Denosumab (a monoclonal antibody that targets the RANK ligand) was noninferior to zoledronic acid (ZA) in delaying the time to a first skeletal-related event (SRE) in patients with newly diagnosed multiple myeloma (NDMM), according to results from a phase III study presented at the 16th International Myeloma Workshop.
“Bone disease is a common complication of multiple myeloma, with approximately 80 percent of patients presenting with detectable lesions,” Noopur Raje, MD, from Massachusetts General Hospital in Boston, said during her presentation of the results. “The results of this study showed that denosumab may be an effective, novel option that is not cleared through the kidneys that may help prevent bone complications.”
In this international, randomized, double-blind trial, Dr. Raje and colleagues evaluated the efficacy and safety of denosumab compared with ZA in 1,718 patients with NDMM. Patients were excluded if they had renal insufficiency (baseline creatinine clearance <30 mL/min).
Patients were randomized 1:1 to receive either denosumab 120 mg administered subcutaneously every four weeks (n=859) or ZA 4 mg administered intravenously every four weeks (n=859) along with anti-myeloma therapy. Baseline demographics and disease characteristics were balanced between both groups, and about one-quarter of patients had poor renal function (≤60 mL/min), Dr. Raje and researchers noted.
During the primary blinded treatment period (median follow-up = 17.4 months), the time to first on-study SRE (primary endpoint) was similar between denosumab- and ZA-treated patients: 43.8 percent and 44.6 percent, respectively. Throughout the study, the median time to first on-study SRE remained similar between both treatment arms: 22.83 months in the denosumab group and 23.98 months in the ZA group.
Treatment with denosumab was noninferior to ZA in delaying time to first on-study SRE (hazard ratio [HR] = 0.98; 95% CI 0.85-1.14; p=0.01). Superiority was not demonstrated for time to first on-study SRE or time to first-and-subsequent on-study SRE (secondary endpoints; p=0.82 and 0.84 for each comparison).
Rates of overall survival (OS) also were similar between the denosumab and ZA groups (HR=0.90; 95% CI 0.70-1.16; p=0.41). There was an improvement in progression-free survival (PFS) among denosumab-treated patients (HR=0.82; 95% CI 0.68-0.99; p=0.036).
“The lack of OS difference is reassuring … and the PFS data is provocative,” Dr. Raje said, but these findings will need further follow-up and investigation.
The rates of treatment-emergent adverse events (AEs) were similar between groups and comparable to known safety profiles, Dr. Raje reported, and led to study protocol discontinuation in 12.2 percent of all patients (12.9% in denosumab-treated patients and 11.5% in ZA-treated patients).
The most common all-grade AEs (occurring in >25% of patients) included diarrhea (33.5% and 32.4%) and nausea (31.5% and 30.4%). Rates of serious AEs were 46 percent in denosumab-treated patients and 47.3 percent in ZA-treated patients; these included hypocalcemia (0.9% and 0.2%) and osteonecrosis of the jaw (4.1% and 2.8%). Notably, fewer AEs potentially related to renal toxicity occurred with denosumab treatment (10.0% and 17.1%).
The study was limited by the lack of information about the patients’ myeloma therapies; the types of therapies could have affected the risk of developing bone lesions, the researchers noted.
Raje N, Terpos E, Willenbacher W, et al. An international, randomized, double blind trial comparing denosumab with zoledronic acid (ZA) for the treatment of bone disease in patients (pts) with newly diagnosed multiple myeloma. Abstract #546. Presented at the 16th International Myeloma Workshop, March 4, 2017; New Delhi, India.