Maintenance therapy has been one of the cornerstones of multiple myeloma (MM) management, aiming to prolong remission duration, delay progression, and improve survival while preserving quality of life. Following advances in induction regimens and the widespread use of autologous stem cell transplantation, the role of post-transplant maintenance therapy has evolved from interferon-based approaches to continuous therapy with immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, and more recently, bispecific antibodies. This review summarizes the modern data of maintenance therapies for MM while also discussing emerging approaches with minimal residual disease (MRD)-based strategies and additional novel agents.

The rapid expansion of therapeutic options for multiple myeloma (MM) has created uncertainty regarding optimal sequencing and clinical application. To address gaps in evidence, the 2025 Bridging the Gaps Consensus Conference convened 16 US MM experts who reviewed data, debated controversies, and voted on 51 questions that were developed using a modified Delphi approach. Eleven consensus recommendations were developed spanning smoldering MM, frontline therapy, transplant, maintenance, and relapsed/refractory disease. Key themes included integration of quadruplet induction, individualized maintenance, and early referral for CAR-T therapy. These expert-derived recommendations provide practical guidance while highlighting areas requiring further investigation.

BACKGROUND:Current treatment of newly diagnosed multiple myeloma involves lenalidomide maintenance therapy given until disease progression. The appropriate duration of maintenance therapy with lenalidomide has been unclear. METHODS:In this phase 3 trial, we enrolled patients with standard-risk newly diagnosed multiple myeloma who were not undergoing up-front autologous stem-cell transplantation. After induction treatment with a proteasome inhibitor-lenalidomide combination, patients were randomly assigned to receive indefinite-duration (continuous) lenalidomide or fixed-duration lenalidomide (for 2 years). The primary end point was overall survival; the trial had 80% power to detect a 50% increase in median survival (from 5 years to 7.5 years), with a two-sided alpha level of 5%, 395 patients undergoing randomization, and 204 deaths occurring during 9 years of follow-up. RESULTS:At the end of induction, 516 patients were randomly assigned to the indefinite-duration group (260 patients) or the fixed-duration group (256 patients). At a median follow-up of 86 months, overall survival did not differ significantly between the groups. With 80 deaths in each group, overall survival at 7 years was 68.6% in the indefinite-duration group and 69.0% in the fixed-duration group (difference, -0.4 percentage points; 95 confidence interval [CI], -9.0 to 8.3; P = 0.93). Progression-free survival at 7 years was 36.1% in the indefinite-duration group and 29.7% in the fixed-duration group (difference, 6.4 percentage points; 95% CI, -2.6 to 15.4). The 5-year cumulative incidence of second primary cancers, excluding nonmelanoma skin cancer, was 11.2% with indefinite-duration lenalidomide and 8.3% with fixed-duration lenalidomide. More adverse events occurred with indefinite-duration lenalidomide; the incidence of nonhematologic events of grade 3 or higher was 48.2% with indefinite-duration therapy and 31.5% with fixed-duration therapy. CONCLUSIONS:In this phase 3 trial involving patients with standard-risk newly diagnosed multiple myeloma who were not undergoing up-front autologous stem-cell transplantation, indefinite-duration maintenance therapy after induction therapy did not result in significantly longer overall survival than fixed-duration maintenance therapy. (Funded by the National Cancer Institute of the National Institutes of Health and Amgen; ENDURANCE ClinicalTrials.gov number, NCT01863550.).

