, followed by the option for ASCT in MRD-positive patients or proceeding straight to lenalidomide maintenance for ≥2 years in MRD-negative patients. The MASTER-2 study ( NCT05231629 ) is also stratifying patients by MRD status following daratumumab-based quadruplet induction—in this case, six cycles of daratumumab, bortezomib, lenalidomide, and dexamethasone (Dara-RVd)—with MRD-negative patients then being randomized to receive a further three cycles of Dara-RVd or HDM-ASCT, followed by maintenance therapy with daratumumab plus lenalidomide. Meanwhile, the PERSEUS phase 3 study ( NCT03710603 ) of Dara-RVd versus RVd is using a different approach, with patients on the Dara-RVd arm receiving Dara-lenalidomide maintenance and stopping the Dara component upon achieving sustained MRD negativity (with the opportunity to then restart Dara upon recurrence of MRD). Results from these studies and others are awaited with interest to see whether outcomes are similar with a deferred HDM-ASCT approach in MRD-negative NDMM.
Furthermore, novel consolidation therapies are being explored as potential alternatives to HDM-ASCT. For example, the phase 3 CARTITUDE-6 trial ( NCT05257083 ) [ 84 ] is comparing the use of the CAR T cell therapy ciltacabtagene autoleucel with HDM-ASCT in conjunction with six cycles of Dara-RVd and lenalidomide maintenance for 2 years, to determine which approach is superior in terms of PFS and sustained MRD-negative CR rate. Meanwhile, a number of studies are being developed to explore the use of bispecific antibodies such as teclistamab, talquetamab, and elranatamab as alternatives to HDM-ASCT—for example, the phase 2 GEM-TECTAL study ( NCT05849610 ) is investigating intensification therapy with teclistamab plus daratumumab, with or without subsequent talquetamab plus daratumumab, in patients with high-risk NDMM.
With such studies in progress, it is likely that the treatment algorithm for patients with NDMM, particularly those who are transplant-eligible, will evolve and become more complex in the future. As shown in Figure 1 , pending data from current and planned studies there may be multiple available treatment pathways for transplant-eligible patients including the use of deferred HDM-ASCT or its replacement with alternative intensification.
5. Conclusions
Based on the latest data from randomized clinical trials in patients with NDMM and given the context of there being numerous highly active novel treatment options and the need for a personalized approach to treatment, incorporating a longer-term strategic view of patient outcome, especially in the era of immune therapy, deferred HDM-ASCT is emerging as a standard-of-care approach for select transplant-eligible patients. With no OS benefit being seen in multiple randomized studies [ 23 , 24 , 25 , 26 , 37 ] of transplant versus non-transplant approaches for NDMM, the increasingly high rates of MRD negativity achieved with quadruplet induction regimens, and the development of MRD- and risk-adapted treatment approaches, NDMM therapy is evolving from a one-size-fits-all approach of upfront HDM-ASCT to a response-adapted, risk-modified and strategic therapeutic paradigm, with the aim of further improving outcomes for patients and enhancing quality of life.
Acknowledgments
The authors gratefully acknowledge 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.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Author Contributions
Conceptualization, writing—original draft preparation, writing—review and editing, C.C.M., M.A.H.-B., S.M. and P.G.R. All authors have read and agreed to the published version of the manuscript.
Conflicts of Interest
C.C.M.: advisory boards for AbbVie, BMS, GSK, Janssen, Karyopharm, Sanofi, and Takeda; consultancy for AbbVie, Janssen, Karyopharm, and Sanofi. M.A.H.-B.: advisory boards for Abbvie, BMS, Celgene, GSK, Janssen, Karyopharm, and Sanofi; research funding from BMS/Celgene, GSK, and Sanofi. S.M.: consultancy for Pfizer. P.G.R.: grants to institution for clinical trials from Bristol Myers Squibb/Celgene, Karyopharm, and Oncopeptides; advisory committees for Bristol Myers Squibb/Celgene, GSK, Karyopharm, Oncopeptides, AMGEN, Adaptive Biotechnologies, and Sanofi.
