Фармакоэкономическая оценка карфилзомиба против ixazomib для лечения повторной и рефрактной множественной миеломы.

Introduction

Multiple myeloma (MM) is a malignant hematologic tumor primarily characterized by the clonal proliferation of plasma cells and the overexpression of monoclonal immunoglobulins. It often results in organ damage, manifesting as anemia, hypercalcemia, multiple osteolytic lesions, and renal insufficiency [ 1 ]. MM accounts for approximately 10% of all hematologic malignancies. Up to 63% of diagnosed patients are over the age of 65, making it the second most common malignancy in the hematologic system [ 2 ]. A study on the burden of MM in China revealed that the disease burden of MM has risen significantly from 1990 to 2021, with a notable increase in prevalence by 14.8%. In 2021, the age-standardized incidence rate, mortality rate, and prevalence in China were 0.8 per 100,000 (95% uncertainty interval [UI], 0.5–1.1), 0.6 per 100,000 (95% UI, 0.4–0.8), and 2.2 per 100,000 (95% UI, 1.4–2.9), respectively. Compared with female patients, male patients had a higher disease burden in terms of incidence, mortality, prevalence, and disability-adjusted life-years (DALYs). The incidence and mortality rates of MM gradually increased from the age group of 20–24 years. Regarding regional disparities, the highest disease burden was observed in provinces with the highest per capita GDP [ 3 ]. Due to the rapid growth and incurable nature, MM’s five-year survival rate in China is only 25% [ 4 ]. Moreover, MM significantly impairs patients’ quality of life through bone pain, osteoporosis, fractures, and renal dysfunction. Current medical technology has yet to cure MM, with patients inevitably facing relapse and resistance to traditional therapeutic drugs, leading to refractory myeloma. The remission rate post-relapse is diminishing, and the survival prognosis is grim [ 5 ].

Since MM is incurable, almost all patients will experience relapses and remissions after treatment, resulting in high long-term treatment costs. Published international retrospective studies have shown that MM patients receiving second-line or subsequent treatments have to bear substantial costs [ 6 ]. The treatment of MM is mostly chemotherapy-based, which requires high medical conditions and often consumes a lot of medical resources, posing a significant economic burden on patients. Peking University People’s Hospital used the national urban employee and urban resident medical insurance database from 2012 to 2016 to analyze the direct medical costs of Chinese MM patients and found that the total treatment cost of MM patients is composed of drug costs and medical service costs. Data statistics from 2012 to 2016 show that the main part of the cost expenditure is drug costs, which account for more than 60%. Compared with medical service costs, drug costs are the largest part of the treatment costs for MM [ 7 ]. Studies both at home and abroad have shown that drug costs account for the main part of the treatment costs for MM.

The advent of proteasome inhibitors has marked a significant advancement in MM treatment. The 2023 edition of the Clinical Oncology Society of China (CSCO) and the revised guidelines for the diagnosis and treatment of MM in China (2022) suggest that for patients with relapsed and refractory multiple myeloma (RRMM), the first relapse should ideally be treated with a combination chemotherapy regimen that includes proteasome inhibitors (carfilzomib, ixazomib, and bortezomib), immunomodulatory agents (pomalidomide and lenalidomide), and possibly other agents, aiming for a 3–4 drug combination to achieve the greatest degree of remission and prolong progression-free survival (PFS). The National Comprehensive Cancer Network (2024 NCCN) also recommends combination therapies involving proteasome inhibitors, immunomodulatory agents, and chemotherapy as a category 1 recommendation for patients with RRMM who have undergone 1–3 lines of treatment.

Carfilzomib for injection is a new-generation proteasome inhibitor used to treat RRMM. The ASPIRE study [ 8 ] demonstrated that carfilzomib, lenalidomide, and dexamethasone (KRd) achieved deeper responses and longer survival compared with chemotherapy regimens, with a 9.5-month and 7.9-month increase in progression-free survival (PFS) and overall survival (OS), respectively. Additionally, the rates of complete response (CR) and very good partial response (VGPR) were significantly improved. As of June 2020, a post hoc analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) indicated that the incidence of peripheral neuropathy was 2.1% with carfilzomib, 5.0% with ixazomib, and 10.9% with bortezomib, highlighting the relatively lower risk of this adverse event with carfilzomib [ 9 ].

