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Cost-effectiveness of lenalidomide maintenance in patients with multiple myeloma who have undergone autologous transplant of hematopoietic progenitor cells

Subjects

Abstract

The objective of this article is to analyze the ratio of cost-effectiveness and budgetary impact of lenalidomide treatment in patients with multiple myeloma who have undergone autologous transplant in Spain. The analyses were based on clinical trials CALGB 100104 and IFM 2005-02, from the perspective of the National Health System. The alternatives compared were the treatment with lenalidomide against maintenance without treatment (MwT). Efficiency measures used were years of life gained (YGs) and quality-adjusted life years (QALYs). According to the CALGB 100104 trial data, the average health costs of patients who were treated with lenalidomide for 120 months was €836,534.31 and without treatment was €528,963.63. The effectiveness of the lenalidomide group was 7.59YGs (5.72 QALY) against 6.58 of MwT (4.61 QALY). The incremental cost-utility ratio (ICUR) was €277,456.72/QALY and the incremental cost-effectiveness ratio was €303,191.05/YGs. From the analysis, the IFM2005-02 trial obtained 5.13 QALY in the lenalidomide group against the 4.98 QALY in the MwT group, with an ICUR of €1,502,780.55/QALY. In terms of budgetary impact, a range between 799 and 1452 patients susceptible to receive treatment with lenalidomide was assumed in Spain. In conclusion, the results show a high ICUR and budgetary impact, which adds uncertainty about the maximum prudent duration of the treatment.

Introduction

Multiple myeloma (MM) is a neoplastic disease that is characterized by a clonal proliferation of plasma cells derived from B cells of the bone marrow [1]. According to the World Health Organization (WHO), the incidence of MM in Spain stands at 2420 cases/year, which means a rate of 3.5 cases every 100,000 inhabitants [2, 3].

The standard treatment consists in the consolidation with high doses of chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT) from the peripheral blood, and afterwards the maintenance treatment. The only drug with indication approved by the European Medicine Agency for the maintenance treatment of adult patients with MM of new diagnosis who have undergone an autologous transplant of stem cells is the lenalidomide (Revlimid®) [1]. It is used in monotherapy, starting with a dose of 10 mg, increasing to 15 mg after 3 months if the patients show good tolerance. The evidence of the treatment in maintenance with lenalidomide is grounded in two clinical trials in phase III: CALGB 100104 [4, 5] and IFM 2005-02 [6].

The phase III trial CALGB 100104 included 460 patients (231 in the treatment arm and 229 in the control arm) randomized to receive maintenance treatment with lenalidomide (10 mg, and after 3 months 15 mg) or placebo. With a median of monitoring of 91 months, the lenalidomide arm showed a better progression-free survival (PFS) than the placebo group (average of 44 vs. 23 months; hazard ratio (HR) 0.57; p < 0.001), and an increase in the overall survival (OS) (HR 0.61; p < 0.001) [5].

In the trial IFM 2005-02, a total of 614 patients (307 on each arm) received two phases of treatment, a consolidation phase, in which patients of both arms received 25 mg of lenalidomide during 21 days in two cycles of 28 days, and the maintenance phase, in which patients received lenalidomide 10 mg or placebo during 21 days in cycles of 28 days, on an ongoing basis. With an average of monitoring of 30 months, the PFS was higher in the group with lenalidomide than in the placebo group (average of 41 vs. 23 months; HR 0.50; p < 0.001) [6]. There was no significant difference in OS.

The global incidence of MM continues to increase; in contrast, the mortality rates have decreased over the past years [7]. The availability of new therapeutic options has contributed to a higher survival of the patients, in exchange for a significant impact on the health budget. Therefore, it is important to consider the cost-effectiveness to facilitate an efficient use [8]. The objective of this article is to estimate the cost-effectiveness ratio of maintenance monotherapy with lenalidomide against maintenance without treatment (MwT) in adult patients with MM of new diagnosis that have undergone auto-HSCT. The estimation is made from the perspective of the Spanish National Health System (SNS), with the collaboration of the Units of Clinical Management of Hematology and Pharmacy of the University Hospitals Virgen De Las Nieves (Granada) and Puerto Real (Cadiz), respectively, that belong to the Andalusian Public Health System.

