Cost-Effectiveness of Post-Autotransplant Lenalidomide in Persons with Multiple Myeloma

Monia Marchetti1, Robert Peter Gale2 and Giovanni Barosi3.

1 Hematology Department, Azienda Ospedaliera  Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.
2 Haematology Research Centre, Department of Immunology and Inflammation, Imperial College London, London, UK.
3 Center for the Study of Myelofibrosis, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy.

Correspondence to: Monia Marchetti, MD, PhD. Hematology Department, Az. Osp. Antonio e Biagio e Cesare Arrigo, via Venezia 16, 15121 Alessandria, Italy. P +39 3668377191 E-mail:   

Published: May 1, 2021
Received: January 20, 2021
Accepted: April 12, 2021
Mediterr J Hematol Infect Dis 2021, 13(1): e2021034 DOI 10.4084/MJHID.2021.034

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Considerable data indicate post-transplant lenalidomide prolongs progression-free survival and probably survival after an autotransplant for multiple myeloma (MM). However, optimal therapy duration is unknown, controversial and differs in the EU and US. We compared outcomes and cost-effectiveness of 3 post-transplant lenalidomide strategies in EU and US settings: (1) none; (2) until failure; and (3) 2-year fixed duration. We used a Markov decision model, which included six health states and informed by published data. The model estimated the lenalidomide strategy given to failure achieved 1.06 quality-adjusted life years (QALYs) at costs per QALY gained of €29,232 in the EU and $133,401 in the US settings. Two-year fixed-duration lenalidomide averted €7,286 per QALY gained in the EU setting and saved 0.84 QALYs at $60,835 per QALY gained in the US setting. These highly divergent costs per QALY in the EU and US settings resulted from significant differences in post-transplant lenalidomide costs and 2nd-line therapies driven by whether post-transplant failure was on or off-lenalidomide. In Monte Carlo simulation analyses which allowed us to account for the variability of inputs, 2-year fixed-duration lenalidomide remained the preferred strategy for improving healthcare sustainability in the EU and US settings.


High-dose chemotherapy, typically with melphalan followed by a haematopoietic cell autotransplant, is the global standard-of-care in persons < 65-70 years with multiple myeloma (MM).[1-5] Substantial data indicate post-transplant lenalidomide prolongs post-transplant progression-free survival (PFS) and probably survival without reducing quality-of-life (QoL) or increasing interval-to-progression after starting subsequent anti-MM therapy/ies.[6-15] Based on these data, post-transplant lenalidomide is approved in the EU and US by the European Medicines Agency (EMA) and US Food and Drug Administration (FDA).
Precisely how long to continue lenalidomide post-transplant is controversial. Two considerations, besides therapy-outcome and cost, affect this calculus.  First, some data, albeit controversial, suggest an increased risk of new cancers in persons receiving continuous post-transplant lenalidomide leading some experts, especially in the EU, to recommend giving post-transplant lenalidomide for 1 or 2 years.[8]  In contrast, the strategy in the US is to give post-transplant lenalidomide until failure. These strategies are not compared in randomized trials, so there is no evidence-based way to decide which is better.
The 2nd consideration is cost. On 1st examination giving continuous post-transplant lenalidomide seems more expensive than the no or fixed duration lenalidomide strategies.  However, this conclusion fails to consider other critical confounding issues. Because high-dose chemotherapy with autotransplant is not curative, most, if not all, recipients relapse or progress. Their subsequent anti-MM therapy will depend on circumstances of therapy failure. For example, persons failing whilst receiving post-transplant lenalidomide are likely to be treated with drugs other than lenalidomide. In contrast, a person failing after no or after stopping fixed duration post-transplant lenalidomide is likely to receive lenalidomide-based therapies. Consequently, a critical economic analysis must consider the cost not only of post-transplant lenalidomide but also costs of drugs used to treat therapy failure and their anticipated clinical outcomes. 
We compared consequences of 3 potential post-transplant interventions: (1) no intervention; (2) 2-year fixed-duration lenalidomide; and (3) lenalidomide until failure (relapse or progression). These strategies were compared in EU and US cost settings. Our analysis considered not only clinical outcomes such as interval from autotransplant to first progression or death from any cause (PFS1), the interval from autotransplant to second progression or death (PFS2) and interval from the start of rescue therapy to second progression or death (2nd PFS), survival and costs but also costs of subsequent therapy/ies.