Ixazomib and carfilzomib are both second-generation proteasome inhibitors. The phase III clinical study TOURMALINE-MM1[ 10 ] and its extension trial in China [ 11 ] showed that the ixazomib, lenalidomide, and dexamethasone (IRd) regimen had good efficacy and safety in treating RRMM, significantly prolonging patients’ PFS and substantially reducing the risk of death compared with the control group. Moreover, the oral administration of ixazomib enhances patient compliance and avoids infusion reactions.

Clinical studies registered in China [ 11 , 12 ] have shown that both carfilzomib and ixazomib exhibit good efficacy and safety in treating RRMM. Although there are differences between the two in terms of administration routes, adverse event profiles, and patient suitability, both significantly improve patient prognosis. These two proteasome inhibitors have been widely used to treat RRMM. Given the lack of direct comparative data and the high treatment costs, it is necessary to evaluate the relative clinical and economic outcomes of the KRd VS IRd to support and inform clinical treatment decisions and to provide a basis for formulating strategic drug policies.

Methods

Population, intervention, and comparator

Data for the KRd were derived from the ASPIRE trial [ 8 ], a phase III, randomized, multicenter study involving patients with RRMM who had received the frontline to the backline treatment. Carfilzomib was administered at an initial dosage of 20 mg/m 2 on day 1 and 2, escalating to a maintenance dosage of 27 mg/m 2 via intravenous injection. Lenalidomide was given at a dosage of 25 mg daily from day 1 to day 21 of each cycle. Dexamethasone was administered at a dosage of 40 mg on four consecutive days per cycle. Owing to long-term safety considerations, patients initially on KRd transitioned to Rd after completing 18 cycles. The primary efficacy endpoint was PFS, with secondary endpoints including OS and overall response rate (ORR).

The IRd regimen data were sourced from the TOURMALINE-MM1 trial [ 13 ], an international, multicenter, randomized, double-blind, placebo-controlled phase III study in patients with RRMM who had at least frontline treatment. Ixazomib was administered orally at a dosage of 4 mg on day 1, 8, and 15 of each cycle. Lenalidomide and dexamethasone were administered orally at the same dosages as in the KRd regimen. Treatment continued until disease progression or death. The primary efficacy endpoint was PFS, with OS as a key secondary endpoint. Both trials followed a 28-d administration cycle.

Model structure

A PSM was developed in EXCEL 365 from a healthcare perspective, with health states including progression-free, progressed disease, and death ( Figure 1 ).

The model assumed that patients initially present in a progression-free state, receiving either KRd or IRd as their primary treatment regimen. As time progresses, patients may either maintain this state, transition to progressive disease (PD) state, or death state. Patients in the PD state can either remain in that state or transition to the death state.

In the absence of explicit subsequent treatment plans for patients in PD in the TOURMALINE-MM1 clinical trial, this study adopts recommendations from the 2024 NCCN Guidelines for MM and the Chinese Guidelines for the Diagnosis and Treatment of MM (2022 Edition). These guidelines suggest the potential use of a combination therapy involving daratumumab, pomalidomide, and dexamethasone as a subsequent treatment option.

Clinical trial data inform the assumption that 46.0% of patients in the carfilzomib group who experience disease progression continue to receive active anticancer therapy, while this proportion is 71.4% for the ixazomib group [ 8 , 13 ]. It is posited in the study that patients who have not received anticancer treatment are receiving the best supportive care. The model in this study accounts for lifetime horizon outcome with a cycle length of 28 d, consistent with the dosing intervals observed in clinical trials.

Network meta-analysis

Given the absence of head-to-head clinical trials directly comparing KRd and IRd, this study employed network meta-analysis (NMA) to obtain indirect comparative evidence. The trials included in the analysis all specified similar inclusion criteria. Each trial enrolled adult patients aged ≥18 years with measurable RRMM. All patients had previously received treatment and had adequate renal, hepatic, and hematologic function. The trial populations were also similar with respect to age, Eastern Cooperative Oncology Group (ECOG) performance status, International Staging System (ISS) stage, receipt of prior stem cell transplant, and the number and distribution of prior treatment regimens.

