Is Denosumab a Safer Alternative to Zoledronic Acid in Newly Diagnosed Myeloma?

Patients with multiple myeloma (MM) can experience osteolytic bone disease that is typically treated with zoledronic acid (ZA) – which can be nephrotoxic. Denosumab (a monoclonal antibody that targets the RANK ligand, a mediator of bone resorption) is not renally cleared, and may offer a safer alternative to ZA for the prevention and treatment of skeletal-related events, according to results of a randomized, phase III trial presented at the 2017 ASCO Annual Meeting.

“I would argue that 100 percent of myeloma patients have some element of bone disease to begin with. If left untreated, a patient will end up with a lot of morbidity and skeletal-related events,” lead author Noopur S. Raje, MD, from the Massachusetts General Hospital Cancer Center in Boston, told ASH Clinical News. “There is data to demonstrate that mortality also increases if a patient has too many of these bone-related complications.”

Dr. Raje and colleagues evaluated the safety and efficacy of denosumab and ZA in adult patients newly diagnosed with MM who had evidence of at least one lytic bone lesion, an Eastern Cooperative Oncology Group performance status score of 0-2, and adequate organ function. Patients were excluded if they had baseline creatinine clearance (CrCl) <30 mL/min.

A total of 1,718 patients (median age = 63 years; range = 29-91 years) were randomized 1:1 to receive denosumab 120 mg administered subcutaneously every 4 weeks (n=859) or ZA 4 mg administered intravenously every 4 weeks (n=859), in addition to anti-myeloma therapy (including immunomodulatory drugs and proteasome inhibitors).

Baseline demographics and disease characteristics were balanced between both groups, and 26.7 percent of patients had poor renal function (≤60 mL/min), Dr. Raje and researchers noted. The length of median cumulative exposure to denosumab and ZA were similar (15.75 months [range = 8.18-25.79 months] and 14.78 months [range = 7.46-24.87 months]).

Overall, denosumab was non-inferior to ZA in delaying the median time to first on-study skeletal-related event (primary endpoint): 22.83 months (range = 14.72 months to not estimable) vs. 23.98 months (range = 16.56-33.31 months; hazard ratio [HR] = 0.98; 95% CI 0.85-1.14; p=0.01)

Secondary endpoints of the study included rates of progression-free survival (PFS) and overall survival (OS) at the time of follow-up. Both analyses favored treatment with denosumab, compared with ZA (HR for PFS = 0.82 [95% CI 0.68-0.99; p=0.036] and HR for OS = 0.9 [95% CI 0.70-1.16; p=0.41]). Fewer patient deaths occurred in the denosumab cohort compared with the ZA cohort (121 [14.1%] vs. 129 [15.0%]).

“Part of the reason denosumab is not yet approved for myeloma was the suggestion of an increased risk of death in patients receiving denosumab, but we did not see any survival difference,” Dr. Raje added.

In the safety analysis (which included 850 denosumab-treated patients and 852 ZA-treated patients), rates of treatment-related adverse events (AEs) were similar in both groups, but slightly lower in the denosumab group: 25.5 percent and 26.1 percent. Rates of grade ≥3 AEs were 5.2 and 5.8 percent, respectively.

“There were significantly lower incidences of adverse events potentially related to renal toxicity with denosumab therapy, compared with zoledronic acid,” Dr. Raje noted in her presentation, with rates of 10.0 percent and 17.1 percent, respectively (p<0.001). This was particularly true for patients with renal insufficiency (defined as baseline CrCl ≤60 mL/min; 12.9% vs. 26.4%; p<0.001).

Though “encouraging,” the study’s results are limited by the lack of information about the patients’ anti-myeloma therapies, which could have affected the risk of developing bone lesions, the researchers noted. The PFS results will need to be confirmed with longer follow-up trials.


Raje NS, Roodman GD, Willenbacher W, et al. Impact of denosumab (DMB) compared with zoledronic acid (ZA) on renal function in the treatment of myeloma bone disease. Abstract #8005. Presented at the 2017 ASCO Annual Meeting, June 4, 2017; Chicago, Illinois.