FcRH5×CD3 bispecific antibody cevostamab in relapsed or refractory multiple myeloma: a phase 1 trial.

Fc receptor-homolog 5 (FcRH5) is a membrane protein that is ubiquitously expressed on myeloma cells. Cevostamab is a first-in-class, FcRH5×CD3 bispecific antibody. GO39775 is a phase 1 dose-escalation and dose-expansion study evaluating fixed-duration cevostamab in relapsed or refractory multiple myeloma. Cevostamab was initiated with step-up dosing and continued at the target dose (TD) once every 3 weeks for 17 cycles (~12 months) unless disease progression or unacceptable toxicity occurred. Primary objectives were to evaluate safety, including determination of the maximum tolerated dose (MTD), and to identify a recommended phase 2 dose and schedule (RP2D) for cevostamab monotherapy. Secondary objectives included determining the rate of response and the duration of response (DOR). As of 24 February 2025, 324 patients had been enrolled; most were heavily pretreated (median prior lines, 6; triple-class refractory, 89.5% (290/324); prior B-cell maturation antigen (BCMA)-targeted therapy, 47.5% (154/324)). The MTD was not reached. Across all TD levels (0.15-252 mg), grade 3 or 4 adverse events (AEs) and serious AEs occurred in 59.6% (193/324) and 60.2% (195/324), respectively. Grade 5 AEs excluding disease progression occurred in 4.6% (15/324); 0.9% (3/324) were considered treatment related (hemophagocytic lymphohistiocytosis, n = 2; disseminated intravascular coagulation in the context of pseudomonal sepsis, n = 1). Objective response and very good partial response or better rates were 42.1% (136/323) and 25.1% (81/323), respectively. Median DOR was 11.2 months (95% confidence interval, 8.3, 15.6). A total of 167 patients received treatment at the 160 mg TD level (RP2D). Objective response and very good partial response or better rates were 44.3% (74/167) and 25.7% (43/167) in all patients and 60.6% (43/71) and 39.4% (28/71) in the BCMA naive, respectively. Median DOR was 10.4 months in all patients and 19.7 months in the BCMA naive, with durable responses maintained after the completion of treatment. Cytokine release syndrome was grade 1 or 2 in the 0.3/1.2/3.6/160 mg triple step-up cohort (RP2D). Cevostamab had manageable safety and induced durable remissions in late-line relapsed or refractory multiple myeloma. ClinicalTrials.gov registration: NCT03275103 .