The U.S. Food and Drug Administration announced earlier today that denosumab, which will be marketed by Amgen under the brand name Xgeva, has been approved to help prevent fractures and to slow bone disease in patients with solid tumors. It was not approved at this time for use in patients with multiple myeloma.

“It wasn’t approved [for myeloma] because the Xgeva-treated subset of multiple myeloma patients had more deaths than the control arm,” said Erica Jefferson, a spokesperson for the Food and Drug Administration (FDA).

Xgeva is an antibody that prevents bone removal and degradation. It is currently marketed at lower doses under the brand name Prolia for the treatment of postmenopausal women with osteoporosis and a high risk of bone fractures.

Two Phase 3 trials showed that Xgeva was superior to Zometa ^[1] (zoledronic acid) at delaying skeletal complications in breast cancer and prostate cancer patients. A third trial that included patients with different solid tumors and multiple myeloma demonstrated that Xgeva achieved similar results in the study participants as Zometa (see related Beacon ^[2] news). In all three trials, the median time until a patient’s first skeletal complication was at least 20 months for patients treated with Xgeva. These trials were the basis of Xgeva’s approval for use in solid tumors.

However, an analysis of the multiple myeloma patients in the third trial showed that there was a two-fold higher risk of death in patients receiving Xgeva than those receiving Zometa.

“Myeloma was only about 10 percent of the treatment population in that study,” said Lisa Rooney, a spokesperson for Amgen. “Mortality was higher in the Xgeva subgroup analysis of patients with multiple myeloma in that trial, but it was a very limited number of patients in that subgroup. So it precludes a definitive conclusion.” The trial included a total of 1,776 patients.

“I fully agree with the FDA decision,” said Dr. S. Vincent Rajkumar of the Mayo Clinic. “The statistically significant, greater than two-fold inferior overall survival with denosumab [Xgeva] compared with zoledronic acid [Zometa] is disconcerting, despite being a subgroup analysis. I would not recommend the use of denosumab in myeloma patients, outside of clinical trials.”

Ms. Rooney stated that Amgen will continue to pursue approval of Xgeva for multiple myeloma and will be conducting a separate study to look specifically at the safety and efficacy of Xgeva in myeloma patients. That clinical trial is not yet recruiting patients.

The most common side effects seen in the Xgeva trials included fatigue, weakness, low phosphate levels, and nausea. The most common severe side effect was shortness of breath.

Osteonecrosis of the jaw, a severe complication associated with bone disease treatments, occurred in 1.8 percent of patients treated with Xgeva and 1.3 percent of patients treated with Zometa.

“Zoledronic acid [Zometa] has recently shown an overall survival benefit in myeloma,” said Dr. Rajkumar. “Therefore, bisphosphonates, especially pamidronate [Aredia] and zoledronic acid, remain the standard of care to prevent skeletal-related events in patients with myeloma who have evidence of bone disease.”

For more information, see the FDA ^[3] and Amgen ^[4] press releases.