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Highlights From the 22nd IMS Annual Meeting

Over three days, the 2025 International Myeloma Society (IMS) Annual Meeting featured dozens of new and updated clinical trial results, illustrating significant advancements in therapy from newly diagnosed (NDMM) to relapsed/refractory multiple myeloma (RRMM).  

Topics included real-world CAR T insights, evolving outpatient (OP) and modified bispecific antibody (bsAb) practices, expanding roles for bsAbs in NDMM and smoldering MM (SMM), tailored approaches for high-risk disease, new analyses of quadruplets, growing evidence for cereblon E3 ligase modulatory drugs (CELMoDs) across treatment settings, emerging experimental agents that highlight the importance of clinical trial participation, and a broad set of new biomarkers that refine risk assessment and treatment response prediction. 

Real-World Insights Reveal CAR T Benefits and Tradeoffs 

Real-world evidence comparing ide-cel and cilta-cel underscored the durable responses and varying toxicity profiles of each CAR T therapy, offering important comparative insights in the absence of head-to-head clinical trials. 

Real-world comparison of ide-cel and cilta-cel via CIBMTR data

  • Intervention: Ide-cel and cilta-cel are BCMA-directed CAR T-cell therapies approved for RRMM. This was a multicenter comparison using Center for International Blood and Marrow Transplant Research (CIBMTR) data (2021–2023) 
  • Population: 1,581 pts were included: 986 received ide-cel and 595 cilta-cel. Baseline characteristics were comparable between the cohorts, but the cilta-cel cohort generally had fewer comorbidities, better Eastern Cooperative Oncology Group (ECOG) performance status, lower rates of extramedullary disease (EMD) and penta-exposed disease, and slightly higher response at infusion 
  • Outcomes: With a median follow-up: 12.0 months for cilta-cel, 12.9 months for ide-cel: 
    • Overall response rate (ORRs) and complete response (CR) rates were higher with cilta-cel: ORR (88.9% vs 75.3%) and CR (36.2% vs 24.4%) 
    • 12-month progression-free survival (PFS) was 72.6% for cilta-cel vs 46.7% for ide-cel and overall survival (OS) was 84.5% vs 73.6%, respectively 
    • Cilta-cel maintained significantly higher odds of ORR (odds ratio [OR] 1.7), CR (OR 1.88), and superior PFS (hazard ratio [HR] 0.47) and OS (HR 0.82) 
    • Cytokine release syndrome (CRS) was of similar frequency overall (79.3% vs 82.1%), but cilta-cel had more grade (G) ≥3 CRS than ide-cel (4.3% vs 2.9%) 
    • Any-grade immune effector cell-associated neurotoxicity syndrome (ICANS) occurred less with cilta-cel (22.3% vs 27.3%), with no differences in severity. Cilta-cel carried additional risk of delayed neurologic toxicities not seen with ide-cel, including parkinsonism (2.7%) and cranial nerve palsies (2.5%) 
    • The 6-month treatment-related mortality (TRM) was higher with cilta-cel (4.0% vs 2.9%). Adjusted analysis confirmed increased TRM risk (HR 1.45) 
  • Takeaway: Cilta-cel demonstrated deeper and more durable responses, with significantly improved PFS and OS compared with ide-cel. However, the benefits came at the cost of higher TRM, increased rates of severe CRS, and unique delayed neurologic toxicities. Shared decision-making should balance efficacy and safety. Proactive neurotoxicity monitoring for cilta-cel therapy is important to ensure long-term safety and best possible outcomes  

Transforming bsAb Care: OP SUD and Other Practices

Multiple real-world studies confirmed that OP or hybrid step-up dosing (SUD) of bsAbs such as teclistamab (tec) and talquetamab (tal) is both safe and practical, especially with prophylactic dexamethasone (dex).  

Limited-duration therapy and reduced-frequency regimens, such as less-frequent elranatamab dosing, demonstrated that individualized schedules can maintain efficacy. Notably, a new analysis comparing prophylactic dex + OP SUD vs standard inpatient (IP) observation examined the potential to reduce financial toxicity and resource burden. These results highlight how community practices can deliver advanced therapies while maintaining convenience, safety, and lower costs. 

Retrospective cohort study of limited-duration bsAb therapy

  • Approach: bsAbs, primarily those targeting BCMA or GPRC5D, were evaluated under a fixed-duration treatment strategy (discontinued treatment without progression) 
  • Population: 78 RRMM pts (median age: 70, range 26–86) who discontinued bsAbs (72% received BCMA-targeted agents, 19% GPRC5D-targeted agents, and 9% BCMA + GPRC5D-targeted agents) for reasons other than disease progression or death and were alive in remission for at least 3 months post-discontinuation  
    • High-risk cytogenetics: 47%; EMD: 8% 
    • Median duration of bsAb therapy: 7 months; 80% in CR at discontinuation 
  • Outcomes: At a median 16-month follow-up, relapse-free survival (RFS) at 2 years was 67% (95% confidence interval [CI], 55%–80%). 2-year RFS outcomes varied by prior therapy: 
    • 1–3 prior lines of therapy (LOT), 79% 
    • 4–5 prior LOT, 78% 
    • ≥6 prior LOT, 48% 

Factors independently predicting inferior RFS included: 

    • EMD (HR 7.88; P=0.004) 
    • Higher number of LOT (HR 1.79; P<0.001)
    • Partial remission at discontinuation vs CR (HR 28.3; P=0.012)