Decision problem and scope. We interrogated the problem of assessing the cost-for-value of 2-year fixed-duration or continuous post-transplant lenalidomide in persons with MM by comparing these strategies with no post-transplant intervention. The economic assessment is conducted from the perspective of the third-party payers in the EU and US.
Model details. We used a 6-state Markov model, which allowed us to follow the monthly evolution of subjects from progression-free on-lenalidomide to progression-free off-lenalidomide, 1st subsequent therapy, 2nd subsequent therapy and death (Figure 1).  We modelled subjects with a median age of 58 years based on data from randomized trials included in the meta-analysis providing baseline PFS1.[6] Subjects should have had a partial or complete response 90 days after their autotransplant. 

Figure 1 Figure 1. Markov model. MT = maintenance therapy (post-transplant lenalidomide)

The progression rate in subjects receiving no post-transplant lenalidomide was assessed in two-time intervals based on PFS1 curves reported in a meta-analysis.[6] An exponential parametric assumption was made to allow model reproducibility. 
The rate of progression in subjects on post-transplant lenalidomide was estimated by adapting the hazard ratio reported by the above intention-to-treat meta-analysis6 since we considered the possibility post-transplant lenalidomide might be stopped because of an adverse event(s) (Table 1),[6,16,18-23,25,26] progression or planned interruption because of a 2-year fixed-duration post-transplant lenalidomide strategy. 

Table 1 Table 1. Input clinical values of the model.[6,16,18-23,25,26]

The relative risk of relapse or progression in subjects stopping lenalidomide for reasons other than relapse or progression was returned to 1 if post-transplant lenalidomide duration was < 12 months, whereas it was decreased progressively as post-transplant lenalidomide duration lengthened beyond 12 months (Table 1) as reported in a retrospective study[16] and a randomized trial.[34] Probabilities of 2nd and 3rd progression were obtained from recent clinical trials (Table 1). The fatality rate was estimated to be 12, 40 and 60 per cent at 1st, 2nd and 3rd failure.[24]  
We assumed subjects relapsing or progressing post-transplant would next receive a therapy based on carfilzomib or daratumumab. Lenalidomide triplets were allowed for subjects failing off post-transplant lenalidomide. A 1:1 ratio was assumed in assigning subjects to a daratumumab- or carfilzomib-based treatment. Nighty per cent of subjects with a 1
st relapse or progression were assumed to receive a 2nd therapy, and 80% of subjects with a 2nd relapse to receive a 3rd line therapy.[17] Subjects were assigned 1:1 to a pomalidomide-based or a daratumumab- or carfilzomib-based therapy according to prior therapy. The modelled strategies were reported in Supplementary Table 1.
Utilities. Utilities were adapted from a study mapping EORTC QLO-30 and an MM-specific quality-of-life (QoL) questionnaire to EQ5D-based utilities.25  We also considered the impact of being on-therapy, including post-transplant lenalidomide.[25]
Costs. Costs were considered in EU and US settings. We used a third payer perspective and included only direct medical costs given in 2018 EU and US euros and dollars. Anti-MM therapies were valued according to ex-factory drug costs for EU and wholesale US cost (Table 2).[27-33] A 3 per cent additional cost was considered for parenteral drugs.[31-33] Theoretical drug costs were reduced by 10 per cent because of treatment schedules and therapy-free months between progression and start of subsequent therapy/ies (Table 2). Post-transplant lenalidomide's monthly cost was calculated for a 21 of 28-day schedule at 10 mg per day.

Table 2 Table 2. Input cost values of the model.

Analyses. Mean costs and mean effectiveness were calculated as discounted costs and discounted quality-adjusted years-of-life (QALYs) associated with each clinical state.  Analysis of life years and costs was limited to a 20-year time horizon which is ≥ twice the median survival reported for persons not receiving post-transplant lenalidomide.6 According to international guidelines, life years and costs were discounted by 3 per cent per year.[15] First-order sensitivity analyses were run for all input co-variates and for ratios amongst co-variates. Furthermore, scenario analyses explored extreme ranges for key variables. Second-order sensitivity analysis was run for each paired comparison; 10,000 Monte Carlo simulations were run by sampling log-normal distributions for hazard ratios, beta distributions for utilities, and gamma distributions for cost.


