Cost-Effectiveness of Zoledronic Acid Versus Clodronate In Patients with Multiple Myeloma From a Canadian Healthcare System Perspective.
Authors: Delea Thomas E. , Ougari Khalid El , Rotter Jason , Wang Alice , Kaura Satyin , Morgan Gareth J 
Published: October 2019

Abstract
Abstract 3812

Background:
The Medical Research Council (MRC) Myeloma IX study compared the intravenous (IV) bisphosphonate, zoledronic acid (ZOL) 4 mg q 3–4 wk with the oral bisphosphonate, clodronate (CLO) 1,600 mg/d PO, in 1,970 patients with newly-diagnosed multiple myeloma (MM). After a median follow-up of 3.7 yrs (max. follow-up 6 years), ZOL prolonged OS (median 50.0 vs. 44.5 months; HR=0.842; p=0.0118), increased PFS (median 19.5 vs. 17.5 months; HR=0.883; P=0.0179), and reduced the incidence of skeletal related events (SREs) (27.0% vs. 35.3%; HR=0.74; P=0.0004) compared with CLO. The incidence of acute renal failure (ARF) was similar in the two groups (5.8% vs. 6.1% with ZOL vs. CLO). The incidence of osteonecrosis of the jaw (ONJ) was 3.5% with ZOL and 0.3% with CLO. The objective of this study was to evaluate the cost-effectiveness of ZOL vs. CLO in patients with newly-diagnosed MM based on the reported findings of the MRC Myeloma IX trial.

Methods:
An economic model was used to project PFS, OS, the incidence of SREs (vertebral and other fractures, radiotherapy, bone surgery, and spinal cord compression) and adverse events (ARF, ONF, thromboembolism, and infection) as well as expected lifetime healthcare costs for patients with newly diagnosed MM who are alternatively assumed to received bishphosphonate therapy with ZOL or CLO. Cost-effectiveness was expressed in terms of the incremental cost per quality-adjusted life-year (QALY) gained with ZOL vs. CLO. Clinical data were based on reported results of the MRC Myeloma IX trial. OS for CLO and ZOL up to 5 years were based on reported Kaplan-Meier survival curves. For CLO, OS after 5 years was projected based on a Weibull survival function fitted to the reported Kaplan-Meier curve. For ZOL, OS after 5 years was obtained by applying the estimated HR for ZOL vs. CLO to the estimated Weibull survival function for CLO. PFS for CLO and ZOL were estimated based on reported medians and the HR for ZOL vs. CLO, assuming proportional hazards Weibull distributions (Kaplan-Meier curves were not reported for PFS). Costs and utility values were obtained from published sources. Costs were in 2009/10 Canadian dollars. Costs and QALY were discounted at 5% annually.

Results:
Expected lifetime costs of bisphosphonate therapy (including administration and monitoring costs) were $11,967 greater with ZOL vs. CLO ($14,267 vs. $2,301). Expected costs of SREs were reduced by $720 with ZOL ($4,152 vs. $4,872). Expected costs of adverse events were increased by $663 with ZOL ($3,225 vs. $2,562). Expected total lifetime costs were increased by $11,878 ($30,103 vs. $18,225). Life expectancy (undiscounted) was increased by 0.83 years with ZOL (6.43 vs. 5.60). QALYs gained from increased PFS and OS with ZOL vs. CLO were 0.56. QALYs gained from SREs averted with ZOL vs. CLO were <0.01. QALYs lost due to adverse events (predominantly ONJ) were 0.02. Total QALYs gained with ZOL vs. CLO (undiscounted) were 0.56 (4.43 vs. 3.87). On a discounted basis, total QALYs gained were 0.37 (3.51 vs. 3.14). Cost effectiveness with ZOL vs. CLO was $32,210 per QALY gained. In probabilistic sensitivity analyses, the probability that ZOL is preferred to CLO was 85% with a cost-effectiveness threshold of $50,000 per QALY and a 98% with a threshold of $100,000 per QALY. Cost-effectiveness was $43,487 per QALY gained if benefits of ZOL on OS are conservatively assumed to persist for 6 years only (i.e., HR for OS=1.0 after 6 years). Results were sensitive to methods used to estimate PFS and OS (i.e., Kaplan Meier or Weibull models, independent or proportional hazards assumption), and the estimated costs and QALYs lost with ONJ.

Conclusions.
The cost per QALY gained with ZOL vs. CLO in patients with newly-diagnosed MM is below the commonly-accepted threshold of $50,000 per QALY gained. More precise estimates await release of additional results from the MRC Myeloma IX study.

Disclosures:
Delea: Novartis: Consultancy, Research Funding. Off Label Use: Zoledronic acid for prevention of skeletal related events in patient with multiple myeloma. Ougari:Novartis: Employment. Rotter:Novartis: Consultancy, Research Funding. Wang:Novartis: Consultancy, Research Funding. Kaura:Novartis: Employment. Morgan:Novartis: Honoraria, Research Funding; Boehringer Ingelheim: Research Funding; Pharmion: Research Funding; Celgene: Research Funding; Chugai: Research Funding; Ortho Biotech: Research Funding.