The most common causes of treatment discontinuation included infections (44% of pts) and ectodermal toxicities (15%). Post-discontinuation risk: 

    • Cumulative incidence of G≥3 infections was 22% at 1 year, 32% at 2 years, and 38% at 3 years 
    • Risk of first severe infection decreased as the time from discontinuation increased 
  • Takeaway: Fixed-duration bsAb therapy in RRMM shows that sustained remissions are achievable, particularly in pts with fewer than 6 prior LOT. Randomized controlled trials are needed to determine whether a limited-duration approach is noninferior to treatment until progression 

Phase 2 MagnetisMM-3 trial of elranatamab less-frequent dosing in RRMM

  • Intervention: Elranatamab administered with priming SUD, transitioning to weekly, biweekly, and then monthly dosing in responders. Prophylactic antimicrobials and immunoglobulin replacement were commonly employed 
  • Population: 47 heavily pretreated RRMM pts, with a median of 5 prior LOT (range 2–22). Almost all (93.6%) triple-class refractory, and almost half (46.8%) penta-drug refractory 
  • Efficacy: ORR was 66.0% (95% CI, 50.7–79.1) and ≥CR was 42.6%, with a median time to response (TTR) of 1.08 months and a median time to ≥CR of 4.76 months 
    • Median duration of response (DOR), 40.8 months (95% CI, 24.0–not estimable) 
    • Median PFS, 27.3 months (95% CI, 4.3–not estimable) 
    • Median OS, 43.6 months (95% CI, 14.9–not estimable; not yet mature) 
  • Safety: All pts experienced an adverse event (AE), and G≥3 AEs were noted in 78.7%. Infections occurred in 70.2% of pts, with 42.6% G3–4. Almost half (51.1%) required immunoglobulin replacement 
    • CRS, 61.7% (G1 34.0%, G2 27.7%, G≥3 0%) 
    • ICANS, 8.5% (all grade 1–2) 
  • Takeaway: In a heavily pretreated US subgroup of RRMM pts, elranatamab induced deep and durable responses with a less-frequent dosing regimen, including once every 4 wks. Elranatamab is typically administered biweekly (only for pts who have achieved partial response or better) according to the label

Outcomes of OP SUD of tec and tal

  • Approach: A retrospective observational study to assess the feasibility and safety of tec and tal treatment initiated with SUD in 3 real-world settings: IP, OP, and hybrid (HY; OP SUD with 48 hours of IP observation) 
  • Population: 120 RRMM pts treated as follows: OP=23 pts (tec=13, tal=10); IP=54 pts (tec=42, tal=12); and HY=43 pts (tec=29, tal=14). Older pts were more frequent in OP (48% ≥75) than in HY (40%) and IP (31%) 
    • ECOG≥2, OP 9%, IP 19%, HY 17% 
    • High-risk cytogenetics, OP 26%, IP 33%, HY 28% 
    • Heavily pretreated, 70%–81% were penta-drug exposed; median prior LOT ~4–6; prior T cell–redirecting therapy more common in IP (24%) and HY (33%) vs OP (9%) 
  • Outcomes: All OP pts (tec and tal) completed SUD, and most OP pts (70%) did not require hospitalization during SUD. The median hospitalization for OP pts with G2 CRS was 4 days, and 1 HY pt discontinued due to ICANS; no discontinuations in OP or IP cohorts were noted. CRS emerged within 14 days as follows: OP 61%, IP 50%, HY 63% 
    • Highest grade observed: OP 22% (G2), IP 7% (G2), HY 37% (G2) 
    • Tocilizumab used: OP 13%, IP 17%, HY 56% 
    • No discontinuations due to CRS 

ICANS emerged within 14 days as follows: OP 4% (G2), IP 6% (various grades), HY 13% (mostly G1) 

    • Steroids used: OP 0%, IP 4%, HY 14% 
    • No hospitalizations for ICANS; one HY pt discontinued therapy 
  • Takeaways: OP initiation of tec or tal with SUD is feasible and safe in community oncology practice. Rates and severity of CRS and ICANS were comparable to IP and HY approaches, with manageable toxicity and minimal need for hospitalization  

Prophylactic dex with OP SUD of bsAbs vs standard-of-care (SOC) IP observation

  • Approach: The cost and feasibility of OP SUD with tec and tal that included prophylactic dex the day after SUD and remote monitoring via Hospital at Home (HaH) with virtual visits, wearable vital sign monitors, and 24/7 nursing access was evaluated and compared to standard 48-hour IP care 
  • Population: 32 pts received OP care (16 treated with tec and 16 with tal). The comparator group consisted of 24 pts receiving standard IP observation (13 tec, 11 tal) 
  • Outcomes: CRS incidence was comparable between OP and IP groups (59% vs 54%), with no G3 or 4 CRS observed in the OP group; the IP group had rare G3 and 4 events. Recurrent CRS with subsequent SUDs was less frequent in OP (32% vs 46%). Prophylactic dex did not reduce CRS incidence but may have mitigated severity and reduced tocilizumab use. ICANS was lower in the OP group (6% vs 17%) 
    • Hospitalization within the first 30 days occurred in 43.8% in the OP group, with a mean of 1.1 IP days per pt vs 7.8 days for standard care 
    • The estimated total tocilizumab-related per-pt cost was $868 in the OP group vs $2,909 in the IP group 
    • Mean estimated cost per pt was $29,911 in the IP group vs $6,444 in the OP group 

OP monitoring was safe, with no severe ICANS beyond G1 detected, and CRS events were managed effectively with OP interventions for G1. Tocilizumab use was significantly lower in the OP group (12.5% vs 42%; P=0.03), correlating with fewer severe CRS events.  

