Raje N, et al. - Denosumab, a monoclonal antibody targeting RANKL, reduces skeletal-related events associated with bone lesions or metastases in patients with advanced solid tumours. Herein, in patients with newly diagnosed multiple myeloma, denosumab vs zoledronic acid was tested as a preventive against the development of skeletal-related events. Denosumab was non-inferior to zoledronic acid for time to skeletal-related events, and could be an additional option for the standard of care for patients with multiple myeloma with bone disease.

• This study represents an international, double-blind, double-dummy, randomised, active-controlled, phase 3 study.
• Study participants included patients from 259 centres and 29 countries.
• These patients, aged 18 years or older with symptomatic newly diagnosed multiple myeloma, with at least one documented lytic bone lesion, were randomly assigned (1:1; centrally, by interactive voice response system using a fixed stratified permuted block randomisation list with a block size of four) to subcutaneous denosumab 120 mg plus intravenous placebo every 4 weeks or intravenous zoledronic acid 4 mg plus subcutaneous placebo every 4 weeks (both groups also received investigators' choice of first-line antimyeloma therapy).
• Patients were stratified on the basis of intent to undergo autologous transplantation, antimyeloma therapy, International Staging System stage, previous skeletal-related events, and region.
• The clinical study team and patients were masked to treatment assignments.
• Non-inferiority of denosumab to zoledronic acid with respect to time to first skeletal-related event in the full analysis set (all randomly assigned patients) was the primary endpoint.
• Analysis of all safety endpoints were carried out in the safety analysis set, which included all randomly assigned patients who received at least one dose of active study drug.

• Enrollment of a total of 1718 patients and random allocation of 859 to each treatment group was done from May 17, 2012, to March 29, 2016.
• The primary endpoint was met; denosumab was found to be non-inferior to zoledronic acid for time to first skeletal-related event (hazard ratio 0·98, 95% CI 0·85–1·14; pnon-inferiority=0·010).
• A total of 1702 patients were included in the safety analysis and they received at least one dose of the investigational drug (850 patients receiving denosumab and 852 receiving zoledronic acid).
• Researchers identified that neutropenia (126 [15%] vs 125 [15%]), thrombocytopenia (120 [14%] vs 103 [12%]), anaemia (100 [12%] vs 85 [10%]), febrile neutropenia (96 [11%] vs 87 [10%]), and pneumonia (65 [8%] vs 70 [8%]) were the most common grade 3 or worse treatment-emergent adverse events for denosumab and zoledronic acid.
• In the denosumab group, renal toxicity was reported in 85 (10%) patients, compared with 146 (17%) in the zoledronic acid group; hypocalcaemia adverse events were reported in 144 (17%) vs 106 (12%).
• No significant difference was apparent in the incidence of osteonecrosis of the jaw between the denosumab and zoledronic acid groups (35 [4%] vs 24 [3%]; p=0·147).
• Pneumonia (71 [8%] vs 69 [8%]) was identified as the most common serious adverse event for both treatment groups.
• In the zoledronic acid group, one patient died of cardiac arrest that was deemed treatment-related.