Model validation. The model forecasted 70%, 52%, and 29% of persons assigned to continuous lenalidomide remained on-therapy after 12, 24 and 48 months. The median therapy duration was 25 months, and the mean duration of therapy 30 months in a 79-month time horizon (39 months in a 20-year horizon). Corresponding rates in a meta-analysis were 70%, 54% and 15% and the mean post-transplant therapy duration 28 months at a median follow-up of 79 months.[6] The model also forecasted mean lenalidomide duration in the 2-year fixed-duration cohort was 18 months like that reported for Arm A1 in the GMMG-MM5 randomized trial.[34]
The model predicted median PFS1 like data from the meta-analysis for no intervention and continuous lenalidomide strategies, 23 and 52 months.[6] Notably, the model did not over-estimate long-term outcomes, which was an 80-month PFS of 31% and survival of 67% for persons receiving continuous lenalidomide. The model also forecasted a 5-year PFS of 36% and survival of 76% for persons receiving 2-year fixed-duration lenalidomide like data from the GMMG-MM5 trial (arms A1 and A2).[34]
Second PFS was estimated to be 23 and 36 months for persons failing on- or off-lenalidomide, respectively.  Similarly, median survival after the first failure was estimated as 45 and 60 months, respectively. These survival rates are like those reported in the GMMG-MM5 trial and in a recent pooled analysis of randomized trials, including continuous post-transplant lenalidomide.[34,39] Finally, the model estimated median survival after 2nd failure of 28 months. Median PFS2 was 84 months for continuous lenalidomide, 82 months for 2-year fixed duration lenalidomide and 63 months for no post-transplant therapy. These figures are higher than reported by the McCarthy meta-analysis because of the assumption currently available highly effective 2nd-line therapies are prescribed.[6]
Baseline analysis. At baseline analyses, continuous and 2-year fixed-duration post-transplant lenalidomide prolonged median survival from 97 to 119 and 113 months, indicating a 6-month advantage for the continuous strategy compared with fixed-duration. Mean life-years and quality-adjusted life-years for the three strategies are displayed in Table 3: continuous post-transplant lenalidomide prolonged mean survival by 21.5 months and fixed-duration by 16.0 months. After adjusting for quality of life, the two strategies' gain was 17.2 and 12.7 quality-adjusted months, respectively.

Table 3 Table 3. Base-case cost-effectiveness analysis

Discounting of future life years further reduced the gain of post-transplant strategies to 12.7 and 10.1 months, respectively, which is about a 40% decrease of the gain.
Cumulative health-care costs for managing post-transplant MM ranged from €1,073,349 to €1,128,805 in EU and from $1,678,162 to $1,872,859 in US in the 20 year time horizon chosen for the analysis. Breakdown of costs (Supplementary Figure 1) reported that 16% (EU) and 22% (US) of the overall healthcare costs of the continuous post-transplant lenalidomide strategy were from to costs of lenalidomide. The same rates were 10% (EU) and 15% (US) for 2-year fixed duration lenalidomide. 3rd-line therapies accounted for 17-20% of overall costs, whereas 2nd-line therapies accounted for 59-77% of overall costs.  By avoiding some 1st failures, 2-year fixed duration strategy saved $146,045 (€88,112) and continuous lenalidomide saved $194,705 (€117,010). Continuous lenalidomide avoided > $200,000 (€120,000) of further therapy costs, but this is 54% and 73% of the post-transplant lenalidomide drug cost. Fixed-duration post-transplant lenalidomide avoided > $150,000 dollars and > €110,000 in the US and EU settings.  These are 62% and 104% of the drug cost for post-transplant lenalidomide. Consequently, post-transplant lenalidomide's resulting incremental cost was especially favourable for the 2-year fixed-duration strategy and even more favourable in the EU setting because the largest part of post-transplant costs was offset by avoided 2nd-line costs.
Future healthcare costs discounting further reduced incremental costs of 2-year fixed-duration post-transplant lenalidomide because more subjects assigned to this strategy receive higher-cost drug triplets at 1st failure. Consequently, in the EU setting, 2-year fixed-duration post-transplant lenalidomide reduced net healthcare cost and avoided €7,286 in costs for every QALY saved.  In contrast, continuous post-transplant lenalidomide achieved 1 QALY at the cost of €29,232.  In the US setting, 2-year fixed-duration post-transplant lenalidomide increased discounted healthcare costs by $60,835 per QALY saved, whereas continuous post-transplant lenalidomide achieved each QALY at the cost of $133,401.
Sensitivity analyses. We tested the results' sensitivity to different time horizons and multiple input co-variates (Figure 2). Results were highly sensitive to the time horizon, the monthly cost of lenalidomide, and the cost of 2nd-line and subsequent therapy/ies. However, 2-year fixed-duration lenalidomide maintained a favourable incremental cost per QALY gained < €50,000 in the EU setting even in persons with a low risk of early relapse or progression, such as individuals achieving a complete post-transplant response.[38,40] Similarly, in the US setting, 2-year fixed-duration lenalidomide maintained an incremental cost per QALY gained < $150,000 despite extreme-range sensitivity analysis.

