Forimtamig, a GPRC5DxCD3 bispecific antibody with a novel 2:1 format, in relapsed/refractory multiple myeloma

We report the results from a Phase 1 study (NCT04557150) evaluating subcutaneous (SC) forimtamig, a novel GPRC5DxCD3 bispecific antibody with a 2:1 configuration, in relapsed/refractory multiple myeloma (RRMM). After dose-escalation, backfilling at optimized target doses in combination with weekly (step-up: Cycle [C] 1 Day [D] 1 and C1D8; target: C1D15) and condensed (step-up: C1D1 and C1D4; target: C1D8) step-up dosing was pursued for benefit-risk assessment. Primary objectives were evaluating safety/tolerability and determining the maximum tolerated dose (MTD) and recommended Phase 2 dose/schedule. Secondary objectives included pharmacokinetics, immunogenicity and anti-tumor activity. In total, 171 patients were enrolled (median age: 64.0 years; high-risk cytogenetics: 32.2%; triple-class refractory: 60.2%). The starting C1D1 dose was 0.05 mg. Dose-limiting toxicities occurred in 20 patients (11.7%). MTD was not identified. Dose-escalation concluded at 7.2 mg target dose due to accumulating toxicity. The most common adverse event (AE) was cytokine release syndrome (75.4%). Grade 5 AEs occurred in 11 patients (6.4%); two events were considered treatment-related. Across all cohorts, the overall response rate (ORR) was 59.6%. At the optimized target doses (0.75 mg/1.5 mg), ORR was 71.7% with the condensed schedule (n = 46) and 47.1% with the weekly schedule (n = 34). Early soluble B-cell maturation antigen reduction and minimal residual disease negativity were associated with improved progression-free survival. SC forimtamig demonstrated potent and durable activity in RRMM, which could be enhanced with a condensed step-up schedule. On-target, off-tumor toxicities were common, highlighting the narrow therapeutic window for GPRC5D as a target for T-cell-engaging bispecific antibodies.