Patients eligible for transplant,   Relapsed/refractory patients,  General MM

Denosumab is cost-effective for the prevention of SREs 

Following phase III data directly comparing denosumab with zoledronic acid (ZA), for the treatment of bone disease in Multiple Myeloma (MM), denosumab was granted approval to treat skeletal-related events (SREs) in MM patients and is edging closer towards approval in the EU. The results of the study, which assessed 1,718 Newly Diagnosed (ND) MM patients, indicated that denosumab was non-inferior to ZA for the prevention of SREs, with decreased renal toxicity and an extended median progression-free survival (PFS) of 10.7 months – read more here.

However, given the differential in cost between the two agents, some argue that there is no need for an expensive new drug when bisphosphonates are readily available and that denosumab should be reserved for patients with renal complications. Others argue that the added renal toxicity of ZA and IV means of administration lead to an added healthcare burden and that with SC administration and the added benefit to PFS, denosumab may prove to be more cost-effective. This question was addressed by Noopur Raje, from the Massachusetts General Hospital Cancer Center, Boston, USA, and colleagues, who carried out a direct cost comparison between denosumab and ZA, and the findings were published in the Journal of Medical Economics in March 2018.

Key Highlights:
Study Design
  • XGEVA Global Economic Model (X-GEM) was used, which incorporates both a societal and payer perspective and used outcomes from the phase III trial (denosumab vs ZA)
  • X-GEM included five health states according to whether patients (pts) were on or off treatment
  • SREs were defined as one of four types; cost was based on the proportion of each type that occurred during the trial, with eight health states used to calculate the associated utility decrements
  • Pts all had NDMM with at least one osteolytic lesion; 10% were unable to receive ZA due to pre-existing renal impairment and were given denosumab
  • SRE rates were adjusted for real-world incidence in MM (using a factor of 2.84)
  • Rate of SREs, serious adverse events (SAEs), PFS, overall survival (OS), and treatment discontinuation were modeled independently and pt compliance/treatment discontinuation was also accounted for
  • Extrapolation of PFS achieved by fitting parametric survival distributions to individual data; extrapolation of OS assumed the same mortality rate for both treatment arms
  • Constant rates of SAEs assumed; the proportion of pts with severe renal impairment set at 10%
  • Drug administration utility decrements were calculated to account for IV vs SC injection
  • Direct and indirect costs accounted for; drug acquisition costs were based on the average selling price
  • Associated costs of SAEs incorporated, as well as mean duration of anti-MM therapy
  • Cost-effectiveness was calculated as:
  • ICER = difference in cost between treatments/difference in health outcomes (measured in quality adjusted life year [QALY])
  • Three additional scenario analyses were carried out for each of these variables: 1) drug acquisition cost changed to wholesale drug cost, 2) efficacy of denosumab changed to that determined in the 15-month landmark analysis, and 3) renal impairment changed from 10% to 25%
Results 
  • Societal perspective vs payer perspective:
    • Incremental cost of using denosumab instead of ZA = $26,329 vs $29,409
    • Incremental benefit (measured by QALY = 0.2439) = $107,939 vs $120,569/QALY gained
    • Net monetary benefit (NMB) = $10,259 vs $7,179 in favor of denosumab
    • Using WAC prices for the same analysis: ICER = $34,895 vs $47,525 per QALY gained
  • Denosumab was found to be cost-effective vs ZA from both perspectives (ICER WTP threshold = $150,000/QALY and both ICERs were below)
  • Results - from societal perspective via different scenarios:
    • Taking into account the landmark analysis: ICER = $74,514/QALY
    • The proportion of pts with severe renal impairment set at 25%: ICER = $64,068/QALY
    • SRE rate set at a lower factor of 2.1 and rates based on landmark analysis: ICER =$102,585/QALY
  • Sensitivity analyses indicated relatively stable results, taking into account key variables
  • Probability of denosumab being cost-effective vs ZA (societal vs payer perspective) = 63% vs 60%

Taking into account a wide range of costs and benefits, denosumab was found to be a cost-effective option for the prevention of SREs in MM in comparison to ZA, from both a societal and payer perspective. A positive NMB was also attributed to denosumab. The added benefit of denosumab to PFS and the lack of renal toxicity were key factors that determined this outcome. The same conclusion was reached for the treatment of SREs in solid tumors, but this study specifically looked at SREs in MM, with direct and indirect medical costs accounted for, allowing a broader view of perceived value. This data will hopefully assist clinicians in the USA who are making a choice between these two regimens.

References
  1. Raje N. 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. J Med Econ. 2018 Mar 5:1-12. DOI: 10.1080/13696998.2018.1445634