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The FDA has accepted the denosumab supplemental Biologics License Application (sBLA) that seeks to expand the currently approved indication for the prevention of fractures and other skeletal-related events in patients with bone metastases from solid tumors to include patients with multiple myeloma.

FDA; multiple myelom... - Click to enlarge in new windowFDA; multiple myeloma. FDA; multiple myeloma

Denosumab is the first fully human monoclonal antibody that binds to and neutralizes RANK ligand (RANKL)-a protein essential for the formation, function, and survival of osteoclasts, thereby inhibiting osteoclast-mediated bone destruction. Denosumab is not cleared by the kidneys. It is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. It is also indicated for the treatment of adults and skeletally-mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity. In the U.S., it is also indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.


The sBLA is based on the efficacy and safety data from the pivotal phase III '482 study (NCT01345019), the largest international multiple myeloma trial ever conducted, which successfully demonstrated that denosumab is non-inferior to zoledronic acid in delaying the time to first on-study skeletal-related event in patients with multiple myeloma. The secondary endpoints of superiority in delaying time to first on-study skeletal-related event and delaying time to first-and-subsequent skeletal-related event were not met in this study. Progression-free survival (PFS) was an exploratory endpoint.


The hazard ratio of denosumab versus zoledronic acid for PFS was 0.82 (95% CI: 0.68, 0.99; descriptive p=0.036) and the median difference in PFS between arms was 10.7 months in favor of denosumab. The safety and tolerability of denosumab were also compared with zoledronic acid in the study. The most common adverse events (greater than or equal to 25%) in both arms were diarrhea and nausea.


More than 90 percent of patients develop osteolytic lesions during the course of the disease. Current treatment options for bone complications are limited to bisphosphonates, including zoledronic acid; these are cleared by the kidneys and are associated with renal toxicity, which is a common complication among multiple myeloma patients. The majority (approximately six out of 10) of all multiple myeloma patients have or will develop renal impairment over the course of the disease. Preventing bone complications is a critical aspect of caring for patients with multiple myeloma because these events can cause significant morbidity.