STRENGTHS AND LIMITATIONS OF THIS STUDY
This is a trial-based economic evaluation based on high-quality data on efficacy and costs collected from a randomised trial.
Utility scores were derived from previously published literature, which may also impair the robustness of our model.
Only grade 3–4 adverse events (AEs) were included, and the cost of grade 1–2 AEs was excluded from the study, which may undermine the robustness of the study.
Introduction
Multiple myeloma (MM), which is characterised by a clonal proliferation of plasma cells in the bone marrow, is the third most commonly diagnosed haematological malignancy. 1 In 2018, it was estimated that 159 985 new cases and 106 105 deaths related to MM occurred worldwide. 2 MM is considered incurable and always relapses continuously. In the past decade, a series of novel agents, such as bortezomib, lenalidomide and thalidomide, have been demonstrated to significantly prolong progression-free survival (PFS) and overall survival (OS) in patients with newly diagnosed multiple myeloma (NDMM). 3 , 7 Based on the results of these studies, combination therapies such as lenalidomide plus dexamethasone (Rd), bortezomib, melphalan and prednisone, and more recently, the combination of lenalidomide, bortezomib and dexamethasone are regarded as the standard of care for patients with MM who are not eligible for autologous stem-cell transplantation (ASCT).
Daratumumab, a human IgGκ CD38-targeting monoclonal antibody, was demonstrated to suppress tumours via direct antitumour effects and an immunomodulatory mechanism that results in the depletion of immunosuppressive cells and the clonal expansion of cytotoxic T cells. 8 , 10 Previously, the effect of daratumumab plus standard-of-care regimens in patients with at least one previous line of therapy was investigated in the CASTOR trial and POLLUX trial, which suggested that daratumumab significantly prolonged PFS and induced increased response rates. 11 12 Recently, the results of the ALCYONE trial, which investigated the effect of bortezomib, melphalan and prednisone with or without daratumumab in patients with NDMM who were ineligible for ASCT, were published. 13 14 After a median follow-up of 40.1 months, bortezomib, melphalan and prednisone with daratumumab (D-VMP) significantly prolonged OS and PFS compared with bortezomib, melphalan and prednisone (VMP). The HRs for death and progression in the D-VMP group compared with the VMP group were 0.60 (95% CI 0.46 to 0.80; p=0.0003) and 0.42 (95% CI 0.34 to 0.51; p<0.0001), respectively.
The substantial improvement in health outcomes indicated that D-VMP is a novel standard treatment regimen for NDMM patients who are ineligible for ASCT. However, the addition of daratumumab to VMP might also be associated with a greater cost than VMP, which could counterbalance the benefit achieved by the addition of daratumumab. Given the substantial increase in healthcare expenditures worldwide in recent years, a detailed pharmacoeconomic analysis to estimate the cost-effectiveness of novel regimens is essential. 15 The objective of this study was to evaluate the cost-effectiveness of D-VMP compared with that of VMP in patients with NDMM who were ineligible for ASCT from the US payer’s perspective.
Materials and methods
Model structure
To carry out the cost-effectiveness analysis, a decision-analytic Markov model was established to simulate the population in the ALCYONE trial, which contained two treatment scenarios, D-VMP versus VMP. The model included three exclusive health states, PFS, progressive disease (PD) and death, which reflected disease progression and mortality in patients with NDMM. All patients were expected to enter the model in the PFS state and transmit from one state to another state during the Markov cycles, as presented in figure 1 . The cycle length of the Markov model was set at 1.5 months for more accurate measurement of outcomes, and the time horizon was set at 20 years. The discount rate in the model was 3% per annum in the decision analytic model, and the willingness-to-pay (WTP) threshold was set at $150 000.00/QALY in the USA. TreeAge 2011 (TreeAge, Williamstown, Massachusetts, USA) was used for model creation and data analysis.