The NMA was conducted using the “gemtc” package in R version 4.2.2 (R Foundation for Statistical Computing, Vienna, Austria), with binary outcomes expressed as hazard ratios (HRs) and 95% confidence intervals (CIs). Since the analysis was based on single-study connections, a fixed-effects model was used to preserve the statistically significant effects observed in the trials. The relationships between interventions were visualized using a network diagram, where each node represents an intervention and the size of the node indicates the sample size of the intervention. A connection between two nodes indicates a direct comparison. Heterogeneity among studies in the indirect comparisons was assessed using the I 2 statistic. For the included studies, heterogeneity was considered substantial when I 2 > 50%, and minimal when I 2 ≤ 50%. Convergence diagnostic plots and trace density plots were constructed to evaluate the robustness of the NMA model and the uncertainty distribution of the parameters.

Survival analysis

Clinical trial follow-up data were sourced from survival curves as reported in the ASPIRE and TOURMALINE-MM1 studies. The Kaplan–Meier (K-M) curves commonly used to model OS and PFS, with median survival times listed in the accompanying Table 1 . Supplementary Figures 1 and 2 display the K-M curves for both PFS and OS. The PFS curve offers a direct measure of the fraction of patients, noted as S(t) 2 , who persist in a state free from disease progression. The deceased patient proportion is determined by taking the survival probability from the OS curve at each time point and subtracting it from 1, represented as 1 − S(t) 1 . The variance in survival rates between the OS and PFS curves at any given time signifies the fraction of patients experiencing disease progression, calculated as S(t) 1 − S(t) 2 [ 14 ].

The long-term survival data for this study were derived by reconstructing the individual patient data (IPD) survival curves from the ASPIRE trial, employing the methodology outlined by Guyot et al [ 15 ]. Initially, K-M curves were constructed to represent the IPD. The IPD were then fitted using parametric survival models. Out of the five standard parametric equations, the most suitable model was selected through a combination of visual inspection, the Akaike information criterion (AIC), the Bayesian information criterion (BIC), and clinical plausibility. The results of this model selection process are presented in Supplementary Table 2 .

For both PFS and OS curves of the KRd group in the ASPIRE trial, the log-logistic distribution emerged as the best-fitting model. This choice was not only supported by its lower AIC and BIC scores but also by its ability to accurately capture the plateau phase of the survival curves. Utilizing the survival function were able to predict the survival probabilities at various time points for patients. This prediction enabled us to estimate the number of patients and associated costs over the entire treatment cycle. Survival outcomes for IRd were estimated using the HRs derived from the NMA, based on the data for KRd ( Table 2 ). The calculation was performed based on the adjustment formula, that is, S IRD = (S KRd )^HR (where S represents the survival rate).

Costs

This study evaluates the total direct medical costs for patients receiving KRd or IRd therapy. Costs considered, as per published literature, include pharmaceutical costs, disease management costs, subsequent treatment costs, and adverse event management costs. All costs were estimated from the perspective of the Chinese healthcare system, with a currency conversion ratio of 1 USD equivalent to 7.177 CNY ( Table 2 ).

Drug costs are determined by the unit price and dosage as utilized in clinical trials [ 8 , 13 ], aligning with the product instructions ( Table 3 ). Carfilzomib, ixazomib, daratumumab, and pomalidomide have all been included in the 2023 medical insurance catalog and are national negotiated varieties. The price information is collected from the Hubei Province centralized procurement database ( https://www.hbyxjzcg.cn:802/Index.aspx ). Other drugs, such as dexamethasone and lenalidomide are also centralized procurement varieties, with unit prices sourced from the Yaozh Network ( https://db.yaozh.com/ ) based on the median bid prices in various provinces in 2024. It is assumed that the average patient’s body weight and body surface area are 66.20 kg and 1.73 m 2 , respectively, which is in line with previously published literature data [ 26 ].

Disease management costs include expenses for intravenous injections, optimal supportive care, post-progression monitoring, and laboratory tests. It is assumed that patients in a state of progression undergo monitoring and testing once per cycle, post-progression monitoring costs, and best supportive care costs informed by published literature [ 16 , 17 ]. Due to the intravenous administration of carfilzomib and daratumumab, the associated intravenous injection costs have been calculated, with the expenses based on the Shanghai Municipal Medical Service Price Standards for the year 2024 [ 27 ]. The subsequent treatment regimen involves a combination of daratumumab with pomalidomide and dexamethasone. The cost per cycle is calculated according to the proportion of patients undergoing further treatment.

Incidence rates of adverse events considered in the model are extracted from the ASPIRE and TOURMALINE-MM1 trials, as detailed in Table 4 . Only events of grade ≥3 with an incidence rate ≥5% are included, such as neutropenia, thrombocytopenia, pneumonia, anemia, diarrhea, hypokalemia, fatigue, and cataract. The cost of managing these adverse events is calculated by multiplying the incidence rate by the intervention cost for a single event, with costs referenced from published literature [ 18–22 ]. It is presumed that most adverse events manifest during the initial treatment cycle.