  • Takeaway: OP SUD of tec and tal with prophylactic dex and remote HaH monitoring is feasible, safe, and cost-effective. Compared to the IP, the OP group saw a reduction of 6.7 hospital days per pt and a 78% reduction in estimated cost per pt compared to IP observation. This approach could reduce pt burden and health care resource utilization 

 bsAbs Expand Options for NDMM and SMM

New findings highlight how bsAbs are advancing into earlier LOT. The first results from the phase 2 LINKER-SMM1 trial show that linvoseltamab may also offer clinical benefit for pts with high-risk SMM, suggesting a potential role for bsAbs in delaying disease progression and redefining early intervention strategies.  

Additionally, phase 2 and early phase 3 data suggests that bsAbs like teclistamab and elranatamab, combined with standard agents, may be feasible and effective in NDMM pts. These findings point to a future where bsAbs may be given earlier in treatment—at least for a subset of pts; phase 3 trials are now under way. 

Phase 2 Linker-SMM1 study of linvoseltamab for high-risk SMM

  • Intervention: Linvoseltamab monotherapy with a 3-wk SUD schedule, followed by 200 mg dose in 28-day cycles (weekly for cycle [C] 1, every 2 wks for C2–5, and every 4 wks for C6–24) 
  • Population: 24 high-risk SMM pts per Mayo criteria (20-2-20; n=18) or PETHEMA criteria (n=6). Median age was 63 yrs 
  • Efficacy: ORR 100% (very good partial response or better [≥VGPR] 74%; ≥CR 37%) 
  • Safety: 92% of pts experienced ≥1 treatment-emergent AE (TEAE), and 38% experienced a G≥3 TEAE. Neutropenia was the only G≥3 hematologic toxicity. Infections occurred in 79% of pts and consisted of mostly low-grade respiratory tract infections. G3 infections were reported in 3 pts. CRS occurred in 10 pts (42%), and most events were G1 (a single G2 event after the 1 mg step-up dose). No ICANS observed and no pts discontinued treatment
  • Takeaway: Linvoseltamab is highly active in SMM with a favorable safety profile. Linvoseltamab will be further investigated in this population

Phase 2 GMMG-HD10/DSMM-XX (MajesTEC-5) of tec

  • Intervention: Tec (a BCMA × CD3 bsAb) combined with daratumumab-based induction regimens: 
    • Tec + daratumumab + lenalidomide (Tec-DR) 
    • Tec + daratumumab + lenalidomide + bortezomib (Tec-DVR) 

Steroid use was limited to early induction cycles. 

  • Population: 50 transplant-eligible (TE) NDMM; median age was 58 years and 49 received treatment with Tec-DR or Tec-DVR as induction therapy  
  • Efficacy: During induction, partial response or better (≥PR) was achieved in 100% of pts across all arms, and all pts with available samples (n=46) achieved minimum residual disease (MRD) negativity at 10⁻⁵ and 10-6 (by next-generation flow cytometry and next-generation sequencing [NGS], respectively). Stem cell collection provided a median yield of 8.1 × 10⁶/kg, with only 1 mobilization failure 
  • Safety: Most pts (89.8%) experienced G3/4 TEAEs, mainly hematologic. No cases of ICANS were reported. G3/4 infections occurred in 34.7%; serious AEs in 53.1%. CRS occurred in 65.3% (all G1/2) 
  • Takeaway: Tec combined with daratumumab-based regimens (with or without bortezomib) as induction therapy in TE NDMM demonstrated unprecedented efficacy, including MRD negativity while maintaining the feasibility of stem cell mobilization and a manageable safety profile 

Phase 3 MagnetisMM-6: part 1 of elranatamab + lenalidomide ± daratumumab

  • Intervention: Elranatamab in combination with lenalidomide and/or daratumumab (EDR) to evaluate the optimal dose of EDR or ER for the recommended phase 3 dose for part 2  
  • Population: 34 transplant-ineligible (TI) NDMM pts treated with EDR, with a median age of 75 (range, 67–83; 38% male). Disease characteristics included 14% Revised Multiple Myeloma International Staging System (R-ISS) stage III, 24% with ≥50% bone marrow (BM) plasma cells (PCs), and none had EMD. ECOG 2 performance status in 3% and 24% considered frail by International Myeloma Working Group (IMWG) scoring 
  • Efficacy: The ORR was 97.3% (95% CI, 85.8–99.9); and 94.6% of pts achieved ≥VGPR, with a median TTR of 1.5 months. At the median follow-up of 7.9 months, most pts (32 of 34) remained on treatment 
  • Safety: All pts reported TEAEs; G3/4 events occurred in 95%  
    • CRS in 62% (all G≤2); 1 G2 ICANS case 
    • Hematologic AEs: 84% any grade, 78% G3/4 
    • Infections: 70% any grade, 19% G3/4; the most common were upper respiratory tract infection (22%) and E. coli urinary tract infection (11%) 
    • Serious infections: 1 G5 Candida pneumonia 
    • High rates of antimicrobial prophylaxis and immunoglobulin replacement, reflecting infection risk management 
  • Takeaway: EDR demonstrated a very high ORR with rapid and deep responses in older, frail, TI NDMM pts. Safety was broadly consistent with known risks of the regimen’s components, though infections and hematologic toxicity remain important concerns. The findings support continued investigation of elranatamab-based combinations in frontline MM 

Tailored Strategies Improve Outcomes in High-Risk MM

New data explored optimized approaches for pts with high-risk or refractory features, including dual-bsAb combinations in EMD via the RedirecTT-1 study, the largest EMD study to date. This study reinforces the value of tailoring therapy intensity and combination strategy to disease biology. 