Population and treatment
A cohort population reflecting the participants of the ALCYONE trial was established. In the analysis, bortezomib was administered subcutaneously for up to nine in 6 week cycles (1.3 mg/m 2 body surface area (BSA) on days 1, 4, 8, 11, 22, 25, 29 and 32 of cycle one and on days 1, 8, 22 and 29 of cycles two through nine); melphalan was administered orally at a dose of 9 mg/m 2 once per day on days 1 through 4 of each cycle; and prednisone was administered orally at a dose of 60 mg/m 2 once per day on days 1 through 4 of each cycle. Moreover, patients in the D-VMP group received intravenous daratumumab at a dose of 16 mg/kg body weight, once per week during cycle one, once every 3 weeks in cycles two through nine and once every 4 weeks thereafter until disease progression or unacceptable toxicity.
Efficacy input
The efficacy data in the analysis were derived from the ALCYONE trial ( table 1 ). The survival data were extracted from the Kaplan–Meier curves using Web Plot Digitizer software ( https://apps.automeris.io/wpd/ ), and then, the transition probabilities were calibrated to fit the survival curves from the ALCYONE trial using Microsoft Excel ( figure 2 ). For adverse events (AEs), only those with a frequency greater than 5% were included in the model. The quality-adjusted life year (QALY), which is regarded as the gold standard measurement for effectiveness data, was used to measure the effectiveness of each group in the analysis. The utility values were obtained from previously published studies ( table 1 ). 16
Table 1
Key clinical data in the model
AEs, adverse events; D-VMPbortezomib, melphalan and prednisone with daratumumabPD, progressive diseasePFS, progression-free survivalVMPbortezomib, melphalan and prednisone
| Parameters | D-VMP | VMP | Distribution | Reference |
| Survival | ||||
| HR for death (95% CI) | 0.60 (0.46–0.80) | – | – | 14 |
| HR for progression (95% CI) | 0.42 (0.34–0.51) | – | – | 14 |
| 3 year OS rate (95% CI) | 78% (73.2–82.0%) | 67.9% (62.6–72.6%) | – | 14 |
| 3 year PFS rate (95% CI) | 50.7% (45.1–55.9%) | 18.5% (14.4–23.1%) | – | 14 |
| Median PFS (month, 95% CI) | 36.4 (32.1–45.9) | 19.3 (18.0–20.4) | – | 14 |
| Probability of AEs (grade 3–4) | ||||
| Neutropenia | 0.399 (0.319–0.479) | 0.387 (0.310–0.464) | – | 13 |
| Thrombocytopenia | 0.344 (0.275–0.413) | 0.376 (0.301–0.451) | – | 13 |
| Anaemia | 0.159 (0.127–0.191) | 0.198 (0.158–0.278) | – | 13 |
| Infection | 0.203 (0.162–0.244) | 0.147 (0.118–0.176) | – | 13 |
| Utility | ||||
| PFS | 0.897 (0.672–1.121) | 0.897 (0.672–1.121) | Beta | 16 |
| PD | 0.766 (0.575–0.958) | 0.766 (0.575–0.958) | Beta | 16 |
Cost input
The cost in the model included the cost of drugs, cost of administration, cost of follow-up (reflecting the frequency of drug administration), cost of tests and the cost of AE-related treatments. The unit prices of drugs were obtained from Red Book Online, and the unit costs of tests, drug administration, follow-up, tests and AE-related treatments were retrieved from the Centers for Medicare & Medicaid Services (CMS) clinical laboratory fee schedule files and previously published literature ( table 2 ). 17 , 19 To calculate the dose of drugs, patients with a height of 176 cm and a weight of 88.9 kg (BSA of 2.1 m 2 ) were assumed to reflect patients in the USA. 20 The subsequent treatment costs of each group after progression were estimated according to the proportion of patients who received regimens. As mentioned in the ALCYONE trial, 32.9% of patients in the D-VMP group and 56.7% of patients in the VMP group received subsequent therapy. The common subsequent therapies included an immunomodulatory drug-containing regimen without a proteasome inhibitor (42.6% in the D-VMP group and 49.5% in the VMP group), a proteasome inhibitor plus an immunomodulatory drug (20% in the D-VMP group and 10.4% in the VMP group), a proteasome inhibitor-containing regimen without an immunomodulatory drug (12.1% in the D-VMP group and 13% in the VMP group) and daratumumab-containing regimens (0.9% in the D-VMP group and 8.4% in the VMP group).