Methods

Design and structure of the pharmacoeconomic model

A cost-utility analysis was made from a partitioned survival [9] model with four mutually exclusive health states: progression free (initial state), progression, progression after following line, and death (final state). A partitioned survival model is a type of economic model used to follow a theoretical cohort through time, and the cohort’s proportion in each state are based upon parametric survival equations. The partitioned survival model is widely used in the modeling of oncological diseases, mainly in advanced metastatic phases [9]. In a partitioned survival model, the time in each health state at any time is determined from the underlying survival curves. For example, the percentage of patients in the first relapse was calculated from the difference between the PFS and the PFS1 and the proportion of patients progressing from the difference between the OS and the PFS1. The model assumes that health states represent a series of events that the patient may experience during the course of their illness, being progressive and mutually excluding. A horizon of 10 years (120 months) was selected in order to reflect the maximum remaining life and to ensure that the relevant differences for both options are observed, both in the costs and in the results of the interventions.

The treatment options (lenalidomide and MwT) were obtained from clinical trials CALGB 100104 and IFM 2001-05, analyzing the data independently, since the lack of similarity in the design and monitoring of both studies prevents performing a meta-analysis. The time in each of the states was estimated from the data of monitoring of OS, PFS, and PFS 2 (PFS2). The results in health were measured as years of life gained (YGs) and quality-adjusted life years (QALYs), which is the time spent in each health state weighted per quality of life (utility).

Effectiveness

The adverse events included in the model were those of grades 3–4 observed in the clinical trials. The methodology described by Fleurence and Hollenbeak [10] was used to estimate the occurrence probability.

Modeling of the curves of OS, PFS, and PFS after the first relapse were carried out to determine the average time that the patient would spend in the states described [5, 11]. The Kaplan–Meier (KM) curves were digitally extracted with the WebPlotDigitizer software (https://apps.automeris.io/wpd/). For each treatment, the patient level data, including event or censor time, the number of patients at that time, the number of deaths, and the number of patients censored during the time interval, were recreated by applying the method suggested by Guyot and Ades [12]. To calculate the average time in each health state, it was necessary to extrapolate the survival curves. The area under the curve (AUC) was calculated by applying the Simpson’s rule, with increases of 1/12 years, and by applying the methodology described by Williams et al. [13]. The costs and quality of life related to each of the therapeutic alternatives depends on the estimated time in each health state. The HR was calculated using Cox regression model to compare the data obtained with the original data. Because OS and PFS were not fully observed, results were extrapolated by using survival functions to both treatment arms independently. In order to determine the most appropriate parametric survival curve, an analysis was conducted based on visual inspection, long-term projections, and statistical tests (Akaike information criteria and Bayesian information criterion) (Annexes). We selected the more plausible models, avoiding the overlap between OS and PFS curves. PFS2 were estimated by applying to the PFS distribution estimates of the HR for PFS vs. PFS2 using the formula:

$${\mathrm{PFS2}}\left[ t \right] = {\mathrm{PFS}}\left[ t \right]^{{\mathrm{HR}}_{{\mathrm{PFS2}}\,{\mathrm{vs.}}\,{\mathrm{PFS}}}}.$$

Quality of life (Utilities)

The utility values were obtained from the cohort of Proskorovsky (2014), which included patients (n = 154) who had undergone autologous transplant in the past 3 months or who had received experimental treatment in the context of a clinical trial [14]. The estimation of EQ-5D values was obtained from the ratings of the specific questionnaire EORTC (European Organization for Research and Treatment of Cancer Quality of Life) QLQ-C30 and QLQ-MY20 through an assignation algorithm after a multiple lineal regression (Table 2). (Dis)utility values associated to the presence of adverse events were not applied or estimated.

Use of resources and costs

The total health costs associated with each one of the concepts considered in the context of the National Health System were estimated. Given the complexity and difficulty to collect all treatment possibilities in subsequent lines after the progression of the disease, a dosage standard treatment were used, taking into consideration the most likely treatment possibilities were agreed, taking into consideration the indications approved by the European Medicines Agency and the positioning reports of the Spanish Agency for Medicines and Health Products (Table 1) [15,16,17,18]. The cost of the treatment was extracted from the official Nomenclator (March 2018) [19] and was assumed to calculate a standard patient with 70 kg of weight and a body surface of 1.7 m2. The duration of the treatment and guideline was based on data sheet, according to the trial CALGB 100104.

