FDA Approves Denosumab for the Prevention of Skeletal-Related Events in Patients with Multiple Myeloma

Expansion of indications is based on results from the pivotal phase III '482 study

On 5 January 2018, Amgen announced that the US Food and Drug Administration (FDA) has approved the supplemental Biologics License Application for denosumab (XGEVA®) to expand the currently approved indication for the prevention of skeletal-related events in patients with bone metastases from solid tumours to include patients with multiple myeloma. The approval is based on data from the pivotal phase III '482 study, the largest international multiple myeloma clinical trial ever conducted, which enrolled 1,718 patients.

Previously, treatment options for the prevention of bone complications were limited to bisphosphonates, which are cleared by the kidneys. Denosumab is not cleared through the kidneys and offers multiple myeloma patients bone protection with a convenient subcutaneous administration.

The '482 study (NCT01345019)was an international, phase III, randomised, double-blind, multicentre trial of denosumab compared with zoledronic acid for the prevention of skeletal-related events in adult patients with newly diagnosed multiple myeloma and bone disease. In the study, 859 patients in each arm were randomised to receive either subcutaneous denosumab 120 mg and intravenous placebo every four weeks, or intravenous zoledronic acid 4 mg (adjusted for renal function) and subcutaneous placebo every four weeks.

The primary endpoint of the study was non-inferiority of denosumab versus zoledronic acid with respect to time to first on-study skeletal-related event (pathologic fracture, radiation to bone, surgery to bone or spinal cord compression). Secondary endpoints included superiority of denosumab versus zoledronic acid with respect to time to first on-study skeletal-related event and first-and-subsequent on-study skeletal-related event and evaluation of overall survival (OS). Progression-free survival (PFS) was an exploratory endpoint. The safety and tolerability of denosumab were also compared with zoledronic acid.

The study met the primary endpoint, demonstrating non-inferiority of denosumab to zoledronic acid in delaying the time to first on-study skeletal-related event in patients with multiple myeloma (HR 0.98, 95% CI: 0.85, 1.14; p = 0.01). The secondary endpoints, delaying time to first skeletal-related event and delaying time to first-and-subsequent skeletal-related events, did not demonstrate superiority. The OS was comparable between denosumab and zoledronic acid, with a hazard ratio of 0.90 (95% CI: 0.70, 1.16; p = 0.41). The median difference in PFS favoured denosumab by 10.7 months (HR 0.82, 95% CI: 0.68-0.99; descriptive p = 0.036). Median PFS was 46.1 months (95% CI: 34.3 months, not estimable [NE], n = 219) for denosumab and 35.4 months (95% CI: 30.2 months, NE, n = 260) for zoledronic acid.

Adverse events observed in patients treated with denosumab were generally consistent with the known safety profile of denosumab. The most common adverse reactions (greater than or equal to 10%) were diarrhoea (34%), nausea (32%), anaemia (22%), back pain (21%), thrombocytopenia (19%), peripheral oedema (17%), hypocalcemia (16%), upper respiratory tract infection (15%), rash (14%) and headache (11%). The most common adverse reaction resulting in discontinuation of denosumab (greater than or equal to 1.0%) was osteonecrosis of the jaw (ONJ). In the primary treatment phase of the '482 study, ONJ was confirmed in 4.1% of patients in the denosumab group (median exposure of 16 months; range: 1 - 50) and 2.8% of patients in the zoledronic acid group (median 15 months, range: 1 - 45 months).

The news release contains forward-looking statements that are based on expectations and beliefs of Amgen.

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

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.