Prevention of skeletal related events in multiple myeloma: Focus on the RANK-l pathway in the treatment of multiple myeloma

More than 90% of patients with multiple myeloma (MM) have osteolytic bone lesions which increase the risk of skeletal-related events (SRE). The cytokine milieu in the bone marrow microenvironment (BMME) of MM plays a key role in myeloma bone disease by impairing the balance between osteoclastogenesis and osteoblastogenesis. This is orchestrated by the malignant plasma cell (MPC) with the ultimate outcome of MPC proliferation and survival at the expense of excess osteoclast activation resulting in osteolytic bone lesions. Prevention of SRE is currently accomplished by the inhibition of osteoclasts. Bisphosphonates (BPs) are pyrophosphate analogues that cause apoptosis of osteoclasts and have been proven to prevent and delay SRE. Denosumab, a fully humanized monoclonal antibody that binds and inhibits receptor activator of nuclear factor-ĸB ligand (RANKL), a key molecule in the BMME crucial for osteoclastogenesis, is also approved for the prevention of SRE in MM. The addition of BPs and denosumab to standard MM treatment affords a survival benefit for patients with MM. Specifically, the addition of denosumab to standard MM treatments results in superior PFS compared to BPs, highlighting the key role of the RANKL pathway in MM. This review focuses on the pathophysiology of myeloma bone disease as well as on the importance of targeting the RANK-L pathway for the treatment of MM and prevention of SRE.