Figure 2 Figure 2

Relative costs were the major driver of the incremental cost per QALY saved: the higher the ratio between 2nd-line lenalidomide-based therapies versus post-transplant lenalidomide, the greater the economic benefit of post-transplant lenalidomide. For cost ratios of carfilzomib, lenalidomide, dexamethasone (KRD) > 4.1 and daratumumab, lenalidomide, dexamethasone (DRD) > 3.0 continuous post-transplant lenalidomide was cost saving in the EU setting.  Similarly, for cost ratios  of  DRD > 2.8 and KRD > 3.1, 2-year fixed-duration lenalidomide was cost-saving in the US setting. 
Two-way sensitivity analysis display chances for post-transplant strategies to be cost-effective (incremental cost < $100,000 per QALY) derive from the interplay between lenalidomide monthly cost and the cost ratio of 2nd-line therapies (Figure 3). Therefore, continuous lenalidomide is potentially cost-effective for lower monthly lenalidomide cost and higher KRD and DRD cost ratios, as happens in the EU setting.  In contrast, 2-year fixed duration lenalidomide may be cost-effective even at higher lenalidomide cost and lower KRD and DRD cost ratios, as in the US setting.

Figure 3 Figure 3

Our study tested different post-transplant strategies in cohorts of subjects in whom individual probabilities of post-transplant failure are unknown and for whom we have only estimated with reasonably wide 95 per cent confidence intervals. However, different persons in these cohorts have different probabilities of post-transplant failure. If these probabilities could be accurately predicted on the subject-level, it would be possible to predict the most cost-effective strategy for that person. Monte Carlo simulation analysis (10,000 runs) allowed us to simultaneously assess multiple input variables' effect on the results and track several individual outcomes as displayed by the scatterplots in Supplementary Figure 2. Continuous post-transplant lenalidomide had a 62% probability of achieving a QALY at a cost < €50,000 in the EU setting, whereas in the US, the probability of achieving one QALY at < $100,000 was only 42%. 2-year fixed-duration lenalidomide had an 81% probability of achieving a QALY at a cost < €50,000 in the EU setting and a 69% probability of achieving a QALY at a cost < $100,000 in the US setting. 
Scenario analyses. We tested the sensitivity of the results to extreme variations of five input variables in order to test the variability of the results according to different settings, namely patient age and therapeutic choices for second and third line. Based on different survival rates in patients younger than 50 years,45 we modelled patients younger than 50 years by decreasing fatality rates by 50% and patients older than 65 years by increasing fatality rates by 50%. Table 4 shows that, as expected, both continuous post-transplant lenalidomide maintenance and two-year lenalidomide have a markedly better cost-utility in younger patients: despite a better cost-utility profile of two-year maintenance, continuous lenalidomide maintenance was also cost-saving in this clinical subgroup.

Table 4 Table 4. Scenario analysis.

We also tested extremely low (20%) and extremely high (80%) shares of KRD, KD and pomalidomide in the second and third line. Table 4 shows that the two maintenance strategies might report a better cost-utility in case of a lower carfilzomib share in the second line and a lower pomalidomide share in the third line.
Finally, we tested whether a strongly shorter PFS2 after lenalidomide might change the results: a PFS2 of 18 months, corresponding to a monthly rate of progression of 0.04 ameliorates the cost-utility profile of both the maintenance strategies. Therefore, continuous lenalidomide might still be a cost-effective option in those patients for whom a shorter PFS2 is expected.