Phase 2 RedirecTT-1 trial of tal + tec for EMD

  • Intervention: Dual-bsAb regimen of tal (GPRC5D × CD3) and tec (BCMA × CD3). Dosing consisted of tal 0.8 mg/kg every 2 wks and tec 3.0 mg/kg every 2 wks, with SUD; pts could switch to every-4-wk dosing after C6 or after C4 with ≥VGPR 
  • Population: 90 pts with RRMM and EMD. The median age was 65, and 22% expressed high-risk cytogenetics. Patients had a median of 4 prior LOT (20% anti-BCMA CAR T, 9% prior bsAb therapy). 84% were triple-class refractory and 36% were penta-drug refractory 
  • Efficacy: The ORR was 79%, with ≥CR of 52%. In anti-BCMA CAR T–exposed pts, ORR was 83% and in bsAb-exposed pts 75%. The 9-month PFS and OS was 64% and 80%, respectively. Responses were durable, with most responders maintaining or deepening remission after switching to every-4-wk dosing 
  • Safety: Most pts (87%) experienced G3/4 AEs, and CRS emerged in 78% (all G1/2). Discontinuations occurred in 9% (5 due to G5 AEs, mostly infections), and 10 pts experienced G5 AEs, with 5 considered drug-related. Other AEs of note included:  
    • ICANS: 12% (G3, 1%; G4, 1%) 
    • Neutropenia: 62% (most common G3/4 AE) 
    • Taste changes (79%), skin-related events (69%), nail changes (56%)—all G1/2 
    • Infections: 79%, with G3/4 in 37% (majority within first 6 months) 
    • Hypogammaglobulinemia: 70%, with 87% requiring intravenous immunoglobulin (IVIG) 
  • Takeaway: Dual targeting with tal and tec resulted in high response rates, deep and durable remissions, and clinical outcomes comparable to CAR T therapy in heavily pretreated RRMM pts with EMD, a group with high unmet treatment need 

Updated Trial Analyses Provide Insights Into Quadruplets for NDMM

Updated analyses were presented from key NDMM trials such as PERSEUS, CEPHEUS, IMROZ, and the phase 2 ISASOCUT study (subcutaneous [SC] isatuximab [isa] combined with bortezomib, lenalidomide, and dex). These analyses highlight pt-reported outcomes and safety findings, offering insights into regimen tolerability and response trends. These results show how pts fare in real-world and clinical trial settings and inform considerations for dosing schedules and management strategies. 

PROs and safety from the phase 3 PERSEUS and CEPHEUS trials

  • Approach: Assess pt-reported outcomes (PROs) and safety in pts who achieve MRD negativity vs those who remain MRD positive. PROs were evaluated at baseline and day 1 C1–8 and every 3rd C (CEPHEUS) or day 1 C1–C3, pre-ASCT, C5, C7 and then every 12 wks (PERSEUS). PROs included pts from the European Organisation for Research and Treatment of Cancer quality of life questionnaire core 30 (EORTC QLQ-C30) 
  • Population: 355/354 and 197/198 NDMM pts received daratumumab + bortezomib + lenalidomide + dex (D-VRd) and bortezomib + lenalidomide + dex (VRd), respectively, in PERSEUS/CEPHEUS 
  • Outcomes: MRD negativity was achieved in 75.2% pts (PERSEUS, D-VRd) and 47.5% (PERSEUS, VRd) pts, and in 60.9% (CEPHEUS, D-VRd) and 39.4% (CEPHEUS, VRd). The TEAE exposure-adjusted incidence rates (EAIR) per 100 pt-mo consistently favored pts who achieved MRD negativity vs MRD-positive pts in the DVRd arm in both trials. EAIR for G3/4 infections/infestations and G3/4 neutropenia were lower in pts who achieved MRD negativity vs MRD-positive pts. With D-VRd, mean change from baseline in EORTC QLQ-C30 global health status in pts who achieved MRD negativity vs MRD-positive pts in PERSEUS was 7.6 vs 3.3, and in CEPHEUS was 8.5 vs 4.2. Similar safety and PRO trends were seen with VRd in both studies 
  • Takeaway: Patients achieving MRD negativity stayed on treatment longer and maintained health-related quality of life despite prolonged treatment 

Model-based assessment of monthly isa dosing

  • Approach: Using data from the phase 3 IMROZ study, the use of isa 10 mg/kg every wk for 4 wks then every 2 wks, then every 4 wks at C18 onwards in combination with VRd vs VRd was compared via simulation to determine if an earlier switch to monthly isa dosing than the current 18-month reduces treatment burden without compromising efficacy 
  • Population: Simulation using modeling of PFS within the IMROZ trial framework with 357 evaluable NDMM pts 
  • Outcomes: Efficacy after switching to monthly regimen after  
    • 12 months (instead of 18) 
      • 60-month PFS rate: 76.2 vs 77.7%; HR, 0.543 vs 0.518
      • 12.4% of pts expected to have shorter time to progression (TTP) by an average 4 months 
    • 6 months (instead of 18 mo)  
      • 60-month PFS rate: 74.9% vs 77.7%; HR, 0.563 vs 0.518 
      • When restricted to pts with 3 mo-stable ≥VGPR status at 6 mo (78.6%), outcomes were comparable to 12-mo switch at population level. 5% of individuals could experience ≥8-month shorter TTP 
  • Takeaway: Isa dosing every 4 wks after 12 months in all NDMM pts or after 6 months in pts achieving stable ≥VGPR status did not compromise treatment efficacy vs switching after 18 months 

