Proven salvage therapies for patients with triple-class exposed or refractory multiple myeloma who progress on B-cell maturation antigen (BCMA)-targeted therapies are lacking. Cevostamab, a FcRH5xCD3 bispecific antibody that facilitates T-cell directed killing of MM cells, has shown promising activity in pts with heavily pre-treated relapsed/refractory MM (RRMM), including those with prior exposure to BCMA-targeted agents, in a Phase I study. FcRH5 is an immunoglobulin domain-containing type I membrane  protein that is expressed exclusively in the B-cell lineage (myeloma cells > normal B cells) and has near ubiquitous expression on myeloma cells. 

CAMMA 2 is a Phase I/II study (NCT05535244) evaluating the efficacy and safety of cevostamab in patients with RRMM who are triple-class refractory and have received a prior BCMA-targeted agent. Initial results from Cohort A1 of this trial were presented during the EHA 2024 oral session.

At data cut-off, with a median follow-up of 11 months, 6/14 responders were still in response. Among all patients, an overall response rate (ORR) of 67% was achieved. ORR and very good partial response or better (≥VGPR) was achieved in 60% and 20% of patients in the prior ADC group, and 73% and 55% of patients in the prior CAR T-cell group, respectively.

Adverse events (AEs) were consistent with the known safety profile of cevostamab. Grade 3–4 AEs in ≥3 patients were neutropenia, anemia, and thrombocytopenia. Cytokine Release Syndrome (CRS) occurred in 71%, with all events were Grade 1–2 and most occurred in C1. One patient with a prior history of epilepsy had a treatment-related AE (Grade 4 Immune effector cell-associated neurotoxicity syndrome [ICANS]) leading to withdrawal of cevostamab. No other AEs leading to withdrawal of cevostamab were reported. There were no Grade 5 (fatal) AEs. 

Peak IL-6 levels are higher in prior ADC patients versus prior CAR-T patients after the 2nd step-up dose and 1st target dose, in line with the higher frequency of CRS events in prior ADC patients versus prior CAR-T patients. At Cycle 4, frequencies of effector T cells in CD8 T cells are numerically higher in responders versus non-responders, in line with reports from other bispecifics CD8 effector T cells in responders have higher frequency of granzyme B-positive cells than those in non-responders.

Conclusion 

J&J dominates the multiple myeloma treatment space by adding two bispecific antibodies approved in the field. TECVAYLI (teclistamab) became the first bispecific antibody to get the regulatory nod for treating RRMM in 2022 in the United States and Europe. Later in 2023, TALVEY (talquetamab) and ELREXFIO (elranatamab) were approved for RRMM. Linvoseltamab from Regeneron is also in line to get regulatory nod. In February 2024,  the US Food and Drug Administration (FDA) accepted for Priority Review the Biologics License Application (BLA) for linvoseltamab to treat adult patients with RRMM that has progressed after at least three prior therapies. The target action date for the FDA decision is August 22, 2024.

Except for TALVEY, all the approved bispecific antibodies are BCMA-directed. Cevostamab is a different bispecific antibody that targets FcRH5, a protein related to BCMA but has a lower expression on normal B cells and CD3. Cevostamab demonstrates high efficacy in triple-class refractory RRMM patients previously treated with BCMA-targeted ADCs or CAR T-cell therapies, showing robust response rates (60% ORR and 20% ≥VGPR after ADC; 73% ORR and 55% ≥VGPR after CAR-T) and promising early signs of response durability in the data presented from the Phase I/II CAMMA 2 study. Adverse events align with cevostamab's established safety profile, with low-grade CRS being the primary concern in clinical trials. These findings underscore cevostamab's potential future utility in managing RRMM patients who have progressed on BCMA-targeted therapies.

Multiple myeloma market is expected to grow in the upcoming years, owing to rise in incident cases, label expansion and penetration of current therapies in earlier lines, high adoption of newer therapies mainly CAR-T cell therapies and anti-BCMA, rich emerging pipeline, and expected increase in investment in the R&D activities. In the heavily pretreated multiple myeloma landscape, CAR T-cell therapies dominate, yet bispecific antibodies have gained approval, prompting comparisons between the two. Despite the preference for CAR-Ts, challenges like manufacturing issues persist. Safety profiles, particularly CRS and ICANS risks, differ, with bispecifics showing lower incidence of Grade 3 or higher CRS. Treatment selection hinges on balancing efficacy and safety, with bispecific antibodies potentially offering advantages for rapidly progressing patients while CAR-Ts remain suitable for those with less aggressive disease. Bispecifics may expand their role broadly in the future.