Denosumab Versus Zoledronic Acid for Reducing Time to Skeletal Events in Multiple Myeloma

Approximately 90 percent of patients diagnosed with multiple myeloma (MM) present with bone lesions and are typically treated with zoledronic acid (ZA), a potentially nephrotoxic agent. In results from a phase III trial published in The Lancet Oncology, the monoclonal antibody denosumab was noninferior to ZA in delaying the time between MM diagnosis and first skeletal-related event, and had similar rates of adverse events (AEs).

Denosumab, which targets the RANK ligand (a mediator of bone resorption) is not renally cleared, explained the authors, led by Noopur Raje, MD, of Harvard Medical School in Boston. “I certainly believe these data will impact clinical care, specifically in patients with renal impairment,” Dr. Raje told ASH Clinical News. “The progression-free survival (PFS) data for denosumab appear to favor denosumab use and, moreover, denosumab seems to be more convenient to use than other therapies.”

The authors compared the safety and efficacy of ZA and denosumab in 1,718 patients (median age = 63 years; range = 29-91 years) with symptomatic, newly diagnosed MM in the randomized, double-blind trial. Participants also were considered at high risk for skeletal-related events, had an Eastern Cooperative Oncology Group performance status score of 0-2, and presented with at least one lytic bone lesion. Patients were excluded if they had a baseline creatinine clearance <30 mL/min.

Patients were randomized to either:

  • subcutaneous denosumab 120 mg plus intravenous placebo every four weeks (n=859)
  • intravenous ZA 4 mg plus subcutaneous placebo every four weeks (n=859)

Participants also received anti-MM therapy (including immunomodulatory drugs and proteasome inhibitors). Treatment with denosumab or ZA continued until patients experienced an on-study skeletal-related event, bone-disease progression, or overall disease progression.

Stratification to treatment arms was based on the following:

  • intention to undergo autologous transplantation
  • anti-MM therapy
  • International Staging System stage
  • previous skeletal-related events (yes vs. no)
  • geographic region

Baseline demographics and disease characteristics were balanced between both groups, and 26.7 percent of patients had poor renal function (≤60 mL/ min), the authors reported. The median treatment duration for denosumab was 17.3 months (range = 8.9-28.5 months) and for ZA was 17.6 months (range = 9.4-28.1 months). The median cumulative exposure to denosumab and ZA were similar (15.8 months [range = 8.18-25.79 months] and 14.78 months [range = 7.46-24.87 months]).

The study’s primary endpoint was met: Denosumab was non-inferior to ZA in delaying the median time to first on-study skeletal-related event: 22.8 months (range = 14.7 – not estimable) versus 24.0 months (range = 16.5-33.3 months; hazard ratio [HR] = 0.98; 95% CI 0.85-1.14; p value for non-inferiority = 0.010).

In a post hoc analysis at 15 months, the time to first skeletal-related event favored denosumab over ZA (HR=0.66; 95% CI 0.44-0.98; p=0.039). Secondary analyses also found that the rate of PFS after 42 months was higher in the denosumab group (HR for PFS = 0.82 [95% CI 0.68-0.99; p=0.036], while OS was not, with HR = 0.90 [95% CI 0.70-1.16; p=0.41]).

A total of 852 patients assigned to ZA and 850 patients assigned to denosumab who had received at least one dose of the investigational drug were subsequently included in the safety analysis. The most frequently reported grade ≥3 treatmentemergent AEs in the denosumab and ZA groups were as follows:

  • neutropenia: 15% vs. 15%
  • thrombocytopenia: 14% vs. 12%
  • anemia: 12% vs. 10%
  • febrile neutropenia: 11% vs. 10%
  • pneumonia: 8% vs. 8%

Similar rates of osteonecrosis of the jaw were reported in patients assigned to denosumab and ZA (4% vs. 3%, respectively; p=0.147). While more patients in the denosumab group reported hypocalcemia (17% vs. 12%), a greater proportion of patients assigned to ZA experienced renal toxicity (17% vs. 10%, respectively; p values not reported). “This difference is of particular importance because MMrelated renal injury is frequent and occurs progressively during disease progression, with a known association between increased renal dysfunction and decreased treatment options, quality of life, and survival,” the authors noted, adding that these results “support denosumab as an additional option to the standard of care for patients with MM.”

Limitations of the analysis include a lack of response data, as well as the exclusion of patients with creatinine clearance of <30 mL/min, which potentially limits the generalizability of the findings.

According to Dr. Raje, future trials are needed with longer follow-up periods to determine the full advantage of denosumab for preventing skeletal events in MM. “I would like to see the use of denosumab in patients with creatinine clearance of <30 mL/min, which is being investigated in an ongoing trial,” she noted. “In addition, there may be a need to study the impact of less-frequent dosing of denosumab, such as every three months, in this patient population.”

The authors reported financial relationships with Amgen, which sponsored this trial.


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. Lancet Oncol. 2018;19:370-81.