Abstract
Background: Multiple myeloma is a plasma cell malignancy with a complex genomic landscape, and relapse remains common despite therapeutic advances. B-cell maturation antigen (BCMA), selectively expressed on malignant plasma cells, has emerged as a pivotal immunotherapeutic target. BCMA-directed therapies, including chimeric antigen receptor T cells (CAR-T) and bispecific antibodies, have achieved unprecedented response rates in relapsed/refractory Multiple myeloma (RRMM), yet their application into clinical practice is challenged by unique toxicities and resistance mechanisms. Summary: This review synthesizes current evidence on balancing the efficacy and toxicity of BCMA targeted therapies. It details the mechanisms driving key immune related toxicities including cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), and immune effector cell–associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) and delayed neurotoxicities. It also explores major resistance pathways such as BCMA antigen loss via genomic deletion or γ secretase mediated shedding. The article further evaluates risk-stratified management framework and discusses strategies to overcome resistance. Key Messages: Optimizing the sequencing of BCMA-directed therapies, along with developing novel combination and multi-targeting strategies, is critical to improving long-term outcomes in RRMM.