This episode provides comprehensive coverage of key clinical trial updates from the 2025 International Myeloma Society (IMS) Annual Meeting in Toronto, with special focus on bispecific antibodies and novel immunotherapies across the multiple myeloma disease continuum—from smoldering disease through relapsed/refractory settings. Dr. Alfred Garfall provides expert commentary on study design, efficacy, safety considerations, and clinical implications.

Topics Covered

1. SMOLDERING MULTIPLE MYELOMA

LINKER-SMM1

Phase 2, open-label study of linvoseltamab monotherapy (200 mg) in patients with high-risk smoldering multiple myeloma by 20/2/20 or PETHEMA criteria, with 2-year treatment duration.

Discussion Points:

• Appropriateness of 2-year treatment duration for precursor condition
• Efficacy and MRD-negative rates
• Safety considerations in asymptomatic population
• Patient selection if available today

2. NEWLY DIAGNOSED MULTIPLE MYELOMA

MajesTEC-5

Phase 2 trial evaluating three teclistamab-daratumumab-based induction regimens in 49 transplant-eligible NDMM patients, followed by auto-transplant and fixed-duration Tec-Dara maintenance.

Discussion Points:

• Post-induction MRD-negativity rates with Tec-DR and Tec-DVR
• Grade 3-5 infection rates and infection-related deaths
• Questionable utility of bortezomib and need for ASCT with 100% MRD-negativity
• High infection prophylaxis requirements

MagnetisMM-6

Phase 1/2 dose-finding study of fixed-dose elranatamab 76 mg Q4W with Dara-Len in 37 transplant-ineligible NDMM patients (median age 75 years).

Discussion Points:

• VGPR or better rates
• Safety profile including infections and CRS/ICANS
• Risk of continuous therapy in elderly/frail population

LINKER-MM4

Phase 1/2 study of linvoseltamab monotherapy in NDMM with both transplant-eligible and transplant-ineligible pathways, exploring three dose levels (50, 100, 200 mg).

Discussion Points:

• Efficacy of single-agent Linvo in NDMM
• Whether any NDMM population could achieve long-term control with single-agent BCMA BsAb
• Safety profile

3. RELAPSED/REFRACTORY MULTIPLE MYELOMA

CAMMA-1

Phase 1b randomized dose-expansion study of cevostamab (FcRH5×CD3 bispecific) combined with pomalidomide-dexamethasone in BCMA-naïve patients with median 2 prior lines of therapy.

Discussion Points:

• Efficacy and safety results
• Positioning in treatment paradigm
• Use before BCMA BsAbs?

Sonrotoclax + Dexamethasone in t(11;14) R/R MM

Phase 1/2 study of sonrotoclax (next-generation BCL2 inhibitor) plus dexamethasone as an all-oral regimen in patients with t(11;14) R/R MM (median 3 prior lines, ~75% triple-exposed).

Discussion Points:

• Efficacy including response rate and PFS
• Safety profile
• Future of BCL2 inhibitors in t(11;14) myeloma in the era of BsAbs and CAR T

RedirecTT-1

Phase 2 trial combining teclistamab + talquetamab in 90 heavily pretreated patients with R/R extraosseous extramedullary disease (84% triple-class refractory, 36% penta-refractory, 20% prior BCMA CAR T).

Discussion Points:

• Response rate and durability in difficult-to-treat population
• Safety concerns with dual bispecific combination
• Off-label use considerations

4. CAR T-CELL THERAPY TOXICITIES

CAR T Immune-Related Adverse Events (UPenn Study - Ho et al)

Large cohort study of 198 patients (125 cilta-cel, 73 ide-cel) examining all adverse events other than CRS, ICANS, IEC-HS, and IECAHT.

Discussion Points:

• Landscape of CAR T IRAEs: incidence, types, and timing
• Risk factors identified for CirAEs
• Mechanism of toxicities and role of CD4+ CAR T-cells
• Clinical implications: Should prophylactic corticosteroids be used? What ALC threshold? Optimal dose/duration? Prospective studies needed?