Immunotherapy in multiple myeloma: Molecular mechanisms, current clinical strategies, resistance, and future perspectives

Immunotherapy has revolutionized the treatment of multiple myeloma (MM), providing durable clinical responses through targeted activation of the immune system. However, disease relapses remain common owing to immune escape, antigen loss, T-cell exhaustion, and the immunosuppressive bone marrow microenvironment, underscoring the need for continued therapeutic innovation.

This review provides a comprehensive overview of the molecular mechanisms, current immunotherapeutic strategies, resistance pathways, and future directions shaping the management of MM.

A comprehensive narrative review was conducted using PubMed, Scopus, and Web of Science to identify relevant English-language publications, including original studies, clinical trials, systematic reviews, meta-analyses, and landmark articles. The evidence was critically synthesized with emphasis on molecular mechanisms, clinical efficacy, biomarkers, therapeutic resistance, and emerging treatment strategies.

Major immunotherapeutic modalities, including monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, CAR-T cell therapy, vaccines, and NK-cell-based approaches, have substantially improved outcomes for patients with relapsed or refractory MM. B cell maturation antigen-directed therapies have demonstrated particularly high response rates, while emerging targets such as GPRC5D and FcRH5 are expanding therapeutic options. Nevertheless, treatment durability is limited by tumor heterogeneity, antigen modulation, immune dysfunction, and therapy-related toxicities. Emerging strategies-including multi-antigen targeting, rational combination regimens, optimized treatment sequencing, biomarker-guided patient selection, and integration of real-world and health-economic evidence-may further improve long-term outcomes.

Immunotherapy has fundamentally reshaped MM management, yet durable disease control remains a major challenge. Advances in precision immunotherapy, next-generation cellular engineering, predictive biomarkers, and personalized combination strategies are expected to overcome resistance, extend remission, and establish more effective and sustainable treatment paradigms.