Table 2
Cost parameters input in the model
| Parameters | Value (range) | Distribution | Resource |
| Daratumumab (20 mg) | 127.132 (101.7056–152.5584) | Gamma | Red Book |
| Bortezomib (3.5 mg) | 1923.58 (1546.064–2319.096) | Gamma | Red Book |
| Melphalan (2 mg) | 12.2124 (9.76992–14.65488) | Gamma | Red Book |
| Prednisone (10 mg) | 0.53 (0.424–0.636) | Gamma | Red Book |
| Administration per unitCPT:96 365 | 74.16 (59.328–88.992) | Gamma | CMS |
| Neutropenia | 8593 (6874.4–10 311.6) | Gamma | 17 |
| Thrombocytopenia | 5020 (4016–6024) | Gamma | 17 |
| Anaemia | 5734 (4587.2–6880.8) | Gamma | 17 |
| Infections | 1192 (953.6–1430.4) | Gamma | 17 |
| Cost of monitoring | 180 (144–216) | Gamma | 18 |
| Routine follow-up of patients per unit | 422 (337.6–506.4) | Gamma | 18 |
| Cost of subsequent therapies (per month) | |||
| Regimen containing proteasome inhibitor without immunomodulatory drug | 9368.33 (7494.664–11 241.996) | Gamma | 19 |
| Regimen containing immunomodulatory drug without proteasome inhibitor | 10 381.33 (8305.064–12 457.596) | Gamma | 19 |
| Regimen containing proteasome inhibitor and immunomodulatory | 19 749.66 (15 799.728–23 699.592) | Gamma | 19 |
| Regimen containing daratumumab | 12 718.0 (10 174.40–15 261.60) | Gamma | 19 |
Sensitivity analyses
To evaluate the parameter uncertainty included in the model, a series of one-way sensitivity analyses were performed. The parameters ranged between ±20%, and the results of the one-way sensitivity analyses are presented as a tornado diagram. Subsequently, a probabilistic sensitivity analysis was carried out based on Monte Carlo simulations with 1000 iterations.
Patient and public involvement
Patients and/or the public were not involved in this study.
Results
Base case analysis
Over a lifetime horizon of 20 years, the D-VMP group was associated with an effectiveness of 6.91 QALY at a cost of $858 695.42, while the VMP group gained an effectiveness of 4.70 QALY at a cost of $357 387.82 ( table 3 ). Overall, the incremental effectiveness and cost of D-VMP versus VMP were 2.21 QALY and $501 307.6, which yielded an incremental cost-effectiveness ratio (ICER) of $226 836.02/QALY. The ICER was much greater than the US WTP threshold ($150 000.00/QALY), indicating that the addition of daratumumab to VMP may not be a cost-effective treatment option for patients with NDMM who are ineligible for ASCT.
Table 3
Base case results of the model
IECR, incremental cost-effectiveness ratioOS, overall survival; PFS, progression-free survival; QALY, quality-adjusted life year
| Model outcomes | D-VMP | VMP |
| Cost ($) | ||
| Costs in PFS | 684 999.90 | 100 587.49 |
| Costs in PD | 173 695.52 | 256 800.33 |
| Total costs | 858 695.42 | 357 387.82 |
| Incremental costs | 501 307.6 | – |
| Effectiveness (QALYs) | ||
| QALYs in PFS | 3.80 | 1.90 |
| QALYs in PD | 3.11 | 2.80 |
| Total effectiveness | 6.91 | 4.70 |
| Incremental effectiveness | 2.21 | – |
| ICER ($/QALY) | 226 836.02 | – |
Sensitivity analyses
The results of the one-way sensitivity analyses are presented in figure 3 . The cost of daratumumab, utility for PFS, cost of subsequent therapies in the VMP group and cost of subsequent therapies in the D-VMP group were the most influential factors in the study. The results of the probabilistic sensitivity analysis showed that the probabilities of D-VMP and VMP being cost-effective were 0% and 100%, respectively, at the WTP threshold of $150 000.00/QALY ( figure 4 ).
