KEY TAKEAWAYS
- The phase 3 aimed to determine if denosumab was equal to zoledronic acid in terms of time.
- The trial achieved its primary objective, demonstrating that denosumab was non-inferior to zoledronic acid in terms of time.
- The study concludes that denosumab is not inferior to zoledronic acid in preventing skeletal-related events in patients with newly diagnosed multiple myeloma.
Multiple myeloma is a medical condition that is distinguished by the production of monoclonal paraproteins and the presence of osteolytic lesions. These lesions often result in skeletal-related events, such as spinal cord compression, pathological fracture, or the need for surgery or radiotherapy to treat affected bones. Denosumab, a monoclonal antibody specifically targeting the receptor activator of nuclear factor kappa-B ligand (RANKL), effectively decreases skeletal-related events commonly associated with bone lesions or metastases in patients diagnosed with advanced solid tumors. This study sought to evaluate the effectiveness and safety of denosumab compared to zoledronic acid for preventing skeletal-related events in patients recently diagnosed with multiple myeloma. In this international, double-blind, double-dummy, randomized, active-controlled, phase 3 study, patients in 259 centers and 29 countries aged 18 years or older with symptomatic newly diagnosed multiple myeloma who had at least one documented lytic bone lesion were randomly assigned (1:1; centrally, by interactive voice response system using a fixed stratified permuted block randomization list with a block size of four) to receive 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).
The study’s main objective was to determine if denosumab was equal to zoledronic acid in terms of the time it took for the first skeletal-related event to occur in all patients randomly assigned to either treatment group. All safety endpoints were evaluated in the safety analysis group, which comprised all randomly assigned patients who received at least one dose of the active study medication. About 1,718 patients were enrolled in the study and assigned randomly, with 859 patients allocated to each treatment group. The clinical trial successfully achieved the primary objective; denosumab demonstrated non-inferiority to zoledronic acid in terms of the time it took for the first skeletal-related event to occur (hazard ratio 0·98, 95% CI 0·85-1·14; P-non-inferiority=0·010).
A total of 1,702 patients were administered at least one dose of the experimental medication and were included in the safety analysis. About 850 patients received denosumab, while 852 patients received zoledronic acid. The most prevalent grade 3 or more severe treatment-related adverse effects for denosumab and zoledronic acid were neutropenia (126 [15%] vs. 125 [15%]), thrombocytopenia (120 [14%] vs. 103 [12%]), anemia (100 [12%] vs. 85 [10%]), febrile neutropenia (96 [11%] vs 87 [10%]), and pneumonia (65 [8%] vs 70 [8%]). Renal toxicity was observed in 85 (10%) patients within the denosumab cohort compared to 146 (17%) patients within the zoledronic acid cohort. Adverse events related to hypocalcemia were reported in 144 (17%) patients in the denosumab group, while 106 (12%) patients in the zoledronic acid group experienced similar events. The occurrence of osteonecrosis of the jaw did not show a significant variation between the denosumab and zoledronic acid cohorts (35 [4%] vs 24 [3%]; P=0·147). The most prevalent adverse severe event observed in both treatment cohorts was pneumonia (71 [8%] vs 69 [8%]). One patient in the group receiving zoledronic acid experienced a fatality due to treatment-related cardiac arrest.
Source: https://pubmed.ncbi.nlm.nih.gov/29429912/
Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT01345019
Raje N, Terpos E, Willenbacher W, Shimizu K, García-Sanz R, Durie B, Legieć W, Krejčí M, Laribi K, Zhu L, Cheng P, Warner D, Roodman GD. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomized, controlled, phase 3 study. Lancet Oncol. 2018 Mar;19(3):370-381. doi: 10.1016/S1470-2045(18)30072-X. Epub 2018 Feb 9. PMID: 29429912.
