Abstract
Simple SummaryLike in solid cancers, the process of dissemination is a critical feature of disease progression in the blood cancer multiple myeloma. At diagnosis, myeloma patients have cancer that has spread throughout the bone marrow, with patients with more disseminatory myeloma having worse outcomes for their disease. In this review, we discuss the current understanding of the mechanisms that underpin the dissemination process in multiple myeloma. Furthermore, we discuss the potential for the use of therapies that target the dissemination process as a novel means of improving outcomes for multiple myeloma patients.Multiple myeloma (MM) is a plasma cell (PC) malignancy characterised by the presence of MM PCs at multiple sites throughout the bone marrow. Increased numbers of peripheral blood MM PCs are associated with rapid disease progression, shorter time to relapse and are a feature of advanced disease. In this review, the current understanding of the process of MM PC dissemination and the extrinsic and intrinsic factors potentially driving it are addressed through analysis of patient-derived MM PCs and MM cell lines as well as mouse models of homing and dissemination. In addition, we discuss how patient cytogenetic subgroups that present with highly disseminated disease, such as t(4;14), t(14;16) and t(14;20), suggest that intrinsic properties of MM PC influence their ability to disseminate. Finally, we discuss the possibility of using therapeutic targeting of tumour dissemination to slow disease progression and prevent overt relapse.
Highlights
Myeloma Research Laboratory, Faculty of Health and Medical Sciences, Adelaide Medical School, Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide 5000, Australia
Studies analysing the expression of cell surface adhesion factors in peripheral blood (PB) plasma cell (PC) compared with bone marrow (BM) PCs from MM patients have shown that circulating MM PCs express lower levels of integrin α4β1 compared with BM-resident
MM cell lines in hypoxic conditions significantly reduced their adherence to BM mesenchymal stromal cells (BMSCs) or to collagen in vitro [48,52], suggesting a mechanism whereby hypoxia may induce the release of MM PCs from the BM niche
Summary
Multiple myeloma (MM) is an incurable haematological malignancy characterised by the uncontrolled proliferation of clonal malignant plasma cells (PCs) in the bone marrow (BM) [1]. Studies using generation sequencing examining clonal evolution during disease progression from MGUS or smouldering MM to MM suggest that the genetic abnormalities leading to MM are already present at the pre-malignant stages in the majority of patients [17,18,19] These studies suggest that the outgrowth of dominant PC clones, and their subsequent population of sites throughout the BM, is a key feature of progression to MM. In support of this, increased incidence of circulating PCs in MGUS and smouldering MM patients is associated with progression [20,21] Taken together, these studies suggest that dissemination of clonal PCs is a key step for the progression to symptomatic disease. We will discuss how this knowledge could be used to develop novel therapeutic strategies to delay disease progression and treat high-risk MM patients
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