Amgen has announced new data from the Xgeva (denosumab) phase 3 '482 study, the largest international multiple myeloma trial ever conducted. The study met its primary endpoint, demonstrating Xgeva is non-inferior to zoledronic acid in delaying the time to first on-study skeletal-related event in patients with multiple myeloma (HR=0.98, 95 percent CI: 0.85, 1.14; p=0.01). The analysis demonstrated that patients on Xgeva had a significantly lower rate of renal adverse events compared to zoledronic acid (10.0 percent versus 17.1 percent, p<0.001). These results will be presented during an oral session at the 53rd Annual Meeting of the American Society of Clinical Oncology (ASCO). The analysis was also selected for the Best of ASCO educational program, which is designed to increase access to practice-changing advances in cancer treatment.

The results presented has showed that in patients with renal insufficiency, defined as having a creatinine clearance (CrCl) of less than or equal to 60 mL/min, the rate of renal adverse events was double in the zoledronic acid arm compared to the Xgeva arm (26.4 percent versus 12.9 percent, respectively). The zoledronic acid label does not recommend treatment in patients with a CrCl of less than 30 mL/min; therefore, patients with severe renal impairment were excluded from this study.1 Median cumulative exposure to Xgeva was 15.75 months compared to 14.78 months for zoledronic acid.

"Bone complications in multiple myeloma patients, including fractures, can have a devastating impact on patients. Current treatment options for these complications are limited to bisphosphonates, including zoledronic acid, which are cleared by the kidneys and can be associated with increased renal toxicity," said Noopur Raje, M.D., director, Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, Boston. "Renal impairment is a common complication in multiple myeloma patients. Denosumab, which is not cleared by the kidneys, may offer a novel, safe and effective option for multiple myeloma patients."

Xgeva is currently indicated for the prevention of fractures and other skeletal-related events in patients with bone metastases from solid tumors and is the number one prescribed agent for this indication in the United States (U.S.). Xgeva is currently not indicated for the prevention of skeletal-related events in patients with multiple myeloma. On April 4, 2017, Amgen announced the submission of a supplemental Biologics License Application to the U.S. Food and Drug Administration and an application for a variation to the marketing authorization to the European Medicines Agency for Xgeva. The submissions to regulatory authorities seek to expand the currently approved Xgeva indication to include patients with multiple myeloma.

"Preventing fractures and other bone complications and preserving renal function are two of the most important aspects to consider when caring for patients with multiple myeloma," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "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, underscoring the need for alternative treatment options. We look forward to making Xgeva, a novel treatment option, available to multiple myeloma patients."

Data from the '482 study were previously presented at the 16th International Myeloma Workshop (IMW), including additional endpoints. These results demonstrated that the hazard ratio of overall survival, a secondary endpoint of the study, was 0.90 for Xgeva as compared to zoledronic acid (95 percent CI: 0.70, 1.16). The hazard ratio of Xgeva versus zoledronic acid for progression-free survival, an exploratory endpoint, was 0.82 (95 percent CI: 0.68, 0.99; descriptive p=0.036). The median difference in progression-free survival between arms was 10.7 months in favor of Xgeva.

The '482 study was an international, phase 3, randomized, double-blind, multicenter trial of Xgeva compared with zoledronic acid in the prevention of fractures and other 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 Xgeva 120 mg and intravenous placebo every four weeks, or intravenous zoledronic acid 4 mg (adjusted for renal function) and subcutaneous placebo every four weeks.

The primary endpoint of the study was non-inferiority of Xgeva 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 Xgeva 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 Xgeva were also compared with zoledronic acid. An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction.