A Systematic Review of Cost-Effectiveness Analyses of Novel Agents in the Treatment of Multiple Myeloma

Simple Summary New treatments in multiple myeloma are embraced by patients and physicians but are also associated with substantial higher costs. To ensure the affordability and accessibility of health care, an evaluation of the outcomes in relation to the costs is increasingly requested. However, an up-to-date summary and assessment of the cost-effectiveness evidence for multiple myeloma treatments is currently lacking. We identified the cost-effectiveness studies currently available and show that novel treatments could improve survival with almost 4 years compared to standard of care. However, additional costs compared to standard of care could increase up to USD 535,530 per patient. The ratio between outcomes and costs is above currently accepted willingness to pay thresholds. Our results show cost-effectiveness ratios should be either improved or less favorable ratios should be accepted to ensure accessibility to promising treatments. Abstract Background: Novel therapies for multiple myeloma (MM) promise to improve outcomes but are also associated with substantial increasing costs. Evidence regarding cost-effectiveness of novel treatments is necessary, but a comprehensive up-to-date overview of the cost-effectiveness evidence of novel treatments is currently lacking. Methods: We searched Embase, Medline via Ovid, Web of Science and EconLIT ProQuest to identify all cost-effectiveness evaluations of novel pharmacological treatment of MM reporting cost per quality-adjusted life year (QALY) and cost per life year (LY) gained since 2005. Quality and completeness of reporting was assessed using the Consolidated Health Economic Evaluation Reporting Standards. Results: We identified 13 economic evaluations, comprising 32 comparisons. Our results show that novel agents generate additional LYs (range: 0.311–3.85) and QALYs (range: 0.1–2.85) compared to backbone regimens and 0.02 to 1.10 LYs and 0.01 to 0.91 QALYs for comparisons between regimens containing two novel agents. Lifetime healthcare costs ranged from USD 60,413 to 1,434,937 per patient. The cost-effectiveness ratios per QALY gained ranged from dominating to USD 1,369,062 for novel agents compared with backbone therapies and from dominating to USD 618,018 for comparisons between novel agents. Conclusions: Cost-effectiveness ratios of novel agents were generally above current willingness-to-pay thresholds. To ensure access, cost-effectiveness should be improved or cost-effectiveness ratios above current thresholds should be accepted.


Introduction
In the last decades, the prognosis of patients with multiple myeloma (MM) improved substantially mainly due to the expanded therapeutical armamentarium [1]. Novel agents, were excluded. Studies reporting on cost-effectiveness of bone marrow transplantation, supportive care, prevention, palliative care, radiotherapy, surgery were excluded thereafter. At last, we only included studies with outcomes of the novel medicines daratumumab, pomalidomide, carfilzomib, elotuzumab, ixazomib and panobinostat, both monotherapy and in combination with other regimens.

Information Sources and Search Strategy
Embase, Medline via Ovid, Web of Science and EconLIT ProQuest were searched on the 25 February 2021. The full search strategy is available in Supplemental A. Results were de-duplicated in Endnote and imported in Rayyan (https://www.rayyan.ai/, last accessed on 29 August 2021). Two authors (M.R.S. and S.D.) independently screened all studies for eligibility, see Supplemental B for criteria. Disagreement was resolved through mutual discussion, and by arbitration by two additional authors (D.G.J.C. and H.M.B.) if necessary.

Data Extraction
We then extracted relevant data using a standardized data extraction form. This data extraction form included the study title and year, author, drugs of interest, total drug costs, LYs, QALYs, Incremental Cost-Effectiveness Ratio (ICER calculated as total costs per incremental LY or QALY) per LY or QALY, time horizon, mathematical model used, discount rates, perspective (e.g., payer or societal perspective), funding and country. QALYs include both quantity and quality of life and are calculated by multiplying life years by the quality of life. Utility values range from one to minus infinity. One represents perfect health and zero represents death. To calculate ICERs, the total costs of regimen A minus the costs of regimen B (incremental costs) are divided by the difference in effects of regimen A and B (incremental LYs or QALYs). ICERS were reported by their reference year and (country-specific) inflation was not implemented.

Quality Assessment
The quality and completeness of reporting was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) [23]. A study that scored below 14 out of 24 items was deemed to be of low reporting quality, [14][15][16][17][18][19] was moderate, and a study was of good reporting quality when scored 20 or higher [24].

Reporting Outcomes and Analysis
We visualized study selection with a PRISMA flowchart ( Figure 1) and tabulated the characteristics and outcomes of the included studies (Table 1). To assess similarities and differences in cost-effectiveness outcomes, we converted a currency different than USD to USD using the currency rate on 1 July 2021 of the IMF [11].   Table S1. ** Reported in the report of Institute for Clinical and Economic Review ("ICER") [33].

Results
We identified and screened a total of 2646 single records. We excluded 2541 records based on title and abstract and reviewed full texts of 105 studies. In the final review, we included a total of 13 studies, (Figure 1). In all studies together, 32 comparisons were made, including comparisons between different lines of therapy. The comparisons included a total of 11 unique intervention regimens and eight different comparators. A summary of the included studies is presented in Table 1 [26][27][28][29][30][31][32][33][34][35][36][37][38].