Background/Objectives: Patients with relapsed/refractory multiple myeloma (RRMM) have poor survival outcomes and limited treatment options. The increasing utilization of multiagent therapies for earlier lines of treatment and novel drug classes including BCMA-targeting agents in subsequent lines of therapy has created a need for innovative treatment platforms in patients who have relapsed after or are refractory to these current standard-of-care approaches. Iopofosine I 131 is a 131iodide (131I)-phospholipid conjugate that exploits the selective uptake and retention of phospholipid ethers through lipid rafts to facilitate tumor delivery of 131I. Methods: The objective of this phase 1 dose-escalation study was to assess the safety and tolerability of single and fractionated dose schedules of iopofosine I 131 + low-dose dexamethasone in heavily pretreated patients with RRMM. Results: The most common AEs overall were cytopenias, notably thrombocytopenia (93.5%), lymphopenia (74.2%), anemia (71%), leukopenia (61.3%), and neutropenia (58.1%). All patients experiencing hematologic adverse events recovered from those events with median time of recovery 21 days post-nadir. Nonhematologic adverse events were mostly limited to Grade 1 and 2. Dose-limiting toxicities included four Grade 4 thrombocytopenia events lasting longer than 7 days, one Grade 4 neutropenia, and one Grade 3 insomnia. The DMC determined 31.25 mCi/m2 was the maximum tolerated dose in the single-dose group, and 20 mCi/m2 × 2 doses was the maximum tolerated dose in the fractionated-dose group. For patients monitored through 85 days following the first infusion, 22 of 26 (84.6%) achieved stable disease after treatment, and 4 of 26 (15.4%) achieved a partial response. Conclusions: A favorable safety and tolerability profile and preliminary clinical activity support further development of iopofosine I 131 in RRMM.

Introduction Effective tumor burden reduction using bridging therapy is correlated with improved progression-free survival (PFS) and safety in patients treated with ciltacabtagene autoleucel (cilta-cel). Here, we further evaluate the correlation between response to bridging therapy before cilta-cel with postinfusion efficacy and safety outcomes. In CARTITUDE-4 (NCT04181827; median follow-up, 33.6 months), a single infusion of cilta-cel significantly improved PFS (weighted hazard ratio [HR], 0.29 [95% CI, 0.22–0.39]) and overall survival (OS; HR, 0.55 [0.39–0.79]; P=0.0009) versus standard of care in patients with lenalidomide-refractory multiple myeloma after 1–3 prior lines of therapy. Methods The design and methods of CARTITUDE-4 have been reported previously. Patients in the cilta-cel arm underwent apheresis, ≥1 cycle of bridging therapy with investigator's choice of either pomalidomide, bortezomib, and dexamethasone (PVd) or daratumumab, pomalidomide, and dexamethasone (DPd), lymphodepletion, and then a single cilta-cel infusion 5–7 days after the start of lymphodepletion. Results Among the 196 patients who received cilta-cel (176 as study treatment, 20 as subsequent therapy), 172 (87.8%) received DPd and 24 (12.2%) received PVd during the bridging period (median, 2 [range, 1–6] bridging cycles). After bridging therapy and before lymphodepletion, 42 patients had very good partial response or better (≥VGPR), 70 had partial response (PR), 61 had minimal response (MR)/stable disease (SD), 20 had progressive disease (PD), and 3 were not evaluable. Thirty-month PFS and OS rates were highest among patients achieving ≥VGPR or PR and lowest among those with MR/SD or PD (Table). No movement or neurocognitive treatment-emergent adverse events (MNTs) were reported in patients with ≥VGPR or PR. One patient with PD and another with best response of SD (unconfirmed PD at cilta-cel infusion) experienced an MNT event. Cranial nerve palsy was more frequent among patients with ≥VGPR relative to other groups, while rates of fatal infections, prolonged thrombocytopenia, and nonrelapse mortality were lowest among those with ≥VGPR (Table). Prolonged neutropenia (grade 3/4 cytopenia not recovered by day 60 after infusion) was also lowest in patients with ≥VGPR before cilta-cel (2.4% vs range of 9.8%–15.7% in patients with PR or lower. Conclusions In patients from CARTITUDE-4, better response to bridging therapy correlated with longer PFS and OS. No MNTs were observed in those who achieved ≥PR after bridging therapy. Poorer responses to bridging therapy were associated with higher rates of fatal infections, prolonged thrombocytopenia and neutropenia, and nonrelapse mortality following infusion. These findings emphasize the importance of optimizing bridging therapy for disease control before treatment with cilta-cel.