Table 1 Treatment lines considered for the second and third treatment lines

The cost of the secondary neoplasms was extracted from the article by LeBlanc et al. [20], who used the average cost of the patient with cancer from the report of the Cancer Care Society. The activities of the process were defined for the estimation of the cost of the adverse events, standards were established, and finally the associated resources were identified. The costs data of the diagnostic tests were extracted from the Official Gazette of the Regional Government of Andalusia [21, 22] and the costs of the medicines sold in pharmacies used for adverse events were extracted from the database Bot-Plus [23]. The costs (excluding drugs) were updated using the consumer price index (CPI) to December 2017 (Table 2) [24].

Table 2 Values of prevalence, effectiveness, and costs in the analysis of budgetary impact and economic evaluation

The different data used were validated by several health professionals (hematologists, pharmacists, and experts in pharmacoeconomics) to ensure that the assumptions reflect the reality of the clinical practice of the National Health System.

Analysis

The outcome measure was the incremental cost-utility ratio (ICUR), expressed as cost per QALY gained from the use of lenalidomide vs. MwT; likewise, incremental cost-effectiveness ratio (ICER) was calculated per year of life gained. QALYs were calculated using the AUC approach. AUC was calculated using the Simpson’s rule, which represents the average time that the patients are in each of the states ABC0→36 months and ABC0→120 months for both alternatives. The statistical design was performed in R open source software and Microsoft Excel 2016.

In order to evaluate the uncertainty of the variables included in the model, three univariate sensitivity analyses were performed: (1) reducing the price of medicines for MM, in the range of 16–43%, according to the experience of the team [19]. (2) Taking into consideration that the patent of lenalidomide expires soon, the price of a hypothetical generic drug was used, thereto the current price of thalidomide (dose of 200 mg/day) was used. (3) Following recommendations from López Bastida et al. [24], sensitivity analyses were carried out with discount rates of 3.5 and 6%.

Subsequently, a probabilistic analysis was carried out with the utility values, which allows the evaluation of the parametric uncertainty of probabilities through 1,000 simulations, to which a probabilistic distribution (β) is assigned. Additionally, this analysis of probabilistic sensitivity was carried out with the reduction in the price of medications (range 16–43%) used in the univariate sensitivity analysis. Finally, follow-up time was extended to 20 years in order to observe the cost and effectiveness with a longer time horizon.

Budgetary impact

Patients who are candidates to auto-HSCT are aged <65 years, without significant comorbidities or serious social problems, while those between 65 and 70 years should be assessed individually. Approximately, the median age of the patients at diagnosis is 70 years, with 27% between 65 and 75 years and a 37% >75 years. Thus, it can be estimated that 33% of the patients diagnosed with MM are candidates for auto-HSCT, so it is estimated that approximately 799 patients diagnosed with MM are candidates for treatment with lenalidomide in maintenance. For the sensitivity analysis, a proportion of 50% and 60% of candidate patients for auto-HSCT was used. Furthermore, the price considered for lenalidomide was that of the hypothetical generic. The time horizon considered was 10 years, and 20 years.

Results

CALGB clinical trial

Figure 1a, b shows the modeling at 120 months. Regarding efficacy, the intervention group obtained an average of 7.59 years of survival (5.72QALY), compared to the 6.58 years (4.61QALY) of the MwT group, which means a difference of 1.01YGs and 1.11 QALY. The average cost of patients treated with lenalidomide at 120 months was €836,534.31. When disaggregating the costs, it is observed that 0.60% (€3,611.82) is due to secondary neoplasms, 1.07% (€6,487.91) to adverse events and 98.33% due to drug treatment (€826,434.58), including maintenance (€535,407.03) with lenalidomide and the following lines (first €130,354 and second €160,673.56 lines). The average cost for the MwT group was €528,963.63, with the pharmacological treatment accounting for 99.30% of the cost (€525,283.96, of them €303,957.26 are for the first line and for the second line a total of €221,326.70). Subsequently, the ICER and ICUR were calculated, which were €303,191.05/YGs and €277,456.72/QALY, respectively. It represents the additional cost to gain a year of life or a QALY if lenalidomide maintenance was given compared to not given (Table 3).

