Amgen today announced results from the Phase 3 ‘482 study, the largest international multiple myeloma trial for the prevention of skeletal-related events ever conducted (n=1,718), were published in The Lancet Oncology.

In this study, denosumab successfully met the primary endpoint, demonstrating non-inferiority to zoledronic acid in delaying the time to first on-study skeletal-related event in patients with multiple myeloma (HR=0.98, 95 percent CI: 0.85-1.14).

On Jan. 5, the U.S. Food and Drug Administration (FDA) approved the supplemental Biologics License Application (sBLA) for denosumab to expand the currently approved indication for the prevention of skeletal-related events in patients with bone metastases from soft tumours to include patients with multiple myeloma.

The approval was based on data from the '482 study.

Additional regulatory applications for denosumab for the prevention of skeletal-related events in patients with multiple myeloma are underway and have been submitted to health authorities worldwide.

Denosumab is the first fully human monoclonal antibody that binds to and neutralizes RANK ligand (RANKL) – a protein essential for the formation, function and survival of osteoclasts, cells which break down bone – thereby inhibiting osteoclast-mediated bone destruction.

“Osteolytic bone disease and renal dysfunction are the most frequent complications of multiple myeloma, affecting up to 90 and 60 percent of patients respectively,” said Noopur Raje, M.D., director, Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, Boston. “Until recently, treatment options for the prevention of skeletal-related events in multiple myeloma were limited to bisphosphonates, which are cleared through the kidneys and can be associated with increased renal impairment. Denosumab, which is not cleared through the kidneys, provides a new treatment option for the prevention of skeletal-related events in patients with multiple myeloma.”

The median time to first on-study skeletal-related event was 22.8 months for denosumab and 24 months for zoledronic acid.

Approximately 60 percent of all first skeletal-related events occurred within the first three months, and 81 percent occurred within the first six months.

Overall survival, a secondary endpoint of the study, was similar between the denosumab and zoledronic acid arms, with a hazard ratio of 0.90 (95 percent CI: 0.70-1.16).

Progression-free survival, an exploratory endpoint not powered for statistical significance, was 46.1 months (95 percent CI: 34.3 months-not estimable [NE], n=219) for XGEVA and 35.4 months (95 percent CI: 30.2 months-NE, n=260) for zoledronic acid on top of standard of care anti-myeloma therapy.

The safety profile was consistent with known adverse events of both denosumab and zoledronic acid.

There were fewer renal treatment-emergent adverse events in the denosumab arm compared to the zoledronic acid arm (10 percent versus 17 percent, respectively).

Hypocalcaemia events were higher in the XGEVA arm compared to the zoledronic acid arm (17 percent versus 12 percent, respectively).

Osteonecrosis of the jaw was observed in 4 percent of the denosumab-treated patients versus 3 percent of the zoledronic acid-treated patients.

The most common treatment-emergent adverse events (greater than 25 percent) were diarrhoea and nausea.

Source: Amgen