Understanding the role of extracellular vesicles in multiple myeloma

Multiple myeloma (MM), a clonal plasma cell malignancy, remains incurable despite promising treatment advances due to high rates of relapse and drug resistance. Current recommendations for therapy are observation for asymptomatic MM with the initiation of therapy only at the time of the emergence of symptomatic disease. In this context, a better understanding of the molecular characteristics that define a higher risk of progression to symptomatic MM would provide the framework for early initiation of systemic treatment. Despite well-established diagnostic and monitoring modalities applicable, there remains a critical need to address specific subsets of MM patients where conventional approaches remain inadequate. A potential approach is the use of liquid biopsy that is able to capture the typical spatial and temporal genomic heterogeneity that occurs in MM more accurately than conventional testing. These biopsies are minimally-invasive and therefore amenable to repeat investigation. Recent published data have demonstrated the potential of both cell free-DNA/RNA and extracellular vesicle (EV) analyses to specifically and accurately identify and monitor tumour burden and disease evolution, and to identify mechanisms of drug resistance in MM patients. EVs are cell-derived membranous vesicles that mediate cell-tocell communication by transferring proteins, lipids and nucleic acids locally and through systemic circulation. Due to their select cell-derived packaged cargo, a key role for EVs in tumour progression and drug resistance has been proposed for both solid tumours and haematological malignancies, including MM. EVs are active regulators in the cross-talk between MM tumour cells and local microenvironment, with the capacity to alter angiogenesis, osteoclast differentiation and immunosuppression. Emerging evidence suggests prognostic and predictive roles for circulating EVs in MM. More recently, several studies have established a link between EVs and autophagy, an important mechanism for the maintenance of cellular homeostasis. Dysregulation of this highly conserved mechanism is linked to cancer progression including MM, where the existence of an interplay between EVs and autophagy is yet to be determined. This review provides an overview of the roles of EVs in MM, their capacity as emerging biomarkers in MM and implications for liquid biopsy for the detection and monitoring of MM. Preliminary original data are also included in this chapter.