In a phase I clinical trial, treatment with the investigational FcRH5×CD3 bispecific antibody cevostamab reduced cancer in more than 40% of patients with multiple myeloma—many of whom had already been through multiple other cancer treatments—and produced a median duration of response of 11.2 months before disease progression.
Cevostamab works by activating patients’ own immune cells, specifically T cells, to attack the myeloma. It is the first therapy to target FcRH5, a protein found on the surface of plasma cells, providing a proof-of-concept for this new target in multiple myeloma. The results were published in Nature Medicine by Adam Cohen, MD, of the Abramson Cancer Center and Perelman School of Medicine at the University of Pennsylvania, and international collaborators.
One goal of this study was to determine the recommended dose and schedule for the phase II study (RP2D). Among the 167 patients who received the monotherapy RP2D, 44.3% of patients had objective responses—defined as at least 50% reduction in myeloma proteins.
“In myeloma, there’s always a need to reach for the next treatment, so having another validated target will give us more options, particularly for patients who might have already tried our currently approved BCMA- or GPRC5D-targeted therapies,” said Dr. Cohen, a Professor of Hematology-Oncology and Director of Myeloma Immunotherapy. “This was a very heavily pretreated population, with a median of six prior lines of treatment, and the field was evolving as this trial was recruiting, so almost half had already received a BCMA-targeted treatment. The fact that we still saw treatment responses in this relapsed/refractory patient population is a real testament to FcRH5 as a new anti-myeloma target.”
Patients in the study who had not received a prior BCMA therapy did better, with a 60.6% response rate and median duration of response lasting 19.7 months in those who received the RP2D.
A total of 324 patients with relapsed/refractory multiple myeloma enrolled in the study between September 2017 and July 2023 at 17 cancer centers across the United States, Canada, Spain, and Australia. The study was designed to give patients a fixed duration of the intravenous medication—17 total infusions, given every 3 weeks over 1 year or until disease progression. This format contrasts with most other bispecific antibodies, which are typically given indefinitely until disease progression.
The side effects were generally manageable. Sixty percent of patients experienced grade 3 or 4 adverse events, with the most common side effects being cytokine-release syndrome, low white blood cells, cough, anemia, diarrhea, nausea, and fatigue. Three patients (1.8%) died from complications related to treatment. The rates of serious infections appeared lower than those previously reported with BCMA-targeted bispecific antibodies, and the side effect profile did not include the types of adverse events typically seen with GPRC5D-targeted bispecific antibodies, which can cause altered taste, dry mouth, and loss of appetite.
“With myeloma requiring lifelong care, we were glad that patients who completed the full course of therapy were able to take a break from treatment,” Dr. Cohen said. “These results have opened the door to new studies investigating a fixed-duration approach for other bispecific antibodies as well.”
Additional clinical trials investigating cevostamab are already underway and planned. At Penn, Dr. Cohen is leading a phase II study of cevostamab as consolidation therapy following chimeric antigen receptor T-cell therapy (ClinicalTrials.gov identifier NCT05801939); the study has completed enrollment, and he presented initial results at the 2025 ASH Annual Meeting & Exposition. A global, randomized phase III clinical trial, called CEVOLUTION, is assessing cevostamab in combination with two other myeloma therapies is expected to begin enrolling this year.
DISCLOSURE: The study was sponsored by Genentech, a member of the Roche Group. Dr. Cohen reports consulting fees and research funding from Genentech/Roche. For full disclosures of the study authors, visit nature.com.
