Doubling Down on Bispecific Antibody Therapy for Myeloma

T-cell–engaging bispecific antibodies are approved as single-agent therapy for patients with relapsed myeloma who have received at least four prior lines of therapy including immunomodulatory agents, proteasome inhibitors, and an anti-CD38 monoclonal antibody. To assess the clinical utility of combining two bispecific agents with different myeloma cell antigenic targets, investigators conducted an industry-sponsored, multicenter, phase 1b–2 trial of talquetamab (anti-CD3 x anti-GPRC5D) plus teclistamab (anti-CD3 x anti-BCMA) in patients with relapsed or refractory myeloma.

Following the dose-escalation phase and utilizing a stepped-up dosing schedule to mitigate severe cytokine release syndrome (CRS), the investigators selected phase 2 doses of 0.8 mg/kg subcutaneous talquetamab plus 3.0 mg/kg teclistamab given with premedications on the same day every two weeks. Responding patients could be transitioned to 4-week dosing intervals. Most patients had undergone prior stem cell transplantation, and several had received prior chimeric antigen receptor T-cell or bispecific antibody therapy.

Among the 94 patients treated across all dose levels, the response rate was 76%. Serious infections occurred in 64% of patients; 11 were fatal. COVID-19 infection arose in 38 patients, with 2 deaths. Eighty-seven patients (93%) required dose modifications or delays due to adverse events, mostly infections; 16% discontinued one or both agents. CRS occurred in 79% of patients, almost all grade 1–2. Immune effector cell–associated neurotoxicity syndrome (ICANS) arose in only 3 patients. Among the 44 patients treated at the phase 2 dose level, the overall response rate was 80%, 52% had a complete response or better, and 86% had an ongoing response at 18 months.