In a phase III trial reported in The Lancet Oncology, Raje et al found that denosumab was noninferior to zoledronic acid in preventing skeletal-related events (SREs) in newly diagnosed multiple myeloma patients with bone disease.
In the double-blind trial, 1,718 patients with at least one documented lytic bone lesion from 259 sites in 29 countries were randomized between May 2012 and March 2016 to receive subcutaneous denosumab 120 mg plus intravenous (IV) placebo every 4 weeks (n = 859) or IV zoledronic acid 4 mg plus subcutaneous placebo every 4 weeks (n = 859), with both groups receiving investigators’ choice of first-line therapy for multiple myeloma.
The primary endpoint was noninferiority of denosumab to zoledronic acid in time to first SRE among all randomized patients. The prespecified noninferiority margin was an upper confidence interval limit of 1.28.
Time to SRE
Denosumab was noninferior to zoledronic acid in time to first on-study SRE (hazard ratio = 0.98, 95% confidence interval = 0.85–1.14, P = .010 for noninferiority; no superiority shown). Median time to first SRE was 22.8 months in the denosumab group vs 24.0 months in the zoledronic acid group. SREs occurred in 44% of the denosumab group and 45% of the zoledronic acid group. Overall, 60% of all first SREs occurred in the first 3 months of the study and 81% occurred in the first 6 months.
The most common grade ≥ 3 adverse events in the denosumab vs zoledronic acid groups were neutropenia (15% vs 15%), thrombocytopenia (14% vs 12%), anemia (12% vs 10%), febrile neutropenia (11% vs 10%), and pneumonia (8% vs 8%). Renal toxicity was reported in 10% vs 17%. Any-grade hypocalcemia occurred in 17% vs 12%. Osteonecrosis of the jaw occurred in 4% vs 3% (P = .147). The most common serious adverse event in both groups was pneumonia (8% in both). One patient in the zoledronic acid group died of cardiac arrest that was considered treatment-related.
The investigators concluded, “In patients with newly diagnosed multiple myeloma, denosumab was noninferior to zoledronic acid for time to skeletal-related events. The results from this study suggest denosumab could be an additional option for the standard of care for patients with multiple myeloma with bone disease.”
The study was funded by Amgen.
Noopur Raje, MD, of the Center for Multiple Myeloma at Massachusetts General Hospital Cancer Center, is the corresponding author for The Lancet Oncology article.
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