Phase 2 ISASOCUT (IFM 2022–05) study of SC isa + bortezomib + lenalidomide + dex in NDMM

  • Intervention: Fixed-dose SC formulation of isa in combination with bortezomib, lenalidomide, and dex (isa SC-VRd) as first-line therapy in TI NDMM pts  
  • Population: 74 pts with median age of 73. Approximately one third (34%) were >75 years. Almost a quarter (22%) of patents had high-risk cytogenetics (19% ISS stage 3, and 18% R-ISS stage 3)  
  • Efficacy: At 8 months, the primary end point (≥VGPR) was reached in 87.8% (95% CI, 78–94), and the ≥CR rate was 24%. MRD negativity rates were 35.1% at 10-5 and 27% at 10-6. No relapses were reported at a median 11.7 months follow-up and dose intensity of isa SC. Response maintained at ≥90% in most pts 
  • Safety: No new safety concerns emerged compared with SC isa. Infusion-related reactions 9.5% (mostly G1). Injection site reactions 27% (89.5% G1, remainder G2). Neurological AEs 47.3% (all grades, not further specified) 
  • Takeaway: The study met its primary end point, demonstrating consistent efficacy of isa in NDMM TI pts. These findings support isa SC-VRd as a new SOC for TI NDMM, offering a less intensive but longer induction regimen 

CELMoD Therapies Expand Options Across Treatment Lines

CELMoDs, a class of next-generation immunomodulatory agents, are designed to enhance tumor cell degradation while stimulating the immune response. Agents such as iberdomide and mezigdomide demonstrated activity across multiple LOT, including in pts previously exposed to standard immunomodulatory imide drugs. These therapies offer potential accessibility for a broad range of pts due to manageable safety profiles and oral administration. 

Phase 1/2 CC-220-MM-001 trial of iberdomide-daratumumab-dex in TI/deferred NDMM

  • Intervention: Iberdomide, daratumumab, and dex (IberDd)  
  • Population: 75 adult pts with NDMM who have no plan for or are ineligible for autologous stem cell transplant (ASCT). 58.7% were ≥75 and 41.3% had high-risk cytogenetics 
  • Efficacy: ORR was 94.7% and deepening and durable responses with follow-up: 
    • ≥CR: 68% 
    • VGPR: 20% 
    • MRD negativity was achieved in 64% of pts overall; MRD-negative CR in 56% 
    • Median DOR and PFS had not yet been reached 
  • Safety: Safety profile consistent with prior analysis; no new safety signals 
    • G3/4 TEAEs: 97.3% 
    • Neutropenia was the most common hematologic toxicity in 78.7% of pts 
    • Infections: 52% 
  • Takeaway: With continued follow-up, iberDd continued to show notable efficacy, deep and durable responses, and manageable toxicity in TI NDMM, even in older and high-risk pts 

Mezigdomide in novel combinations

  • Intervention: Mezigdomide, an oral CELMoD, was evaluated in combination with dex (mezi-d) and novel agents (tazemetostat, the BET inhibitor BMS-986158, and the MEK inhibitor trametinib [TRAM])
  • Population: 56 RRMM pts with progressive disease after their last regimen. Half (n=28) had received prior T-cell–redirecting therapies (TCRTs) including BCMA CAR T, GPRC5D CAR T, T-cell engagers (TCEs), and trispecific constructs. The remaining 28 pts had received non-TCRT regimens 
  • Efficacy: Mezi-d–based regimens induced marked proliferation and activation of CD4+ and CD8+ T cells, as well as natural killer (NK) and NK T–cell populations, regardless of prior TCRT exposure. Therapy promoted a shift toward an effector memory phenotype in CD8+ T cells, with reductions in naïve, central memory, and CD45RA+ effector-memory T-cell (TEMRA) subsets 
    • These immune dynamics mirrored those observed with mezi-d in non-TCRT populations, suggesting consistent immune activation capacity across heavily pretreated pts 
  • Safety: No new safety signals were reported specific to prior TCRT exposure 
  • Takeaway: Mezi-d–based regimens enhance T-cell and NK cell activation and proliferation in RRMM pts, including those previously exposed to TCRTs 

Experimental Therapies Highlight Need for Clinical Trial Consideration

First-in-human and phase 1/2 data showcased innovative therapeutics. These included a novel trispecific antibody and CAR T constructs to other novel agents, including the antibody-drug conjugate (ADC) HDP-101, the BCL-2 inhibitor sonrotoclax, and dual-target CAR Ts.  

These agents demonstrated encouraging efficacy and safety profiles that support continued clinical development. Importantly, the data highlights emerging questions about how best to combine or sequence these potent therapies.  

Many of these trials enrolled pts who were heavily pretreated and refractory to multiple standard therapies. Efficacy in this difficult-to-treat population appears encouraging, underscoring the importance of clinical trial participation. Until optimal sequencing and combination strategies are defined, clinical trial participation remains essential. 

