Extracellular vesicles in multiple myeloma-bone marrow niche crosstalk: from cellular dialogue to clinical perspectives

Multiple myeloma (MM) is a haematological neoplasia defined by the clonal expansion of malignant plasma cells within the intricate and dynamic ecosystem of the bone marrow (BM). Although genetic aberrations intrinsic to tumour cells play a critical role in MM initiation, the advancement and aggressiveness of the disease are heavily influenced by ongoing signalling exchanges and persistent interactions with the surrounding microenvironment. Extracellular vesicles (EVs) are increasingly recognized as essential messengers in this reciprocal communication, acting as membrane-encapsulated vehicles able to transfer biologically active molecules. Through both local and distant signaling, EVs coordinate complex molecular pathways that modify recipient cell behaviour and maintain a supportive microenvironment conducive to MM progression. The present review offers a critical and up-to-date synthesis of current knowledge on EVs derived from both tumour cells and non-malignant populations within the BM milieu, including stromal, immune, and endothelial cells, and their role in shaping the pathophysiology of MM. Specifically, we examined how EV-mediated communication contributes to enhanced tumor proliferation, immune surveillance escape and the onset of resistance to therapeutic agents. We further explore the translational relevance of EVs, with a focus on their emerging potential as non-invasive biomarkers for disease monitoring and as novel agents or delivery systems in therapeutic interventions. Further mechanistic researches, as well as the optimization of reliable isolation methodologies, in parallel with rigorous and well-designed clinical investigations, will be essential to enable the effective translation of EV-based approaches into clinical practice and to support the development of more effective and targeted treatment strategies in MM patients.