Denosumab offers alternative to zoledronic acid in multiple myeloma
medwireNews: Phase III study data show that the RANKL-targeting monoclonal antibody denosumab is noninferior to zoledronic acid for the prevention of bone disease in patients with newly diagnosed multiple myeloma.
Noopur Raje (Massachusetts General Hospital Cancer Center, Boston, USA) and team also found no significant difference in overall survival (OS) between patients in each treatment group, and an improvement in progression-free survival (PFS) among those receiving denosumab.
The international trial included 1718 patients aged 18 years or older with symptomatic newly diagnosed multiple myeloma who had at least one lytic bone lesion. Participants were randomly assigned to receive subcutaneous denosumab 120 mg plus intravenous placebo every 4 weeks or intravenous zoledronic acid 4 mg plus subcutaneous placebo every 4 weeks, both alongside the clinicians' choice of first-line antimyeloma therapy.
As reported in The Lancet Oncology, 44% of 859 patients given denosumab and 45% of 859 patients given zoledronic acid experienced a first on-study skeletal-related event (pathologic fractures, surgery or radiation to bone, or spinal cord compression), with 60% of events occurring in the first 3 months and 81% occurring in the first 6 months.
The median time to first on-study skeletal-related event was 22.8 months in the denosumab group and 24.0 months in the zoledronic acid group, indicating that denosumab was noninferior to zoledronic acid for this outcome (hazard ratio=0.98).
Survival rates were also similar between the two treatments, with 121 deaths recorded in the denosumab group and 129 recorded in the zoledronic acid group, and the corresponding median OS times were 49.5 months and not reached.
In addition, median PFS was significantly longer with denosumab than with zoledronic acid, at 46.1 versus 35.4 months, which the researchers say “provides suggestive clinical evidence of a potential antimyeloma effect based on RANKL inhibition.”
Raje et el describe the safety profiles as “acceptable and consistent with known adverse events of both therapies,” and point out that the rate of renal treatment-related adverse events was lower with denosumab than with zoledronic acid (10 vs 17%).
The authors conclude: “Denosumab represents a potential new treatment option for the prevention of skeletal-related events in patients with multiple myeloma.
“The lower risk of renal adverse events compared with zoledronic acid makes denosumab an attractive option for patients with multiple myeloma, in whom renal disease is a substantial challenge.”
In an accompanying comment, Meletios Dimopoulos and Efstathios Kastritis, both from the National and Kapodistrian University of Athens in Greece, write: “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.”
They say that several questions remain and point out that the study only included patients with myeloma-related bone disease at diagnosis, meaning the benefits are unclear in those without bone disease.
Dimopoulos and Kastritis also highlight the higher cost of denosumab compared with zoledronic acid, which could substantially increase the cost of myeloma therapy.
Finally, they question the value of anti-RANKL therapy in the context of new treatment options such as anti-CD38 monoclonal antibodies and immunotherapies, particularly as RANKL is also implicated in T-cell function.
By Laura Cowen
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