Circulating small extracellular vesicles (sEV) represent promising non-invasive biomarkers that may aid in the diagnosis and risk-stratification of multiple myeloma (MM), an incurable blood cancer. Here, we comprehensively isolated and characterized sEV from human MM cell lines (HMCL) and patient-derived plasma (psEV) by specific EV-marker enrichment and morphology. Importantly, we demonstrate that HMCL-sEV are readily internalised by stromal cells to functionally modulate proliferation. psEV were isolated using various commercial approaches and pre-analytical conditions (collection tube types, storage conditions) assessed for sEV yield and marker enrichment. Functionally, MM-psEV was shown to regulate stromal cell proliferation and migration. In turn, pre-educated stromal cells favour HMCL adhesion. psEV isolated from patients with both pre-malignant plasma cell disorders (monoclonal gammopathy of undetermined significance [MGUS]; smouldering MM [SMM]) and MM have a similar ability to promote cell migration and adhesion, suggesting a role for both malignant and pre-malignant sEV in disease progression. Proteomic profiling of MM-psEV (305 proteins) revealed enrichment of oncogenic factors implicated in cell migration and adhesion, in comparison to non-disease psEV. This study describes a protocol to generate

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Multiple myeloma is an incurable clonal plasma cell malignancy characterised by osteolytic bone lesions and the presence of a monoclonal immunoglobulin. The bone disease caused by myeloma is a major cause of morbidity with the related complications of pathological fractures, hypercalcaemia and bone pain affecting both quality of life and patient survival. The osteolytic lesions arise due to an imbalance of osteoclast and osteoblast function, arising from complex interactions between myeloma cells, bone marrow stromal cells and the bone marrow microenvironment. These advances in understanding of the pathophysiology have directly led to improvements in patient management and outcomes. Recent advances in myeloma bone disease are reviewed, including the role of novel and emerging therapies, and evidence-based management strategies for myeloma bone disease are discussed.