Decoding immunotherapy resistance in multiple myeloma: genetic insights and approaches to counter resistance.

Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells and presents major therapeutic challenges due to its intrinsic heterogeneity and frequent development of resistance to immunotherapy. Although recent advances in immunotherapeutic strategies, including immunomodulatory drugs (IMiDs), chimeric antigen receptor T-cell (CAR-T) therapies, monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), and bispecific antibodies (BsAbs), have significantly improved patient outcomes, disease relapse remains nearly inevitable. This review systematically categorizes resistance mechanisms to immunotherapy in MM by examining intrinsic tumor cell factors, including genetic and epigenetic alterations, modulation or loss of target antigens, immune effector cell dysfunction such as T-cell exhaustion, and the complex suppressive features of the bone marrow microenvironment. In addition, we discuss the application of emerging technologies such as single-cell sequencing and CRISPR/Cas9-based functional screening to uncover resistance pathways and guide target discovery. Finally, we highlight rational strategies to overcome resistance, including synergistic combination regimens, development of next-generation therapeutics, and approaches to reprogram the tumor microenvironment. These insights provide a conceptual framework for the design of more effective and durable immunotherapeutic interventions in MM.