State-of-the-Art Management of Complications of Myeloma and Its Treatment

Figure 1

Pathophysiology of myeloma bone disease. Black arrows indicate increased production or activation, and red arrows indicate decreased production or inhibition. Normal bone metabolism involves the constant rebuilding of bone by osteoblasts and resorption of bone by osteoclasts, intricately balanced through appropriate cytokine signaling (usually associated with an increased OPG to RANKL ratio). The presence of myeloma cells in the bone marrow milieu results in upregulation of osteoclastic activity compared with osteoblastic bone formation resulting in lytic lesions. The malignant plasma cells interact with stromal cells, causing increased cytokine signaling through IL-6 and TNF-𝛽. This results in increased RANKL expression by bone marrow stromal cells, stimulation of plasma cell growth, and drug resistance. In addition, malignant plasma cells produce inhibitors of Wnt signaling (DKK1 and sFRPs). Wnt inhibition results in downregulation of OPG production and upregulation of RANKL. The interaction of RANK with its ligand (RANKL) leads to osteoclast activation via signaling by NF-κB. In addition, malignant plasma cells produce MIP-1𝛼, which directly stimulates osteoclasts. Therapy with bisphosphonates results in osteoclast inhibition and osteoblast activation. The novel monoclonal antibody, denosumab, which neutralizes RANKL, is currently the subject of clinical investigations for bone disease therapy in patients with multiple myeloma. MM: multiple myeloma, IL-6: interleukin 6, VEGF: vascular endothelial growth factor, TNF-𝛼: tumor necrosis factor-𝛼, BMSC: bone marrow stromal cell, MIP-1𝛼: macrophage inhibitory protein-1𝛼, OB: osteoblast, OC: osteoclasts, OPG: osteoprotegerin, DKK1: dickkopf, sFRPs: serum frizzle related proteins, VCAM-1: vascular cell adhesion molecule-1, RANK: receptor activator for nuclear factor κB, JunN: c-Jun N-terminal protein kinase, Wnt, Wnt glycoproteins (bind to sFRPs).