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Tartrate-resistant-acid-
phosphatase-positive
osteoclast in cell culture

In a phase 3 trial, denosumab proved non-inferior to zoledronic acid for delaying skeletal-related events (SREs) in patients with multiple myeloma (MM).

The median time to first on-study SRE was 23 months in the denosumab arm and 24 months in the zoledronic acid arm.

There were fewer renal adverse events (AEs) but more hypocalcemia AEs in the denosumab arm.

“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,” said Noopur Raje, MD, of Massachusetts General Hospital Cancer Center in Boston.

“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.”

Dr Raje and her colleagues conducted this phase 3 trial of denosumab and reported the results in The Lancet Oncology. The trial was sponsored by Amgen, the company developing denosumab.

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

In this trial, researchers compared denosumab to zoledronic acid for the prevention of SREs in adults with newly diagnosed MM and bone disease.

The team randomized 1718 patients to receive subcutaneous denosumab at 120 mg and intravenous placebo every 4 weeks (n=859) or intravenous zoledronic acid at 4 mg (adjusted for renal function at baseline) and subcutaneous placebo every 4 weeks (n=859). All patients also received investigators’ choice of first-line MM 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 denosumab to zoledronic acid for time to first on-study SRE (pathologic fracture, radiation to bone, surgery to bone, or spinal cord compression).

The primary endpoint was met. The median time to first on-study SRE was 22.8 months for patients in the denosumab arm and 24 months for those in the zoledronic acid arm (hazard ratio [HR]=0.98; 95% confidence interval [CI]: 0.85-1.14; P non-inferiority=0.010).

Approximately 60% of all first SREs occurred within the first 3 months, and 81% occurred within the first 6 months.

Overall survival, a secondary endpoint, was similar between the denosumab and zoledronic acid arms (HR=0.90; 95% CI: 0.70-1.16; P=0.41).

There were fewer renal treatment-emergent AEs in the denosumab arm than the zoledronic acid arm—10% and 17%, respectively. There were more hypocalcemia AEs in the denosumab arm than the zoledronic acid arm—17% and 12%, respectively.

The incidence of osteonecrosis of the jaw was 4% in the denosumab arm and 3% in the zoledronic acid arm.

The most common grade 3 or higher treatment-emergent AEs (in the denosumab and zoledronic acid arms, respectively) were neutropenia (15% in both arms), thrombocytopenia (14% and 12%), anemia (12% and 10%), febrile neutropenia (11% and 10%), and pneumonia (8% in both arms).

The most common serious AE was pneumonia (8% in both arms).

Treatment-emergent AEs led to study drug discontinuation in 13% of patients in the denosumab arm and 12% in the zoledronic acid arm.

One patient in the zoledronic acid arm died of cardiac arrest that was deemed treatment-related. No other deaths were considered treatment-related.


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