Phase 1/2a trial of HDP-101

  • Intervention: HDP-101, a novel ADC targeting BCMA carrying a synthetic amanitin payload, is being evaluated in adaptive dosing strategies, including split dosing and premedication (corticosteroids/antihistamines), to reduce treatment-related toxicity 
  • Population: 34 RRMM pts (median age 68.5, range 43–82; median of 7 prior treatment regimens, range 2–15). Prior therapies included BCMA-targeted CAR T and bsAbs in some pts 
  • Efficacy: Pharmacokinetics showed dose-proportional exposure with ~10-day half-life and minimal free amanitin in serum. But no clinical responses were observed below a dose of 90 μg/kg. Starting at 90 μg/kg, objective responses emerged: 
    • 90 μg/kg dose: 2/10 pts with PR 
    • 112.5 μg/kg dose: 2/3 ongoing pts with PR 
    • 100 μg/kg dose: 3/6 pts responded, including a stringent CR lasting >19 months in a pt previously treated with BCMA CAR T and GPRC5D/CD3 bsAb therapy 
  • Safety: HDP-101 was well tolerated overall, with no drug-related deaths, infusion reactions, or pulmonary or ocular toxicities 
  • Takeaway: HDP-101 showed a favorable safety profile up to 112.5 μg/ kg/cycle. Weekly or split dosing with premedication significantly reduced AEs. HDP-101 demonstrated early indications of efficacy at ≥90 μg/kg, including a durable, stringent CR in a heavily pretreated pt 

Sonrotoclax + dex in pts with t(11;14)-positive RRMM

  • Intervention: Sonrotoclax, a next-generation selective BCL2 inhibitor with higher potency and shorter half-life than venetoclax, was studied in combination with dex at 320 or 640 mg/day 
  • Population: 50 RRMM pts with t(11;14) translocation with a median of 3 (range 1–12) prior LOT; a high proportion were triple-class refractory 
  • Efficacy: The ORR was 64.3% in the 320-mg group and 80.6% in the 640-mg group. ≥VGPR was observed in 35.7% pts in the 320-mg group and 55.6% in the 640-mg group. Median TTR was 0.7 months in both cohorts. PFS was 6.6 months (320 mg) and 13.3 months (640 mg) 
  • Safety: The most frequent TEAEs were fatigue (35.7%) at 320 mg, insomnia (38.9%), and diarrhea (38.9%) at 640 mg (all G1/2) 
    • G≥3 hematologic toxicity, 7.1% (320 mg) vs 25.0% (640 mg) 
    • G≥3 infections, 21.4% (320 mg) vs 11.1% (640 mg) 
  • Takeaway: The all-oral combination of sonrotoclax + dex displayed a favorable tolerable profile with low rates of infection and hematologic toxicity and promising dose-related efficacy in pts with t(11;14)-positive RRMM. Additional combinations with sonrotoclax are being investigated 

Phase 1 TRIgnite-1 Study of ISB 2001

  • Intervention: ISB 2001 is a first-in-class BCMA × CD38 × CD3 trispecific TCE administered SC weekly across 9 dose levels (DLs; 5–2,700 μg/kg), with double SUD on days 1 and 4 
  • Population: 35 heavily pretreated RRMM pts with a median of 6 prior LOT, all triple-exposed, 71% penta-exposed, and 71% CD38-refractory. Prior BCMA-targeted therapy was received by 46% and 43% had prior T cell–redirected therapy (bsAbs and/or CAR T). High-risk disease features included cytogenetic risk (40%) and EMD (34%) 
  • Efficacy: ORR was 74% across all DLs. For all active doses ≥50 μg/kg, the ORR, CR rate, and VGPR rate were 79%, 30%, 64%, respectively; MRD negativity was 75%. Responses were rapid (median TTR 35 days) and durable (81% of responders ongoing, median DOR not yet reached). Pharmacodynamics confirmed consistent T-cell activation, supporting the intended mechanism 
  • Safety: No dose-limiting AEs were observed. AEs of note included:  
    • CRS: any grade, 69% (G1–2 only) 
    • Infections: any grade, 74%; G3/4: 29% 
    • Neutropenia: any grade, 51%; G3/4: 43% 
    • ICANS were rare (3%, G1 only) 
  • Takeaway: ISB 2001 demonstrated robust anti-MM activity and manageable safety in a heavily pretreated RRMM population, including pts with prior BCMA and CAR T/bsAb exposure. Efforts to optimize dose and schedule are under way 

Phase 1 study of arlocabtagene autoleucel

  • Intervention: Arlocabtagene autoleucel (arlo-cel), a GPRC5D-targeted CAR T-cell therapy, was evaluated in 2 dose expansion cohorts: 75 × 106 cells and 150 × 106 cells 
  • Population: 84 RRMM pts (24 pts at 75 × 106 dose, 26 pts at 150 × 106 dose) who were heavily pretreated with a median of 5 prior treatment regimens. All pts had prior proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapy 
  • Efficacy: After a median follow-up of 19.9 months (75 × 106) and 24.0 months (150 × 106), the ORR was 92% (75 × 106) and 91% (150 × 106), respectively. The CR rate was 58% (75 × 106) vs 43% (150 × 106). The median DOR was 16.4 months (75 × 106) vs 13.6 months (150 × 106). Clearance of soluble BCMA was comparable across DLs 
  • Safety: G3/4 TEAEs occurred in 75% of the 75 × 106 group vs 69% in the 150 × 106 group. CRS occurred in 75% of the 75 × 106 group and 88% of the 150 × 106 group; all were G1/2 and resolved. ICANS occurred in 1 pt per cohort (G1 event, both resolved). On-target/off-tumor nail, skin, and oral toxicities were similar across cohorts, all G1/2. Overall safety profile remained consistent with prior reports 
  • Takeaway: Arlo-cel at both DLs demonstrated comparable efficacy and safety, suggesting a favorable benefit-risk balance in RRMM  

