Several presentations at the 2025 American Society of Clinical Oncology (ASCO) and European Hematology Association (EHA) Annual Meetings introduced new and updated study data in multiple myeloma (MM), along with potentially significant advancements in therapy. Data presented at the meetings included the following:
Quads as gold standard for high-risk newly diagnosed MM (NDMM)
Data Reinforces Daratumumab Quads as a Gold Standard in NDMM
Data from the CEPHEUS, PERSEUS, and ADVANCE trials confirm daratumumab-based quadruplet regimens as the new frontline standard for NDMM, delivering superior MRD negativity and survival benefits regardless of transplant eligibility.
Phase 3 CEPHEUS trial: dara-VRd
Intervention: VRd ± daratumumab
Patient population: 289 non–transplant-eligible (TNE) post hoc analysis
Efficacy: The overall MRD negativity rate (10-5) for DVRd vs VRd was 60.4% vs 39.3% (odds ratio [OR] 2.37; 95% confidence interval [CI] 1.47–3.80; P=0.0004)
Sustained MRD negativity rate (10-5 ) for DVRd vs VRd at ≥12 months and ≥24 months was 47.2% vs 28.3% (OR 2.28; 95% CI 1.40–3.72; P=0.0010) and 40.3% vs 22.8% (OR 2.30; 95% CI 1.3–3.83; P=0.0015)
The overall rate of complete response or better (≥CR) for DVRd vs VRd was 80.6% vs 61.4% (OR 2.73; 95% CI 1.71–4.34; P<0.0001)
Overall survival (OS) favored DVRd vs VRd (hazard ratio [HR] 0.66; 95% CI 0.42–1.03)
Safety: No unexpected adverse events (AEs) were detected
Takeaway: Results reinforce the strong efficacy of DVRd in the TNE NDMM population
Phase 3 PERSEUS trial: dara-VRd with dara-len maintenance
Intervention: Daratumumab + bortezomib + lenalidomide + dex (D-VRd) induction/consolidation followed by DR maintenance or VRd induction/consolidation followed by R maintenance
Patient population: 709 TE patients
Efficacy: At 47.5-mo median follow-up, ≥12-month sustained MRD negativity rates were higher with D-VRd (64.8%) vs VRd (29.7%) overall and across clinically relevant subgroups (age ≥65 years and high-risk cytogenetics). Sustained (≥24-month) MRD negativity rates were also higher with D-VRd (55.8%) vs VRd (22.6%). DVRd vs VRd reduced functionally high risk (FHR) rates (3.1% vs 6.8%), and rates of FHR or pre-progression deaths were lower (5.4% vs 11.0%) in the first 18 months
Safety: NR
Takeaway: Findings support D-VRd as the standard of care for transplant-eligible (TE) NDMM
Phase 2 ADVANCE trial: dara-KRd
Intervention: KRd ± daratumumab (autologousstem cell transplant [ASCT] offered to patients who were MRD+ after 8 cycles) followed by lenalidomide maintenance
Patient population: 306 NDMM patients
Efficacy: MRD negativity rate (next-generation sequencing [NGS], 10-5) after up to 8 cycles (primary end point) was significantly higher in patients receiving D-KRd than in those receiving only KRd (59% vs 36%, adjusted OR = 2.5, 95% CI: 1.5–4.2; P<0.0007)
Safety: AEs of interest (DKRd vs KRd) included cardiac AEs (13% vs 16%), infections (61% vs 53%), and acute kidney injury (1% vs 4%). Serious AEs occurring in >1% of patients (DKRd vs KRd) included pyrexia (5% vs 2%), chest pain (0% vs 3%), pneumonia (3% vs 10%), and acute kidney injury (0% vs 3%)
Takeaway: DKRd demonstrated a statistically significant, 2.5-fold higher MRD-negativity rate compared to KRd.
Isatuximab Quads Break New Ground in High-Risk Myeloma
Isatuximab-based quadruplet regimens significantly deepen MRD negativity in high-risk patients, offering new hope for improved long-term outcomes.
