Xgeva Receives FDA Approval for Prevention of Skeletal Events in Multiple Myeloma

The FDA has extended the approved indications for denosumab (Xgeva, Amgen) to include the prevention of skeletal-related events in patients with bone metastases with multiple myeloma. The medication was at that point approved to prevent skeletal events in patients with bone metastases from solid tumors.

The approval depends on information from the pivotal phase 3 ‘482 examinations, the largest international multiple myeloma clinical trial ever conducted, which enrolled 1,718 patients.

Noopur Raje, MD, director of the Center for Multiple Myeloma at the Massachusetts General Hospital Cancer Center in Boston said, “Up to 40% of patients stay untreated for the prevention of bone complications, and the percentage is highest among patients with renal impairment at the time of diagnosis”.

“Denosumab, which isn’t cleared through the kidneys, offers multiple myeloma patients bone protection with a convenient subcutaneous administration, giving patients a novel treatment option.”

Previously, treatment options for the prevention of bone complications were limited to bisphosphonates, which are cleared by the kidneys.

Denosumab is a totally human monoclonal antibody that binds to and neutralizes RANK ligand (RANKL). RANKL is a protein essential for the formation, function, and survival of osteoclasts, which break down bone in this manner inhibiting osteoclast-mediated bone destruction.

Denosumab is the number one prescribed bone-targeting agent in the U.S. in patients with bone metastases from solid tumors for the prevention of skeletal-related events. The ‘482 examination was an international, phase 3, randomized, double-blind, multicenter trial of denosumab compared and zoledronic acid for the prevention of skeletal-related events in adult patients with newly diagnosed multiple myeloma and bone disease.

In the examination, a total of 1,718 patients (859 on each arm) were randomized to get either subcutaneous denosumab 120 mg and intravenous placebo at regular intervals, or intravenous zoledronic corrosive 4 mg (adjusted for renal function) and subcutaneous placebo at regular intervals.

The primary endpoint has noninferiority of denosumab versus zoledronic acid as for time to first on-study about the skeletal-related event (pathological fracture, radiation to bone, surgery to bone, or spinal cord compression).

Secondary endpoints have superiority of denosumab versus zoledronic acid as for time to first on-study about the 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 Progression and tolerability of denosumab were also compared and zoledronic acid. The examination met the primary endpoint, showing noninferiority of denosumab to zoledronic acid as for time to first on-study about the skeletal-related event with multiple myeloma (hazard ratio [HR], 0.98; 95% confidence interval [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 show superiority. Overall survival was comparable with a HR of 0.90 (95% CI, 0.70– 1.16; P = 0.41) between denosumab and zoledronic acid.

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.

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