Navigating the Immune Landscape: Balancing Efficacy and Toxicity of B-Cell Maturation Antigen-Targeting Agents in Multiple Myeloma.

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 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, immune effector cell-associated neurotoxicity syndrome, and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome 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.