Denosumab was noninferior to zoledronic acid at delaying skeletal-related events in patients with newly diagnosed multiple myeloma and one or more lytic bone lesions, according to findings from an international randomized trial.

In a phase 3 double-blind, double-dummy, controlled trial, patients were randomly assigned to receive either subcutaneous denosumab or intravenous zoledronic acid, plus the investigator’s choice of first-line antimyeloma therapy. The primary endpoint of noninferiority of denosumab at preventing time to first skeletal-related event, compared with zoledronic acid, was met, reported Noopur Raje, MD , of the Massachusetts General Hospital Cancer Center, Boston, and colleagues.

Median progression-free survival, an exploratory endpoint, was significantly longer with denosumab – 46.1 months vs. 35.4 months – translating into a hazard ratio of 0.82 (P = .036) for progression on denosumab. There was no difference in overall survival, however.

Denosumab is a monoclonal antibody that binds to and inactivates receptor activator of nuclear factor kappa-B ligand, a promoter of osteoclast formation, activation, and survival. Zoledronic acid is a bisphosphonate that may have antimyeloma effects, the investigators noted.

“The greater progression-free survival with denosumab than with zoledronic acid is compelling in view of the previous preclinical and clinical evidence supporting an anti-RANKL[receptor factor kappa-B ligand]–mediated, antimyeloma effect. These results, in combination with the improved renal adverse event profile, support denosumab as an additional option to the standard of care for patients with multiple myeloma,” the investigators wrote in The Lancet Oncology .

The trial included 1,718 patients age 18 and older treated at 259 centers in 29 countries. All patients had newly diagnosed multiple myeloma with at least one documented lytic bone lesion. The patients were randomly assigned to denosumab or zoledronic acid, and were stratified by intent to undergo autologous stem cell transplant, antimyeloma therapy regimen, stage according to the International Staging System , previous skeletal-related events, and region.

As noted, the trial met the primary endpoint of noninferiority of denosumab, with a hazard ratio for time to first skeletal-related event vs. zoledronic acid of 0.98 (P = .010)­­­­.

The safety analysis, which included all patients who were randomized and received at least one dose of study medication (850 on denosumab and 852 on zoledronic acid) showed that the agents were associated with similar incidences of neutropenia, thrombocytopenia, anemia, febrile neutropenia, and pneumonia. The incidence of renal toxicity, however, was lower with denosumab than with zoledronic acid (10% vs. 17%, respectively), whereas hypocalcemia was higher with denosumab (17% vs. 12%). There were no significant differences in the incidence of osteonecrosis of the jaw, a common problem with osteoclast inhibitors.

There was one treatment-related death, a case of cardiac arrest in a patient treated with zoledronic acid.

The investigators noted that the study was limited by a lack of response data, and by the fact that patients with creatinine clearance less than 30 mL/minute were not enrolled because of study blinding and the product label of zoledronic acid.

The study was sponsored by Amgen. Dr. Raje and multiple coauthors disclosed personal fees from Amgen and other companies. Three of the coauthors are current or former Amgen employees.

SOURCE: Raje NS et al. Lancet Oncol. 2018 Feb 8. doi: 10.1016/S1470-2045(18)30072-X .


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