Multiple myeloma in the marrow: pathogenesis and treatments

Abstract

Multiple myeloma (MM) is a B cell malignancy resulting in osteolytic lesions and fractures. In the disease state, bone healing is limited owing to increased osteoclastic and decreased osteoblastic activity, as well as an MM-induced forward-feedback cycle where bone-embedded growth factors further enhance tumor progression as bone is resorbed. Recent work on somatic mutation in MM tumors has provided insight into cytogenetic changes associated with this disease; the initiating driver mutations causing MM are diverse because of the complexity and multitude of mutations inherent in MM tumor cells. This manuscript provides an overview of MM pathogenesis by summarizing cytogenic changes related to oncogenes and tumor suppressors associated with MM, reviewing risk factors, and describing the disease progression from monoclonal gammopathy of undetermined significance to overt MM. It also highlights the importance of the bone marrow microenvironment (BMM) in the establishment and progression of MM, as well as associated MM-induced bone disease, and the relationship of the bone marrow to current and future therapeutics. This review highlights why understanding the basic biology of the healthy and diseased BMM is crucial in the quest for better treatments and work toward a cure for genetically diverse diseases such as MM.

Keywords: Fairfield, H., C. Falank, L. Avery & M. R. Reagan. 2016. Multiple myeloma in the marrow: pathogenesis and treatments. In “MARROW,” ed. by M. Zaidi. Ann. N.Y. Acad. Sci. 1364: 32-51.; bone marrow; bone marrow niche; multiple myeloma; treatments.

FIGURE 1

The bone marrow microenvironment: osteoclastic and vascular niches. Schematic of the bone marrow microenvironment and its role in multiple myeloma. Pathogenesis and progression of MM is carried out via pathological bone resorption, resulting in the formation of lytic bone lesions and the degradation of bone density. Additionally, cells within the BMM may contribute to MM cell migration, adhesion, quiescence and tumor formation, which triggers the release of soluble growth factors, collectively promoting invasion of the microvasculature by the MM tumor.