Results offer another pathway when standard therapies fail
A phase 1 clinical trial has demonstrated encouraging results for cevostamab, an investigational bispecific antibody that targets a novel protein in multiple myeloma, potentially providing a new treatment pathway for patients whose disease has progressed despite multiple prior therapies. The findings, published in Nature Medicine, suggest the therapy could expand the range of available targets for treating relapsed and refractory disease.
Multiple myeloma is a cancer of plasma cells and, despite substantial advances in treatment over recent decades, remains largely incurable. While many patients achieve prolonged remissions with current therapies, most will eventually experience disease relapse and require additional lines of treatment. As patients exhaust available therapeutic options, identifying new targets becomes increasingly important.
The study evaluated cevostamab, a bispecific antibody designed to direct a patient's own T cells to attack myeloma cells. The treatment is the first therapy to target FcRH5, a protein found on the surface of plasma cells, providing proof of concept for a completely new therapeutic target in multiple myeloma.
Researchers enrolled 324 patients with relapsed or refractory multiple myeloma between September 2017 and July 2023 across 17 cancer centres in Australia, the United States, Canada, and Spain. Many participants had already received extensive treatment, reflecting a patient population with significant unmet clinical need.
A key objective of the trial was to establish the recommended dose and schedule for future phase 2 studies. Among the 167 patients who received the recommended phase 2 dose as monotherapy, 44.3% achieved an objective response, defined as at least a 50% reduction in myeloma proteins. The median duration of response was 11.2 months before disease progression occurred.
The findings are notable given the heavily pretreated nature of the study population. Participants had received a median of six previous lines of therapy, and almost half had already been treated with therapies targeting B-cell maturation antigen (BCMA), one of the major existing targets in multiple myeloma immunotherapy.
"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," Adam Cohen, Professor of Haematology-Oncology and Director of Myeloma Immunotherapy at the Abramson Cancer Center and Perelman School of Medicine at the University of Pennsylvania, said.
"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," Professor Cohen said.
Investigators observed even stronger outcomes among patients who had not previously received BCMA-targeted therapy. In this subgroup, the response rate reached 60.6%, with a median duration of response of 19.7 months.
Another notable aspect of the trial was the use of a fixed-duration treatment strategy. Patients received up to 17 intravenous infusions administered every three weeks over approximately one year, unless disease progression occurred earlier. This differs from many currently available bispecific antibody therapies, which are commonly administered continuously until disease progression.
For patients living with a chronic cancer requiring ongoing therapy, a fixed-duration approach may offer periods free from treatment while maintaining disease control. Researchers believe this concept warrants further investigation across other bispecific antibody programmes.
"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," Professor Cohen said.
"These results have opened the door to new studies investigating a fixed-duration approach for other bispecific antibodies as well," Professor Cohen said.
The safety profile was generally consistent with expectations for this class of therapy. Sixty per cent of patients experienced grade 3 or 4 adverse events. The most commonly reported side effects included cytokine release syndrome, low white blood cell counts, cough, anaemia, diarrhoea, nausea and fatigue. Three patients, representing 1.8% of the study population, died from treatment-related complications.
Researchers also noted that rates of serious infection appeared lower than those reported in studies of some BCMA-targeted bispecific antibodies. In addition, the treatment did not demonstrate the characteristic adverse effects often associated with GPRC5D-targeted therapies, such as altered taste, dry mouth and loss of appetite.
The results have prompted further clinical development. Additional studies of cevostamab are already underway, including investigations of its use as consolidation therapy following CAR T-cell treatment. A global randomised phase 3 trial evaluating cevostamab in combination with other myeloma therapies is also expected to commence enrolment.
For clinicians managing patients with relapsed and refractory multiple myeloma, the study provides early evidence supporting FcRH5 as a viable therapeutic target. While longer-term efficacy and safety data are still needed, the results suggest cevostamab may eventually offer another treatment option for patients whose disease has progressed following existing targeted therapies.