Extramedullary presentations of multiple myeloma (MM) involving the central nervous system (CNS) carry a dismal prognosis. Although historically rare, management of extramedullary disease-including CNS manifestations-has become increasingly clinically relevant as advances in systemic therapies have prolonged control of medullary disease. CNS manifestations may occur across a variety of clinical settings and at different time points throughout the disease course. Common symptoms include visual changes, headaches, loss of sensation, confusion, and seizures. MRI identifies leptomeningeal enhancement and/or parenchymal lesions in approximately 90% of cases, and lumbar puncture with cerebrospinal fluid testing for clonal plasma cell populations is confirmatory. Encouragingly, the incorporation of novel therapeutic agents has improved historically poor outcomes in CNS MM. Novel immunotherapeutic approaches using CAR T-cell therapy and bispecific T-cell-engaging antibodies have recently demonstrated significant efficacy in consolidating responses. Multimodality treatment strategies incorporating intrathecal chemotherapy, systemic novel agents, radiation therapy, and immunotherapy hold promise for achieving more durable responses in this devastating manifestation of MM.

Background: Anitocabtagene autoleucel (anito-cel) is an autologous anti–BCMA chimeric antigen receptor (CAR) T-cell therapy with a novel D-domain binder under development for patients (pts) with relapsed and/or refractory multiple myeloma (RRMM). D-Domain attributes, including small size, simple structure, and fast off-rate, facilitate high transduction efficiency, stable CAR expression, and decreased risk of tonic signaling. In the Phase 1 trial (NCT04155749), at a median follow-up of 38.1 months, the median PFS was 30.2 months for all pts and 34.3 months for pts achieving a complete response (CR) or better, and no delayed or non-ICANS neurotoxicities or immune effector cell (IEC)-associated enterocolitis have been observed. Updated results from the fully enrolled, ongoing iMMagine-1 Phase 2 registrational trial (NCT05396885) are presented in this report. Methods: Eligible pts were ≥18 years, triple-class exposed, had progressed after ≥3 LoT, had measurable disease, and were refractory to their last LoT. Following leukapheresis, optional bridging, and anito-cel manufacturing, pts received lymphodepletion chemotherapy and a single infusion of anito-cel (target dose of 115×106 CAR+ T cells). The primary endpoint is overall response rate (ORR) by Independent Review Committee (IRC) and assessed using 2016 International Myeloma Working Group (IMWG) criteria. MRD is assessed by next-generation sequencing, toxicity is graded per CTCAE version 5.0, and CRS and ICANS are graded by the ASTCT consensus criteria. This analysis reports the investigator-assessed safety and efficacy outcomes for all pts infused with anito-cel in the iMMagine-1 trial. Results: At a data cut-off of May 1, 2025, 117 pts had received anito-cel under the final manufacturing process with a median follow-up of 12.6 months. Median age was 64 years (range, 38 -78) and racial distribution was 89 (76%) White, 17 (15%) Black or African American, and 11 (9%) Asian or Other. Median time from MM diagnosis was 7.2 years (range, 1.0 - 23.1), and median prior LoT was 3 (range, 3 - 8) with 51% receiving only 3 prior LoT. All pts (n=117, 100%) were refractory to their last LoT, 100 (86%) were triple-class refractory, 47 (40%) were penta-drug refractory, 18 (15%) had extramedullary disease, and 44 (38%) had high-risk cytogenetics. Ten pts (9%) received outpatient infusion of anito-cel. Investigator-assessed ORR per IMWG criteria was 97% (114/117) with a CR/sCR rate of 68% (79/117) with a median time to first response of 1.0 month (range, 0.9 - 13.4). Of those evaluable for MRD testing (n=75), 70 (93%) achieved MRD negativity at the level of 10-5 with a median time to MRD negativity of 1.0 month (range, 0.9 – 6.4), and MRD negativity at the level of 10-6 was achieved in 78% (53/68). Using Kaplan-Meier methods, the PFS rates at 12- and 18-month milestone timepoints were 79% and 66%, respectively, with 12- and 18-month OS rates being 95% and 90%, respectively. Median PFS and OS have not been reached. The most common grade 3/4 treatment emergent adverse events (AEs) were cytopenias: 77 pts (66%) with neutropenia, 28 (24%) with anemia, and 28 (24%) with thrombocytopenia. Grade 3/4 infections were reported in 11 pts (9%). Ninety-nine pts (85%) had CRS Gr1 or less, including 17 (15%) with no CRS, and 114 (97%) had