Utility values

For this study, the utility values associated with PFS and PD were obtained from the research conducted by Zeng, X et al. [ 23 ], which reported values of 0.810 and 0.715, respectively. Additionally, the study accounts for the decrement in utility values due to adverse events of grade ≥3. These values were sourced from relevant literature, reflecting the impact of such events on patients’ quality of life [ 24 , 25 ]. The implicit assumption associated with this approach was that utilities in ASPIRE patients were considered to be similar to those in TOURMALINE-MM1 patients.

Main outcome

It captures outputs like direct medical expenses accrued over a patient’s lifetime and the gain in quality-adjusted life years (QALYs). The economic evaluation is conducted using the incremental cost-effectiveness ratio (ICER) as the primary outcome. In accordance with the Chinese Drug Economics Evaluation Guidelines (2020 Edition), the study adopts a willingness-to-pay (WTP) threshold for QALYs that is three-time GDP per capita of 2024. If the ICER is below this threshold, which is equivalent to $40,023.27, the treatment is cost-effective. Given the extended duration of the study, both costs and health outcomes are adjusted with an annual discount rate of 5% to reflect their present value.

Sensitivity analysis

The robustness of the model outcomes was assessed through both one-way sensitivity analysis and probabilistic sensitivity analysis. One-way sensitivity analysis is conducted to evaluate the influence of individual parameters on the ICER. Given that carfilzomib and ixazomib are subject to priced through government negotiation, and other drugs are included in centralized procurement, the range of drug price variation is conservatively set from −20% to 0. Correspondingly, the analysis for disease management costs, adverse event costs, and other variables is set to fluctuate by ±15% around the base case values [ 28 ].

Probabilistic sensitivity analysis, on the other hand, allows for a comprehensive examination of the simultaneous impact of all parameter variations within the model. The study performs 10,000 Monte Carlo simulations, each drawing from the respective distributions of the variables to estimate the incremental costs and QALYs for each simulated treatment plan. Probability data and health utility parameters are modeled using a beta distribution, while cost parameters are assumed to follow a gamma distribution. The outcomes are visualized using an incremental cost-effectiveness scatter plot, and a cost-effectiveness acceptability curve is constructed to delineate the probability of the treatment plan being considered economically viable across a range of WTPs.

Results

Network meta-analysis

The basic characteristics of the included studies are shown in Supplementary Table 1 . The trial populations were similar with respect to age, ECOG performance status, ISS stage, receipt of prior stem cell transplant, and the number and distribution of prior treatment regimens. The I 2 values indicated acceptable heterogeneity among the studies.

Using ixazomib combination therapy as the reference group, the forest plot from the NMA ( Supplementary Figure 3(A) and 4(A) ) showed that the carfilzomib regimen had a HR of 0.89 (95% CI: 0.41–1.90) for PFS and an HR of 0.85 (95% CI: 0.53–1.35) for OS compared with the ixazomib regimen.

Convergence trace plots demonstrated the convergence of the parameters, with the traces showing stable horizontal lines, indicating that the parameters had converged. The density plots displayed unimodal distributions, suggesting that the parameter estimates were relatively concentrated and the uncertainty was minimal. The convergence trace plots and density plots are shown in Supplementary Figures 3(B,C) and 4(B,C) .

Base-case analysis

In the base-case analysis, the KRd group demonstrated a significant reduction in total direct medical costs, amounting to $69,226.51 less than the IRd group over the study’s time horizon. The health outcomes, quantified in QALYs, indicated that the KRd group achieved a higher value, with an additional 0.54 QALYs gained, as detailed in Table 5 . It suggests that the KRd regimen is economically dominant, offering both lower costs and improved health outcomes compared to the IRd regimen.

A deeper examination of cost components revealed that the most substantial cost discrepancy between the two groups was attributable to drug expenses. The KRd group’s drug costs were $105,236.10, reflecting a saving of $71,330.02 relative to the IRd group’s expenditure of $176,566.11. In contrast, the KRd group exhibited a modest increase in other cost categories, with disease management costs being slightly higher at $10,898.13 compared to the IRd group’s $8,802.16, and adverse event costs marginally elevated at $75.02 versus $67.50 for the IRd group.

