Efficacy and specific toxicity profiles of GPRC5D- versus BCMA-targeted bispecific antibodies in relapsed/refractory multiple myeloma: a meta-analysis of clinical trials and real-world studies.

Abstract

Patients with relapsed/refractory multiple myeloma (RRMM) experience poor outcomes following multiple lines of therapy. Available evidence has largely pooled disparate immunotherapy platforms. The present systematic review and meta-analysis was performed to describe, separately by target, the efficacy and toxicity spectra of BCMA×CD3-directed, GPRC5D×CD3-directed, and dual-target bispecific antibody therapy in RRMM, in order to inform toxicity monitoring and supportive-care planning. The Cochrane Library, Embase, Web of Science, and PubMed were systematically searched up to January 28, 2026, to identify clinical trials and real-world studies evaluating GPRC5D×CD3 or BCMA×CD3 bispecific antibodies and their combinations for RRMM. Methodological quality was appraised with the Methodological Index for Non-Randomized Studies. Proportions and 95% confidence intervals (CIs) were pooled utilizing fixed-effects or random-effects models in R, selected according to heterogeneity. Twenty-seven studies-comprising 13 single-arm clinical trials and 14 real-world investigations involving 4,045 patients-met the inclusion criteria. The pooled objective response rate (ORR) for bispecific antibodies in RRMM was 65.54%. Target-stratified subgroup analysis yielded an ORR of 78.51% for GPRC5D×CD3 combined with BCMA×CD3, 69.67% for GPRC5D×CD3 alone, and 60.85% for BCMA×CD3 alone. The pooled minimal residual disease-negativity rate was 23.6%. Regarding safety, distinct antigen-specific toxicity spectra emerged across different targets. The BCMA×CD3 group exhibited elevated incidences of any-grade infection (56.37%) and grade 3-4 infection (26.37%), accompanied by pronounced hematological toxicity. The GPRC5D×CD3 group was characterized by epithelium-related toxicity: the incidence of grade 1-2 taste-related changes was 69.89%, that of any-grade nail-related adverse events (AEs) was 42.33%, and that of any-grade non-rash skin-related AEs was 58.3%; however, grade 3-4 nail-related AEs reached only 0.21%, and grade 3-4 non-rash skin-related AEs reached only 0.33%. The dual-target group bore a substantial burden of infection (84.53%) and hematological toxicity. Bispecific antibodies demonstrate clear antimyeloma activity in RRMM. BCMA×CD3-directed therapy is mainly related to infection and hematological toxicity, whereas GPRC5D×CD3-directed therapy is distinguished by epithelium-related toxicity, although severe events are rare. https://www.crd.york.ac.uk/PROSPERO/ identifier, CRD420261296139.