Phase 1 trial of arlo-cel in pts with 1–3 prior regimens

  • Intervention: Arlo-cel administered as a single infusion at the recommended phase 2 dose (150 × 106 CAR T-cells) following lymphodepleting chemotherapy  
  • Population: 31 RRMM pts with a median of 2 prior regimens; 29% received 3 prior regimens. High-risk features included 26% with del(17p), t(4;14), or t(14;16); 68% with 1q21 gain/amp; 32% with EMD 
  • Efficacy: There was a total of 24 evaluable pts; median follow-up was 15.8 months. ORR was 96% and CR rate was 63%. At follow-up, 15 of 24 responses were ongoing. Median PFS not reached; 12-month PFS rate was 74%. MRD negativity (at 10-5) was 75% (12 of 16 tested pts) 
  • Safety: TEAEs occurred in all pts; G3/4 in 87%. CRS occurred in 84% of pts (all G1/2, resolved). In addition, ICANS occurred in 10% (all G1/2, resolved). On-target/off-tumor effects included nail (39%), skin (42%), oral (42%) changes; all G1/2. Other neurotoxicity occurred in 6.5% (gait disturbance, ataxia, dysarthria; fully resolved) and infections occurred in 55% (all G1/2) 
  • Takeaway: Arlo-cel demonstrated deepening and durable responses in RRMM pts with 1 to 3 prior LOT, including those with high-risk disease. A phase 3 study of arlo-cel vs standard regimens has been initiated 

Phase 1 TANDEMM trial of concurrent administration of BCMA and GPRC5D CAR T cells

  • Intervention: Concurrent infusion of two CAR T-cell therapies—BCMA-targeted (MCARH125) and GPRC5D-targeted (MCARH109)—manufactured from a single apheresis and administered after lymphodepleting chemotherapy. Patients were treated at three DLs: BCMA-CAR alone (DL 0,150 × 106 cells) and BCMA-CAR + GPRC5D-CAR in varying doses (DL 1 [50 × 106 cells of MCARH109 and 150 × 106 cells of MCARH125] and DL 2 [150 × 106 cells of each]) 
  • Population: 19 RRMM pts who had ≥3 prior LOT; 15 pts received treatment across DL 0 to 2. The majority (67%) in DLs 1/2 had prior BCMA therapy exposure (67%) 
  • Efficacy: ORR was 87% (13/15). By DL: 100% response at DL 0 (BCMA alone) and 78% response at DLs 1 and 2 (dual CAR). Median PFS was 20.1 months (95% CI, 17.5–not reached [NR]) for DL0 and 18.2 months (95% CI, 6.4–NR) for DLs 1 and 2. Antigen downregulation was linked to relapse; responders had enrichment of CD8+ memory T-cell populations. Expansion of one CAR product (BCMA) was reduced when both products were given together 
  • Safety: All pts experienced CRS; G2 CRS in 3 pts, but no G≥3 CRS was reported. G3 immune effector cell–associated hemophagocytic syndrome emerged in 2 pts (DL 0 and 2). No cases of non-ICANS neurologic toxicity were seen 
  • Takeaway: This proof-of-concept dose-escalation safety trial provided early evidence of the safety and efficacy of concurrent dual-target CAR T-cell therapy against BCMA and GPRC5D products manufactured from a single apheresis 

New Biomarkers for Risk and Response

Emerging data highlighted new biomarkers that improve risk assessment and predict treatment outcomes, including MRD tracking via circulating tumor DNA. These findings potentially shift MM closer to an individualized treatment approach guided by immune and genomic profiling.  

Two additional studies validated genomic-based models that better classify high-risk MM. The consensus model and new IMS/IMWG criteria aim to unify how high-risk disease is identified, improving trial design and individualized treatment strategies. 

ClonoSEQ MRD testing from BM and circulating tumor DNA

  • Approach: A retrospective analysis conducted at the Mayo Clinic to evaluate the clonoSEQ NGS assay for detecting MRD in peripheral blood (PB). Its diagnostic performance was compared with BM MRD and conventional biomarkers (M protein, free light chain ratio, EMD, and treatment response) 
  • Population: 149 PB plasma samples from 100 pts with secretory MM who had a known dominant clonotype identified in BM; pts included those at diagnosis, in remission, and with relapsed/progressive disease 
  • Outcomes: PB MRD negativity (10-6) correlated with deep clinical responses (CR and VGPR; P<0.001). In contrast, PB MRD positivity was associated with disease activity, including abnormal free light chain ratio (74%), detectable M protein (78%), and EMD (26%). Using BM MRD as a reference standard, PB MRD positivity had a specificity of 90.1%, positive predictive value (PPV) of 94.9%, sensitivity of 33.9%, and a negative predictive value (NPV) of 21.7%. In pts achieving ≥VGPR, PB MRD negativity showed 84% specificity, 93.6% PPV, 80.6% sensitivity, and 60% NPV 
  • Takeaway: PB MRD assessment with clonoSEQ offers a high-specificity, pt-friendly alternative to BM MRD testing in MM, with PB MRD positivity reliably indicating residual disease and PB MRD negativity strongly correlating with deep response. 

