Extracellular Vesicles as Master Regulators of Immune Modulation in Multiple Myeloma

Multiple myeloma (MM) is a genetically and clinically heterogeneous plasma cell malignancy characterised by clonal expansion of differentiated B cells within the bone marrow (BM). Patients start with monoclonal gammopathy of undetermined significance (MGUS) and progress to an intermediate stage called smouldering multiple myeloma (SMM), characterised by several genetic alterations that represent the genomic backbone of the malignant clone. Immune checkpoint pathways play a central role in shaping an immunosuppressive BM niche, contributing to T-cell dysfunction, immune evasion, and therapeutic resistance. Key inhibitory receptors such as PD-1, CTLA-4, TIM-3, LAG-3, and CD47 are frequently dysregulated, promoting T-cell exhaustion, anergy, and senescence. Emerging evidence highlights extracellular vesicles (EVs) as critical mediators of intercellular communication in MM. MM-derived EVs carry bioactive cargo, including proteins and miRNAs, that reprogram immune and stromal cells, enhancing tumour progression and immune escape. Notably, EV-associated immune checkpoint molecules contribute to the establishment of a permissive microenvironment. This review provides an integrated overview of immune checkpoint dysregulation and EV-mediated immunomodulation in MM, emphasising their role in disease pathogenesis and progression. Furthermore, we discuss the therapeutic potential of targeting immune checkpoints and exploiting EVs as novel biomarkers and drug delivery systems, highlighting their promise for improving precision medicine approaches in MM.