References
1. Sung H. Ferlay J. Siegel R.L. Laversanne M. Soerjomataram I. Jemal A. Bray F. Global Cancer Statistics 2020: Globocan Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries CA Cancer J. Clin. 2021 71 209 249 10.3322/caac.21660 33538338
2. Siegel R.L. KMiller D. Wagle N.S. Jemal A. Cancer Statistics, 2023 CA Cancer J. Clin. 2023 73 17 48 10.3322/caac.21763 36633525
3. NIH National Cancer Institute Surveillance, Epidemiology, and End Results Program Cancer Stat Facts: Myeloma 2023 Available online: https://seer.cancer.gov/statfacts/html/mulmy.html (accessed on 23 October 2023)
4. Palumbo A. Avet-Loiseau H. Oliva S. Lokhorst H.M. Goldschmidt H. Rosinol L. Richardson P. Caltagirone S. Lahuerta J.J. Facon T. Revised International Staging System for Multiple Myeloma: A Report from International Myeloma Working Group J. Clin. Oncol. 2015 33 2863 2869 10.1200/JCO.2015.61.2267 26240224 PMC4846284
5. Greipp P.R. Miguel J.S. Durie B.G. Crowley J.J. Barlogie B. Blade J. Boccadoro M. Child J.A. Avet-Loiseau H. Kyle R.A. International Staging System for Multiple Myeloma J. Clin. Oncol. 2005 23 3412 3420 10.1200/JCO.2005.04.242 15809451
6. van de Donk N.W.C. Pawlyn C. Yong K.L. Multiple Myeloma Lancet 2021 397 410 427 10.1016/S0140-6736(21)00135-5 33516340
7. Palumbo A. Bringhen S. Mateos M.V. Larocca A. Facon T. Kumar S.K. Offidani M. McCarthy P. Evangelista A. Lonial S. Geriatric Assessment Predicts Survival and Toxicities in Elderly Myeloma Patients: An International Myeloma Working Group Report Blood 2015 125 2068 2074 10.1182/blood-2014-12-615187 25628469 PMC4375104
8. Facon T. Dimopoulos M.A. Meuleman N. Belch A. Mohty M. Chen W.M. Kim K. Zamagni E. Rodriguez-Otero P. Renwick W. A Simplified Frailty Scale Predicts Outcomes in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma Treated in the First (Mm-020) Trial Leukemia 2020 34 224 233 10.1038/s41375-019-0539-0 31427722 PMC7214253
9. D’Agostino M. Terragna C. van Duin M. Editorial: Risk Factors in Multiple Myeloma Identified before and During Treatment: Are We Ready to Personalize Treatment? Front. Oncol. 2023 13 1247808 10.3389/fonc.2023.1247808 37588098 PMC10425881
10. Bar N. Firestone R.S. Usmani S.Z. Aiming for the Cure in Myeloma: Putting Our Best Foot Forward Blood Rev. 2023 101116 10.1016/j.blre.2023.101116 37596172
11. Richardson P.G. Miguel J.F.S. Moreau P. Hajek R. Dimopoulos M.A. Laubach J.P. Palumbo A. Luptakova K. Romanus D. Skacel T. Interpreting Clinical Trial Data in Multiple Myeloma: Translating Findings to the Real-World Setting Blood Cancer J. 2018 8 109 10.1038/s41408-018-0141-0 30413684 PMC6226527
12. Joseph N.S. Kaufman J.L. Dhodapkar M.V. Hofmeister C.C. Almaula D.K. Heffner L.T. Gupta V.A. Boise L.H. Lonial S. Nooka A.K. Long-Term Follow-up Results of Lenalidomide, Bortezomib, and Dexamethasone Induction Therapy and Risk-Adapted Maintenance Approach in Newly Diagnosed Multiple Myeloma J. Clin. Oncol. 2020 38 1928 1937 10.1200/JCO.19.02515 32298201 PMC7587409
13. Callander N.S. Baljevic M. Adekola K. Anderson L.D. Campagnaro E. Castillo J.J. Costello C. Devarakonda S. Elsedawy N. Faiman M. Nccn Guidelines(R) Insights: Multiple Myeloma, Version 3.2022 J. Natl. Compr. Cancer Netw. 2022 20 8 19 10.6004/jnccn.2022.0002 34991075
14. Kumar S. Baizer L. Callander N.S. Giralt S.A. Hillengass J. Freidlin B. Hoering A. Richardson P.G. Schwartz E.I. Reiman A. Gaps and Opportunities in the Treatment of Relapsed-Refractory Multiple Myeloma: Consensus Recommendations of the Nci Multiple Myeloma Steering Committee Blood Cancer J. 2022 12 98 10.1038/s41408-022-00695-5 35768410 PMC9243011
15. Munshi N.C. Anderson L.D. Jr. Shah N. Madduri D. Berdeja J. Lonial S. Raje N. Lin Y. Siegel D. Oriol A. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma N. Engl. J. Med. 2021 384 705 716 10.1056/NEJMoa2024850 33626253