either no CRS or CRS resolution ≤10 days of anito-cel infusion. Any grade CRS was observed in 100 pts (85%) with 82 (70%) Gr1, 17 (15%) Gr2, and 1 (1%) Gr5. Median onset was 4 days (range, 1-17) with a median duration of 2 days (range, 1-9). Any grade ICANS was observed in 9 pts (8%) with 4 (3%) Gr1, 4 (3%) Gr2, and 1 (1%) Gr3. No delayed or non-ICANS neurotoxicities including no Parkinsonism, no cranial nerve palsies, and no Guillain-Barré syndrome have been observed. No IEC-associated enterocolitis and no secondary primary malignancies of T-cell origin have been reported. Conclusions: Ongoing results from the Phase 2 iMMagine-1 trial demonstrate deep and durable efficacy and manageable safety in a heavily pre-treated, refractory 4L+ RRMM population. No delayed or non-ICANS neurotoxicities including no Parkinsonism, no cranial nerve palsies, no Guillain-Barré syndrome, and no IEC-associated enterocolitis have been observed across the Phase 1 or Phase 2 iMMagine-1 studies to date. Updated data including safety and efficacy outcomes in all patients at a later data cut-off date will be presented.

The NCCN Guidelines for Multiple Myeloma (MM) provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with MM. These NCCN Guidelines Insights highlight the important updates and changes specific to systemic therapy for patients with newly diagnosed as well as previously treated MM included in Version 1.2025 of the NCCN Guidelines for MM.

Multiple myeloma has been regarded as incurable, with steady and sizeable risk of progression even for patients without high-risk features. The development of better upfront therapies, namely anti-CD38 monoclonal antibody-containing quadruplet combination therapy (QUAD) with autologous stem cell transplant (ASCT) and better disease classification, outlined in the 2025 International Myeloma Society/International Myeloma Working Group (IMS/IMWG) consensus of high-risk disease, creates the opportunity to refine disease and treatment-response features that may identify a population with very low risk of progression, and for whom initial therapy may have been definitive. We studied a cohort of patients (pts) with newly diagnosed MM (NDMM) who received QUAD induction followed by ASCT, was monitored with serial measurable residual disease (MRD) by next generation sequencing and often had treatment cessation upon confirmation of MRD negativity (MRDneg) at 10-5threshold. MRD assessments were performed post induction, post ASCT and at least yearly thereafter regardless of conventional IMWG response. We retrospectively reclassified pts in standard risk (SR) or high risk using the 2025 IMS/IMWG consensus. We described the outcomes of patients with SR NDMM who also achieved sustained MRDneg (S-MRDneg, two consecutive MRD negative tests ≥ 12 months apart, not interrupted by a positive test) at 10-5 threshold. We utilized Cox regression to estimate the protective effect of S-MRDneg on progression-free (PFS) and overall survival (OS) by inputting MRD as time-varying covariate. We identified 213 patients who started therapy >3 years prior to data cut, 128 (60%) were classified as SR. Median age was 61 years (IQR 56-68), 58% were male, 30% of racial-ethnic minority, 20% harbored t(11;14), 28% gain/amp(1q), and 6% t(4;14) or t(14;16). After median follow up of 45.4 mo, 72 patients reached S-MRDneg for a cumulative incidence of S-MRDneg of 56%. Among these SR patients with S-MRDneg, 63 (88%) discontinued therapy upon confirmation of MRDneg and were monitored with sequential MRD assessment. Among S-MRDneg SR patients there has only been one death (due to COVID infection, in absence of disease progression) and 2 disease progressions. The 5-year PFS for patients who reached S-MRDneg was 97% vs. 62% for those who did not, and 5-year OS rates were 99% and 88% respectively. S- MRDneg had a strong protective effect in PFS (HR=0.17, 95% C.I. 0.04-0.62, P=0.007) and OS (HR=0.10, 95% C.I. 0.01-0.94, P=0.04). Overall, there were 200.8 patient-year of observation beyond S-MRDneg with only 2 progressions, resulting in an event rate of 1.0%/year. Patients with 2025 IMS/IMWG consensus-defined SR NDMM who received QUAD + ASCT and achieve S-MRDneg have exceptional outcomes in absence of any subsequent therapy with 5-year PFS of 97% and OS of 99%. Given the very low rate of progression events, 1.0%/year, many may not require myeloma therapy for the remaining of their lifetime. Future efforts should validate these findings and develop strategies to increase the proportion of SR patients fitting this definitive therapy frame.