ASCT in the TE arm or 2 cycles Isa-KRd in the TNE arm
Isa-KRd consolidation (4 cycles)
2 years Isa-KR maintenance
A switch to carfilzomib administration from twice weekly to once weekly implemented in 2021
Patient population: 219 TE and 26 TNE patients with high-risk NDMM, defined as ≥1 high-risk cytogenetic aberration—del(17p), t(4;14), t(14;16), ≥3 copies 1q21—in combination with International Staging System (ISS) stage II/III
Efficacy: MRD negativity rate (next-generation flow cytometry [NGF] 10-5) after consolidation (primary end point) was 73.2%
Overall, 58.4% reached MRD negativity, ≥CR
≥1- and ≥2-year-sustained MRD negativity was achieved in 64.8% and 40.6% of patients, respectively
Reaching and remaining in an MRD-negative state led to a significant PFS benefit (HR 0.15 [0.07−0.29]; P<0.0001)
Safety: Carfilzomib once weekly resulted in fewer discontinuations than twice-weekly dosing (0.6% and 4.8%, TE pts), with more dose reductions in the once-weekly dosing group (9.5% and 5.5%, TE pts)
Takeaway: Isa-KRd resulted in unprecedented rates of MRD negativity, sustained MRD negativity, and survival, thus supporting the use of isa-KRd as a standard-of-care regimen in a high-risk MM population
Phase 3 IMROZ study:isa-VRd
Intervention: Isatuximab + bortezomib + lenalidomide + dex (isa-VRd) followed by isatuximab + lenalidomide + dex (isa-Rd) vs bortezomib + lenalidomide + dex (VRd) followed by lenalidomide + dex (Rd)
Patient population: 446 NDMM patients with 1q21+ chromosomal status (36% [isa-VRd arm];39% [VRd arm] of patients)
Efficacy: Treatment with isa-VRd significantly prolonged PFS vs VRd in patients with 1q21 (with or without high-risk chromosomal abnormalities) and in patients with isolated 1q21+ and led to higher rates of CR and MRD negativity. MRD-negative CR and sustained MRD negativity (≥12 months) were also greater with isa-VRd vs VRd treatment in patients with 1q21+ or isolated 1q21+
Safety: NR
Takeaways: Consistent PFS benefit with isa-VRd vs VRd regardless of 1q21 status
Phase 3 IsKia trial:isa-KRd
Intervention: KRd ± isatuximab
Isa-KRd patients received full-dose induction (4 cycles) followed by ASCT and full-dose isa-KRd consolidation (4 cycles) and, thereafter, 12 28-day light consolidation cycles
Patients in the KRd arm received the same KRd schedule used in the other arm
Patient population: 302 TE patients
Efficacy: The rates of MRD negativity at the 10-6 cutoff (by NGS) after full-dose consolidation were 67% with isa-KRd vs 48% with KRd (OR 2.29; P<0.001); the rates of 10-6 1-year sustained MRD negativity after light consolidation were 52% with Isa-KRd vs 38% with KRd (OR 1.82; P=0.012). The 10-6 1-year sustained MRD negativity advantage with Isa-KRd vs KRd was retained in all subgroups, such as patients with ≥2 high-risk cytogenetic abnormalities and Revised 2-ISS III/IV
Safety: In the isa-KRd vs KRd arms:
The main grade 3–4 hematologic AEs during light consolidation were neutropenia (17% vs 18%) and thrombocytopenia (2% vs 3%); the main grade 3–4 nonhematologic AEs included infections (8% vs 5%), gastrointestinal (4% vs 4%), and vascular AEs (3% vs 1%)
Discontinuations occurred in 3% vs 2%, respectively
There were 2 treatment-related deaths (1 cerebral ischemia, 1 pulmonary embolism) in the isa-KRd group vs 0 in the KRd group
Takeaway: Isa-KRd significantly increased the rate of 10-6 sustained MRD negativity relative to what was seen with KRd, including in patients with high-risk disease
MRD-Guided Strategies Show Promise
Rather than trying to achieve universal MRD negativity, the MIDAS and PREDATOR trials demonstrate that MRD status informs key treatment decisions—such as whether to proceed with or defer stem cell transplantation or intervene early upon MRD recurrence—enabling more individualized strategies for patients.