16. Berdeja J.G. Madduri D. Usmani S.Z. Jakubowiak A. Agha M. Cohen A.D. Stewart A.K. Hari P. Htut M. Lesokhin A. Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T-Cell Therapy in Patients with Relapsed or Refractory Multiple Myeloma (Cartitude-1): A Phase 1b/2 Open-Label Study Lancet 2021 398 314 324 10.1016/S0140-6736(21)00933-8 34175021
17. Moreau P. Garfall A.L. van de Donk N. Nahi H. San-Miguel J.F. Oriol A. Nooka A.K. Martin T. Rosinol L. Chari A. Teclistamab in Relapsed or Refractory Multiple Myeloma N. Engl. J. Med. 2022 387 495 505 10.1056/NEJMoa2203478 35661166 PMC10587778
18. Lesokhin A.M. Tomasson M.H. Arnulf B. Bahlis N.J. Prince H.M. Niesvizky R. Rodriotaguez-Otero P. Martinez-Lopez J. Koehne G. Touzeau C. Elranatamab in Relapsed or Refractory Multiple Myeloma: Phase 2 Magnetismm-3 Trial Results Nat. Med. 2023 29 2259 2267 10.1038/s41591-023-02528-9 37582952 PMC10504075
19. Chari A. Minnema M.C. Berdeja J.G. Oriol A. van de Donk N. Rodriguez-Otero P. Askari E. Mateos M.V. Costa L.J. Caers J. Talquetamab, a T-Cell-Redirecting Gprc5d Bispecific Antibody for Multiple Myeloma N. Engl. J. Med. 2022 387 2232 2244 10.1056/NEJMoa2204591 36507686
20. Dimopoulos M.A. Moreau P. Terpos E. Mateos M.V. Zweegman S. Cook G. Delforge M. Hajek R. Schjesvold F. Cavo M. Multiple Myeloma: Eha-Esmo Clinical Practice Guidelines for Diagnosis, Treatment and Follow-up(Dagger) Ann. Oncol. 2021 32 309 322 10.1016/j.annonc.2020.11.014 33549387
21. Child J.A. Morgan G.J. Davies F.E. Owen R.G. Bell S.E. Hawkins K. Brown J. Drayson M.T. Selby P.J. Party Medical Research Council Adult Leukaemia Working High-Dose Chemotherapy with Hematopoietic Stem-Cell Rescue for Multiple Myeloma N. Engl. J. Med. 2003 348 1875 1883 10.1056/NEJMoa022340 12736280
22. Koreth J. Cutler C.S. Djulbegovic B. Behl R. Schlossman R.L. Munshi N.C. Richardson P.G. Anderson K.C. Soiffer R.J. Alyea E.P. 3rd High-Dose Therapy with Single Autologous Transplantation Versus Chemotherapy for Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis of Randomized Controlled Trials Biol. Blood Marrow Transpl. 2007 13 183 196 10.1016/j.bbmt.2006.09.010 17241924
23. Perrot A. Lauwers-Cances V. Cazaubiel T. Facon T. Caillot D. Clement-Filliatre L. Macro M. Decaux O. Belhadj K. Mohty M. Early Versus Late Autologous Stem Cell Transplant in Newly Diagnosed Multiple Myeloma: Long-Term Follow-up Analysis of the Ifm 2009 Trial Blood 2020 136 (Suppl. S1) 39 10.1182/blood-2020-134538
24. Richardson P.G. Jacobus S.J. Weller E.A. Hassoun H. Lonial S. Raje N.S. Medvedova E. McCarthy P.L. Libby E.N. Voorhees P.M. Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma N. Engl. J. Med. 2022 387 132 147 10.1056/NEJMoa2204925 35660812 PMC10040899
25. Attal M. Lauwers-Cances V. Hulin C. Leleu X. Caillot D. Escoffre M. Arnulf B. Macro M. Belhadj K. Garderet L. Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma N. Engl. J. Med. 2017 376 1311 1320 10.1056/NEJMoa1611750 28379796 PMC6201242
26. Gay F. Musto P. Rota-Scalabrini D. Bertamini L. Belotti A. Galli M. Offidani M. Zamagni E. Ledda A. Grasso M. Carfilzomib with Cyclophosphamide and Dexamethasone or Lenalidomide and Dexamethasone Plus Autologous Transplantation or Carfilzomib Plus Lenalidomide and Dexamethasone, Followed by Maintenance with Carfilzomib Plus Lenalidomide or Lenalidomide Alone for Patients with Newly Diagnosed Multiple Myeloma (Forte): A Randomised, Open-Label, Phase 2 Trial Lancet Oncol. 2021 22 1705 1720 34774221 10.1016/S1470-2045(21)00535-0