Introduction QUAD induction with a proteasome inhibitor, an immunomodulatory agent, anti-CD38 monoclonal antibody, and dexamethasone followed by ASCT lead to high proportion of MM patients (pts) achieving MRD negativity with improved outcomes. MM harboring t(11;14) has unique biological features and may have different kinetics of response to systemic therapy, as described in the pre-QUAD era. It is unknown whether MRD reduction dynamics in t(11;14)pos are similar to t(11;14)neg MM and if t(11;14) status affects the role of MRD as prognostic factor. Methods We analyzed 302 pts. with newly diagnosed MM (NDMM) who received QUAD induction followed by ASCT. Post ASCT consolidation/maintenance varied and was informed by MRD status per clinical trial design (N=111) or institutional practice (N=191). All patients had MRD assessed post induction, post ASCT and at least yearly thereafter regardless of International Myeloma Working Group response. We describe achievement of MRD negativity and sustained MRD negativity (S-MRD, two consecutive MRD negative tests ≥ 12 months apart, not interrupted by a positive test) at 10-5 and 10-6 thresholds. We utilized Cox regression to build predictive models of disease progression by inputting MRD as time-varying covariate. Results Median age of the pts. was 62 years (IQR 56-69), and 47 (16%) had t(11;14)pos MM. Median duration of follow up was 40.6 mo., 36.5 mo. for t(11;14)pos and 41.5 mo. for t(11;14)neg pts. MRD negativity rate at 10-5threshold for t(11;14)pos vs. t(11;14)neg patients was 9% vs. 31% (P=0.01), 36% vs. 59% (P=0.03), and 51% vs. 75% (P<0.001) at post induction, post ASCT and at any time on follow up, respectively. Corresponding figures for 10-6 threshold were 4% vs. 16% (P=0.03), 23% vs. 46% (P=0.05), and 45% vs. 62% (P=0.03), respectively. The rates of S-MRD negativity at 10-5 threshold were 38% vs. 45% (P=0.41), and at 10-6threshold 30% vs. 37% (P=0.35). Median time to achieve MRD negativity at 10-5 was 13.6 vs 7.7 vs. mo (P=0.002) and at 10-6 was 29.0 vs. 11.6 mo. (P=0.023) for t(11;14)pos vs t(11;14)neg, respectively. Four-year progression-free survival (PFS) was 93% for t(11;14)pos and 73% for t(11;14)neg patients (P=0.017). Among pts with no high-risk chromosome abnormalities [del(17p); t(4;14),t(14;16), gain/amp(1q)], 4-year PFS was 100% vs. 86% for t(11;14)posvs t(11;14)neg pts (P=0.06). In multivariate analysis, both the achievement of S-MRD negativity at 10-5 (HR 0.37, P<0.001) and the presence of t(11;14) (HR 0.32, P=0.58) were associated with reduced risk of progression or death. Due to small number of PFS events (N=3, all in patients who did not achieve S-MRD negativity) the protective effect of MRD could not be demonstrated exclusively among t(11;14)pos patients. Conclusion In the setting of QUAD therapy + ASCT with MRD-adapted post ASCT therapy, patients with t(11;14)pos MM have outstanding prognosis despite slower conversion to MRD negativity than in t(11;14)neg pts. The overall rate of S-MRD negativity appears comparable in t(11;14)pos and t(11;14)neg patients. In the setting of QUAD + ASCT therapy for NDMM, both S-MRD negativity and t(11;14)pos status are associated with lower risk of progression or death.