Sensitivity analysis

One-way sensitivity analysis confirms the robustness of the study’s findings, as parameter variations do not alter the conclusion of economic dominance for the KRd regimen. The tornado diagram ( Figure 2 ) illustrates that the prices of ixazomib and carfilzomib, along with the utility value associated with the progression state, exert the most substantial influence on the outcomes.

The probabilistic sensitivity analysis further substantiates these findings. With a WTP threshold established at three times the per capita GDP of $40,023.27 for the year 2024, the cost-effectiveness scatter plot, derived from 10,000 Monte Carlo simulations, demonstrates that the majority of data points are concentrated in the fourth quadrant. This signifies that the KRd is associated with lower costs and higher QALYs, as depicted in Figure 3 . This distribution suggests that the KRd regimen is likely to be more cost-effective than the IRd regimen across a wide range of scenarios. The cost-effectiveness acceptability curve ( Figure 4 ) provides a compelling visual representation of this conclusion, showing that at the specified WTP threshold, the probability of the KRd treatment being more economical than the IRd treatment is 100%.

Discussion

RRMM is associated with high morbidity, mortality, and reduced survival times. The combination of proteasome inhibitors with traditional chemotherapy and glucocorticoids has been shown to enhance patient survival and decrease medical costs. Carfilzomib and ixazomib, as next-generation proteasome inhibitors, have demonstrated efficacy in improving patient outcomes in clinical studies. However, the economic viability of these treatments for Chinese RRMM patients warrants further investigation. Given the absence of direct comparative studies, this research utilized meta-analysis to obtain efficacy data from the ASPIRE and TOURMALINE-MM1 trials, ensuring that the dosing regimen is consistent with Chinese clinical practice and enhancing data reliability.

Economic evaluation results suggest that the KRd combination regimen is more economically feasible under a threshold of three times the per capita GDP for 2024. One-way sensitivity analysis identified the unit prices of ixazomib and carfilzomib, as well as the utility value of the progression state, as key parameters influencing the outcomes, yet these did not overturn the study’s conclusions. Probabilistic sensitivity analysis, based on 10,000 Monte Carlo simulations, confirmed that the probability of KRd being more economically advantageous than IRd is consistently 100% across varying WTP thresholds. The findings correspond to the base-case analysis, validating the model’s stability.

Although there are no specific economic studies comparing these two regimens in China, relevant pharmacoeconomic studies based on indirect comparisons between KRd and IRd have been conducted in the United States. Carlson et al. [ 29 ] conducted an economic evaluation from the perspective of the US health system, constructing a PSM to assess second- and third-line treatment regimens, including carfilzomib and ixazomib. The HRs for PFS were obtained through NMA, while OS data were derived based on the HRs of PFS and OS. The study results showed that the KRd regimen had lower total costs ($492,872 vs. $622,378) and higher health outcomes (3.45 QALYs vs . 3.27 QALYs), thereby demonstrating the cost-effectiveness advantage of KRd over IRd, which is consistent with the findings of this study. Djatche et al. [ 30 ] assessed the economic value of three MM treatment regimens – KRd, IRd, and Erd – from the perspective of the US health system. The results indicated that KRd may be the most valuable compared with the other treatment regimens.

The study by Campioni et al. [ 31 ] compared the cost-effectiveness of KRd versus Rd. The results showed that the KRd regimen had a higher total cost (€117,534 vs . €53,165), but also generated greater health outcomes (2.63 QALYs vs . 1.75 QALYs), thus demonstrating the cost-effectiveness advantage of KRd over Rd. Although it was not an economic evaluation of KRd versus IRd, the study pointed out that the ASPIRE trial is the key clinical trial for KRd. The National Institute for Health and Care Excellence (NICE) [ 32 ] in the UK reviewed the economic assessment report submitted by Takeda for the ixazomib-containing combination therapy. This report cited the TOURMALINE-MM1 study, which evaluated the efficacy of ixazomib compared with other treatment options using NMA. In this report, the Economic Review Group (ERG) deemed the TOURMALINE-MM1 study to be of high quality and to have a low risk of bias.

