New therapeutic target expands options for multiple myeloma

In a phase 1 clinical trial, treatment with the investigational bispecific antibody cevostamab reduced cancer in more than 40% of patients with multiple myeloma, many of whom had already undergone multiple other cancer treatments, and produced a median duration of response of 11.2 months before the cancer progressed.

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Cevostamab works by activating patients' own immune cells, specifically T cells, to attack myeloma. It is the first therapy to target FcRH5, a protein found on the surface of plasma cells, providing proof of concept for this new target in multiple myeloma, which develops from malignant plasma cells. The results were published today in Nature Medicine by Adam Cohen, MD, from 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 2 study (RP2D). Among the 167 patients who received the monotherapy RP2D, 44.3% had objective responses—defined as at least a 50% reduction in myeloma proteins.

The value of more options

Although most patients with myeloma aren't cured, it is considered a highly treatable disease with an improved prognosis in recent years because of the continued development of new therapies. For most patients with multiple myeloma, the disease journey begins with a combination of therapies after diagnosis, in some cases followed by an autologous stem cell transplant. Unfortunately, almost all patients eventually experience a relapse.

When the cancer returns, they receive another therapy until the cancer progresses, then repeat the process. Patients may experience remissions for months or years at a time. However, once the cancer has stopped responding, or become refractory, to a specific therapy target, additional therapies with the same target may not work.

"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 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 prior BCMA therapy did better, with a 60.6% response rate and a median duration of response of 19.7 months among those who received the RP2D.

Fixed duration gives patients a break from treatment

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; Penn Medicine was the top-enrolling site. The study was designed to give patients a fixed duration of the intravenous medication—17 total infusions, given every three weeks over one 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: 60% of patients experienced grade 3 or 4 adverse events, with the most common side effects being cytokine release syndrome (CRS), low white blood cells, cough, anemia, diarrhea, nausea and fatigue. Three patients (1.8%) died with 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," Cohen said. "These results have opened the door to new studies investigating a fixed-duration approach for other bispecific antibodies as well."

Further research is already underway

Additional clinical trials investigating cevostamab are already underway and planned. At Penn, Cohen is leading a phase 2 study of cevostamab as consolidation therapy following CAR T-cell therapy; the study has completed enrollment, and he presented initial results at the 2025 ASH Annual Meeting. A global, randomized phase 3 clinical trial assessing cevostamab in combination with two other myeloma therapies is expected to begin enrolling this year.

More information: Adam D. Cohen et al, FcRH5×CD3 bispecific antibody cevostamab in relapsed or refractory multiple myeloma: a phase 1 trial, Nature Medicine (2026). DOI: 10.1038/s41591-026-04522-3

Provided by Perelman School of Medicine at the University of Pennsylvania