Cost–effectiveness of lenalidomide plus low-dose dexamethasone for newly diagnosed multiple myeloma patients ineligible for stem cell transplantation in China

The constructed decision analytic model contained two treatment scenarios, Rd versus BCT, for the lifetime simulation in the model cohort of Chinese patients with ndMM. To simulate the survival outcomes and direct medical costs associated with the model cohort over the lifetime, the decision analytic model adopted a Markov model design to simulate ndMM and rrMM, respectively. The Markov model simulating ndMM and rrMM included health states for PFS, progressive disease survival (PDS) and death to simulate disease progression and mortality. The model cohort was simulated in the Markov model for ndMM under the two treatment scenarios. The patients with developed PDS from the Markov model for ndMM were further simulated in the Markov model for rrMM until patients were deceased. Based on the latest Chinese clinical guideline, the decision analytic model took Rd and two BCT, bortezomib plus dexamethasone regimen (VD), and bortezomib in combination with cyclophosphamide and dexamethasone (VCD) as the treatments for rrMM. Given the fact that rrMM was unlikely to respond to the treatments used in the previous treatment lines, Rd was selected as the treatment for rrMM in the patients who received BCT for ndMM in the model. Instead, VD and VCD were selected as the treatment for rrMM in the patients who received Rd for ndMM in the model. The cycle length of the Markov model for ndMM and rrMM was set to 1 month for more accurate measurement of outcomes, which included PFS, overall survival (OS), quality-adjusted life years (QALY) and lifetime direct medical costs. The decision analytic model discounted the health benefits and direct medical costs by 3% per annum by following the China Health Economics Evaluation Guideline. The structure of the decision analytic model assessing the cost–effectiveness of Rd relative to BCT for ndMM is illustrated in Figure 1.

The main source of the data used to estimate model variables was the relevant published literature that was found through systematic searches in the main English and Chinese bibliographic databases. The literature search time window was set between May 2013 and May 2018. Literature search strategies were developed according to the definitions of the model variables. The model variables for patient age and gender distribution were estimated through a single-arm meta-analysis of the reported age and gender from identified observational studies including Chinese ndMM patients [9–53]. The clinical effectiveness and the distributions of serious adverse events, which were defined as grade 3 or 4 adverse events and associated with Rd and BCT for ndMM and rrMM, were based on the collected data from identified randomized clinical trials [54–59]. The reported median progression-free survival (PFS) and OS associated with Rd and BCT were applied to a survival function formula [S(t) = e^-λt] to estimate the monthly risk of disease progression and monthly risk of mortality after disease progression. A single-arm meta-analysis approach was used for pooled estimation of the monthly risks of disease progression and mortality associated with the same treatment regimen. The overall therapeutic effect of BCT was estimated by a weighted average calculation of the distribution of specific treatment regimens and their corresponding absolute clinical efficacy. The reported serious adverse events associated with the same treatment in the identified randomized clinical trials were pooled to calculate the distributions that were used to estimate overall medical costs of managing serious adverse events per treatment cycle. The quality of life was rarely measured in Chinese MM patients. The identified studies [60–67] reporting quality of life associated with ndMM and rrMM in other countries were used to estimate the model variable for utility associated with PFS and PDS in ndMM and rrMM patients after the country adjustment, which was conducted by applying the ratio of the quality of life associated with the age- and gender-matched general populations of the study country and China [68–71]. Additionally, the quality of life measured by QLQ-C30 in the quality of life studies was converted to a utility value of EQ-5D using the conversion formula developed by Proskorovsky et al. [72]. The bottom-up method was used to estimate the model variables for drug acquisition costs according to drug price, treatment dosage, treatment schedule, treatment duration (treatment cycles) and patient body surface area estimated from the weighted mean of height and weight associated with Chinese ndMM patients in the identified observational studies. The medical costs associated with the management of serious adverse events of Rd and BCT in Chinese ndMM patients were estimated from an expert survey of adverse event management and the unit prices of health resources in a Chinese tier III tertiary care hospital. The medical costs associated with the treatment administration of bortezomib and rrMM were based on the estimations from a previous cost–effectiveness analysis assessing Rd relative to two bortezomib-based treatment regimens in Chinese rrMM patients [73]. All costs were adjusted to the Chinese currency in 2018 using Chinese historical annual inflation rate. The estimated model variables are summarized in Table 1.

The constructed decision analytic model with the estimated model variables was used to conduct the following cost–effectiveness analysis. First, the constructed decision analytic model with the base-case values of the model variables was used to conduct base-case analysis for the point estimation of PFS, OS, quality-adjusted life years (QALY) and the distributions of lifetime medical costs under the two treatment scenarios for Rd versus BCT. The point estimations of QALY and lifetime medical costs associated with two treatment scenarios were used to calculate the incremental cost–effectiveness ratio (ICER) per gained QALY for Rd relative to BCT. The recommended Chinese cost–effectiveness threshold, three-times the 2018 Chinese gross domestic product per capita (GDPPC) per gained QALY [74], was used to interpret the cost–effectiveness of Rd in the base-case analysis. Second, the constructed decision analytic model was used to conduct one-way sensitivity analysis to explore the change of ICER associated with the varying the 95% CI or the +/-25% of the base-case value of each model variable. Finally, the constructed decision analytic model with β distributions of model variables for model cohort demographics and clinical efficacies associated with Rd and BCT for ndMM and rrMM was used to conduct a probabilistic sensitivity analysis through 10,000 Monte Carlo simulations. The generated ICERs from the 10,000 simulations were plotted to estimate the median value and 95% credible interval of ICER for Rd relative to BCT. The cost–effectiveness acceptability curve for Rd relative to BCT was created under the willingness-to-pay per gained QALY from zero to three-times the 2018 Chinese GDPPC.

