Bone Disease in Multiple Myeloma: Biologic and Clinical Implications

Abstract

Multiple Myeloma (MM) is a hematologic malignancy characterized by the proliferation of monoclonal plasma cells localized within the bone marrow. Bone disease with associated osteolytic lesions is a hallmark of MM and develops in the majority of MM patients. Approximately half of patients with bone disease will experience skeletal-related events (SREs), such as spinal cord compression and pathologic fractures, which increase the risk of mortality by 20-40%. At the cellular level, bone disease results from a tumor-cell-driven imbalance between osteoclast bone resorption and osteoblast bone formation, thereby creating a favorable cellular environment for bone resorption. The use of osteoclast inhibitory therapies with bisphosphonates, such as zoledronic acid and the RANKL inhibitor denosumab, have been shown to delay and lower the risk of SREs, as well as the need for surgery or radiation therapy to treat severe bone complications. This review outlines our current understanding of the molecular underpinnings of bone disease, available therapeutic options, and highlights recent advances in the management of MM-related bone disease.

Keywords: bisphosphonates: zoledronic acid; bone metastasis; denosumab; multiple myeloma.

Figure 1

An overview of the interplay between multiple myeloma (MM) cells, osteoclasts, and osteoblasts in multiple myeloma, which favors bone resorption. MM cells induce IL−6 and DKK1 cytokine upregulation in osteoblasts, which, in effect, upregulates the osteoclast-activating protein, RANKL, while downregulating the anti-resorptive protein, osteoprotegerin (OPG). OPG binds and inhibits RANKL, while MM cells also agonize IL−3 and sclerostin productions. Denosumab directly inhibits RANKL while bisphosphonates (BPs) (i.e., clodronate, pamidronate, and zoledronic acid) inhibit osteoclasts and osteoclast precursors to prevent osteoclast-induced bone resorption. Created with BioRender.com (accessed on 7 May 2022).