What Is Cevostamab’s Mechanism of Action in Multiple Myeloma?

Results from a phase 2 trial (NCT05801939) assessing cevostamab consolidation therapy after BCMA chimeric antigen receptor (CAR) T-cell therapy for patients with multiple myeloma demonstrated that 63% of patients had a complete response (CR)/stringent CR before cevostamab, 81% had one when treated on cycle 8 day 1, and 93% had one 1 year post CAR T-cell therapy. Additionally, at enrollment, 100% of patients had minimal residual disease (MRD) negativity, 95% had MRD negativity on cycle 8 day 1, and 93% had MRD negativity at 1 year post CAR T.

Adam Cohen, MD, presented these updated findings at the 2025 American Society of Hematology (ASH) Annual Meeting and Exhibition in Orlando, Florida. A total of 27 patients were treated, and 7 are still receiving treatment.

The hypothesis surrounding this trial was that consolidation with BCMA CAR T-cell therapy may allow for reinvigoration of persisting CAR-positive T cells against BCMA-positive multiple myeloma, eliminate the residual BCMA-low/negative multiple myeloma cells by redirecting endogenous T cells against FcRH5, and improve rates of sustained MRD negativity and duration of response.

Cohen, director of myeloma immunotherapy and associate professor of medicine (hematology-oncology) at the Hospital of the University of Pennsylvania in Philadelphia, spoke with CancerNetwork® at ASH and focused on the mechanistic treatment benefits offered by cevostamab. He also noted there were additional data from other studies highlighting the possibility that targeting 2 antigens may provide better outcomes than targeting one.

Transcript:

The real benefit here is that by targeting 2 antigens, the CAR hits the BCMA and then cevostamab hits FcRH5; you limit the chance that the myeloma cells are going to escape. We know that BCMA loss is a mechanism of escape from T-cell–directed therapies. Even in patients who don’t lose it completely, there’s this phenomenon where the BCMA is downregulated, or these residual cells express lower levels, and that might allow them to escape surveillance from the remaining CARs. Now you come in and hit a different target, and you might be able to eliminate that BCMA-negative or -low reservoir of cells. That’s part of the hypothesis and why we think it might work better. There are data from other CARs and bispecific trials where targeting 2 antigens may be a little better than just targeting one.

Reference

Cohen A, Susanibar-Adaniya S, Garfall A, et al. Phase 2 study of cevostamab consolidation following BCMA CAR T cell therapy: preliminary safety, efficacy, and correlative data from the “STEM” (Sequential T Cell-Engagement for Myeloma) trial. Blood. 2025;146(suppl 1):699. doi:10.1182/blood-2025-699