Fig. 1
figure1

Modelling at 120 months of a cohort of 1000 patients in 1 each of the states for the different groups of clinical trials. a Modelling of the intervention group in the CALGB trial. b Modelling of the maintenance without treatment (MwT) group in the CALGB trial. c Modelling of the intervention group in the IFM trial. d Modelling of the MwT group in the IFM trial© 2019.

Table 3 Cost-incremental effectiveness of the treatment with lenalidomide vs. maintenance without treatment, with a time horizon of 120 months

When carrying out the sensitivity analysis by reducing the price of drugs for MM (range 16–43%) values ICER and ICUR were obtained as €238,739.94/YGs and €218,476.11€/QALY, respectively (Table 3). When reducing the cost of lenalidomide to the price of a hypothetical generic drug, the average cost was €450,793.18 and €364,678.65 for MwT and lenalidomide, respectively. Thus, treatment with lenalidomide was dominant (lower cost and greater effectiveness than MwT).

Table 4 shows the probabilistic sensitivity analyses with the values of utility, obtaining an ICUR of €447,361.82/QALY, ranging between 1,943,619.30 and dominated (less effectiveness of lenalidomide and higher cost). If this probabilistic sensitivity analysis is carried out with a reduction in the price of medicines (range 16–43%), it is observed that the ICUR was €173,068.33/QALY, ranging between 1,563,607.20 and dominated (Table 4).

Table 4 Cost-incremental effectiveness of the treatment with lenalidomide vs. the standard treatment, case, base, and sensitivity analysis

IFM clinical trial

Figure 1c, d show the modeling used at 120 months. No differences were observed between the lenalidomide group and the MwT group in AG (6.91 years) (Table 3), so the ICER was limited to a comparison of costs. The average cost of the patients in the group of the lenalidomide at 120 months was €829,919.07. When disaggregating the costs, it is observed that 0.70% (€5,895.41) of the total are secondary neoplasms, adverse events 0.18% (€1,549.45), and pharmacological treatment 99.11% (€822,544.49). The average cost for the control group was €600,228.83, with the pharmacological treatment accounting for 99.36% (€596,397.59).Thus, the lenalidomide group implies an incremental cost of €229,690.25, without differences in the years of life. Regarding the QALY, the intervention group obtained an average of 5.13 QALY, compared to the 4.98 QALY in the MwT group, with a difference of 0.15 QALY. The ICUR was €1,502,780.55/QALY. When carrying out the sensitivity analysis reducing the price of the drugs for MM (range 16–43%), the average cost of those in the lenalidomide group was €611,295.31, being €406,703.86 for those in the MwT group, and the ICUR of €1,421,209.43/QALY, which indicates the cost per QALY gained in the lenalidomide arm vs. the MwT group. When reducing the cost of lenalidomide to the price of a hypothetical generic, the average cost was €505,007.04 and €510,841.80 for MwT and lenalidomide, respectively, and thus an ICUR of 38,174.73 was obtained.

When performing a probabilistic sensitivity analysis with utility values, the ICUR was €519,822.55/QALY, ranging between 4,264,139.49 and dominated (less effectiveness of lenalidomide and higher cost). In addition, if this probabilistic analysis with the utility is performed by decreasing the price of medicines (range 16–43%), an ICUR of €548,395.05/QALY is observed, ranging between €4,496,167.45/QALY and dominated (Table 4).

Budgetary impact

With a time horizon of 10 years, the treatment with lenalidomide would cost €633.52 million, compared to the €423.50million of the standard treatment, which means a difference of €210 million euros. When carrying out the sensitivity analysis, increasing the proportion of subjects susceptible to receive treatment, the difference of cost was €313.49 and €347.20 million (Table 5).The estimation to 20 years offers a difference of 3462 million between both alternatives (Figure 2).

Fig. 2
figure2

Evolution of the budgetary impact (in millions of euros) at 20 years of a cohort of 799 patients after auto-HSCT for multiple myeloma, in patients receiving maintenance with lenalidomide vs. MwT. MwT: maintenance without treatment; auto-HSCT: autologous hematopoietic stem cell transplantation.

