Dr Cohen on FcRH5 as a Therapeutic Target in Multiple Myeloma

[The] expression [of FcRH5] is near ubiquitous on myeloma cells, but other than that, [there is] limited expression on normal cells of the body, so [agents directed at this target are associated with] a clean safety profile in terms of off-tumor, on-target toxicities.

Adam D. Cohen, MD, a professor of medicine in the Division of Hematology-Oncology at the Hospital of the University of Pennsylvania, a member of the Abramson Cancer Center, as well as director of Myeloma Immunotherapy and co-director of the Amyloidosis Program at the University of Pennsylvania, discussed FcRH5 as a therapeutic target in multiple myeloma and the mechanism of action of the investigational bispecific antibody cevostamab (RG6160).

One of the appeals of FcRH5 as a target is its expression pattern, according to Cohen. The antigen is highly expressed on plasma cells, which are the precursors that give rise to myeloma, and its expression is near ubiquitous across myeloma cells, he explained. Beyond the plasma cell compartment, however, FcRH5 has limited expression on normal tissues, Cohen noted. Some expression is seen on mature B cells, but the antigen does not appear to be present on other normal cells of the body, which confines potential on-target, off-tumor toxicity [associated with FcRH5-targeting agents] primarily to the late B-cell and plasma cell lineage and translates into a relatively clean safety profile, he said.

Cohen added that FcRH5 expression appears to be independent of the expression of BCMA and GPRC5D, which are antigens targeted by several currently approved myeloma therapies. Because of that independence, myeloma cells that lose expression of BCMA or GPRC5D would still be expected to retain FcRH5 expression, preserving it as a therapeutic target, he explained.

Turning to cevostamab specifically, Cohen explained the investigational agent is a T-cell–engaging bispecific antibody. One arm of the molecule binds CD3 on T cells, and the other binds the FcRH5 protein on myeloma cells, he said. By physically bridging the 2 cell types, the antibody brings T cells into contact with myeloma cells and activates them, allowing the T cells to kill the malignant plasma cells directly within the patient, according to Cohen.

Cevostamab has been explored in a phase 1 trial (NCT03275103), in which single-agent treatment (n = 323) generated an objective response rate (ORR) of 42.1%, including a very good partial response (VGPR) or better rate of 21.5%, in patients with relapsed/refractory multiple myeloma who had received a median of 6 prior lines of therapy. Among patients treated at the recommended phase 2 dose of 160 mg per day (n = 167), the ORR and VGPR or better rates were 44.3% and 25.7%, respectively.