Multiple myeloma (MM) is a plasma cell malignancy with approximately 150,000 new cases each year worldwide . In 2018, approximately 56,676 new MM cases were reported in Asia, including 6313 in Japan, 1905 in Korea, 168 in Singapore, and 227 in Malaysia [2,3,4,5,6]. In 2016, approximately 270 new cases of MM were reported in Hong Kong . From 2011 to 2012, 1023 new cases of MM were reported in Taiwan .
MM is characterized by osteolytic lesions, renal dysfunction, hypercalcemia, anemia, reduced levels of normal immunoglobulins, and increased infection risk . Bone destruction is one of the devastating consequences of MM [10, 11]; the severity of bone destruction correlates with tumor burden and prognosis . The interaction of MM cells with the bone marrow microenvironment deregulates a number of signaling pathways, causing the increased release of factors that potentiate osteoclast formation and activation while inhibiting osteoblast differentiation, leading to greater bone resorption and the suppression of bone formation, respectively [10, 13]. Deregulation of the receptor activator of nuclear factor-kappa B (RANK)/RANK ligand (RANKL) signaling pathway has been primarily linked to the pathogenic increase in osteoclast activity observed in MM [10, 13]. Additional osteoclastogenic factors implicated are the macrophage inflammatory protein 1α (MIP-1α), interleukin-1 (IL-1), IL-3, and IL-6 [10, 13].
A study of patients with MM in China, Hong Kong, Japan, Korea, Singapore, Taiwan, and Thailand revealed that the median age at diagnosis was 62 years , which is lower than that reported for the USA (69 years) . Asian patients as a whole are more likely to have advanced disease due to the delay in diagnosis compared to Western countries, with rates of International Staging System (ISS) stages I, II, and III of 19.9%, 36.1%, and 44.0%, respectively. Overall, 60.2% of Asian patients had documented bone lesions, ranging from 28.5% of patients in Thailand to 80.0% of patients in Japan, consistent with rates reported in Western countries .
Intravenously administered (IV) bisphosphates, such as zoledronic acid, are considered the standard of care in the management of myeloma bone disease with demonstrated efficacy across tumor types [16,17,18]. However, despite the use of IV bisphosphonates, a substantial number of patients with MM develop skeletal complications . In addition, bisphosphonate use is discouraged in patients with renal dysfunction , particularly based on the evidence that approximately 60% of patients present with renal dysfunction during the course of the disease . Denosumab is a monoclonal antibody targeting RANKL that has been shown to reduce skeletal-related events (SREs) associated with bone lesions in patients with MM [21,22,23].
In patients with solid tumors that had metastasized to bone, denosumab 120 mg subcutaneously administered (SC) every 4 weeks (Q4W) was superior to zoledronic acid in delaying time to SREs [11, 22, 24,25,26,27]. Subsequently, SC denosumab 120 mg Q4W was found to be noninferior to IV zoledronic acid 4 mg Q4W for preventing SREs in a phase 3 study in patients with newly diagnosed MM . Overall survival was similar in both groups (median 49.5 months for denosumab vs not estimable for zoledronic acid; HR 0.90 [95% CI 0.70–1.16], P = 0.41). An exploratory endpoint of this study, progression-free survival (PFS), showed a numerical advantage for denosumab of 10.7 months, compared to zoledronic acid (median 46.1 vs 35.4 months; HR 0.82 [95% CI 0.68–0.99], descriptive P = 0.036) . For Asian patients with MM, there is no direct comparison between these two drugs in the literature. Herein, we assess the consistency of Asian patients receiving denosumab or zoledronic acid with the full study population.