27. Cavo M. Gay F. Beksac M. Pantani L. Petrucci M.T. Dimopoulos M.A. Dozza L. van der Holt B. Zweegman S. Oliva S. Autologous Haematopoietic Stem-Cell Transplantation Versus Bortezomib-Melphalan-Prednisone, with or without Bortezomib-Lenalidomide-Dexamethasone Consolidation Therapy, and Lenalidomide Maintenance for Newly Diagnosed Multiple Myeloma (Emn02/Ho95): A Multicentre, Randomised, Open-Label, Phase 3 Study Lancet Haematol. 2020 7 e456 e468 32359506 10.1016/S2352-3026(20)30099-5
28. Yong K. Wilson W. de Tute R.M. Camilleri M. Ramasamy K. Streetly M. Sive J. Bygrave C.A. Benjamin R. Chapman M. Upfront Autologous Haematopoietic Stem-Cell Transplantation Versus Carfilzomib-Cyclophosphamide-Dexamethasone Consolidation with Carfilzomib Maintenance in Patients with Newly Diagnosed Multiple Myeloma in England and Wales (Cardamon): A Randomised, Phase 2, Non-Inferiority Trial Lancet Haematol. 2023 10 e93 e106 36529145 10.1016/S2352-3026(22)00350-7
29. Costa L.J. Chhabra S. Medvedova E. Dholaria B.R. Schmidt T.M. Godby K.N. Silbermann R. Dhakal B. Bal S. Giri S. Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone with Minimal Residual Disease Response-Adapted Therapy in Newly Diagnosed Multiple Myeloma J. Clin. Oncol. 2022 40 2901 2912 10.1200/JCO.21.01935 34898239
30. Landgren O. Hultcrantz M. Diamond B. Lesokhin A.M. Mailankody S. Hassoun H. Tan C. Shah U.A. Lu S.X. Salcedo M. Safety and Effectiveness of Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Daratumumab Combination Therapy for Patients with Newly Diagnosed Multiple Myeloma: The Manhattan Nonrandomized Clinical Trial JAMA Oncol. 2021 7 862 868 10.1001/jamaoncol.2021.0611 33856405 PMC8050789
31. Moreau P. Attal M. Hulin C. Arnulf B. Belhadj K. Benboubker L. Bene M.C. Broijl A. Caillon H. Caillot D. Bortezomib, Thalidomide, and Dexamethasone with or without Daratumumab before and after Autologous Stem-Cell Transplantation for Newly Diagnosed Multiple Myeloma (Cassiopeia): A Randomised, Open-Label, Phase 3 Study Lancet 2019 394 29 38 10.1016/S0140-6736(19)31240-1 31171419
32. Voorhees P.M. Kaufman J.L. Laubach J. Sborov D.W. Reeves B. Rodriguez C. Chari A. Silbermann R. Costa L.J. Anderson L.D. Jr. Daratumumab, Lenalidomide, Bortezomib, and Dexamethasone for Transplant-Eligible Newly Diagnosed Multiple Myeloma: The Griffin Trial Blood 2020 136 936 945 10.1182/blood.2020005288 32325490 PMC7441167
33. Maura F. Weinhold N. Diamond B. Kazandjian D. Rasche L. Morgan G. Landgren O. The Mutagenic Impact of Melphalan in Multiple Myeloma Leukemia 2021 35 2145 2150 10.1038/s41375-021-01293-3 34012133
34. Samur M.K. Roncador M. Samur A.A. Fulciniti M. Bazarbachi A.H. Szalat R. Shammas M.A. Sperling A.S. Richardson P.G. Magrangeas F. High-Dose Melphalan Treatment Significantly Increases Mutational Burden at Relapse in Multiple Myeloma Blood 2023 141 1724 1736 10.1182/blood.2022017094 36603186 PMC10273091
35. Rustad E.H. Yellapantula V. Leongamornlert D. Bolli N. Ledergor G. Nadeu F. Angelopoulos N. Dawson K.J. Mitchell T.J. Osborne R.J. Timing the Initiation of Multiple Myeloma Nat. Commun. 2020 11 1917 10.1038/s41467-020-15740-9 32317634 PMC7174344
36. Radivoyevitch T. Dean R.M. Shaw B.E. Brazauskas R. Tecca H.R. Molenaar R.J. Battiwalla M. Savani B.N. Flowers M.E.D. Cooke K.R. Risk of Acute Myeloid Leukemia and Myelodysplastic Syndrome after Autotransplants for Lymphomas and Plasma Cell Myeloma Leuk. Res. 2018 74 130 136 10.1016/j.leukres.2018.07.016 30055822 PMC6219911
37. Straka C. Schaefer-Eckart K. Hertenstein B. Bassermann F. Salwender H. Langer C. Krönke J. Kull M. Schilling G. Schieferdecker A. Long-Term Outcome of a Prospective Randomized Trial Comparing Continuous Lenalidomide/Dexamethasone with Lenalidomide/Dexamethasone Induction, Mel140 with Autologous Blood Stem Cell Transplantation and Single Agent Lenalidomide Maintenance in Patients of Age 60-75 Years with Newly Diagnosed Multiple Myeloma Blood 2022 140 (Suppl. S1) 287 288
