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Denosumab noninferior to zoledronic acid for bone disease in myeloma
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Denosumab appeared noninferior to zoledronic acid in time to skeletal-related events for the treatment of bone disease among patients with newly diagnosed multiple myeloma, according to a study published in The Lancet Oncology.
The safety profile of both agents appeared similar.
Among patients with multiple myeloma, bone lesions develop due to changes in the bone microenvironment, including inhibition and increased function of osteoblasts.
“This process leads to an imbalance in the bone homoeostasis mechanism due to increased bone resorption rates and decreased bone formation activity, resulting in the development of clinically relevant lytic bone lesions and hypercalcemia,” Noopur Raje, MD, director of Center for Multiple Myeloma at Massachusetts General Hospital Cancer Center, and colleagues wrote. “Because the multiple myeloma-induced lytic lesions are slow to heal, if at all, patients with multiple myeloma face a lifelong and increasing risk of developing a skeletal-related event (defined as pathological fractures, surgery or radiation to bone, or spinal cord compression) that often leads to diminished quality of life, and increased morbidity and mortality.”
Denosumab (Xgeva, Amgen) — a monoclonal antibody targeting RANKL — has been shown to reduce skeletal-related events from bone lesions or metastases among patients with advanced solid tumors.
Raje and colleagues studied 1,718 patients with newly diagnosed multiple myeloma who had at least one documented lytic bone lesion.
Researchers randomly assigned patients to either subcutaneous 120 mg denosumab plus IV placebo every 4 weeks or IV 4 mg zoledronic acid and subcutaneous placebo every 4 weeks. All patients received investigators’ choice of first-line antimyeloma therapy.
Noninferiority of denosumab to zoledronic acid for time to first skeletal-related event among all randomly assigned patients served as the study’s primary endpoint.
During the study, 44% of patients had at least one skeletal-related event, with 60% of events occurring within the first 3 months and 81% occurring within the first 6 months.
Denosumab appeared noninferior to zoledronic acid for time to first skeletal-related event (HR = 0.98; 95% CI, 0.85-1.14).
OS appeared similar between the two groups.
The safety analysis included 1,702 patients who received at least one dose of active therapy. The most common grade 3 or higher adverse events for denosumab and zoledronic acid included neutropenia (15% vs. 15%), thrombocytopenia (14% vs. 12%), anemia (12% vs. 10%), febrile neutropenia (11% vs. 10%) and pneumonia (8% vs. 8%). Ten percent of patients in the denosumab group developed renal toxicity compared with 17% of the zoledronic acid group. Seventeen percent of the denosumab group experienced hypocalcemia adverse events compared with 12% of the zoledronic acid group.
Incidence of osteonecrosis of the jaw did not appear significantly different between the groups (4% vs. 3%).
One patient in the zoledronic acid group died of treatment-related cardiac arrest.
In an accompanying editorial Meletios A. Dimopoulos, MD, and Efstathios Kastritis, MD, of National and Kapodistrian University of Athens and Alexandra Hospital in Athens, raised some unanswered questions about the treatment of bone disease among patients with multiple myeloma.
“Only patients with myeloma-related bone disease at diagnosis were enrolled and the benefits of denosumab [among] patients without bone disease are uncertain,” they wrote.
Additionally, the optimal durations of denosumab and zoledronic acid therapy have not been clearly defined, according to Dimopoulos and Kastritis. They also raised concerns about patients with renal dysfunction.
“Although denosumab is a new standard of care for patients with myeloma-related bone disease, to conclude that it should be given to all patients with myeloma would be premature,” they wrote. – by Cassie Homer
Disclosures: Amgen funded the study. Raje reports personal fees from Amgen, Bristol-Myers Squibb, Celgene, Merck, Novartis, Roche and Takeda, as well as research funding from AstraZeneca. Please see the study for all other authors’ relevant financial disclosures. Dimopoulos reports honoraria from Amgen, Celgene, Janssen, Novartis and Takeda. Kastritis reports honoraria from Amgen, Genesis Pharma, Janssen, Prothena and Takeda.
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