Denosumab noninferior to zoledronic acid in multiple myeloma bone disease
Denosumab is noniferior to zoledronic acid in delaying skeletal-related events (SREs) with less renal toxicity in patients with multiple myeloma, according to a study presented at the EHA Congress 2017 in Madrid, Spain.
“Multiple myeloma is characterized by osteolytic bone disease, with up to 80 patients of patients presenting with detectable lesions,” according to Dr Evangelos Terpos from the University of Athens School of Medicine and Alexandra General Hospital in Athens, Greece. These patients were usually given regular bisphosphonates, such as zoledronic acid, to protect against lytic lesions in the bones.
Denosumab is a human monoclonal antibody which targets the osteoclast-activating factor RANKL, which has been associated with an increased risk for bone disease in multiple myeloma.
During a median follow-up of 17.4 months, patients receiving denosumab had similar time to first on-study SRE as those treated with zoledronic acid (median, 22.83 vs 23.98 months). [EHA 2017, abstract S782]
Denosumab also achieved the primary endpoint of noninferiority to zoledronic acid in terms of time to first on-study SRE (hazard ratio [HR], 0.98; p=0.01), although superiority was not demonstrated (p=0.82).
“In this high-risk study population, the effect of antiresorptive therapy may only be evident later in the treatment course,” said the researchers.
As such, a post hoc landmark analysis was performed at 15 months, which revealed that denosumab was superior to zoledronic acid with regards to time to first SRE (HR, 0.66; p=0.039).
Progression-free survival was longer with denosumab than with zoledronic acid (median, 46.09 vs 35.38 months, HR, 0.82; p=0.036). Although there were fewer deaths with denosumab than with zoledronic acid (14.1 percent vs 15.0 percent), the secondary endpoint of overall survival did not differ between the two groups (HR, 0.90; p=0.41).
The head-to-head trial randomized 1,718 patients 1:1 to subcutaneous denosumab 120 mg or intravenous zoledronic acid 4 mg, both administered once every 4 weeks in addition to antimyeloma therapy. Patients with kidney disease were excluded if their baseline creatinine clearance was <30 mL/min.
Common treatment-emergent adverse events (TEAEs), ie, occurring in >25 percent of patients, such as diarrhoea and nausea were similar in both groups.
Consistent with known safety profile of each drug, denosumab was associated with higher rates of hypocalcaemia (16.9 percent vs 12.4 percent) and positively adjudicated osteonecrosis of the jaw (4.1 percent vs 2.8 percent), while zoledronic acid was associated with a greater renal toxicity (17.1 percent vs 10.0 percent; p<0.001), especially in those with creatinine clearance of ≤60 mL/min (26.4 percent vs 12.9 percent).
TEAEs leading to treatment discontinuation occurred in 12.9 percent of denosumab-treated patients and 11.5 percent of zoledronic acid-treated patients.