In persons with MM receiving an autotransplant, giving post-transplant lenalidomide until relapse or progression prolongs median PFS and survival by about 2 years.[6] Put otherwise, about 5 persons need to receive post-transplant lenalidomide for 2 years to avoid one relapse or progression over a 5-year horizon. Achieving this gain involves the cost of post-transplant lenalidomide and subsequent therapy/ies.[31,32,41] However, analyzing the cost of post-transplant lenalidomide is complex. Issues include: (1) numbers needed to treat to avoid failure; (2) duration; and (3) post-failure outcomes and interventions. 
Post-transplant maintenance's optimal duration is unknown: direct and indirect data from prospective studies report a prolonged failure-free period after stopping post-transplant lenalidomide in persons receiving it failure-free for > 2 years.[16,34,39] These data suggest a fixed-duration strategy of post-transplant lenalidomide might be as effective at a lower cost compared with continuous post-transplant lenalidomide.  Because of this possibility, we compared the cost-effectiveness of different post-transplant strategies: (1) no intervention; (2) continuous post-transplant lenalidomide; and (3) 2-year fixed-duration lenalidomide.  The model was based on simplified modelling of failure rates and costs but calibrated to provide survival rates and mean post-transplant lenalidomide durations like published randomized trials.[6,34]
Outputs of our model indicate continuous lenalidomide is cost-effective in the EU setting but costs more than $100,000 per QALY in the US setting. 2-year fixed-duration lenalidomide significantly prolonged PFS and quality-adjusted survival at an acceptable cost per life-year gained in EU and US settings. In the EU setting, 2-year fixed-duration lenalidomide reduced overall healthcare costs in the baseline 20-year horizon. Different costs between the EU and US settings resulted predominately from cost ratios for 2nd-line and subsequent therapy/ies compared with post-transplant lenalidomide cost.[42]
Sensitivity analyses of the model highlighted some interesting issues. First, economic advantages driven by the lower rate of failure while receiving post-transplant lenalidomide were more evident in shorter time horizons. In the long-term, advantages were partially balanced by the healthcare costs for subsequent therapy/ies. Second, the incremental cost per QALY gained by post-transplant lenalidomide versus no intervention was highly dependent on subsequent therapy/ies costs. Higher costs for therapies containing lenalidomide or pomalidomide in persons failing after stopping post-transplant lenalidomide favoured giving post-transplant lenalidomide whereas higher costs for subsequent therapy(ies) without lenalidomide or pomalidomide in persons failing while receiving lenalidomide were against post-transplant lenalidomide (Figure 2, Figure 3). Third, there was an increase in the cost-for-benefit ratio of post-transplant lenalidomide as the rate of 2nd failure increased in persons previously failing off-lenalidomide. We also tested other lenalidomide fixed-durations, including 1- and 3-year fixed-durations with no substantial change in our conclusions.
Our analysis focused on cost-effectiveness, typically expressed as cost per QALY. However, this widely accepted approach does not consider the economic value of a quality life saved, termed the value of a statistical life (VSL), which is about €225,000 ($250,000) per year. In our analysis, lenalidomide given until failure saves more lives than 2-year fixed-duration lenalidomide but at a considerable cost per QALY saved. The 2-year fixed duration strategy in the EU saves substantial health care costs. In the US setting, it results in substantially less cost per QALY. Neither calculation is adjusted for VSL saved, which may be an important offset to some patients, families, physicians, policy-makers, and societies.
Our study has several limitations. 1st, the results have no universal value because they depend on the time horizon adopted and country-specific drug costs.[43] 2nd, our analyses used a 3rd- party payer perspective but did not consider indirect costs from productivity loss, a relevant social burden for young persons with MM.[44] 3rd, unit costs of treatments resembled ex-factory costs and not true acquisition costs. This could result in relevant mismatches. Finally, we did not cover model costs of palliative and end-of-life care. 


Our modelling indicates the most favourable value-for-cost of post-transplant lenalidomide in persons with MM is associated with a 2-year fixed-duration strategy. However, continuous lenalidomide maintenance showed an acceptable cost-utility in younger patients and in those for whom a shorter PFS2 is expected. Definite conclusions require validation in controlled clinical trials, which consider safety, efficacy, and cost.
We compared our results with other published clinical and economic outcomes of continuous post-transplant lenalidomide (Supplementary Figure 2 and Table 2). These studies used partitioned survival but considered different health states and comparators. All studies included survival data from the CALBG 100104 study, whereas 2 studies included data from the IFM trial or other studies (Supplementary Table 3). Time horizons were also different, ranging from 10 years to a lifetime. Consequently, incremental life-years gained ranged from 1 to 3.64 years. Overall incremental costs ranged from €147,707 to $476,690 and incremental cost per QALY from €30,709 to €277,456.