38. Sive J. Cuthill K. Hunter H. Kazmi M. Pratt G. Smith D. British Society of Haematology Guidelines on the Diagnosis, Investigation and Initial Treatment of Myeloma: A British Society for Haematology/UK Myeloma Forum Guideline Br. J. Haematol. 2021 193 245 268 10.1111/bjh.17410 33748957
39. Dhakal B. Shah N. Kansagra A. Kumar A. Lonial S. Garfall A. Cowan A. Poudyal B.S. Costello C. Gay F. Astct Clinical Practice Recommendations for Transplantation and Cellular Therapies in Multiple Myeloma Transpl. Cell Ther. 2022 28 284 293 10.1016/j.jtct.2022.03.019 35306217
40. Rajkumar S.V. Multiple Myeloma: 2022 Update on Diagnosis, Risk Stratification, and Management Am. J. Hematol. 2022 97 1086 1107 10.1002/ajh.26590 35560063 PMC9387011
41. mSMART Treatment Guidelines: Multiple Myeloma 2023 Available online: https://www.msmart.org/mm-treatment-guidelines (accessed on 23 October 2023)
42. Gandolfi S. Vekstein C. Laubach J.P. O’Brien A. Masone K. Munshi N.C. Anderson K.C. Richardson P.G. The Evolving Role of Transplantation in Multiple Myeloma: The Need for a Heterogeneous Approach to a Heterogeneous Disease Clin. Adv. Hematol. Oncol. 2018 16 564 574 30148829
43. Dunavin N.C. Wei L. Elder P. Phillips G.S. Benson D.M. Jr. Hofmeister C.C. Penza S. Greenfield C. Rose K.S. Rieser G. Early Versus Delayed Autologous Stem Cell Transplant in Patients Receiving Novel Therapies for Multiple Myeloma Leuk. Lymphoma 2013 54 1658 1664 10.3109/10428194.2012.751528 23194056 PMC3769940
44. Remenyi P. Varga G. Mikala G. Reti M. Gopcsa L. Batai A. Csukly Z. Lengyel L. Torbagyi E. Barta A. Early Versus Delayed Autologous Stem Cell Transplantation and Interferon Maintenance in Multiple Myeloma: Single-Center Experience of 18 Years Transpl. Proc. 2016 48 177 184 10.1016/j.transproceed.2015.12.031 26915865
45. Lemieux C. Muffly L.S. Iberri D.J. Craig J.K. Johnston L.J. Lowsky R. Shiraz P. Rezvani A.R. Frank M.J. Weng W.K. Outcomes after Delayed and Second Autologous Stem Cell Transplant in Patients with Relapsed Multiple Myeloma Bone Marrow Transpl. 2021 56 2664 2671 10.1038/s41409-021-01371-1 34163014 PMC8715953
46. Van Oekelen O. Nath K. Mouhieddine T.H. Farzana T. Aleman A. Melnekoff D.T. Ghodke-Puranik Y. Shah G.L. Lesokhin A. Giralt S. Interventions and Outcomes of Patients with Multiple Myeloma Receiving Salvage Therapy after Bcma-Directed Car T Therapy Blood 2023 141 756 765 10.1182/blood.2022017848 36327160 PMC10082354
47. Dhakal B. Szabo A. Chhabra S. Hamadani M. D’Souza A. Usmani S.Z. Sieracki R. Gyawali B. Jackson J.L. Asimakopoulos F. 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 10.1001/jamaoncol.2017.4600 29302684 PMC5885822
48. Cho Y.K. Irby D.J. Li J. Sborov D.W. Mould D.R. Badawi M. Dauki A. Lamprecht M. Rosko A.E. Fernandez S. Pharmacokinetic-Pharmacodynamic Model of Neutropenia in Patients with Myeloma Receiving High-Dose Melphalan for Autologous Stem Cell Transplant CPT Pharmacomet. Syst. Pharmacol. 2018 7 748 758 10.1002/psp4.12345 30343510 PMC6263666
49. Gordillo C.A. Parmar S. Blanco M. Delille E.M. Assal A. Mapara M. Reshef R. Gastrointestinal Toxicity of High-Dose Melphalan in Autologous Hematopoietic Stem Cell Transplantation: Identification of Risk Factors and a Benchmark for Experimental Therapies Ann. Hematol. 2021 100 1863 1870 10.1007/s00277-020-04378-8 33388856 PMC11531332
50. Palumbo A. Cavallo F. Gay F. Di Raimondo F. Yehuda D.B. Petrucci M.T. Pezzatti S. Caravita T. Cerrato C. Ribakovsky E. Autologous Transplantation and Maintenance Therapy in Multiple Myeloma N. Engl. J. Med. 2014 371 895 905 10.1056/NEJMoa1402888 25184862
