Second Primary Malignant Neoplasms After T-Cell–Engaging Bispecific Antibody Therapy

Importance: T-cell-engaging bispecific antibodies (BsAbs) are increasingly used in B-cell non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). As these agents transition into earlier courses of therapy and broader clinical use, understanding their safety profile is critical. While second primary malignant neoplasms (SPMs) represent a key long-term safety signal, small sample sizes, single-arm trials, short follow-up, and heterogeneous reporting have limited reliable estimation of their frequency. Objective: To estimate the frequency of reported SPMs after BsAb therapy and evaluate whether study-level characteristics and reporting definitions influence observed estimates. Data Sources: PubMed and Embase were searched from inception through October 1, 2025, following a prespecified protocol registered in PROSPERO. Study Selection: Clinical trials and real-world studies of BsAbs in adults with NHL or MM reporting SPM outcomes. Data Extraction and Synthesis: Data were extracted following PRISMA guidelines. Pooled SPM frequencies were calculated using random-effects meta-analysis of single proportions. Main Outcomes and Measures: Reported SPM occurrence during available follow-up was categorized as (1) total SPMs reported, (2) SPMs leading to treatment discontinuation, and (3) SPMs leading to death. Results: Of 494 records, 20 studies (26 cohorts; 2551 patients) met inclusion criteria. Among 8 studies (10 cohorts; 1003 patients) reporting total SPMs, random-effects meta-analysis yielded a pooled estimated proportion of 3.5% (95% CI, 1.8-6.9) at a median (range) follow-up of 17.4 (5.7-25.6) months. Disease-specific estimates were 3.8% (95% CI, 2.3-6.3) for NHL and 3.4% (95% CI, 0-76.7) for MM. A total of 6 studies (8 cohorts; 748 patients) reporting SPMs leading to treatment discontinuation showed a pooled estimate of 2.2% (95% CI, 1.5-3.1). A total of 19 studies (24 cohorts; 2330 patients) reporting SPMs leading to death yielded a pooled estimate of 1.4% (95% CI, 1.1-1.9). In exploratory meta-regression analyses of prespecified study-level covariates (follow-up duration, disease category, prior therapy courses, and age), no variables were associated with total SPM estimates. Conclusions and Relevance: In this systematic review and meta-analysis, despite relatively short follow-up, SPMs were a measurable and clinically relevant complication of BsAb therapy. Heterogeneous and inconsistent reporting currently complicates their comprehensive assessment, highlighting the need for standardized long-term safety surveillance in clinical trials examining BsAbs.