Daratumumab
Three studies assessed the ICERs of the addition of daratumumab added to a backbone of Rd and/or bortezomib-dexamethasone (Vd) [27][28][29]. The ICER per QALY gained for daratumumab-Rd (DRd) versus Rd ranged from USD 187,728 to USD 1,369,062 [28,29]. The ICER per QALY gained for DVd versus Vd was USD 213,164 and USD 284,180 in two studies [27,28] One study evaluated DVd against Rd and calculated an ICER per QALY gained of USD 50,704 in second line and USD 60,359 in third line [29]. Moreover, daratumumab monotherapy was compared with pomalidomide monotherapy (Pom) for which the ICERs per QALY gained were USD 156,385 [25]. Daratumumab monotherapy was dominated by pomalidomide-dexamethasone (Pom-d) in another study [26]. All outcomes are presented in Table 2.

Pomalidomide
Two studies evaluated the ICERs of pomalidomide. Pom-d was associated with a higher number of LYs and QALYs compared to a high dose of dexamethasone monotherapy (HiDex), though with higher costs, resulting in an ICER of USD 93,304 per QALY gained [30]. Pelligra et al. compared Pom-d to Kd and showed better outcomes at lower costs for Pom-d [26].

Elotuzumab
Clinical data of the ELOQUENT-2 study were used in two studies evaluating the addition of elotuzumab to Rd (ERd). Calculated QALYs gained with ERd were comparable in both studies independent whether it was used as second or third line of therapy. The ICERs per QALY gained of ERd versus Rd were rather similar in the two studies and around USD 430,000 in second line and USD 480,000 in third line [29,32].

Ixazomib
In three studies Ixazomib-Rd (IRd) was compared to Rd and in one of these studies also to Vd. Both of the studies comparing IRd with Rd used clinical data of the TOURMALINE-MM1 study and showed comparable ICERs per QALY gained (second line: USD 454,684 versus USD 433,794 and third line: USD 508,021 versus USD 484,582) [29,32]. In the third study comparing IRd with Vd and Rd, the ICERs per QALY gained were lower, USD 94,455 and USD 228,030, respectively [37].

Panobinostat
Panobinostat in combination with Vd (Pano-Vd) dominated Rd in two studies, with lower costs and better outcomes. Incremental LYs were 1.68 and 2.02 and QALYs 1.19 and 1.42 [29,33].

Second vs. Third Line of Treatment
In addition to separate studies, the cost-effectiveness of KRd, IRd and ERd compared with Rd was described in a report by the Institute for Clinical and Economic Review ("ICER"). The ICERs per QALY gained of this report were presented in the article of Djatche et al. and were lower in second line versus third line [32,33]. The ICERs were also lower in second versus third line in the study of Carlson et al., comparing DVd, DRd, KRd, ERd and IRd with Rd (Table 2) [29].