Phase 3 MIDAS trial: isa-KRd
Intervention: KRd ± isatuximab
Patients achieving postinduction MRD negativity (NGS 10-5) following isa-KRd induction were randomized to receive either 6 additional cycles of isa-KRd (Arm A) or ASCT followed by 2 cycles of isa-KRd (Arm B) followed by lenalidomide maintenance
MRD-positive patients after induction (≥10-5) were randomized to either single ASCT + 2 cycles of Isa-KRd (Arm C) or tandem ASCT (Arm D) followed by isatuximab-iberdomide maintenance
Patient population: 485 MRD-negative and 233 MRD-positive TE patients
Efficacy: The premaintenance MRD negativity rates at 10-6 (primary end point) were 84% in Arm A and 86% in Arm B (OR 1.17, 95% CI 0.64–2.76, P=0.64)
Safety: No new safety signals were identified beyond what was observed in the induction phase
Takeaway: MRD negativity rates at 10-6 before maintenance were not significantly different between the ASCT-based approach and isa-KRd consolidation alone; in patients who did not achieve MRD negativity (10-5), tandem ASCT did not significantly improve MRD negativity rates at 10-6 before maintenance. The similar rates of sustained MRD negativity suggest that up-front ASCT may not be necessary. This study, published in the New England Journal of Medicine, is ongoing to collect sustained MRD negativity rates and PFS data
Phase 2 PREDATOR-MRD trial: daratumumab or observation for MRD reappearance
Intervention: Eligible patients were followed for MRD status (≥10-5) in the bone marrow with regular 4-month intervals for a maximum of 2 years; patients who became MRD-positive were randomized for observation or daratumumab treatment
Patient population: 54 MM patients who completed 1 or 2 prior lines of therapy achieved CR with MRD-negativity and were not receiving any antimyeloma treatment
Efficacy: MRD re-emerged in 29 patients (median time to MRD reappearance: 11.3 months, range, 0–23.8). MRD-positive patients without signs of significant paraprotein relapse or clinical progression (n=24) were randomized to daratumumab (n=12) or the observation arm (n=12)
After a median follow-up of 17.9 months, median event-free survival was not reached in the daratumumab arm vs 9.5 mos in the observation arm (HR=0.20, 95% CI: 0.05−0.76; P=0.0097)
After initiating daratumumab treatment, 7 of 12 patients (58.3%) achieved MRD negativity
Safety: No patients died during the study. The most common AEs with daratumumab (vs observation) were infection (58% vs 16%) and pain (33% vs 8%)
Takeaway: Early intervention with daratumumab in MM patients experiencing MRD relapse delays clinical progression and can restore MRD negativity in a significant proportion
Investigating Elranatamab For Transplant-Ineligible NDMM
Use of elranatamab for TIE NDMM patients highlights the expanding arsenal of next-generation therapies aiming to improve outcomes and personalize care for patients.
Efficacy: At the median follow-up of 4.6 months, treatment was ongoing in 33 patients. The confirmed ORR (95% CI) was 91.9% (78.1–98.3)
Safety: Cytokine release syndrome (CRS) occurred in 62.2%, all grade ≤2; 1 case of grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS) was reported. Infections occurred in 64.9% (grade 3/4, 18.9%). Hematological treatment-emergent AEs (TEAEs) occurred in 78.4% (grade 3/4, 70.3%)
Takeaway: In patients with TIE NDMM, elranatamab in combination with daratumumab and lenalidomide demonstrated a manageable safety profile consistent with the known toxicities of components and a high and early response rate. Enrollment in other dose levels is ongoing
Relapsed MM Immunotherapies: Progress in Early and Late Disease
In early relapse, belamaf and isatuximab (via subcutaneous administration) demonstrate significant value. Late-relapse patients benefit from advances in bispecific antibodies—linvoseltamab and talquetamab—and CAR T-cell therapies. Notably, long-term data from CARTITUDE-1 on the use of ciltacabtagene autoleucel (cilta-cel), now published in the Journal of Clinical Oncology, marks a major milestone in long-term outcomes for late-relapse treatment.
