Navigating the Therapeutic Landscape of Multiple Myeloma: Immunotherapy, Microenvironment, and Resistance

Immunotherapies, including chimeric antigen receptor (CAR) T cells, bispecific T-cell engagers (BiTEs), and antibody-drug conjugates (ADCs), have revolutionized the treatment landscape for multiple myeloma (MM). Despite robust initial response rates, achieving durable remissions remains challenging due to frequent relapses driven by complex therapeutic resistance mechanisms. In this review, we comprehensively examine intrinsic tumor resistance, such as innate and acquired antigen escape mediated by genomic alterations, structural variations, and epigenetic silencing. Furthermore, we highlight the critical role of the highly permissive bone marrow microenvironment in blunting the efficacy of modern therapies. Cellular compartments, including mesenchymal stromal cells, osteoclasts, and expanded immunosuppressive immune populations, actively foster tumor survival, promote metabolic competition, and T-cell exhaustion. We also review the unique clinical toxicities associated with T-cell-redirecting modalities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Ultimately, deciphering the complex interplay between malignant plasma cells and their surrounding microenvironment is essential for optimizing treatment sequencing, preventing effector cell exhaustion, and designing next-generation therapeutic strategies to secure long-term, durable responses for patients.