51. Gay F. Oliva S. Petrucci M.T. Conticello C. Catalano L. Corradini P. Siniscalchi A. Magarotto V. Pour L. Carella A. 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 10.1016/S1470-2045(15)00389-7 26596670
52. Grazziutti M.L. Dong L. Miceli M.H. Krishna S.G. Kiwan E. Syed N. Fassas A. van Rhee F. Klaus H. Barlogie B. Oral Mucositis in Myeloma Patients Undergoing Melphalan-Based Autologous Stem Cell Transplantation: Incidence, Risk Factors and a Severity Predictive Model Bone Marrow Transpl. 2006 38 501 506 10.1038/sj.bmt.1705471 16980998
53. Chakraborty R. Hamilton B.K. Hashmi S.K. Kumar S.K. Majhail N.S. Health-Related Quality of Life after Autologous Stem Cell Transplantation for Multiple Myeloma Biol. Blood Marrow Transpl. 2018 24 1546 1553 10.1016/j.bbmt.2018.03.027 29626515 PMC6108907
54. Roussel M. Hebraud B. Hulin C. Perrot A. Caillot D. Stoppa A.M. Macro M. Escoffre M. Arnulf B. Belhadj K. 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 61 1323 1333 10.1080/10428194.2020.1719091 32090636
55. Ziccheddu B. Biancon G. Bagnoli F. De Philippis C. Maura F. Rustad E.H. Dugo M. Devecchi A. De Cecco L. Sensi M. Integrative Analysis of the Genomic and Transcriptomic Landscape of Double-Refractory Multiple Myeloma Blood Adv. 2020 4 830 844 10.1182/bloodadvances.2019000779 32126144 PMC7065476
56. Landau H.J. Yellapantula V. Diamond B.T. Rustad E.H. Maclachlan K.H. Gundem G. Medina-Martinez J. Ossa J.A. Levine M.F. Zhou Y. Accelerated Single Cell Seeding in Relapsed Multiple Myeloma Nat. Commun. 2020 11 3617 10.1038/s41467-020-17459-z 32680998 PMC7368016
57. Misund K. Bruinink D.H.O. Coward E. Hoogenboezem R.M. Rustad E.H. Sanders M.A. Rye M. Sponaas A.M. van der Holt B. Zweegman S. Clonal Evolution after Treatment Pressure in Multiple Myeloma: Heterogenous Genomic Aberrations and Transcriptomic Convergence Leukemia 2022 36 1887 1897 10.1038/s41375-022-01597-y 35643867 PMC9252918
58. Ragon B.K. Shah M.V. D’Souza A. Estrada-Merly N. Gowda L. George G. DeLima M. Hashmi S. Kharfan-Dabaja M.A. Majhail N.S. Impact of Second Primary Malignancy Post-Autologous Transplantation on Outcomes of Multiple Myeloma: A Cibmtr Analysis Blood Adv. 2023 7 2746 2757 10.1182/bloodadvances.2022009138 36827681 PMC10275699
59. Brink M. Minnema M.C. Visser O. Levin M.D. Posthuma E. Broijl A. Sonneveld P. van der Klift M. Roeloffzen W.W.H. Westerman M. Increased Mortality Risk in Multiple-Myeloma Patients with Subsequent Malignancies: A Population-Based Study in The Netherlands Blood Cancer J. 2022 12 41 10.1038/s41408-022-00640-6 35292622 PMC8924210
60. Thibaud S. Mia B. Van Oekelen O. Mouhieddine T.H. Schaniel C. Ghodke-Puranik Y. Aleman A. Upadhyaya B. Lancman G. Lagana A. Comprehensive Characterization of Prolonged Unexplained Cytopenias in Relapsed/Refractory Multiple Myeloma Patients Following Bcma-Directed Car-T Cell Therapy Blood 2022 140 (Suppl. S1) 614 616 10.1182/blood-2022-165646
61. Arora M. Chen Y. Hageman L. Wu J. Landier W. Francisco L. Kung M. Ness E. Bosworth A. Pamukcuoglu M. Morbidity Burden in Survivors of Multiple Myeloma Who Underwent Autologous Transplantation: A Bone Marrow Transplantation Survivor Study Cancer 2020 126 3322 3329 10.1002/cncr.32941 32413187 PMC9145592
62. Chakraborty R. Yi J. Rybicki L. Preussler J. Deol A. Loren A. Savani B. Jim H.S.L. Cerny J. Reynolds J. Patient-Reported Outcomes in Long-Term Survivors of Autologous Hematopoietic Cell Transplantation in Multiple Myeloma Transpl. Cell Ther. 2023 29 388.e1 388.e6 10.1016/j.jtct.2023.02.011 PMC10718487 36870388
63. D’Souza A. Lonial S. What the Princess Bride Teaches Us About Outcomes in Multiple Myeloma J. Clin. Oncol. 2021 39 2423 2425 10.1200/JCO.21.01137 34111942