Patient population: 302 patients who received ≥1 prior line of treatment including lenalidomide
Efficacy: Patients treated with belamaf-Pd achieved a 5-fold improvement in CR-based MRD negativity vs PVd (24% vs 5%). Patients who did not achieve CR-based MRD negativity had a clinically meaningful benefit in PFS with BPd vs PVd
Safety: NA
Takeaway: MRD negativity was associated with a robust benefit in PFS and OS. Patients treated with BPd achieved a higher CR-based MRD negativity than did those receiving PVd
Intervention: Isa subcutaneous (SC) on-body delivery system (OBDS), an investigational wearable bolus injector, versus isa IV + pomalidomide + dexamethasone (Pd)
Patient population: 531 patients who had received ≥1 prior line of therapy
Efficacy: After a median follow-up of 12 months, ORR was 71.1% in the SC OBDS arm and 70.5% in the IV arm (relative risk 1.008, 95% CI=0.903–1.126)
Safety: Grade ≥3 TEAEs occurred in 82% of patients in the SC OBDS arm and 76% of patients in the IV arm with treatment discontinuation rates of 8% and 9%, respectively. Injection site reactions occurred in 4% of patients in the SC arm and 0.4% of patients in the SC arm; all were of Grade 1–2. 99% of OBDS injections were completed without interruption
Takeaway: Results showed noninferiority of isa SC OBDS relative to what was seen with isa IV, supporting the potential use of isa SC delivered via the OBDS to improve patient experience and practice efficiency. These results are published in the Journal of Clinical Oncology
Intervention: Linvoseltamab + carfilzomib (linvo-cfz) or linvo + bortezomib (linvo-btz)
Patient population: 42 RRMM patients who had progressed after ≥3 lines of therapy, or ≥2 lines of therapy if either triple-class exposed or double-class refractory. Prior btz or cfz was allowed if previously tolerated and ≥6 months had elapsed since last exposure
Efficacy:
Linvo-btz ORR was 85%; the 6-month PFS rate was 78% (95% CI 52–91)
Linvo-cfz ORR was 91% at dose level (DL)1 (linvo 100 mg) and 100% at DL1b (linvo 150 mg) before the start of before initiation of cfz. For DL1, the PFS rate was 99% (95% CI 71–99) at 6 months and 83% (95% CI 55–94) at 12 months
Safety:
Linvo-btz: common TEAEs were neutropenia (any grade 54.2%; G3–4 50%), thrombocytopenia (54.2%; 37.5%), and CRS (58.3%; 0%). ICANS was reported in 4 pts (all Gr 1–2). Infections were reported in 75% (G3–4 37.5%); 2 patients died of infection
Linvo-cfz: Most common TEAEs were neutropenia (any grade 78%; G3-4, 61%), thrombocytopenia (61%; 39%), and CRS (61%; 0%). One patient experienced ICANS (G1). Infections were reported in 89% of patients (G≥3 44%)
Takeaway: Both linvo combinations induced high response rates with a safety profile consistent with the individual drugs, supporting further development
Phase 1b TRIMM-3 study: talquetamab + cetrelimab
Intervention: Cetrelimab (cet), a programmed cell death receptor-1 (PD-1) monoclonal antibody, combined with talquetamab (tal)
Patient population: 44 RRMM patients
Efficacy: ORR was 70% and 6-month duration of response (DOR) and PFS rates were 93% and 72%, respectively. In patients with prior CD3 redirecting antibody therapy, ORR was 68% and 6-month DOR and PFS rates were 92% and 65%, respectively
Safety: GPRC5D-related AEs were common (taste changes 82% [39% G1/43% G2]; nail 75% [all G1/2]; skin 73% [all G1/2]; and rash 39% [mostly G1/2]). PD-1-related AEs occurred in 7 pts. Grade 3/4 AEs occurred in 82% of patients (commonly neutropenia [41%] and anemia [39%]). CRS occurred in 61% of patients (all G1/2). ICANS occurred in 1 pt (G1). Infections and hypogammaglobulinemia occurred in 80% (27% G3/4) and 57% of patients. One death occurred (pneumonia)
