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The FDA has approved the supplemental Biologics License Application for denosumab to expand the currently approved indication for the prevention of skeletal-related events in patients with bone metastases from solid tumors to include patients with multiple myeloma. The approval is based on data from the pivotal, phase III '482 study, which enrolled 1,718 patients.

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"Up to 40 percent of patients remain untreated for the prevention of bone complications, and the percentage is highest among patients with renal impairment at the time of diagnosis," said Noopur Raje, MD, Director, Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, Boston. "Denosumab, which is not cleared through the kidneys, offers multiple myeloma patients bone protection with a convenient subcutaneous administration, providing patients with a novel treatment option."


The '482 study was an international, randomized, double-blind, multicenter trial of denosumab compared with zoledronic acid for the prevention of skeletal-related events in adult patients with newly diagnosed multiple myeloma and bone disease. In the study, a total of 1,718 patients (859 on each arm) were randomized to receive either subcutaneous denosumab 120 mg and IV placebo every 4 weeks, or IV zoledronic acid 4 mg (adjusted for renal function) and subcutaneous placebo every 4 weeks.


The primary endpoint of the study was non-inferiority of denosumab versus zoledronic acid with respect to time to first on-study skeletal-related event (pathologic fracture, radiation to bone, surgery to bone, or spinal cord compression). Secondary endpoints included superiority of denosumab versus zoledronic acid with respect to time to first on-study skeletal-related event and first-and-subsequent on-study skeletal-related event and evaluation of overall survival. Progression-free survival was an exploratory endpoint. The safety and tolerability of denosumab were also compared with zoledronic acid.


The study met the primary endpoint, demonstrating non-inferiority of denosumab to zoledronic acid in delaying the time to first on-study skeletal-related event in patients with multiple myeloma (HR=0.98, 95% CI: 0.85, 1.14; p=0.01). The secondary endpoints, delaying time to first skeletal-related event and delaying time to first-and-subsequent skeletal-related events, did not demonstrate superiority. Overall survival was comparable between denosumab and zoledronic acid, with a hazard ratio of 0.90 (95% CI: 0.70, 1.16; p=0.41). The median difference in progression-free survival favored denosumab by 10.7 months (HR=0.82, 95% CI: 0.68-0.99; descriptive p=0.036). Median progression-free survival was 46.1 months (95% CI: 34.3 months, not estimable [NE], n=219) for denosumab and 35.4 months (95% CI: 30.2 months, NE, n=260) for zoledronic acid.