First vs. Second Line of Treatment
Patel et al. compared daratumumab in first line with daratumumab in second line of treatment. In the used model, patients who received DRd in first line got Kd subsequently, while patients who received Rd in first line were treated with daratumumab-Kd (DKd) in second line. Lifetime healthcare costs were higher when daratumumab was used in the first line of treatment versus second line (USD 1,434,937 versus USD 1,112,101). The LYs and QALYs gained were higher over the first two lines of therapy when daratumumab was prescribed in first line (4.87 vs. 4.34 QALYs), resulting in an ICER of USD 618,018 per QALY gained [38]. All incremental costs, incremental QALYs and corresponding ICERs are depicted in Figure 2.
Our results show that novel agents generate additional LYs ranging from 0.311 to 3.85, and additional QALYs ranging from 0.1 to 2.85 compared to backbone regimens. Comparisons between regimens containing two novel agents resulted in 0.02 to 1.10 LYs and 0.01 to 0.91 QALYs gained. This comes with high costs: lifetime healthcare costs ranging from USD 60,413 to USD 1,434,937 per patient and incremental costs compared to backbone therapies ranging from dominated to USD 535,530 per patient [25][26][27][28][29][30][31][32][34][35][36][37][38] The ICERs we found were in only 12 (out of 32) comparisons beneath the generally accepted willingness-to-pay (WTP) threshold of USD 150,000 per QALY gained in the USA [25][26][27][28][29][30][31][32][33][34][35][36][37][38]56]. Three of these were comparisons between two novel treatment; thus, only nine comparisons were between a backbone therapy combined with a novel agent and a backbone therapy only. The European WTP thresholds in a systematic review from 2013 and later were between USD 10,196 and USD 34,097 per QALY gained [12,57]. However, higher WTP thresholds are reported by Health Technology Assessment (HTA) agencies (e.g., up to USD 95,072 in the Netherlands) [58]. Nevertheless, none of the ICERs per QALY gained (except for dominating regimens, i.e., Pano-Vd and comparisons between Pom-d and daratumumab monotherapy and Kd) fell below the WTP threshold of USD 34,097 [25][26][27][28][29][30][31][32][33][34][35][36][37][38]57] With the WTP threshold of USD 150,000 per QALY gained taken in account, compared with backbone therapies Vd and Rd, carfilzomib and panobinostat are below the WTP in most cases [29,31,[33][34][35]. The ICER per QALY gained of pomalidomide is below the WTP threshold against Kd, daratumumab monotherapy and HiDex [25,26,30]. Although daratumumab, elotuzumab and ixazomib are associated with great gains in LYs and QALYs, these medicines result in an ICER per QALY gained above USD 150,000 in most cases [25,[27][28][29]32,37]. Costs are in many cases too high, making accessibility a concern. Our results show that accessibility to these novel promising medicines can only be realized if either the costs are reduced substantially, for example with price negotiations, or by accepting that the ratio between the additional benefits and the costs are above the currently known WTP thresholds (i.e., increase the WTP thresholds for MM treatments).
The regimen with the most favorable results was Pano-Vd, as this regimen dominated Rd in two studies that used clinical data of the PANORAMA-1 study [29,33]. It should be noted that Pano-Vd might not be the preferred treatment from a clinical or patient perspective, when taking other factors into account, such as adverse events [54]. The least favorable results were obtained in one study comparing DRd with Rd with an ICER of USD 1,369,062 per QALY gained, although another study conflicted with these results with ICERs per QALY gained of USD 187,728 in second line and USD 216,360 in third line with the same regimens. Although the total costs for DRd were similar in both studies, the estimated costs for Rd and the outcomes (both Lys and QALYs) show large differences. Outcomes reported by Carlson Zhang et al. (2018) base their estimates on 10 years while their model estimates show more than 30% of the patients is still alive at that time. By restricting the time horizon to 10 years, outcomes of these patients beyond 10 years are not included in their estimates [28,29].
Two studies made a total of eight comparisons between regimens in second and third line of treatment. In all cases, the incremental QALYs were higher in second line and ICERs per QALY gained were lower in second line [29,32]. One study compared daratumumab in first versus second line, in this case daratumumab in second line was more cost-effective [38].
Although most papers scored well on the CHEERS checklist, few papers characterized heterogeneity and/or provided reasons for the underlying model and discount rates. A discount rate of 3% was used in all, except one study (i.e., 92%) in our review against 71% in Asrar et al. 2020 [15,25]. Gaultney et al. reported in 2009 that only 23% of their included economic evaluations used a discount rate [21]. This implies that the reporting quality of cost-effectiveness studies is improving over time. However, only seven papers characterized heterogeneity and seven provided reasons for the underlying model [25][26][27]29,31,37,38]. This impedes comparability and we suggest these as areas for improvement for reporting future cost-effectiveness studies.
There are some limitations to this systematic review. First, we only included evidence of cost-effectiveness evidence available through peer-reviewed publications. Additional cost-effectiveness evidence is generated through national HTA bodies such as the National Institutes of Care and Excellence (NICE) in the United Kingdom [59,60]. All novel agents described in this study underwent review by NICE and the corresponding HTA reports are publicly available through the NICE web site [61]. Future studies could additionally take data from national HTA bodies into account for systematic review. Second, ICERs were reported by their reference year and (country-specific) inflation was not implemented. This possibly leads to a small underestimating of costs in older studies, although all included studies were of 2016 and later.
In the near future, some of the discussed drugs will be out of patent, for example lenalidomide in 2022 [62]. We expect that generic variants of these drugs will be sold at lower prices than the prices used in the currently identified publications [63]. The impact of lower prices for generics on the cost-effectiveness will depend on the regimens that are compared. If the price of a backbone drug is lower but present in both regimens of the comparison, the impact on the ICERs is negligible. Nevertheless, an update of our research in the future could provide more insight in the impact of generic variants on the cost-effectiveness.
All economic evaluations described estimated treatment effects based on data from RCTs. However, generalizability of findings from RCTs to the real-world population is poor [64,65]. Furthermore, all studies included in this review used drug list prices, potentially overestimating true costs for resource use. These factors might lead to overestimation of drug effectiveness and resource use, resulting in inaccurate cost-effectiveness estimates. Future studies should aim to additionally include real-world evidence, for example generated through expanded access pathways of experimental drugs [66][67][68].

Conclusions
This systematic review gives insight in the current progress in cost-effectiveness studies of the novel agents daratumumab, pomalidomide, carfilzomib, elotuzumab, ixazomib and panobinostat. We hereby set the stage for future systematic reviews for cost-effectiveness analyses reporting quality according to the CHEERs guidelines and allowing for comparisons between regimens and hopefully sequential treatment paradigms in the future.
To ensure access to novel, better treatments for MM patients now and in the future, there should be a paradigm shift toward improving cost-effectiveness. For example, by using dosing schemes with more favorable cost-effectiveness ratios, or by lowering prices with price negotiations by health care payers. If this is not possible, we should wonder whether we are on the right path with increasing costs, while WTP thresholds remain on the same level.