Table 5 Cost of patient with multiple myeloma in maintenance with lenalidomide or without treatment at 10 years, assuming different scenarios according to the proportion of patients with autologous transplant of hematopoietic progenitor cells

Discussion

Currently, maintenance treatment used in adults with MM of new diagnosis, who have undergone auto-HSCT, have been thalidomide, bortezomib, and lenalidomide (historically, melphalan, dexamethasone, interferon, etc.). However, it must be taken into consideration that lenalidomide is the first medicine authorized for this indication, that there are no comparative studies with available alternatives, and that the use of thereof is not established as a standard, so other therapeutic options have not been taken into consideration in the analysis performed [11, 25]. In this sense, the treatment with lenalidomide is associated to a longer time to progression of the disease, but according to the present study, it is not efficient for the SHS. The different analysis carried out show some ICUR and ICER higher than €173,000 compared to the MwT treatment, due to its high cost, although its effectiveness is relevant.

For more than a decade, the incorporation of new drugs for the treatment of MM has implied a great budgetary impact. In this sense, it has been seen that among those patients with relapse, the medication for MM implies 90–95% of the total healthcare cost of these patients; this cost is very similar to those described in this study [26]. An economic evaluation carried out with data of Medicare (USA) showed that although the drugs introduced in the therapy (thalidomide, bortezomib, lenalidomide) significantly increased the survival with respect to chemotherapy, they were not cost-effective, since they were 2.03 times more expensive than chemotherapy [27]. In this sense, in 2016 a systematic revision of economic evaluation studies was published on the new therapies for the treatment of MM, which included a total of 8 studies (19 comparisons). Most of the studies evaluated treatment in relapse, with bortezomib being the most evaluated drug (7 studies). It was concluded that the new treatments compared with the alternatives, show better results in health and higher costs, with an average of $54,630 per year of life and $68,261/QALY. It should be noted that in most studies, the new drugs for patients with MM were cost-effective, although using a threshold of up to $100,000/QALY [28].

No economic evaluation analysis of maintenance treatment with lenalidomide has been found in the literature. Two communications to congresses have been identified with contradictory results to those described here. The first one describes that the treatment reduces the direct costs to 5 years, due to the delay in the progression of the disease [29]. In this article similar results are found when there is a reduction in the price of lenalidomide close to 80%. However, this time horizon is insufficient and inadequate for this model, since it allows the cost of rescue therapy in the MwT arm, but it does not include the cost of the rescue therapies for the lenalidomide arm. For its part, the communication of Xie et al. [30] concludes that the average potential economic impact on total healthcare costs of a US health plan is small (4.4% at 3 years) due to the low proportion of patients susceptible to receiving this treatment on the USA and the delay in relapse and the already common use of lenalidomide in post-ASCT maintenance.

Our study presents several limitations that must be taken into consideration for the interpretation of the results. The main limitation is related to the standardization of resources per patient and the need to use cost data extracted from the literature. The costs of relapses in the treatment of bone, kidney, or blood disease have not been taken into consideration, nor the economic loss due to the lack of labor productivity; the latter is in accordance with this type of economic analysis from the perspective of the payer or service provider. On the other hand, it would have been advisable to analyze the data from the two trials together, allowing less uncertainty in the estimates. However, Gao et al. [31] showed that there is a high heterogeneity that limits the performance of meta-analysis. This heterogeneity may be attributable to differences in the characteristics of the patients (cytogenetic abnormalities, IFM includes patients with second transplants), treatment phases (IFM trial included two cycles of lenalidomide in consolidation also in the control group), target dose (15 vs. 10 mg in the IFM), and average of duration of the treatment and follow-up. At the IFM, the early completion of the trial resulted in patients receiving maintenance for a median of 3 years. On the other hand, the CALGB trial did not have a consolidation phase and the maintenance phase with lenalidomide was longer, up to the progression of the disease). The results were differentiated in the obtaining of the benefit in OS, only in the CALGB study [32, 33]. It must be taken into consideration that the way of using lenalidomide in the CALGB study is the basis for the use approved in the technical report, so we understand that the assessments made on this study may be considered more reliable for decision in this setting.