PURPOSE:The management of multiple myeloma (MM) is becoming increasingly more complex. The approval of novel treatment approaches provides much-needed opportunities but also raises questions and controversies about how to optimally sequence therapies and select treatments for individual patients. METHODS AND RESULTS:A panel of experts assembled to discuss current controversies in the care of patients with MM across the disease continuum. Workshop topics included: management of smoldering MM; treatment selection for transplant-eligible and transplant-ineligible patients; risk assessment and the possibility of risk-adapted treatment; use of measurable residual disease (MRD) as a clinical trial end point and to guide treatment decisions; management of early relapse; management of triple class-refractory MM; treatment sequencing; and novel therapies. CONCLUSION:Many controversies remain regarding the management of patients with MM related to risk assessment, treatment selection and sequencing, and the optimal use of current therapies while balancing efficacy, toxicity, patient considerations, and treatment logistics. Ongoing research efforts are needed to further define the optimal use of current therapies and to develop more efficacious therapies for all patients and for particular subset populations with unmet need.

Introduction: Multiple myeloma (MM) with t(11;14), present in approximately 16-24% of patients with MM, represents a unique disease subset with distinct features. BCL2 inhibition has shown efficacy in this subgroup; however, no BCL2-targeted therapies are currently approved for MM. Sonrotoclax (BGB-11417), a next-generation BCL2 inhibitor, is a more selective and pharmacologically potent inhibitor of BCL2 than venetoclax, with a shorter half-life and no drug accumulation. BGB-11417-105 (NCT04973605) is an ongoing phase 1b/2 study to evaluate the safety and efficacy of sonrotoclax as monotherapy or in combination therapy in patients with t(11;14)-positive relapsed/refractory (R/R) MM. Initial data from BGB-11417-105 showed that sonrotoclax + dexamethasone (dex) was well tolerated and induced deep and durable responses in heavily pretreated patients. Presented here are preliminary results in the sonrotoclax + carfilzomib (K) + dex dose-escalation cohorts of BGB-11417-105. Methods: Eligible patients have R/R MM with centrally confirmed t(11;14) and have received ≥3 prior lines of therapy, including a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody (patients in certain regions did not require prior anti-CD38). Patients receive oral sonrotoclax (320 or 640 mg) once daily + oral or intravenous dex (40 mg) once weekly + intravenous K (56 mg/m2 [K56] or 70 mg/m2 [K70]) on days 1, 8, and 15 of each 28-day cycle until disease progression or unacceptable toxicity. Study endpoints include safety per NCI-CTCAE v5.0 and investigator-assessed overall response rate (ORR) per International Myeloma Working Group guidelines. Results: As of May 16, 2025, a total of 20 patients were enrolled and had been treated in 1 of 3 cohorts: sonrotoclax 320 mg + K56 + dex (n=11), sonrotoclax 320 mg + K70 + dex (n=7), or sonrotoclax 640 mg + K56 + dex (n=2; enrollment ongoing). The median follow-up in all patients was 7.3 months (range, 1.7-22.2 months). Across cohorts, the median age was 65 years (range, 51-77 years), 75% were male, and 50% were White. Patients had a median of 4 prior lines of therapy (range, 2-8); 65% of patients had ≥4 prior lines, 85% were triple-class exposed, and 20% were triple-class refractory. At data cutoff, 13 patients (65%) remained on study treatment; 6 patients discontinued due to disease progression, and 1 withdrew consent. The most common all-grade treatment-emergent adverse events (TEAEs) were insomnia (40%), fatigue (35%), nausea (30%), anemia (30%), and back pain (30%). Grade ≥3 TEAEs occurred in 12 patients (60%), grade ≥3 hematologic TEAEs occurred in 7 (35%), and grade ≥3 infections occurred in 5 (25%). Cardiac disorders occurred in 3 patients (15%; grade 2 arrhythmia, n=1; grade 2 atrial