Cost-Effectiveness of Frailty-Adjusted Therapy in Transplant Non-Eligible Patients with Newly Diagnosed Multiple Myeloma - an Economic Evaluation of the Fitness Trial
Authors: Dawkins Bryony , Gkountouras Georgios , Meads David , Pawlyn Charlotte , Royle Kara-Louise , Senior Ethan R , Everritt Dax , Bird Jenny , Bowcock Stella , Drayson Mark , Gillson Sharon , Olivier Catherine , Jenner Matthew W. , Jones John R , Kaiser Martin F , Kishore Bhuvan , Rabin Neil , Owen Roger G , de Tute Ruth M , Parrish Christopher , Cairns David A. , Chant Alan , Jackson Graham , Cook Gordon 
Published: December 2024

Introduction: Older and frailer patients with multiple myeloma (MM) are less able to tolerate some therapies which may explain the inferior health outcomes they experience. The UK Myeloma Research Alliance Myeloma XIV FiTNEss trial (NCT0372004) is a phase III, multi-centre, randomised controlled trial for newly diagnosed MM patients not eligible for stem cell transplant that compares a standard (reactive) therapeutic dosing strategy (RT) to a pre-emptive frailty-adjusted dosing strategy (FA). FA uses IMWG-based scores to determine patients' level of frailty and adapts the dosing strategy accordingly in an effort to reduce toxicity and early treatment cessation. We conducted an economic evaluation alongside the FiTNEss clinical trial to determine the value of FA vs RT in Unfit/Frail patients over 12 months.
Methods: The FiTNEss trial randomised newly diagnosed MM patients to either standard reactive dose modification in light of toxicity (RT) vs upfront pre-emptive dose-modification according to IMWG FS (FA), of induction therapy comprising the oral triplet ixazomib, lenalidomide and dexamethasone (IRd). The primary end point of the first randomisation was to compare early treatment cessation of induction therapy delivery with the triplet IRd between patient cohorts. The primary endpoint of the second randomisation was to compare progression free survival for maintenance lenalidomide (R) plus placebo and lenalidomide plus ixazomib (IR). The economic evaluation adopted the cost-utility framework and presents cost per quality-adjusted life year (QALY). Health-related quality of life (HRQoL) was captured on the EQ-5D-3L measure at baseline, 2, 6 and 12 months. Health care resource use was captured using patient reported forms at the same time points, supplemented by hospital incident forms. Costs included resources required for the frailty assessment, medication costs (including second line therapies for those progressing or stopping first line therapy), primary care costs (e.g. GP visits) and secondary care costs (e.g. hospital visits and stays). We conducted a complete case (CC) analysis, using cases who had provided full cost and HRQoL follow-up data, and an intention-to-treat (ITT) analysis using multiple imputation to deal with missing data. Estimates were adjusted for trial minimisation factors. We present cost and QALYs per trial arm and incremental cost-effectiveness ratios (ICERs). Sampling uncertainty is characterised in the probability of cost-effectiveness given the UK willingness to pay for QALY gains (£20,000-£30,000).
Results: The FiTNEss trial recruited 733 patients from 04/08/2020 until 01/03/2024 from 84 sites in the UK; 535 patients were Unfit/Frail. The cost of the frailty assessment was modest (£28.50 based on an assumed 30 minutes of research nurse time). A total of 163 patients were included in the CC sample. The number of treatment cycles completed was slightly higher among Unfit/Frail in the FA arm (7.84 [95%CI 7.3:8.39] vs 7.73 [95%CI 7.19:8.27], p=0.78). Mean per patient primary care costs were lower in the FA arm (£107 [95%CI £75:£138] vs £194 [95%CI £112:£276], p=0.05); but mean secondary care costs were higher in the FA arm (£3,582 [95%CI £2324:£4841] vs £2,036 [95%CI £1295:£2777], p=0.04), driven by higher unplanned hospital admitted days. The adjusted differences in costs and QALYs between trial arms for the CC analysis were £7,431 [95%CI £-3532:£18394, p=0.14] and 0.072 ([95%CI 0.022:0.141], p=0.07) (ICER = £103,208), respectively; and for the ITT analysis were £250 [95%CI £-6841:£7340, p=0.95] and 0.02 ([95%CI -0.021:0.06], p=0.35) (ICER = £12,943), respectively. Thus, FA was more costly on average when considering medication and health care use costs but offered QALY gains over RT. At the UK cost-effectiveness threshold of £20,000-30,000 FA has a 52-54% probability of cost-effectiveness.
Conclusions: This preliminary analysis suggests that frailty-adjustment of induction therapy in newly diagnosed TNE MM is likely to lead to non-trivial benefits in QALYs over 12 months, but higher levels of secondary care use and medication costs compared to standard dosing. Based on the ITT analysis, the FA strategy is likely to be considered cost-effective in Unfit/Frail patients. Future planned research extrapolating HRQoL benefits over a longer time horizon, where cheaper maintenance therapies are used, may give a more accurate estimate of the value of FA.