Another limitation is related to the estimates of survival and the period of the developed clinical trials that was used for the construction of the survival curves for the economic evaluation, which was prior to 2010, when the new treatments for relapse, which were considered for the costs of therapies, were not available. Although it affects both arms, this assumption could imply an infraestimated efficacy of the MwT arms, thus entailing a misestimation of the cost, and this would perhaps suggest that lenalidomide treatment could have a lesser ICER than calculated, though far from a cost-effectiveness threshold. The reader should take into consideration that this decision was taken in an effort to approximate the analyses undertaken to the actual reality.

It must be taken into consideration that the researchers of the IFM study decided to stop the study when a risk of second neoplasms appeared, a risk that later was considered surpassed by the benefits of the treatment. Therefore, a close follow-up must be carried out to control the possible appearance of complications and toxicity of the therapy, allowing patients the survival benefit [32, 34].

The model of partitioned survival analysis used is characterized by the fact that the number of patients in each health state has been determined directly from the underlying survival curves. This model has two advantages over the Markov model: it avoids the need to estimate the transition probabilities and avoids additional assumptions, for example, if death was allowed to all heath states; however, it limits the possibilities of performing sensitivity analysis [35]. This type of model is frequently used to evaluate cancer treatments [9].

The fact that the utility values were estimated from an algorithm using the data obtained from a specific questionnaire of quality of life could suppose a limitation. It should be noted that the literature shows the success in obtaining the utility values of the questionnaire EQ5D from the specific questionnaires for cancer patients of the EORTC-QLQ family [36,37,38]. Specifically, the recent study by Kharroubi et al. [39] has shown that the estimation of the values of EQ-5D for MM, based on the aforementioned questionnaire, was good. On the other hand, it must be taken into consideration that the preference values used were calculated for the United Kingdom (UK), limiting the applicability of its transfer to the Spanish context. However, a study that compared the utility values obtained through the questionnaire EQ-5D in different countries (Germany, Holland and Spain) with those of the United Kingdom concluded that the sets of Spanish and British values were similar, ensuring an adequate transferability [40].

It is worth noting a phase II clinical trial performed in 22 hospitals in Japan evaluating the efficacy of lenalidomide in consolidation and subsequent maintenance treatment. For that purpose, 41 patients were enrolled initially (3 drops out), and finally, only 23 received both phases (maintenance and consolidation). A status of progressive disease was observed in nine patients (23.7%). At a median follow-up of 35.7 months, PFS at 2 years was 76.3% and the OS at 2 years was 92.1%. The authors concluded that lenalidomide in consolidation and maintenance therapy are effective and safe, and provide favorable response rates in patients with MM [41].

It would be advisable to carry out more studies to determine some aspects on which there is uncertainty such as the determination of the maximum prudent time of treatment, or the association with corticosteroids [42, 43]. Maintenance treatment with lenalidomide shows an improvement in the PFS and the OS of patients with MM after auto-HSCT [33, 41]; however, it is not cost-effective considering the usual limits of availability to pay. Taking into consideration the high values of ICUR and budgetary impact, the relation benefit/risk/cost is doubtful, especially in patients without high risk of relapse [43]. In this sense, in Spain there is no explicit Spanish willingness to pay threshold, but it has been estimated that this value is between €22,000 and €25,000/QALY [43, 44], these values being much lower than the ICUR described in this article. Therefore, it would be advisable to revise the price downwards in a considerable amount to improve efficiency and to reduce the budgetary impact. Thus, treatment with lenalidomine is an important therapeutic advance that should be made available to patients, but according to the results of this study, its price level is disproportionate, and this means a serious problem for the sustainability of public health systems and the accessibility of treatment in private healthcare.

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Olry de Labry Lima, A., Gimeno-Ballester, V., Ríos Tamayo, R. et al. Cost-effectiveness of lenalidomide maintenance in patients with multiple myeloma who have undergone autologous transplant of hematopoietic progenitor cells. Bone Marrow Transplant 54, 1908–1919 (2019). https://doi.org/10.1038/s41409-019-0574-5

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  • Cost-effectiveness of lenalidomide

    • Antonio Olry de Labry Lima
    • , Antonio Matas Hoces
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    Bone Marrow Transplantation (2020)

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