Denosumab Approved in Europe for Myeloma

David M. Reese, MD

The European Commission has approved denosumab (Xgeva) for the prevention of skeletal-related events (SREs) in adult patients with multiple myeloma, according to Amgen, the developer of the RANK ligand inhibitor.

The expanded indication was based on data from the phase III 482 study, in which denosumab demonstrated noninferiority to zoledronic acid (Zometa) at delaying the time to the first SRE in patients with multiple myeloma (0.98; 95% CI, 0.85-1.14; P for noninferiority = .010).

The median time to first on-study SRE was similar between the denosumab arm (22.8 months; 95% CI, 14.7-not estimable) and zoledronic acid group (24.0 months; 95% CI, 16.5-33.3). The multiple events analysis of time to first and subsequent SREs also did not show superiority for denosumab (rate ratio, 1.01; 95% CI, 0.89-1.15; P = .84).

The approval follow’s a positive recommendation from the European Medicines Agency’s Committee for Medicinal Products for Human Use, and applies to all 28 countries in the European Union.

"Many patients with multiple myeloma have bone lesions at diagnosis, which can result in serious and devastating complications, including broken bones, the need for surgery or radiation to the bone and spinal cord compression," David M. Reese, MD, senior vice president of Translational Sciences and Oncology at Amgen, said in a statement.

"Until now, treatment options for the prevention of bone complications were limited to bisphosphonates, which unlike Xgeva, are cleared by the kidneys and can be associated with increased renal toxicity. We are pleased with the expanded indication for Xgeva in Europe, underscoring our dedication to advancing care for patients with multiple myeloma," added Reese.

The 482 study included 1718 patients at 259 medical centers in 29 countries from May 2012 to March 2016. Patients were randomly assigned to either 120 mg of subcutaneous denosumab administered along with an intravenous placebo (n = 859) or subcutaneous placebo along with 4 mg of intravenous zoledronic acid, with adjustments for renal function (n = 859). Treatment was administered every 4 weeks in each arm. Adult patients with symptomatic newly diagnosed multiple myeloma who had at least 1 documented lytic bone lesion were eligible.

The median overall survival was 49.5 months with denosumab versus non-estimable with zoledronic acid (HR, 0.90; 95% CI, 0.70-1.16; P = .41) after 121 deaths in the denosumab group and 129 in the zoledronic acid group.

Median progression-free survival (PFS) favored the denosumab arm (46.1 vs 35.4 months; HR, 0.82; 95% CI, 0.68-0.99; descriptive P = .036) after 219 PFS events in the denosumab group and 260 in the zoledronic acid arm.

The median time on-study was 27.2 months (IQR, 20.5-34.1) for denosumab and 27.1 months (IQR, 20.3-34.2) for zoledronic acid, and the median time on study drug was 25.0 months (IQR, 19.4-32.2) for denosumab and 24.0 months (IQR, 17.7-31.3) for zoledronic acid. Median times to first SRE were not estimable for either treatment.

Supportive analyses by actual strata, alternative censoring, and inverse probability of censoring showed similar results.

In the safety analysis, 10% of patients in the denosumab group experienced renal toxicity versus 17% in the zoledronic acid group. Hypocalcemia adverse events (AEs) were slightly more common in the denosumab arm group (17% vs 12%). Incidence of osteonecrosis of the jaw was not significantly different between the denosumab (4%) and zoledronic acid groups (3%; P = .147).

The most common grade ≥3 treatment-emergent AEs for both the denosumab and zoledronic acid groups were neutropenia (15% for both) thrombocytopenia (14% vs 12%), anemia (12% vs 10%), febrile neutropenia (11% vs 10%), and pneumonia (8% for both) The most common serious AE for both treatment groups was pneumonia (8% for both). One patient in the zoledronic acid group died of cardiac arrest that was deemed treatment-related.

Based on these findings, the FDA approved denosumab in this setting in January 2018.

Raje N, Terpos E, Willenbacher W, et al. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study [published online February 9, 2018]. Lancet Oncol. doi/10.1016/ S1470-2045(18)30072-X.