Published Data Highlights Pivotal Denosumab Results in Multiple Myeloma SRE Prevention

According to recently published results of the&nbsp;international, double-blind randomized phase III 482 Study&nbsp;in&nbsp;<em>The Lancet Oncology,&nbsp;</em><sup>&nbsp;</sup>denosumab was noninferior to zoledronic acid (Zometa) in preventing skeletal-related event in patients with newly diagnosed multiple myeloma.

Noopur Raje, MD

According to recently published results of the international, double-blind randomized phase III 482 Study in The Lancet Oncology,1denosumab (Xgeva) was noninferior to zoledronic acid (Zometa) in preventing skeletal-related event (SREs) in patients with newly diagnosed multiple myeloma.

Findings of the trial showed denosumab was equal to zoledronic acid in delaying time to first SRE (hazard ratio [HR], 0.98; 95% CI, 0.85-1.14;Pfor noninferiority = .010). Based on these findings, the FDA approved denosumab in January 2018 for the prevention of SREs in patients with multiple myeloma.

The median time to first on-study SRE was similar between the denosumab arm (22.8 months; 95% CI, 14.7-not estimable) and zoledronic acid group (24.0 months; 95% CI, 16.5-33.3). The multiple events analysis of time to first and subsequent SREs also did not show superiority for denosumab (rate ratio, 1.01; 95% CI, 0.89-1.15;P= .84).

“Osteolytic bone disease and renal dysfunction are the most frequent complications of multiple myeloma, affecting up to 90 and 60 percent of patients respectively,” lead study author Noopur Raje, MD, director, Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, said in a press release.

“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,” added Raje.

Researchers for the 482 Study recruited 1718 patients at 259 medical centers in 29 countries from May 2012 to March 2016. Patients were randomly assigned to either 120 mg of subcutaneous denosumab administered along with an intravenous placebo (n = 859) or subcutaneous placebo along with 4 mg of intravenous zoledronic acid, with adjustments for renal function (n = 859). Treatment was administered every 4 weeks in each arm. Adult patients with symptomatic newly diagnosed multiple myeloma who had at least 1 documented lytic bone lesion were eligible.

The median overall survival was 49.5 months with denosumab versus non-estimable with zoledronic acid (HR, 0.90; 95% CI, 0.70-1.16;P= .41) after 121 deaths in the denosumab group and 129 in the zoledronic acid group.

Median progression-free survival (PFS) favored the denosumab arm (46.1 vs 35.4 months; HR, 0.82; 95% CI, 0.68-0.99; descriptiveP= .036) after 219 PFS events in the denosumab group and 260 in the zoledronic acid arm.

The median time on-study was 27.2 months (IQR, 20.5-34.1) for denosumab and 27.1 months (IQR, 20.3-34.2) for zoledronic acid, and the median time on study drug was 25.0 months (IQR, 19.4-32.2) for denosumab and 24.0 months (IQR, 17.7-31.3) for zoledronic acid. Median times to first SRE were not estimable for either treatment.

Supportive analyses by actual strata, alternative censoring, and inverse probability of censoring showed similar results.

In the safety analysis, 10% of patients in the denosumab group experienced renal toxicity versus 17% in the zoledronic acid group. Hypocalcemia adverse events (AEs) were slightly more common in the denosumab arm group (17% vs 12%). Incidence of osteonecrosis of the jaw was not significantly different between the denosumab (4%) and zoledronic acid groups (3%;P= .147).

The most common grade ≥3 treatment-emergent AEs for both the denosumab and zoledronic acid groups were neutropenia (15% for both) thrombocytopenia (14% vs 12%), anemia (12% vs 10%), febrile neutropenia (11% vs 10%), and pneumonia (8% for both) The most common serious AE for both treatment groups was pneumonia (8% for both). One patient in the zoledronic acid group died of cardiac arrest that was deemed treatment-related.

Writing in an accompanying editorial, Meletios A. Dimopoulos, MD, and Efstathios Kastritis, MD, both with the Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, said that more studies are needed to determine the optimal administration strategy for denosumab, and to learn whether discontinuation is associated with a rebound in osteoporotic fractures, especially in patients who have not received bisphosphonates.2

“The cost of denosumab is high compared with zoledronic acid, and the need for continuous therapy might substantially increase the cost of myeloma therapy. Additionally, new treatment options are available, including anti-CD38 monoclonal antibodies,” they wrote. “What would be the added value of denosumab or zoledronic acid in the context of such therapies? What would the effect of anti-RANKL therapy be in the context of immunotherapies, considering that RANKL is also implicated in T-cell function? Although denosumab is a new standard of care for patients with myeloma-related bone disease, to conclude that it should be given to all patients with myeloma would be premature.”


  1. Raje N, Terpos E, Willenbacher W, et al. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study [published online February 9, 2018].Lancet Oncol. doi/10.1016/ S1470-2045(18)30072-X.
  2. Dimopoulos MA, Kastritis E. Denosumab for myeloma bone disease: ready for prime time? [published online February 9, 2018].Lancet Oncol.doi 10.1016/ S1470-2045(18)30075-5.