Phase 1b study of the anti-CD38 antibody mezagitamab in patients with relapsed/refractory multiple myeloma

• In a phase 1b study in relapsed/refractory myeloma, the anti-CD38 antibody mezagitamab was well tolerated and showed preliminary activity.

• At the recommended phase 2 dose of 600 mg, the overall response rate was 47% and median duration of response was 22.1 months.

This phase 1b trial aimed to determine the safety, tolerability, and preliminary efficacy of mezagitamab, a subcutaneously administered anti-CD38 monoclonal antibody, in patients with relapsed/refractory multiple myeloma (RRMM). Eligible patients had received ≥3 prior lines of treatment including an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and a steroid, or ≥2 prior lines where one included a PI+IMiD, and were refractory/intolerant to ≥1 IMiD and ≥1 PI. Fifty patients were enrolled: 44 received mezagitamab monotherapy (dose-escalating cohorts at 45-1200 mg) and six received mezagitamab 300 mg in combination with pomalidomide+dexamethasone. Patients received mezagitamab weekly for eight doses, every other week for eight doses, then monthly. No dose-limiting toxicities were reported with single-agent mezagitamab and the recommended phase 2 dose was determined as 600 mg. The most common drug-related treatment-emergent adverse events (TEAEs) were fatigue in the monotherapy cohorts (9/44 patients) and neutropenia in the combination cohort (4/6 patients); neutropenia was the only drug-related grade ≥3 TEAE to occur in >1 patient. No infusion reactions occurred, and four injection-site reactions were reported. Three patients discontinued treatment due to TEAEs. Among 22 patients receiving 600 mg mezagitamab, the overall response rate was 47% and median duration of response was 22.1 months. Mezagitamab had a manageable safety profile and activity in patients with RRMM, with comparable outcomes to those reported with other anti-CD38 therapies in patients with advanced RRMM. Further development of mezagitamab in myeloma is not planned, but given its encouraging safety, studies are underway in autoimmune conditions with underlying abnormal autoantibodies.