FDA Approves Denosumab for the Prevention of Skeletal-Related Events in Patients With Multiple Myeloma

Today, the U.S. Food and Drug Administration (FDA) approved the supplemental Biologics License Application (sBLA) for denosumab (Xgeva) 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 phase III ‘482 study, the largest international multiple myeloma clinical trial ever conducted, which enrolled 1,718 patients.

“Up to 40% 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. “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.”

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

About the ‘482 Study

The ‘482 study was an international, phase III, 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 at 120 mg and intravenous placebo every 4 weeks, or intravenous zoledronic acid at 4 mg (adjusted for renal function) and subcutaneous placebo every 4 weeks.

The primary endpoint of the study was noninferiority of denosumab vs 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 vs 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 densoumab were also compared with zoledronic acid.

Trial Findings

The study met the primary endpoint, demonstrating noninferiority of denosumab to zoledronic acid in delaying the time to first on-study skeletal-related event in patients with multiple myeloma (hazard ratio [HR] = 0.98, 95% confidence interval [CI] = 0.85–1.14; P = .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 = .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 = .036). Median progression-free survival was 46.1 months (95% CI = 34.3 months to not estimable, n = 219) for denosumab and 35.4 months (95% CI = 30.2 months to not estimable, n = 260) for zoledronic acid.

Adverse events observed in patients treated with denosumab were generally consistent with its known safety profile. The most common adverse reactions (≥ 10%) were diarrhea (34%), nausea (32%), anemia (22%), back pain (21%), thrombocytopenia (19%), peripheral edema (17%), hypocalcemia (16%), upper respiratory tract infection (15%), rash (14%), and headache (11%).  

The most common adverse reaction resulting in discontinuation of denosumab (≥ 1%) was osteonecrosis of the jaw. In the primary treatment phase of the ‘482 study, osteonecrosis of the jaw was confirmed in 4.1% of patients in the denosumab group (median exposure of 16 months; range = 1–50 months) and 2.8% of patients in the zoledronic acid group (median = 15 months, range = 1–45 months).

More About Denosumab

Denosumab 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, and for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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