Discussion
In recent years, an increasing number of treatment options have emerged, and these options have significantly prolonged the survival time of patients with MM. Daratumumab is a human IgGκ CD38 monoclonal antibody. In the ALCYONE trial, D-VMP was demonstrated to be superior to VMP in prolonging the survival of patients with NDMM who were ineligible for ASCT. However, in the current study, we assessed the economic value of D-VMP versus VMP in NDMM patients based on the results of the ALCYONE trial. Overall, the incremental effectiveness and cost of D-VMP versus VMP were 2.21 QALY and $501 307.6, respectively, which yielded an ICER of $226 836.02/QALY. Based on the WTP threshold of $150 000.00/QALY, the addition of daratumumab to VMP may not be a cost-effective treatment option for patients with NDMM who are ineligible for ASCT.
In the past decade, daratumumab has been administered to patients receiving at least one previous line of therapy, and several studies have investigated the pharmacoeconomic profile of daratumumab in the setting of relapsed or refractory MM. Pelligra et al first reported a cost-effectiveness analysis to compare pomalidomide, carfilzomib and daratumumab in patients with heavily pretreated relapsed/refractory MM from a US payer’s perspective. 19 Overall, pomalidomide was associated with a similar increase in effectiveness compared with daratumumab and carfilzomib (incremental QALYs of 0.01 and 0.05, respectively). However, the cost of pomalidomide was less than that of daratumumab (incremental cost: -$8919) and that of carfilzomib (incremental cost: -$195), which indicated that pomalidomide, not daratumumab or carfilzomib, might be a cost-effective treatment option from the US payer’s perspective. In another study, the addition of daratumumab to Rd or bortezomib and dexamethasone (Vd) was also proven to not be cost-effective due to the high price of daratumumab. 21 Currently, triplet regimens (such as lenalidomide, bortezomib and dexamethasone (RVd) or thalidomide, bortezomib and dexamethasone (VTd)) are recommended as the standard induction therapies for transplant-eligible patients with NDMM. Recently, the GRIFFIN and CASSIOPEIA trials have suggested that the addition of daratumumab to RVd and VTd results in an improvement in the rate of minimal residual disease negativity. In a cost-effectiveness analysis conducted by Yamamoto et al , they compared first-line and second-line use of daratumumab for transplant-eligible patients with NDMM, which indicated that the addition of daratumumab to first-line RVd and VTd regimens is a dominant strategy compared with reserving its use in the second-line setting. 22 However, more than half of patients with NDMM are deemed ineligible for ASCT because of common comorbidities and complications of MM. Treatment initiation with a 2-drug regimen of Rd or triple therapy with RVd or bortezomib, melphalan and prednisone is generally recommended for standard-risk patients with NDMM who are ineligible for ASCT. Narsipur et al established a Markov model to compare the cost-effectiveness of three separate regimens—daratumumab, lenalidomide and dexamethasone triple therapy (DRd); bortezomib and lenalidomide plus dexamethasone triple therapy (VRd); and Rd in patients with MM ineligible for ASCT based on the MAIA and SWOG S0777 studies. 23 Ultimately, Rd therapy had a lower cost ($329 867) than VRd therapy ($385 434) and DRd therapy ($626 900). The progression-free QALYs (PFQALYs) were 1.24, 1.35 and 1.52 for the Rd, VRd and DRd therapies, respectively. With a WTP threshold of $150 000 per PFQALY, VRd was not cost-effective compared with Rd therapy (ICER: $530 256 per PFQALY). Compared with VRd (ICER: $1 396 318 per PFQALY) and Rd therapy (ICER: $1 060 832), DRd was not cost-effective. Recently, the results of the ALCYONE trial indicated that adding daratumumab to VMP is a novel standard treatment regimen for NDMM patients who are ineligible for autologous stem-cell transplantation. However, the addition of daratumumab to VMP might also be associated with a greater cost than VMP, which could counterbalance the benefit achieved by the addition of daratumumab. In a study conducted by Cao et al , a three-state Markov model was developed from the perspective of US payers to investigate the cost-effectiveness of D-VMP and VMP regimens. 