This study used R statistical software to conduct data analysis regarding the estimations of the model variables from the collected data from the literature review. Microsoft Excel 2013 was used to construct the decision analytic model and perform the cost–effectiveness analysis.

The lifetime simulation of the constructed decision analytic model without discounting projected that Rd was associated with 0.597 years (5.496 vs 4.899 years) than BCT in Chinese ndMM patients. Further comparisons of the survival types associated with the two treatment scenarios indicated that the gained PFS associated with Rd for ndMM accounted for 72.2% of the gained OS associated with Rd. Based on the plotted OS curves associated with the two treatment scenarios (Figure 2), Rd was associated with higher median OS (58 vs 51 months) and also 5-year survival rate (48.6 vs 41.2%) compared with BCT in the Chinese ndMM patients. When taking into account the quality of life associated with the model health states, the Rd treatment was associated with more QALY than the BCT treatment scenario over the lifetime simulation of Chinese ndMM patients (3.384 QALY vs 2.966 QALY, QALY gain: 0.418). Because PFS had a higher quality of life than PDS, the gained QALY through PFS associated with Rd accounted more for all gained QALY (76.3%) when compared with the proportion of gained PFS in the gained OS under the Rd treatment scenario. The health outcomes associated with the two treatment scenarios over the lifetime model simulation are summarized in Table 2.

The lifetime simulation of the constructed decision analytic model without discounting projected that the Rd treatment scenario was associated with ¥19,031 more lifetime medical costs than the BCT treatment scenario (¥483,787 vs ¥464,756, ¥1 = US $0.15 as of December 2018). The comparisons of the distributions of lifetime direct medical costs by the classified categories indicated that the Rd treatment scenario saved ¥35,599 for treatment administration, ¥12,225 for the management of serious adverse events and ¥35,940 for the management of rrMM. However, these saved costs associated with the Rd treatment scenario could not fully offset the increased drug acquisition costs of Rd over BCT (¥258,305 vs ¥156,127). The distribution of undiscounted lifetime medical costs associated with the two treatment scenarios is summarized in Table 2.

With discounting the QALY and direct medical costs in the constructed decision analytic model, the base-case analysis estimated that the Rd treatment scenario was associated with more gained QALY (3.032 QALY vs 2.679 QALY, difference: 0.354 QALY) and also higher lifetime direct medical costs (¥455,527 vs ¥437,920, difference: ¥17,607). The calculated point estimation of ICER per gain QALY for Rd relative to BCT was ¥49,793, which is slightly lower than the 2018 Chinese GDPPC (¥64,644). Thus, the cost–effectiveness of Rd relative to BCT for ndMM in Chinese patients was found to be highly attractive according to the cost–effectiveness threshold recommended by WHO.

The performed one-way sensitivity analysis identified that the change of ICER per gained QALY associated with Rd relative to BCT under the uncertainty of model variables ranged from a reduction of ¥113,549 under the number of VTD treatment cycles for ndMM to an increase of ¥301,353 under the 95% CI of the monthly risk of disease progression associated with PAD for ndMM. Among the model variables reducing the ICER per gained QALY associated with Rd, the treatment cycles and monthly risk of disease progression associated with BCT and the quality of life of ndMM patients under Rd treatment could reduce the ICER over ¥50,000. Among the model variables increasing the ICER per gained QALY associated with Rd, the monthly risk of disease progression under VTD regimen and PAD regiments and the treatment cycles of Rd in ndMM patients could increase the ICER per gained QALY for Rd versus BCT by over ¥50,000. The results of the one-way sensitivity analysis are illustrated in Figure 3. Additionally, the price of lenalidomide was expected to be changed in the future, the impact of reducing the price of lenalidomide on the cost–effectiveness was assessed. The cost–effectiveness of Rd relative to BCT for ndMM in Chinese patients was dominant when the price of lenalidomide was reduced by 20% or more (Figure 4).

Based on the plotted distribution of the 10,000 ICERs from the Monte Carlo simulations, the median ICER associated with Rd was ¥32,294 per gained QALY with a 95% credible interval that ranged from -¥473,973 to ¥573,580. If taking one- to three-times the 2018 GDPPC as the cost–effectiveness thresholds, the cost–effectiveness proportions of Rd relative to BCT for ndMM in Chinese patients were 69.1, 84.9 and 90.8%, respectively. The cost–effectiveness acceptability curve associated with the two treatment scenarios under the cost–effectiveness threshold from one- to three-times of 2018 Chinese GDPPC is illustrated in Figure 5.