Abstract: 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.


Keywords: multiple myeloma, denosumab, RANKL, bisphosphonates, skeletal-related events


INTRODUCTION

Multiple myeloma (MM) is a plasma cell neoplasm that accounts for 13% of all hematologic cancers. With an age-adjusted incidence of nearly 6 per 100,000 persons per year, MM is the second most common hematological malignancy.1 MM is characterized by malignant proliferation of monoclonal plasma cells in the bone marrow with resultant elevation in monoclonal paraprotein, hypercalcemia, renal dysfunction, anemia and osteolytic lesions.2,3 Diffuse osteopenia, pathologic fractures, focal lytic lesions and bony pain are common clinical manifestations in patients with MM. Using Positron Emission Tomography and Computed Tomography (PET-CT) and Magnetic Resonance Imaging (MRI), bone involvement can be found in 91 and 95% of MM patients respectively.4 These osteolytic bone lesions result in an increased risk of skeletal-related events (SRE). SRE are defined as pathological fractures, radiation or surgery to bone, spinal cord compression and hypercalcemia that often lead to diminished quality of life and increased morbidity and mortality.5,6 Approximately 60% of MM patients will develop a fracture during their disease course.7

Via interactions with the bone marrow microenvironment (BMME), malignant plasma cells (MPC) are able to orchestrate the production of osteoclast-activating factors and osteoblast-inhibitory factors which leads to asynchronous bone turnover, net bone loss and osteolytic lesions.8 MPC and stromal cells secrete factors such as RANKL, macrophage inflammatory protein 1 alpha (MIP-1α), interleukin 3 (IL-3), and interleukin 6 (IL-6), which increase osteoclast activity and additional factors such as dickkopf-1 (Dkk-1) and secreted frizzled-related protein 2 (sFRP-2) which inhibit osteoblast function.9–12 Signaling between MPC and osteocytes induce osteocyte apoptosis which leads to increased RANKL and sclerosin secretion. The former recruits and activates osteocytes while the later inhibits osteoblast function.13 RANKL in particular is a key mediator of osteoclast formation, activation and survival. In MM, production of RANKL is significantly increased by osteocytes, bone marrow stromal cells and MPC resulting in increased osteoclast activity and increased bone resorption.13–15 MPC ability to upregulate RANKL secretion in the BMME results in a vicious cycle of osteoclast activation, increased bone resorption and MPC proliferation and survival.14,16–18

Bisphosphonates (BPs) were the first class of drugs approved for treating MM bone disease. By causing osteoclast apoptosis, BPs such as zoledronic acid (ZA) and pamidronate led to a decrease and a delay in the development of SRE in MM.19–22 Furthermore, BPs have been found to reduce mortality and improve overall survival in MM which suggests that BPs have an anti-MM effect due to their disruption of the feedback loop between MPC and osteoclasts.23 Denosumab, a fully human monoclonal antibody that binds RANKL and inhibits the RANK pathway has proven to be non-inferior to ZA in delaying SRE in a phase III trial and resulted in superior progression free survival.24,25 This review focuses on the role of the RANKL pathway in the prevention of SRE and in the treatment of MM.

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