64. Hassoun H. Jacobus S.J. Richardson P.G. Zonder J.A. Voorhees P.M. Kaufman J.L. Yee A.J. Scott E.C. Torka P. Libby E. Multivariable Analyses of Prognostic Factors for Progression-Free Survival (Pfs) and Complete Response (Cr) with Lenalidomide, Bortezomib, and Dexamethasone (Rvd) Alone Versus Rvd Plus Autologous Stem Cell Transplantation (Asct) in Patients (Pts) with Newly Diagnosed Multiple Myeloma (Ndmm) in the Determination Phase 3 Trial Blood 2022 140 (Suppl. S1) 4834 4838
65. Anderson K.C. Auclair D. Adam S.J. Agarwal A. Anderson M. Avet-Loiseau H. Bustoros M. Chapman J. Connors D.E. Dash A. Minimal Residual Disease in Myeloma: Application for Clinical Care and New Drug Registration Clin. Cancer Res. 2021 27 5195 5212 10.1158/1078-0432.CCR-21-1059 34321279 PMC9662886
66. Avet-Loiseau H. Ludwig H. Landgren O. Paiva B. Morris C. Yang H. Zhou K. Ro S. Mateos M.V. Minimal Residual Disease Status as a Surrogate Endpoint for Progression-Free Survival in Newly Diagnosed Multiple Myeloma Studies: A Meta-Analysis Clin. Lymphoma Myeloma Leuk. 2020 20 e30 e37 10.1016/j.clml.2019.09.622 31780415 PMC7444731
67. Munshi N.C. Avet-Loiseau H. Anderson K.C. Neri P. Paiva B. Samur M. Dimopoulos M. Kulakova M. Lam A. Hashim M. A Large Meta-Analysis Establishes the Role of Mrd Negativity in Long-Term Survival Outcomes in Patients with Multiple Myeloma Blood Adv. 2020 4 5988 5999 10.1182/bloodadvances.2020002827 33284948 PMC7724898
68. Mohty M. Avet-Loiseau H. Harousseau J.L. Potential Future Direction of Measurable Residual Disease Evaluation in Multiple Myeloma Blood 2023 142 1509 1517 10.1182/blood.2023020284 37471603
69. Ficek J. Kalaitzaki E. Yuan S.S. Tosolini A. Du L. Kremer B.E. Davy K. Zhou H. Chen T.T. Association of Minimal Residual Disease Negativity Rates with Progression Free Survival in Frontline Therapy Trials for Newly Diagnosed Multiple Myeloma: A Meta-Analysis Clin. Lymphoma Myeloma Leuk. 2023 23 e213 e221 10.1016/j.clml.2023.02.005 36907767
70. Coffey D.G. Maura F. Gonzalez-Kozlova E. Diaz-Mejia J.J. Luo P. Zhang Y. Xu Y. Warren E.H. Dawson T. Lee B. Immunophenotypic Correlates of Sustained Mrd Negativity in Patients with Multiple Myeloma Nat. Commun. 2023 14 5335 10.1038/s41467-023-40966-8 37660077 PMC10475030
71. Leypoldt L.B. Tichy D. Besemer B. Hanel M. Raab M.S. Mann C. Munder M. Reinhardt H.C. Nogai A. Gorner M. Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone for the Treatment of High-Risk Newly Diagnosed Multiple Myeloma J. Clin. Oncol. 2023 Online ahead of print 10.1200/JCO.23.01696 PMC10730063 37753960
72. Belotti A. Ribolla R. Crippa C. Chiarini M. Giustini V. Ferrari S. Peli A. Cattaneo C. Roccaro A. Frittoli B. Predictive Role of Sustained Imaging Mrd Negativity Assessed by Diffusion-Weighted Whole-Body Mri in Multiple Myeloma Am. J. Hematol. 2023 98 E230 E232 10.1002/ajh.26995 37317959
73. Fonseca R. Arribas M. Wiedmeier-Nutor J.E. Kusne Y.N. Velez M.G. Kosiorek H.E. Butterfield R.D.J. Kirsch I.R. Mikhael J.R. Stewart A.K. Integrated Analysis of Next Generation Sequencing Minimal Residual Disease (Mrd) and Pet Scan in Transplant Eligible Myeloma Patients Blood Cancer J. 2023 13 32 10.1038/s41408-023-00794-x 36878906 PMC9988896
74. Oliva S. Genuardi E. Paris L. D’Agostino M. Rogers J. Rota-Scalabrini D. Jacob A.P. Patriarca F. Luppi M. Bertazzoni P. Prospective Evaluation of Minimal Residual Disease in the Phase Ii Forte Trial: A Head-to-Head Comparison between Multiparameter Flow Cytometry and Next-Generation Sequencing EClinicalMedicine 2023 60 102016 10.1016/j.eclinm.2023.102016 37396800 PMC10314153
75. Martinez-Lopez J. Wong S.W. Shah N. Bahri N. Zhou K. Sheng Y. Huang C.Y. Martin T. Wolf J. Clinical Value of Measurable Residual Disease Testing for Assessing Depth, Duration, and Direction of Response in Multiple Myeloma Blood Adv. 2020 4 3295 3301 10.1182/bloodadvances.2020002037 32706892 PMC7391154
