JNJ-79635322, a trispecific antibody targeting BCMA, GPRC5D, and CD3, demonstrated 100% overall response rate at the recommended phase 2 dose (100 mg) in BCMA/GPRC5D-naïve relapsed/refractory multiple myeloma patients. The agent shows promise as a potential replacement for individual bispecific antibodies with superior oral toxicity profile and fixed-duration therapy option.
Study Design & Population
Phase 1 dose-escalation trial (NCT05652335)
- Sample size: 76 patients across dose cohorts (50-300 mg)
- Population: Relapsed/refractory multiple myeloma patients exposed to CD38 monoclonals, proteasome inhibitors, and immunomodulatory agents
- Design: First-in-human, dose-escalation study with step-up dosing optimization
- Primary endpoint: Safety, tolerability, and recommended phase 2 dose determination
Key Findings
- Overall response rates by dose: 55.0% (50-300 mg mixed, n=20), 66.7% (50 mg, n=21), 100% (100 mg, n=27), 100% (300 mg, n=8)
- Recommended phase 2 dose: 100 mg every 4 weeks with 5 mg step-up dose
- BCMA/GPRC5D-naïve patients (85% of cohort): 100% ORR, 96.3% VGPR rate at RP2D
- BCMA/GPRC5D-exposed patients: 55.0% ORR
- 12-month PFS rate: 95% at RP2D (limited by one treatment-related death)
- CRS incidence: 56.5% overall; 69.2% without prophylactic tocilizumab vs 20.0% with prophylaxis
- Improved oral toxicity profile: Lower dysgeusia rates (grade 1), no mucositis, dysphagia, or significant weight loss vs talquetamab
Clinical Implications
- Dual targeting mechanism may overcome resistance to single bispecific antibodies while improving specificity
- Prophylactic tocilizumab significantly reduces CRS rates, enabling outpatient dosing strategy
- Fixed-duration therapy option (18 cycles) may improve patient quality of life compared to continuous bispecific therapy
- Superior oral toxicity profile compared to GPRC5D-targeting agents like talquetamab may improve patient tolerance
Limitations
- Early-phase data with small cohorts, particularly at higher doses
- Short follow-up limits durability assessment and long-term safety profile
- Single-arm design prevents direct comparison with existing bispecific antibodies
- Limited data in heavily BCMA/GPRC5D-exposed population