flutter, n=1; grade 1 tachycardia, n=1), and hypertension in 4 patients (20%; grade 1/2, n=2; grade 3, n=2). Eight patients (40%) experienced a serious TEAE; the most common serious TEAE was pneumonia (15%). Dose-limiting toxicities were reported in 2 patients (transient grade 3 thrombocytopenia and acute kidney injury). No TEAEs led to death, sonrotoclax discontinuation, or sonrotoclax dose reduction. Four patients died during the study, all for reasons unrelated to study treatment. In 19 response-evaluable patients across dose groups, the ORR was 84% (95% CI, 60%-97%), which included 32% (95% CI, 13%-57%) of patients with a complete response (CR)/stringent complete response (sCR). The median time to response was 1.0 months (range, 0.9-6.1 months). Median duration of response and median progression-free survival were not reached.Conclusions: Sonrotoclax + K + dex combination therapy demonstrated a tolerable safety profile and encouraging antimyeloma activity, with an 84% ORR and a 32% CR/sCR rate in heavily pretreated patients with t(11;14)-positive R/R MM. Enrollment in BGB-11417-105 is ongoing, and additional treatment combinations with sonrotoclax are being investigated.

ABSTRACT:The therapeutic success of first-line quadruplet (QUAD) induction therapy and autologous stem cell transplantation (ASCT) has reinvigorated an interest in fixed-duration therapy, yet optimal short-term efficacy end point for treatment cessation is unknown. Using data from a phase 2 clinical trial and a prospective institutional database, we tested the predictive performance of 5 short-term efficacy end points among 221 patients who received QUAD + ASCT followed by treatment cessation if minimal residual disease (MRD) by next-generation sequencing negative for 2 consecutive time points. Efficacy end points tested were International Myeloma Working Group-defined stringent complete response, MRD <10-5 (single data point), MRD <10-6, sustained MRD (S-MRD; 2 consecutive assessments at least 1 year apart) <10-5, and S-MRD <10-6. We built 5 parallel Cox regression models for each efficacy end point with progression-free survival (PFS) as the outcome. Best fitting models were determined using the Akaike information criterion (AIC) and Heagerty and Zheng C-index. The best fitting model (AIC, 417.2; C statistic, 0.757) was based on S-MRD <10-5 (hazard ratio, 0.23; 95% confidence interval, 0.11-0.47). Similar results were seen for predicting the risk of progression/MRD resurgence among 121 patients undergoing MRD-guided treatment cessation. S-MRD <10-5 is the best predictor of PFS and yields the best predictive models for the risk of MRD resurgence or progression in the setting of fixed-duration therapy. This trial was registered at www.clinicaltrials.gov as #NCT03224507.

Introduction: Despite significant improvement in the survival of patients with newly diagnosed multiple myeloma (NDMM), a subset of patients continues to experience poor outcomes. Accurate classification of such high-risk patients is crucial to contextualize new therapies and develop risk-adapted strategies. One of the most frequently used classification tools identifies NDMM patients as high-risk when they harbor del(17p), t(4;14) or t(14;16), hereafter referred to as “old” high-risk (old-HiR). Recently, the International Myeloma Society (IMS) and International Myeloma Working Group (IMS/IMWG) published a new consensus high-risk (new-HiR) definition which combines certain cytogenetic abnormalities, next generation sequencing data (TP53 mutation, biallelic del1p), and elevated beta-2-microglobulin (B2M) without renal impairment. While the 2025 IMS/IMWG classification was predominantly developed among patients treated with triplet combinations, the MM treatment paradigm has rapidly evolved to include monoclonal antibody-based quadruplets (QUAD) with autologous stem cell transplant (ASCT) and further improved outcomes. We aimed to characterize the performance of the 2025 IMS/IMWG classification in the QUAD+ASCT population and compare the old-HiR vs. new-HiR models. Methods: We