76. Costa L.J. Chhabra S. Medvedova E. Schmidt T.M. Dholaria B. Godby K.N. Silbermann R. Bal S. D’Souza A. Giri S. Outcomes of Mrd-Adapted Treatment Modulation in Patients with Newly Diagnosed Multiple Myeloma Receiving Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (Dara-Krd) and Autologous Transplantation: Extended Follow up of the Master Trial Blood 2022 140 (Suppl. S1) 7275 7277 10.1182/blood-2022-156730
77. Sborov D.W. Laubach J. Kaufman J.L. Reeves B. Rodriguez C. Chari A. Silbermann R. Costa L.J. Anderson L.D. Jr. Nathwani N. Daratumumab (Dara) + Lenalidomide, Bortezomib, and Dexamethasone (Rvd) in Patients with Transplant-Eligible Newly Diagnosed Multiple Myeloma (Ndmm): Final Analysis of Griffin Proceedings of the 19th International Myeloma Society (IMS) Annual Meeting (2022) Los Angeles, CA, USA 25–27 August 2022 Abstract OAB-057
78. Goldschmidt H. Mai E.K. Bertsch U. Fenk R. Nievergall E. Tichy D. Besemer B. Durig J. Schroers R. von Metzler I. Addition of Isatuximab to Lenalidomide, Bortezomib, and Dexamethasone as Induction Therapy for Newly Diagnosed, Transplantation-Eligible Patients with Multiple Myeloma (Gmmg-Hd7): Part 1 of an Open-Label, Multicentre, Randomised, Active-Controlled, Phase 3 Trial Lancet Haematol. 2022 9 e810 e821 36328040 10.1016/S2352-3026(22)00263-0
79. Perrot A. Lauwers-Cances V. Touzeau C. Decaux O. Hulin C. Macro M. Stoppa A.-M. Chretien M.L. Karlin L. Mariette C. Daratumumab Plus Ixazomib, Lenalidomide, and Dexamethasone as Extended Induction and Consolidation Followed by Lenalidomide Maintenance in Standard-Risk Transplant-Eligible Newly Diagnosed Multiple Myeloma (Ndmm) Patients (Ifm 2018-01): A Phase Ii Study of the Intergroupe Francophone Du Myélome (Ifm) Blood 2021 138 (Suppl. S1) 464
80. Touzeau C. Perrot A. Hulin C. Manier S. Macro M. Caillot D. Karlin L. Decaux O. Jacquet C. Tiab M. Daratumumab Carfilzomib Lenalidomide and Dexamethasone as Induction Therapy in High-Risk, Transplant-Eligible Patients with Newly Diagnosed Myeloma: Results of the Phase 2 Study Ifm 2018-04 J. Clin. Oncol. 2022 40 (Suppl. S16) 8002 10.1200/JCO.2022.40.16_suppl.8002
81. Weisel K. Besemer B. Haenel M. Lutz R. Mann C. Munder M. Goerner M. Reinhardt H.C. Nogai A. Ko Y.-D. Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone (Isa-Krd) in Patients with High-Risk Newly Diagnosed Multiple Myeloma: Planned Interim Analysis of the Gmmg-Concept Trial Blood 2022 140 (Suppl. S1) 1836 1838 10.1182/blood-2022-156309
82. Derman B.A. Kansagra A. Zonder J. Stefka A.T. Grinblatt D.L. Anderson L.D. Jr. Gurbuxani S. Narula S. Rayani S. Major A. Elotuzumab and Weekly Carfilzomib, Lenalidomide, and Dexamethasone in Patients with Newly Diagnosed Multiple Myeloma without Transplant Intent: A Phase 2 Measurable Residual Disease-Adapted Study JAMA Oncol. 2022 8 1278 1286 10.1001/jamaoncol.2022.2424 35862034 PMC9305600
83. O’Donnell E.K. Mo C.C. Nadeem O. Yee A.J. Branagan A.R. Laubach J. Gammon M.T. Lively K.J. Packer L. Harrington C.C. A Phase II Study of Once Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Isatuximab in Newly Diagnosed, Transplant-Eligible Multiple Myeloma (the Skylark Trial) Blood 2022 140 (Suppl. S1) 7282 7283 10.1182/blood-2022-156328
84. Boccadoro M. San-Miguel J. Suzuki K. Van De Donk N.W.C.J. Cook G. Jakubowiak A. Madduri D. Afifi S. Stevens A.-S. Schecter J.M. Dvrd Followed by Ciltacabtagene Autoleucel Versus Dvrd Followed by Asct in Patients with Newly Diagnosed Multiple Myeloma Who Are Transplant Eligible: A Randomized Phase 3 Study (Emagine/Cartitude-6) Blood 2022 140 (Suppl. S1) 4630 4632 10.1182/blood-2022-157021