Takeaway: Tal-cet showed deep and durable responses in patients with RRMM and prior CD3-redirecting antibody therapy. These proof-of-concept data are encouraging for PD-1 inhibition in RRMM and further support tal as a versatile combination partner
Phase 2 IMMAGINE-1 study of anito-cel
Intervention: Anitocabtagene autoleucel (anito-cel), an autologous anti-BCMA CAR T-cell therapy with a novel D-domain binder
Patient population: 86 RRMM patients triple-class exposed who had progressed after ≥3 lines of therapy had measurable disease and were refractory to their last line of therapy
Efficacy: Investigator-assessed ORR was 97% with a CR rate of 62%; 93.1% evaluable patients achieved MRD negativity (10-5). At 12 months, the DOR, PFS, and OS rates were 75.6%, 78.5%, and 96.5%, respectively
Safety: The most common grade ≥3 TEAEs were cytopenias: 54% neutropenia, 22% anemia, and 20% thrombocytopenia. Any-grade CRS was observed in 81 pts (83%), with 67 (68%) Grade 1, 13 (13%) Grade 2, and 1 (1%) Grade 5. ICANS was observed in 9 pts (9%)
Takeaway: Ongoing preliminary results demonstrate deep and durable efficacy and manageable safety (with notable low incidence of ICANS considering rates of neurotoxicity observed for cilta-cel and ide-cel are 21% and 18%, respectively) for anito-cel in RRMM
Long-Term Results From CARTITUDE-1 Redefining Outcomes in Late-Relapse Myeloma
Intervention: Cilta-cel (single injection)
Patient population: 97 patients with heavily pretreated RRMM who historically have an expected median PFS of <6 months and median OS of ~1 year
Efficacy: Of treated patients, 32 (33.0%) remain alive and progression free for ≥5 years. Compared with patients who had progressive disease within 5 years, biomarkers that were significantly associated with ≥5 years of progression-free status included a higher fraction of naive T cells in the drug product, lower neutrophil-to-T-cell ratio, higher hemoglobin and platelets at baseline, and higher effector-to-target ratio. Overall, at 60.3 months median follow-up, the median OS was 60.6 months
Safety: No new cases of movement and neurocognitive disorders were reported
Takeaway: First evidence that cilta-cel achieves deep responses that are long lasting in heavily pretreated patients
Trispecific Antibodies Reveal the Next Frontier for RRMM
First-in-human phase 1 data for two novel trispecific antibodies demonstrated impressive response rates and manageable safety profiles in heavily pretreated RRMM.
Phase 1 first-in-human dose-escalation study of ISB 2001
Intervention: ISB 2001, a first-in-class trispecific BCMA×CD38×CD3-targeting T-cell engager. Patients received 8 dose levels (5–1,800 µg/kg)
Patient population: 35 RRMM patients exposed to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 therapies and refractory or intolerant to established therapies. Prior BCMA-targeted and/or T-cell-directed therapies were allowed
Efficacy: ORR was 74% across all 8 doses (79% at doses ≥50 µg/kg), including a stringent CR of 17%. The median time to response was 36 days
Safety: No dose-limiting toxicity or deaths occurred. Serious AEs were reported in 8 patients. CRS was reported in 24 (69%, G1/2). One patient with ICANS (G1); no other neurologic AEs
Takeaway: ISB 2001 was well tolerated with manageable CRS, no ICANS, and robust antimyeloma activity regardless of prior CAR T, T-cell engagers, BCMA therapies, CD38-refractoriness, extramedullary disease, or high-risk cytogenetics, thus representing a potential therapy for late-relapse patients.
