Non-relapse mortality with bispecific antibodies: A systematic review and meta-analysis in lymphoma and multiple myeloma.

Bispecific antibodies (BsAb) are associated with distinct immune-related toxicities that impact morbidity and mortality. This systematic review and meta-analysis examined non-relapse mortality (NRM) with BsAb therapy in B-cell non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). A PubMed and Embase search up to October 2024 identified 29 studies (21 NHL, 8 MM) involving 2,535 patients. The overall NRM point estimate was 4.7% (95% CI 3.4-6.4%) with a median follow-up of 12.0 months. We noted no significant difference in NRM across disease entities (NHL: 4.2%, MM: 6.2%, p=0.22). In NHL, prespecified subgroup analyses revealed increased NRM in real-world studies compared to clinical trials. For MM, an association between NRM and higher response rates and longer follow-up was noted. Meta-regression comparing BsAb and CAR-T therapies (n=8,592) showed no significant NRM difference when accounting for key study-level confounders (p=0.96). Overall, infections were the leading cause of NRM, accounting for 71.8% of non-relapse deaths. Of the infection-related deaths, 48% were attributed to COVID-19. In a pre-specified sensitivity analysis excluding COVID-19-fatalities, the overall NRM estimate was 3.5% (95% CI 2.6-4.6%). Taken together, these results provide a benchmark for the estimated NRM with BsAb therapy and highlight the paramount importance of infection reporting, prevention, and mitigation.