Comparative incidence of infections and cytopenias in BCMA- vs GPRC5D-targeting bispecific antibodies for relapsed/refractory multiple myeloma: A systematic review and meta-analysis of proportions.

Abstract

e19505 Background: Bispecific antibodies (BsAbs) targeting BCMA and GPRC5D have demonstrated substantial efficacy in relapsed/refractory multiple myeloma (RRMM). However, treatment is associated with significant infectious and hematologic toxicities. While individual trials report variable safety outcomes, a target-specific pooled analysis of these adverse events is lacking. Methods: We performed a systematic review and meta-analysis of proportions of phase 1/2 clinical trials evaluating BCMA-targeting (teclistamab, elranatamab, linvoseltamab) and GPRC5D-targeting (talquetamab) BsAbs administered at recommended phase 2 or approved doses in adults with RRMM. Primary outcomes were grade ≥3 infections and grade ≥3 neutropenia. Secondary outcomes included any-grade infections, any-grade and grade ≥3 anemia, any-grade and grade ≥3 neurotoxicity. Event proportions were pooled using random-effects models with variance-stabilizing transformation. Heterogeneity was assessed using I² and τ² statistics. Sensitivity analyses included leave-one-out diagnostics and alternative estimators. Results: Seven trial arms from phase 1/2 clinical trials, comprising 806 patients with RRMM, were included in the quantitative synthesis. Among BCMA-targeting BsAbs, the pooled incidence of grade ≥3 infections was 28.9% (95% CI 21.7–37.3) with substantial heterogeneity (I²=86%, P<0.01)). GPRC5D-targeting BsAbs demonstrated comparable pooled rates of grade ≥3 infections infections across dosing schedules, with overlapping confidence intervals and similarly high heterogeneity. Grade ≥3 neutropenia was common, with higher pooled rates observed among BCMA-targeting agents (45.5%, 95% CI 33.2–58.3; I²=92%, P < 0.01) compared with GPRC5D-targeting BsAbs. Any-grade infections occurred frequently across both targets (BCMA: 71.0%, 95% CI 66.1–75.4; I²=56%, P = 0.03). Hematologic toxicity was frequently observed across both targets. Among BCMA-targeting BsAbs, the pooled incidence of any-grade anemia was 41.6% (95% CI 35.4–48.0; I²=68%, P <0.01), while grade ≥3 anemia occurred in 31.5% of patients (95% CI 28.0–35.3; I²=25%, P=0.24). Any-grade neurotoxicity was infrequent, with a pooled incidence of 7.3% (95% CI 4.8–10.9; I²=59%, P=0.02), and grade ≥3 neurotoxicity was rare (0.49%, 95% CI 0.12–2.00; I²=0%, P=0.88). Sensitivity analyses confirmed the robustness of pooled estimates. Conclusions: Although pooled rates of grade ≥3 infections were comparable between BCMA- and GPRC5D-targeting BsAbs, BCMA-targeting agents demonstrated numerically higher rates of severe neutropenia. These findings support the need of prospective comparative safety studies, individualized risk stratification and proactive supportive-care strategies when selecting BsAbs therapy in patients with RRMM.