The Efficacy and Safety of B-Cell Maturation Antigen (BCMA) Antibody-Drug Conjugates (ADC) in Development against Cancer: A Systematic Review.

Objectives: B-cell maturation antigen (BCMA)-targeted antibody-drug conjugates (ADCs) have emerged as promising therapies for relapsed/refractory multiple myeloma (RRMM), but the overall efficacy and safety profile is unclear. This study aimed to synthesize the available evidence on the safety and efficacy of BCMA-ADCs in development for RRMM. Methods: A systematic search was conducted using six bibliographic databases and ClinicalTrials.gov up to November 2024. Studies were eligible if they were human clinical trials or animal studies evaluating BCMA-ADCs and reported efficacy and safety outcomes. Data extraction and quality assessments were conducted using validated tools, including ROBINS-I and SYRCLE's risk of bias tool. Results: A total of 21 studies were included: 16 clinical trials and five animal studies. Key findings included that belantamab mafodotin demonstrated variable but generally durable response rates (32%-85%) and a broad range of progression-free survival (PFS) (2.8-36.6 months), albeit with ocular toxicities in 51%-96%. Among newer candidates, MEDI2228 showed median PFS 5.1-6.6 months with 14% discontinuation for ocular symptoms, while AMG 224 had an overall response rate (ORR) of 23% (9/40) with anemia 21%, thrombocytopenia 24%, and ocular adverse events (AEs) 21%. Animal studies supported the tumor-eradicating potential of all BCMA-ADC candidates, although safety signals such as hepatic and renal toxicity were noted with HDP-101. The risk of bias assessment revealed generally moderate to serious concerns in human trials, while the overall quality of the animal studies was acceptable. Conclusions: BCMA-targeted ADC candidates show encouraging efficacy in RRMM, particularly belantamab mafodotin. However, frequent AEs, especially ocular and hematologic toxicities, underscore the need for optimization in ADC design. Further research should prioritize enhancing safety while maintaining clinical benefit.