Amgen announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion to expand the current indication for Xgeva (denosumab) to cover skeletal-related events in patients with multiple myeloma. If approved, Xgeva will be indicated for the prevention of skeletal-related events in adults with advanced malignancies involving bone. The application included new data from the phase 3 '482 study, the largest international multiple myeloma trial for the prevention of skeletal-related events ever conducted.

In the '482 study, Xgeva 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 per cent CI: 0.85-1.14). The median time to first on-study skeletal-related event was 22.83 months for Xgeva and 23.98 months for zoledronic acid. The safety profile was consistent with known adverse events of Xgeva.

"More than 90 per cent of patients with multiple myeloma develop bone lesions over the course of the disease. These can result in fractures and other bone complications," said David M. Reese, M.D., senior vice president of Translational Sciences and Oncology at Amgen. "The positive opinion from the CHMP to expand Xgeva's indication to cover skeletal-related events in patients with multiple myeloma is an important step forward in Amgen's commitment to improving care for multiple myeloma patients at risk for developing bone complications."

Bone complications, also known as skeletal-related events, are defined as radiation to bone, pathologic fracture, surgery to bone and spinal cord compression.

Xgeva 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. On January 5, 2018, the US Food and Drug Administration (FDA) approved the supplemental Biologics License Application (sBLA) for 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. Additional regulatory applications for Xgeva for the prevention of skeletal-related events in patients with multiple myeloma are underway and have been submitted to health authorities worldwide.

Following the CHMP positive opinion, the centralized European marketing authorization of Xgeva will be expanded to cover the multiple myeloma patient population. Norway, Iceland and Liechtenstein, as members of the European Economic Area (EEA), will take corresponding decisions on the basis of the decision of the European Commission.

The '482 study was an international, phase 3, randomized, double-blind, multicenter trial of Xgeva compared with zoledronic acid in the prevention of skeletal-related events in adult patients with newly diagnosed multiple myeloma and bone disease. In the study, a total of 1,718 patients (859 on each arm) were randomized to receive either subcutaneous Xgeva 120 mg and intravenous placebo every four weeks, or intravenous zoledronic acid 4 mg (adjusted for renal function at baseline) and subcutaneous placebo every four weeks, plus investigators' choice first-line antimyeloma therapy. Skeletal surveys using conventional radiography were obtained every 12 to 24 weeks per protocol. The primary endpoint of the study was non-inferiority of Xgeva 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). The safety and tolerability of Xgeva were also compared with zoledronic acid. An open-label extension of the study is ongoing.

Multiple myeloma is the second most common hematologic cancer, and it develops in plasma cells located in the bone marrow microenvironment. It is typically characterized by osteolytic bone lesions as well as renal failure, which are both part of diagnosis (CRAB criteria). Each year an estimated 114,000 new cases of multiple myeloma are diagnosed worldwide, resulting in more than 80,000 deaths per year.

More than 90 percent of patients develop osteolytic lesions during the course of the disease. Preventing bone complications is a critical aspect of caring for patients with multiple myeloma, because these events can result in significant morbidity.  Current treatment options to prevent bone complications are limited to bisphosphonates, including zoledronic acid, which are cleared through the kidneys. Approximately 60 per cent of all multiple myeloma patients have or will develop renal impairment over the course of the disease.

Xgeva targets the RANKL pathway to prevent the formation, function and survival of osteoclasts, which break down bone. Xgeva is indicated for the prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumours. Xgeva is also indicated for treatment of adults and skeletally mature adolescents with giant cell tumour of bone that is unresectable or where surgical resection is likely to result in severe morbidity. Additionally, Xgeva is indicated in the US for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.