Cevostamab Shows Durable Responses in Relapsed/Refractory Multiple Myeloma

Fixed-duration cevostamab, a first-in-class FcRH5/CD3 bispecific antibody, demonstrated manageable safety and induced durable remissions in patients with relapsed/refractory multiple myeloma, according to results from the phase 1 GO39775 trial (NCT03275103) published in Nature Medicine.

Across all target-dose levels, the objective response rate (ORR) was 42.1% (n = 136/323), and the very good partial response (VGPR) or better rate was 25.1% (n = 81/323), with a median duration of response (DOR) of 11.2 months (95% CI, 8.3-15.6). Among the 167 patients treated at the 160-mg RP2D, the ORR was 44.3% (n = 74/167), and the VGPR or better rate was 25.7% (n = 43/167); in patients without prior BCMA-targeted therapy (n = 71), the rates rose to 60.6% (n = 43/71) and 39.4% (n = 28/71), respectively. The median DOR was 10.4 months (95% CI, 6.2-15.0) in all patients treated at the RP2D and 19.7 months (95% CI, 10.0-36.4) in the BCMA-naive subgroup, with responses maintained after completion of treatment.

Additional efficacy data showed that the ORR was 36.2% (n = 21/58) among patients with any prior BCMA-targeted CAR T-cell therapy, 17.2% (n = 5/29) among those with any prior BCMA-directed bispecific antibody, and 43.8% (n = 14/32) among those with any prior BCMA-targeted antibody-drug conjugate (ADC).

"[The study] validates FcRH5 as a good target for myeloma therapy. It’s the first trial to do that, and so this is clearly an active agent," lead author Adam D. Cohen, MD, director of myeloma immunotherapy and associate professor of medicine at the Abramson Cancer Center of the University of Pennsylvania, stated in an interview with CancerNetwork^® regarding these findings. “Fixed-duration therapy is a good concept that this trial is helping to establish, and hopefully that will become the future. We’ll be able to maybe tailor the duration of therapy to the response or to the setting and not have to keep people on therapy forever. Quality of life is important, especially in a late [treatment] line [or] incurable setting, [so] drugs that that don’t cause a lot of nuisance or quality of life toxicities can be very important.”

GO39775 is an open-label, multicenter, phase 1 dose-escalation and dose-expansion study of fixed-duration cevostamab. The agent was initiated with step-up dosing and continued at the target dose once every 3 weeks for 17 cycles or approximately 12 months unless disease progression or unacceptable toxicity occurred.

As of February 24, 2025, 324 patients with relapsed/refractory multiple myeloma had been enrolled. Patients were heavily pretreated, with a median of 6 prior lines of therapy; 89.5% (n = 290/324) were triple-class refractory, and 47.5% (n = 154/324) had received prior BCMA-targeted therapy.

The primary objectives of the study were to evaluate safety, including determination of the MTD, and to identify the RP2D and schedule for cevostamab monotherapy. Secondary objectives included the rate of response and the DOR.

The maximum tolerated dose (MTD) was not reached. Across all target-dose levels from 0.15 to 252 mg, grade 3 or 4 adverse events (AEs) occurred in 59.6% of patients (n = 193/324), and serious AEs occurred in 60.2% (n = 195/324). Grade 5 AEs excluding disease progression occurred in 4.6% of patients (n = 15/324), of which 0.9% (n = 3/324) were considered treatment related (hemophagocytic lymphohistiocytosis, n = 2; disseminated intravascular coagulation in the context of pseudomonal sepsis, n = 1).

The most common any-grade AEs were cytokine release syndrome (CRS; 77.8%), neutropenia (33.3%), and cough (31.5%). At the 160-mg target-dose level—the recommended phase 2 dose (RP2D)—the most frequent grade 3 or 4 toxicities were reversible neutropenia (28.7%), anemia (18.0%), and thrombocytopenia (10.8%), and grade 3 or 4 infections occurred in 15.6% of patients.

In the 0.3/1.2/3.6/160 mg triple step-up cohort, all CRS events were grade 1 or 2, with a median time to resolution of 1 day; CRS was managed with tocilizumab in 30.0% of patients. The authors reported that cevostamab did not cause substantial dysgeusia, weight loss, nail changes, desquamation, or ataxia—toxicities associated with GPRC5D-targeted therapies.

Limitations of the study included small patient numbers in the step-up dosing cohorts and non-uniform, relatively short follow-up, along with a higher rate of penta-drug-refractory disease in some subgroups.

“This [study] gets to this sequencing question of ‘How do we optimally use all these different T-cell agents? What’s the optimal timing?’ We need more studies and more data,” Cohen concluded. “Some of these questions maybe have answers in the real-world setting, so we encourage centers to pool their data.”

Reference

Cohen AD, Richter J, Trudel S, et al. FcRH5×CD3 bispecific antibody cevostamab in relapsed or refractory multiple myeloma: a phase 1 trial. Nat Med. Published online July 22, 2026. doi:10.1038/s41591-026-04522-3