CTCs as a critical biomarker

  • Approach: An assessment of the prognostic impact of circulating tumor cells (CTCs) in NDMM and primary PC leukemia (pPCL) pts using flow cytometry, independent of established risk models 
  • Population: 2,364 pts with NDMM and 68 with pPCL from clinical trials and real-world settings across five European groups. Median age was 63, and 54% were TE. Induction regimens were predominantly triplet-based (88.9%), with fewer doublets (2.2%) or quadruplets (9.2%) 
  • Efficacy: Median CTC percentage was 0.017 and consistent across centers. Logarithmic stratification by CTC level identified five subgroups with distinct median PFS: 
    • ≤0.001%: 77 months 
    • 0.001%–0.01%: 51 months 
    • 0.01%–0.1%: 40 months 
    • 0.1%–1%: 31 months 
    • ≥1%: 16 months (similar to pPCL at 15 months; P<0.0001). 

Higher CTC levels consistently predicted inferior PFS (HR 1.17, 95% CI 1.11–1.24, P<0.001), and the prognostic value remained consistent across subgroups, independent of R-ISS, 1q gain/amplification, induction regimen, or transplant status. In addition, CTC cutoffs between 0.01% and 0.1% reliably stratified pts in both trial and real-world settings and stratified pts with established risk factors: standard-risk pts with high CTCs had outcomes similar to those with high-risk cytogenetics but low CTCs (42 vs 36 months, P=0.48). 

  • Takeaway: Baseline CTC levels are a powerful independent prognostic biomarker in NDMM, and stratification by logarithmic CTC ranges identifies clinically meaningful subgroups and improves risk discrimination 

High-risk genomic consensus model validation

  • Approach: To validate, via an NGS panel, the revised IMS/IMWG high-risk genomic model for MM. High-risk is considered if pts present one of the following: 
    • del(17p) 
    • a TP53 mutation 
    • a biallelic del(1p32) 
    • a combination of t(4;14) or t(14;16) or t(14;20)/and either a gain of 1q or a monoallelic del(1p32) 
    • a combination of 1q gain and monoallelic del(1p32) 
  • Population: Between 2019 and 2024, 6,735 NDMM pts and 1,588 pts at first relapse were evaluated (from France). The PFS analysis included 2,703 pts, with ≥18 months follow-up 
  • Outcomes: High-risk prevalence was 23.9% and 36.7% at diagnosis and first relapse, respectively. When a high beta-2 microglobulin level (≥5.5 mg/L) in the context of normal renal function was added as a nongenomic risk factor, 31.4% of NDMM pts were classified as high-risk. Median follow-up was 35 months overall, and PFS was 29 months for high-risk NDMM and 51 months for non-high-risk (P<0.0001). For high-risk transplanted pts, PFS was 47 months vs 62 months for transplanted non-high-risk pts: (P<0.0001). The impact of individual abnormalities was as follows: 
    • del(17p), TP53 mutation, biallelic del(1p32), and combined lesions (t[4;14], t[14;16], t[14;20] with 1q gain or del[1p32]) all associated with significantly worse PFS than standard-risk pts
    • With the accumulation of ≥2 high-risk criteria, median PFS falls dramatically (33 months with 1 vs 10 months with ≥2) 
  • Takeaway: This study validates the IMS/IMWG revised genomic definition of high-risk MM in a large real-world cohort. Roughly one third of NDMM pts met high-risk criteria, with clear evidence of significantly inferior PFS compared with standard-risk disease 

IMS/IMWG risk-assessment criteria

  • Approach: To evaluate the IMS/IMWG novel criteria for high-risk MM in a real-world prospective cohort 
  • Population: 332 consecutive NDMM pts in Greece were enrolled and prospectively stratified by novel IMS/IMWG high-risk MM criteria and existing staging systems (ISS, R-ISS, R2-ISS). 60 pts (18%) were classified as high-risk per the novel criteria (80% of these high-risk pts would not have been categorized as such by traditional tools) 
  • Outcomes: At a median follow-up: 37.5 months, pts identified as high-risk by the novel criteria had significantly worse outcomes than standard-risk pts: 
    • PFS was 25.5 months; doubled risk of progression/death (HR 2.15)  
    • OS was 30.0 months; 2.5-fold increased mortality (HR 2.50) 
    • TTP was not reached, but 85% had higher progression risk (HR 1.85) 

Findings remained significant in multivariate analysis, confirming the independent prognostic utility of the criteria. Subgroup analyses demonstrated consistently inferior OS for high-risk vs standard-risk pts across age (>65, no high-dose melphalan with ASCT), performance status (ECOG ≥2), and treatment intensity (including quadruplets). 

  • Takeaway: The novel IMS/IMWG high-risk MM criteria identified pts with significantly adverse prognoses overlooked by established staging systems, suggesting that a substantial subset of NDMM pts classified as standard-risk by traditional tools have aggressive disease 

 

Jointly provided by the MMRF and RedMedEd. 

Support for this activity has been provided through sponsorships from Legend Biotech USA Inc., Pfizer Inc., and Sanofi and by educational grants from AbbVie Inc. and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC.