The biology and clinical relevance of extracellular vesicles (EVs) to multiple myeloma (MM) were recently detailed in a review in Frontiers in Oncology written by Antonia Reale, MD, of Monash University in Melbourne, Australia, and colleagues.

“Increasing evidence suggests that the interrogation of EVs and EV-RNA may represent a reliable non-invasive and alternative strategy to aid in the diagnosis, prognosis and treatment of solid tumours, highlighted by the recent introduction of EV-based liquid biopsy into clinical practice guidelines for prostate cancer,” Dr Reale and colleagues wrote.

EVs, in general, provide a means of communication between cells and are known to transfer molecules between cells, with multiple possible functional consequences. By packaging molecules within a lipid bilayer, EVs can protect molecules, such as RNA, from breaking down in the extracellular space while transporting contents between cells. In cancer, EVs may support a tumor microenvironment that is conducive to tumor growth. EVs also display markers associated with their cells-of-origin, which make them a possible diagnostic and therapeutic target.

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According to Dr. Reale and colleagues, most research on EVs in MM currently centers on RNA-based applications. EVs vary in their RNA contents, which is based on the source material from which they are derived. In MM, EVs appear to be a component of cross-talk between plasma cells and the stroma, with RNA from EVs having potential impacts on MM complications and possible treatment failure. For example, some research has shown angiogenic properties associated with RNA derived from EVs related to MM. EVs in patients with MM have also been implicated in the development of resistance to proteasome inhibitor therapy.

While EV-based liquid biopsy has become established in prostate cancer clinical practice guidelines, Dr Reale and colleagues indicated that more advances in this technology are needed to expand this approach to other cancer types such as hematological malignancies. While EVs can be isolated from multiple biofluid sources, currently it is not clear whether to use serum or plasma as a source for analysis in MM. Specific protocols ranging from sample handling to RNA sequence interpretation also are often not reported in studies of EVs, with optimal approaches not established for some methods.

For development of therapeutic targets for MM based on EVs, Dr Reale and colleagues indicated that additional data from patient cohorts may help to answer questions regarding the biology of EV development, EV heterogeneity, and EV targeting, release, and physiological effects. The researchers also noted that some surface-related features of EVs may make them amenable to drug delivery, and they may also serve as a conduit for therapies based on gene editing or RNA-based engineering.

“One could envisage that combinatorial liquid biopsy strategies incorporating EVs, cell-free nucleic acids and proteomics/metabolomics may represent a readily accessible and realistic opportunity for improving our understanding and management of the incurable blood cancer MM,” Dr Reale and colleagues concluded in their review.


Reale A, Khong T, Mithraprabhu S, Spencer A. Translational potential of RNA derived from extracellular vesicles in multiple myeloma. Front Oncol. 2021;11:718502. doi:10.3389/fonc.2021.718502