24 Adding daratumumab to VMP provided an additional 3.00 LYs or 2.03 QALYs, at a cost of $262 526 per LY or $388 364 per QALY, which indicates that D-VMP was not a more cost-effective regimen than VMP. However, in another similar study directed by Li et al , the use of daratumumab plus VMP compared with VMP alone produced a gain of 3.931 LYs. 25 When adjusted for quality of life, D-VMP provided 5.593 QALYs, which was 2.417 QALYs more than for patients receiving VMP alone. The patients in the D-VMP group cost an additional $74 670, resulting in an ICER of $18 995/LY, or $30 893/QALY compared with the VMP group. The results of these two studies are completely different; therefore, further exploration is needed to address this issue. In this study, we explored the cost-effectiveness of daratumumab combined with VMP for the treatment of NDMM from a US payer’s perspective. The results of our study were similar to the study directed by Cao et al , which further confirmed that adding daratumumab to VMP was not a cost-effective treatment option in the setting of patients with NDMMwho were ineligible for ASCT.
Based on the results of the sensitivity analyses, the model was most sensitive to the cost of daratumumab, utility for PFS, the cost of subsequent therapies in the VMP group and the cost of subsequent therapies in the D-VMP group. Although the addition of daratumumab could significantly improve the survival of patients with NDMM, the high price of this novel drug might severely impair its benefit. Thus, the production of drugs with low price and high efficacy is urgently needed. In addition, the effectiveness of PFS for the D-VMP group and VMP group was 3.80 QALYs and 1.90 QALYs, respectively, and the effectiveness of the PD state for the D-VMP group and VMP group was 3.11 QALYs and 2.80 QALYs, respectively. Survival time in the PFS state was the key parameter influencing incremental effectiveness. Thus, selecting the subgroup of patients with the best survival benefit from D-VMP is highly important.
It should be addressed that this model has several limitations. The final analysis of OS in the ALCYONE trial was performed after 330 deaths were observed. The results of our model were based on a prespecified interim analysis for OS, and only 209 deaths were observed. Thus, updating the model when the final OS is published is highly important. Second, only the first subsequent line of treatment was considered in the model based on the published information of the ALCYONE trial to simplify the model. However, most patients receive multiple lines of therapy according to present practice. Third, the utility scores were derived from previously published literature, which may also impair the robustness of our model. Fourth, only grade 3–4 AEs were included, and the cost of grade 1–2 AEs was excluded from the study, which may undermine the robustness of the study. Fortunately, the results of the one-way sensitivity analyses demonstrated that the economic results were not sensitive to AE-related parameters.
Conclusions
In this study, we evaluated the cost-effectiveness of D-VMP compared with VMP in patients with NDMM who were ineligible for ASCT. Based on the results of the present study, D-VMP may not be a more cost-effective option than VMP from the US payer’s perspective.
Footnotes
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Prepublication history for this paper is available online. To view these files, please visit the journal online ( https://doi.org/10.1136/bmjopen-2023-076914 ).
Patient consent for publication: Not applicable.
Ethics approval: Not applicable.
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient and public involvement: Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.
Data availability statement
Data are available upon reasonable request.
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