According to data published in a research letter in Lancet Oncology, the use of denosumab, a monoclonal antibody targeting receptor activator of nuclear factor-κB ligand (RANKL), for the prevention of skeletal-related events in older patients with multiple myeloma has increased dramatically, even in patients without renal dysfunction, following its January 5, 2018, approval by the US Food and Drug Administration (FDA) for this indication.1,2

The FDA approval of denosumab in the setting of multiple myeloma was based on results of a recent noninferiority trial that compared denosumab with the bisphosphonate zoledronic acid in patients with newly diagnosed multiple myeloma characterized by at least 1 lytic lesion and adequate renal function (ie, creatinine clearance of at least 30 mL/min) (NCT01345019). The findings from this study showed denosumab to be noninferior to zoledronic acid regarding time to skeletal-related events.3

Of note, while bisphosphonates, which are eliminated through the kidneys, are not recommended in patients with severe renal dysfunction given their association with renal toxicity,4 the pharmacokinetics and pharmacodynamics of denosumab are not affected by kidney function, although hypocalcemia has been reported in some patients with renal impairment receiving denosumab without adequate calcium supplementation.2

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This retrospective analysis used Medicare fee-for-service claims data to investigate use of denosumab and bisphosphonates (eg, zoledronic acid, palmidronate) in older patients with multiple myeloma prior to (January 1, 2017, to January 4, 2018) and following (January 5, 2018, to March 31, 2019) FDA approval of denosumab in this setting.1


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For the 15,872 patients included in the analysis, the percentage of denosumab used was only 0.1% of all bone-modifying doses used in the period prior to FDA approval, increasing to 38.1% in the post-FDA approval period. Notably, large increases in denosumab uptake were noted in both patients with and without renal dysfunction, with adjusted incidence rate ratios of postapproval versus preapproval denosumab use of 17.9 and 36.0 in these 2 patient populations, respectively.1

Other characteristics of patients more likely to receive denosumab included older age and rural residence.1 

The study authors commented that routine use of denosumab in patients with multiple myeloma “is difficult to justify except in patients with renal dysfunction or in those unable to tolerate bisphosphonates” given the increased expense and more frequent dosing of denosumab compared with bisphosphonate therapy, as well as the rapid bone loss associated with the discontinuation of denosumab.1

In their concluding remarks, the study authors stated that “further research should examine the role of rebates and reimbursements as incentives for the widespread adoption of more costly drugs that have not demonstrated superiority.”1

Disclosure: Some of the authors disclosed financial relationships with pharmaceutical and medical device companies. For a full list of disclosures, please refer to the original study.

References

  1. Gupta  A, Wang P, Abbas Ali S, et al.  Use of bone-modifying agents among Medicare beneficiaries with multiple myeloma [published online December 12, 2019]. JAMA Oncol. DOI: 10.1001/jamaoncol.2019.5426
  2. Denosumab (Xgeva) [package insert]. Thousand Oaks, CA: Amgen, Inc; 2019.
  3. 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: 370-381.
  4. Zoledronic acid (Zometa®) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2018.