The National Medical Insurance Catalog aims to reduce the disease burden for the insured population and meet patients’ reasonable medication needs. Both ixazomib and carfilzomib are included in the medical insurance catalog, and their current prices have seen a significant drop compared to the initial launch prices. This has greatly reduced the medical burden on Chinese patients and improved their access to these medications. However, considering the principle of restricting drug reimbursement to specific indications under the medical insurance, carfilzomib is limited to use in combination with dexamethasone for patients with RRMM, while ixazomib does not have an indication for combination therapy. Given that the clinical treatment of RRMM is mainly based on combination therapy as recommended by guidelines, the accessibility of carfilzomib combination regimens is higher for patients choosing combination therapy.

There were several limitations to this study. First, the lack of detailed subsequent treatment data in clinical trials led to assumptions based on clinical guidelines, which may influence the results. In this study, a partitioned survival model (PSM) was employed, which involves segmenting or separating the OS curve to represent different health states. The model directly utilizes a set of survival curves to determine the number or proportion of individuals in each state, necessitating a complete estimation of PFS and OS for both treatment regimens to perform calculations. The ASPIRE study reported a median follow-up time for PFS of 48.8 months, with over 75% of individuals experiencing progression or death. For OS, the median follow-up time was 67.1 months, with 67.4% of individuals reaching death. Given the limited duration of clinical trials, this study employed a parametric approach to simulate and extrapolate long-term survival data. The extrapolated survival curves estimated median PFS and OS to be 28.37 months and 47.52 months, respectively, within the CIs of the K-M curves. Further validation of the study’s conclusions can be pursued through real-world studies in subsequent research. Second, the utility values were derived from quality of life surveys of RRMM patients from abroad. The method for obtaining these utility values was conducted by the Dutch-Belgian Hemato-Oncology Cooperative Group, utilizing the EuroQol 5-Dimension (EQ-5D) questionnaire to directly collect utility data among MM patients. The utility values for the disease progression phase were extrapolated by subtracting the impact of disease progression from the PFS utility values associated with specific treatment regimens. This study assumes that the utility values for the two trial populations are identical, and the negative utility decrements due to adverse events are sourced from various references, which may introduce bias in the estimation of patient health outcomes. Despite incorporating utility values from a non-domestic population into the model, sensitivity analysis indicates that changes in health state utility values within a certain range do not significantly affect the results. Third, this study conducted an indirect comparison of the two treatment regimens through NMA. However, differences in patient selection, treatment strategies, and follow-up design between the ASPIRE and TOURMALINE trials may influence the results. For instance, the ASPIRE trial permits patients to switch to Rd maintenance therapy after 18 cycles, whereas the TOURMALINE trial continues treatment until disease progression, which could affect the long-term extrapolation of PFS and OS. Moreover, disparities in the proportion of subsequent treatments between the two trials may introduce confounding factors. These limitations restrict the statistical power of the indirect comparison, and head-to-head trials are still needed for future validation.

Conclusion

Based on indirect evidence from NMA, from the perspective of the Chinese healthcare system, the KRd regimen is not only cost-saving but also more efficacious than the IRd regimen in the treatment of RRMM patients. KRd appears to offer potential economic and clinical advantages over IRd in the Chinese healthcare context. Article highlights Current medical technology has not yet been able to cure MM, and patients inevitably face relapse and resistance to traditional treatment drugs, leading to the development of refractory myeloma. After relapse, the remission rate decreases, and the prognosis for survival becomes very grim. The use of next-generation proteasome inhibitor-based combination regimens can significantly improve patient survival and provide new therapeutic options for patients with RRMM. Patients with MM often face a substantial disease burden, and selecting a clinically safe, effective, and cost-efficient treatment regimen is essential for them. We used the method of NMA to successfully address the problem of the inability to directly compare carfilzomib with ixazomib. The results of the study indicate that the combination of carfilzomib with lenalidomide and dexamethasone is the absolute advantage regimen.

Supplementary Material

Supplemental Material

Author contributions

L Wang proposed the research idea, was in charge of advancing the research process, and drafted the initial manuscript. F Chen was responsible for data collection and statistical analysis, as well as drafting the initial manuscript. Y Ma was in charge of literature search and drafting the initial manuscript. X Lin conducted model construction and computation, as well as drafting the initial manuscript. J Liu designed the research methodology and participated in the revision of the final manuscript and Y Zhang conducted formal analysis and critical review of the manuscript, and R You was responsible for project supervision, funding acquisition, and manuscript revision and review.

Disclosure statement

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Ethics approval and consent to participate

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Availability of data and materials

The model developed during this study is not publicly available due to confidentiality. The input data supporting the model are from previously reported publications and reports, which have been cited. No new data were generated or analyzed during this study.

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