Xgeva Approved to Prevent Skeletal-Related Events in Patients With Myeloma

Xgeva (denosumab) was granted approval by the Food and Drug Administration (FDA) to prevent skeletal-related events (SREs) in patients with multiple myeloma, according to Amgen, the developer of the drug.

The approval is based on data from the phase 3 482 study, which were presented at the 16th International Myeloma Workshop in New Delhi. In the trial, Xgeva demonstrated noninferiority to Zometa (zoledronic acid) at delaying the time to the first SRE in patients with multiple myeloma.

The median time to first on-study SRE was similar between the treatments, at 22.83 months with Xgeva versus 23.98 months with the bisphosphonate zoledronic acid. The median progression-free survival was 10.7 month higher in the Xgeva arm. There was also a nonstatistically significant trend in overall survival (OS) favoring Xgeva.

"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," Noopur Raje, M.D., director, Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, said in a statement. "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."

Xgeva directly affects bone resorption through the inhibition of the RANK ligand, which is instrumental in the formation, function, and survival of osteoclasts. The monoclonal antibody was initially approved in 2010, based on a direct comparison with Zometa for patients with prostate cancer, breast cancer and other solid tumors. This trial also included patients with advanced multiple myeloma; however, the agent was not approved for this indication at that time, warranting the initiation of the 482 study.

The phase 3 482 study, which began enrolling in April 2011, included 1,718 patients with newly diagnosed multiple myeloma. There were 859 patients in each arm. The ECOG performance status was between 0 and 2 and all patients had adequate organ function. Creatinine clearance (CRCL) was at least 30 mL/min for all patients enrolled.

In the experimental arm, subcutaneous Xgeva was administered at 120 mg along with an intravenous placebo. In the comparator arm, a subcutaneous placebo was administered along with Zometa at 4 mg intravenously, with adjustments for renal function. Treatment was administered every four weeks in each arm.

Secondary endpoints of the study focused on superiority for the RANK ligand inhibitor versus the bisphosphonate for time to first SRE and time to first and subsequent SRE, which were defined as fracture, radiation to bone, surgery to bone or spinal cord compression. In the initial analysis, these secondary endpoints were not met.

Adverse events (AEs) in the study were consistent with the known safety profile for Xgeva. The most common AEs in the Xgeva arm were diarrhea (33.5 percent vs 32.4 percent with Zometa) and nausea (31.5 percent vs 30.4 percent).

Zometa has been a standard of care for patients with multiple myeloma for the prevention of SREs, since it was approved in 2002. In a 1018-patient study, Zometa reduced the risk of death by 22 percent and SREs by 25 percent compared with the bisphosphonate pamidronate in multiple myeloma. The median OS with Zometa was 32.4 months compared with 23.4 months with pamidronate.

In addition to other approvals, Xgeva is currently indicated for the prevention of SREs in patients with bone metastases from a solid tumor, based upon three large studies comparing the agent with Zometa in 5723 patients. Across these trials, the median time to first SRE was 27.7 months with Xgeva compared with 19.5 months with Zometa.

In the three trials, which used similar dosing schemes as the 482 study, the most common AEs were fatigue/asthenia, hypophosphatemia and nausea. The most common AEs leading to discontinuation were osteonecrosis and hypocalcemia. Severe hypocalcemia, when vitamin D supplementation was utilized, was experienced by 3 percent of those treated with Xgeva versus 1.4 percent with Zometa. When supplements were not used, these rates were 3.9 percent and 1.0 percent, for Xgeva and Zometa, respectively.

Across the studies, renal-related dose adjustments or pauses were not required for patients taking Xgeva. Eighteen percent of those in the Zometa arm required a dose adjustment based on baseline CRCL levels. Once treatment had started, dosing pauses due to serum creatinine levels were required for 10 percent of patients in the Zometa arm.

"Bone complications can be devastating for patients with multiple myeloma. Previously, treatment options for the prevention of bone complications were limited to bisphosphonates, which unlike XGEVA, are cleared by the kidneys," David M. Reese, M.D., senior vice president of Translational Sciences and Oncology at Amgen, said in a press release. "We are pleased that the FDA has approved the expanded indication for XGEVA, providing a new option for patients and physicians, underscoring our commitment to advancing care for patients with multiple myeloma."