evaluated a cohort of NDMM patients who received QUAD induction, ASCT and risk-adapted post-ASCT therapy. We retrospectively reclassified patients as standard risk (new-StR) or high risk (new-HiR) using the 2025 IMS/IMWG classification. We evaluated the cumulative incidence of progression (CIP) at 18 and 36 months to demonstrate the ability of the new system to identify functional high-risk patients (patients experiencing disease progression within 18 and 36 months from start of initial therapy, respectively). We subsequently compared old-HiR vs. new-HiR classification. Best fitting models were determined using Akaike's information criterion (AIC), an information theory approach. Results: Among 310 patients, 89 (29%) were classified as new-HiR. Median age was 62 years (IQR 56-68), 55% were male, 33% of racial-ethnic minority, 6% harbored t(11;14), 56% any del(17p), 51% gain/amp(1q), 14% del(1p), 27% t(4;14), and 12% t(14;16). After a median follow up of 41.6 mo, the 4-year PFS was 49% vs. 84% for new-HiR vs. new-StR (HR 4.17, 95%CI 2.58-6.73; p<0.001). The CIP at 18 months was 15% vs. 3% for new-HiR vs new-StR and at 36 months was 33% vs. 10%, respectively. For the same population, 4-year PFS for old-HiR vs. old-StR was 55% vs. 83% (HR 3.34, 95% CI 2.08-5.36, P<0.001). Overall, the new model produced the best fitness, with delta AIC = 9.3 (delta AIC>2 being generally considered meaningful). Furthermore, we demonstrate that the presence of old-HiR abnormalities did not affect outcomes of patients with new-HiR (P=0.70) or new-StR (P=0.56). In contrast, when we applied the new criteria to patients with old-HiR we were able to successfully classify two cohorts with very distinct outcomes (median PFS NR vs 49.3 mo, for new-StR vs new-HiR, respectively, p=0.05) similar to when we applied new criteria for old-StR patients (median PFS NR vs. 40.7 mo for new-StR vs new-HiR; p=0.007). We further explored the frequently used 3-tier system based on cumulative number of high-risk chromosomal abnormalities [HRCA; del(17p), t(4;14), t(14;16) and gain/amp(1q)]. Among patients with new-HiR, the presence of 1 (P=0.99) or 2+ HRCA (P=0.49) did not affect outcomes. Conclusions: The 2025 IMS/IMWG consensus criteria for high-risk MM appears to be more prognostic in the setting of modern QUAD+ASCT (HR 4.17) compared to triplet+ASCT where the criteria were first created and validated (HR 2.17-2.94). Among patients with new-HiR, presence of old-HiR abnormalities or application of 3-tier HRCA system did not further improve the classification. Ultimately, the new simplified 2-tier system incorporating genomic data and B2M is most relevant in the era of QUADs and identifies patients at risk of early relapse with greater accuracy.

Autologous stem cell transplantation (ASCT) has been the prime consolidative strategy to increase the depth and duration of response in newly diagnosed multiple myeloma (NDMM), albeit with short- and long-term toxicities. Minimal residual disease (MRD) is an important early response endpoint correlating with clinically meaningful outcomes and may be used to isolate the effect of ASCT. We report the impact of ASCT on MRD burden and generate a benchmark for evaluation of novel treatments as consolidation. We collected MRD by next generation sequencing (NGS; clonoSEQ®) post induction and post-ASCT in consecutive patients (N = 330, quadruplet, N = 279; triplet, N = 51). For patients receiving quadruplets, MRD < 10-5 post-induction was 29% (MRD < 10-6 15%) increasing to 59% post-ASCT (MRD < 10-6 45%). Among patients with MRD > 10-5 post-induction, ASCT lowered the MRD burden>1 log10 for 69% patients. The use of quadruplet induction (vs. triplet) did not reduce the effect of ASCT on MRD burden. Reduction in MRD burden with ASCT was most pronounced in patients with high-risk chromosome abnormalities.This dataset provides granular data to delineate the impact of ASCT on MRD as legacy consolidative strategy in NDMM and provides an important benchmark for evaluation of efficacy of TCRT as experimental consolidative strategy.