Phase 1 first-in-human study of JNJ-79635322
Intervention: JNJ-79635322 (JNJ-5322), a next-generation trispecific antibody dually targeting BCMA and GPRC5D via T-cell redirection. Patients received JNJ-5322 as fixed Q2W or Q4W SC doses (0.4-300 mg), including 100 mg Q4W, the putative RP2D
Patient population: 126 RRMM patients previously exposed to a proteasome inhibitor, immunomodulatory drug, and anti-CD38 monoclonal antibody
Efficacy: After a follow-up of 8.2 months, the ORR was 86% at the RP2D (n=36), and 73% overall (n=124). ORR was 100% at the RP2D among patients naïve to anti-BCMA/-GPRC5D therapies (n=27). The median time to first response was 1.2 months
Safety: The most common AEs included CRS (59%, G1/2); 2% experienced ICANS (all grade 1), and the following AEs were also observed: nail AEs (56%, G1/2), taste AEs (56%, G1/2), neutropenia (48%; 41%, G3/4), and nonrash skin AEs (47%; 1% G3/4). Infection was detected in 75% (28% G3/4). 5 patients had dose-limiting toxicities and 4 died due to AEs
Takeaway: JNJ-5322 offers high ORRs, especially for BCMA/GPRC5D treatment-naive patients
CTCs as an Independent Risk Factor
One study assessed the independent prognostic value of circulating tumor cells (CTCs) and determined their applicability to clinical practice. Investigators collected data from 2,446 NDMM patients from multiple centers in Europe. High CTC levels (≥1%) were strongly correlated to inferior PFS (HR 1.18, 95% CI 1.12−1.24, P<0.001). The study showed that CTCs are an independent risk factor in NDMM and that a cutoff in the range of 0.01−0.1% is useful in categorizing progression risk.
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.
If you or a loved one has been exploring treatment options for relapsed or refractory multiple myeloma, you may have heard of CAR T-cell therapy—a highly effective treatment option that reprograms your own immune system to fight cancer.
In a pivotal move, the FDA recently removed the Risk Evaluation and Mitigation Strategy (REMS) requirements for CAR T-cell therapies used in multiple myeloma. REMS are specialized safety programs that CAR T centers must follow to minimize the risk associated with the treatment. Other treatments for multiple myeloma have REMS programs in place.
This decision marks a major shift in how these therapies can be delivered—and it’s one that could open doors for patients who were previously unable to benefit from CAR T.
Removing REMS Means Removing Roadblocks
Limited treatment centers, burdensome pre-approvals, and strict inpatient administration rules have made CAR T difficult to access for many patients and providers. By removing REMS, the FDA has helped streamline the pathway to treatment.
One of the most promising effects of this change?
Reaching patients who’ve been historically underserved.
Right now, only about 20% of eligible myeloma patients receive CAR T therapy, largely due to where they live. Patients in rural or underserved areas often face long-distance travel and financial hurdles that put CAR T out of reach. Without REMS, more treatment centers can begin offering CAR T, potentially improving access in these regions and allowing more patients to receive timely care.
Paving the Way for Progress
As CAR T becomes more accessible, the MMRF sees even greater opportunities on the horizon. This momentum is essential in our mission to accelerate precision medicine and improve outcomes for all myeloma patients.
A Vote of Confidence in the Myeloma Community
The FDA’s decision is more than a policy shift. It’s a signal of trust in the hematology/oncology community. It shows that providers have demonstrated the knowledge and experience needed to manage the risks associated with CAR T, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), without the need for special certifications or safety checks.
What This Means for Patients
If CAR T isn’t an option for you because of where you live, this change could be the turning point. Now is the time to speak with your care team about whether CAR T is a fit for you, and to revisit clinical trial opportunities that may have been previously out of reach.
You can ask your doctor:
Am I eligible for CAR T therapy?
What do I need to prepare for CAR T?
What side effects will I have on CAR T?
Where is the nearest CAR T center?
Is there a clinical trial I can enroll in?
For more support and guidance, the MMRF Patient Navigation Center is here to help you understand your options, connect to care, and navigate the next steps in your myeloma journey.
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