Molecular Impact of the Tumor Microenvironment on Multiple Myeloma Dissemination and Extramedullary Disease

Abstract

Multiple myeloma (MM) is the most common malignant monoclonal disease of plasma cells. Aside from classical chemotherapy and glucocorticoids, proteasome inhibitors, immunomodulatory agents and monoclonal antibodies are used in the current treatment scheme of MM. The tumor microenvironment (TME) plays a fundamental role in the development and progression of numerous solid and non-solid cancer entities. In MM, the survival and expansion of malignant plasma cell clones heavily depends on various direct and indirect signaling pathways provided by the surrounding bone marrow (BM) niche. In a number of MM patients, single plasma cell clones lose their BM dependency and are capable to engraft at distant body sites or organs. The resulting condition is defined as an extramedullary myeloma (EMM). EMMs are highly aggressive disease stages linked to a dismal prognosis. Emerging literature demonstrates that the dynamic interactions between the TME and malignant plasma cells affect myeloma dissemination. In this review, we aim to summarize how the cellular and non-cellular BM compartments can promote plasma cells to exit their BM niche and metastasize to distant intra-or extramedullary locations. In addition, we list selected therapy concepts that directly target the TME with the potential to prevent myeloma spread.

Keywords: TME; malignant plasma cells; multiple myeloma; targeted therapy; tumor microenvironment.

Figure 1

The complex organization of cancer initiation, progress, and distant metastasis of MM. MM is defined by the clonal expansion of a malignant plasma cell population upon genetic/epigenetic aberrations within the bone marrow (BM). The acquisition of secondary mutations in MM leads to further generation of sub-clones with a more aggressive phenotype. The dynamic influence of the TME and treatment-related mechanisms drive the progression of MM into even more aggressive disease stages. The malignant plasma cell clones can disseminate into the blood or to distant body sites or organs including soft tissue, liver, kidney and CNS. APRIL, a proliferation-inducing ligand; CNS, central nervous system; ECM, extracellular matrix; EGF, epidermal growth factor; EV, extracellular vesicle; IL, Interleukin; MIP-1, macrophage inflammatory protein 1; MM, multiple myeloma; NK, natural killer; TGF-b, transforming growth factor beta; TME, tumor microenvironment; TNF-α, Tumor necrosis factor alpha.