RANK Ligand Is a Therapeutic Target in Multiple Myeloma

Osteolytic bone disease is a frequent and severe complication of multiple myeloma (MM). MM cells interact with stromal cells in the bone marrow niche to create an environment that is favorable for tumor growth, in particular by inducing differentiation and activity of bone-resorbing osteoclasts, while concomitantly inhibiting differentiation and activity of bone-depositing osteoblasts. This results in a net loss of bone and subsequent skeletal morbidity including fracture, bone pain, and hypercalcemia. RANK ligand (RANKL), a member of the tumor necrosis factor (TNF) cytokine family, is required for differentiation, activation, and survival of osteoclasts and thus plays a critical role in cancer-induced bone disease. Under normal circumstances, RANKL activity is attenuated by its endogenous inhibitor, osteoprotegerin (OPG), a soluble TNF receptor family protein that prevents RANKL from binding to its receptor RANK, expressed on osteoclasts. However, in MM, both RANKL and OPG are dysregulated, resulting in excess RANKL available to stimulate osteoclastic bone resorption. An increased RANKL/OPG ratio is associated not only with the extent of bone disease in patients with MM but also with the prognosis for overall survival. In preclinical models of MM, pharmacologic inhibition of RANKL has been demonstrated to ablate osteoclasts and thus prevent MM-associated bone disease. In addition, RANKL inhibition led to decreased tumor burden in these models, demonstrating the dependence of MM on osteoclast activity. Clinical studies currently underway are evaluating the potential of denosumab, a fully human monoclonal antibody targeting RANKL, to prevent or treat cancer-induced bone disease in MM and other cancer types.