  1. Mikhael J, Ismaila N, Cheung N, et al. treatment of multiple myeloma: ASCO and CCO joint clinical practice guideline. J Clin Oncol. 2019;37:1228-1263. doi: 10.1200/JCO.18.02096 PMid:30932732
  2. Jain T, Sonbol MB, Firwana B, et al. High-dose chemotherapy with early autologous stem cell transplantation compared to standard dose chemotherapy or delayed transplantation in patient with newly diagnosed multiple myeloma: a systematic review and meta-analysis. Biol Blood Marrow Transplant. 2019;25(2):239-247. doi: 10.1016/j.bbmt.2018.09.021 PMid:30244101
  3. Su B, Zhu X, Jiang Y, et al. A meta-analysis of autologous transplantation for newly diagnosed multiple myeloma in the era of novel agent. Leuk Lymphoma. 2019;60(6):1381-1388. doi: 10.1080/10428194.2018.1543874. PMid:30516074
  4. Dhakal B, Szabo A, Chhabra , et al. Autologous transplantation for newly diagnosed multiple myeloma in the era of novel agent induction: a systematic review and meta-analysis. JAMA Oncology. 2018;4(3):343-350. doi: 10.1001/jamaoncol.2017.4600. PMid:29302684 PMCid:PMC5885822
  5. Barosi G, Gale RP. Is lenalidomide the standard-of-care after an autotransplant for multiple myeloma? Leukemia. 2019;33(3):588-596. doi: 10.1038/s41375-019-0383-2. PMid:30692596
  6. McCarthy PL, Holtein SA, Petrucci MT, et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis. J Clin Oncol. 2017:35(29):3279-3289. doi: 10.1200/JCO.2017.72.6679 PMid:28742454 PMCid:PMC5652871
  7. Holstein SA, Jung SH, Richardson PG, et al. Updated analysis of CALBG (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma: a randomized, double-blind, phase 3 trial. Lancet Haematol. 2017;4(9):e431-e442. doi: 10.1016/S2352-3026(17)30140-0.
  8. Diamond B, Mclachlan K, Chung DJ, et al. Maintenance therapy and need for cessation studies in multiple myeloma: focus on the future. Best Pract Res Clin Hematol. 2002:33(1):101140. doi: 10.1016/j.beha.2020.101140. PMid:32139006
  9. Mian I, Milton DR, Shah N, et al. Prolonged survival with a longer duration of maintenance lenalidomide after autologous hematopoietic stem cell transplantation for multiple myeloma. Cancer. 2016;122(24):3831-3837. doi: 10.1002/cncr.30366 PMid:27680710 PMCid:PMC5138119
  10. Jagannath S, Abonous R, Durie BGM, et al. impact of post-ASCT maintenance therapy on outcomes of patients with newly diagnosed multiple myeloma in Connect MM. Blood Adv. 2018;2(13):1608-1615. doi: 10.1182/bloodadvances.2018017186 PMid:29986853 PMCid:PMC6039656
  11. Fonseca R, Parikh K, Ung B, Ni Q, Argawal A. Maintenance after lenalidomide, bortezomib, and dexamethasone induction with newly diagnosed multiple myeloma and high-risk cytogenetics: an enhanced medical record analysis. HemaSphere. 2018;2:230-231.  
  12. Cherniawsky H, Sandhu I, Chu M, et al. Lenalidomide maintenance chemotherapy: an analysi of real world data in multiple myeloma patient treated with autologous stem cell transplant and bortezomib-based induction. HemaSphere 2018;2(supplement 2): 968
  13. Tay J, Vij R, Norkin M. Impact of active maintenance treatment (MT) compared with no MT on the quality of life (QOL) of patients with multiple myeloma (MM) following first autologous stem cell transplant (ASCT). Blood. 2017; 130 (Supplement 1).  
  14. Kumar SK, Dispenzeri A, Fraser R, et al. Early relapse after autologous hematopoietic cell transplantation remains a poor prognostic factor in multiple myeloma but outcomes have improved over time. Leukemia. 2018;32(4):986-995. doi: 10.1038/leu.2017.331 PMid:29263438 PMCid:PMC5871538
  15. Attema AE, Brouwer WBF, Claxton K. Discounting in economic evaluations. Pharmacoeconomics. 2018;36(7):745-758. doi: 10.1007/s40273-018-0672-z PMid:29779120 PMCid:PMC5999124
  16. Amsler IG, Jeker B, Taleghani BM, et al. Prolonged survival with increasing duration of lenalidomide maintenance after autologous transplant for multiple myeloma. Leukemia Lymphoma. 2019;60(2):511-514. doi: 10.1080/10428194.2018.1473577 PMid:30616438  
  17. Offidani M, Morè S, Corvatta L, et al. Factors associated with the probability to skip subsequent lines of therapy: analysis of 321 multiple myeloma (MM) patients in a single tertiary centre. Clin Lymphoma Myeloma Leuk. 2019;19 (supplement 10): e275  
  18. Dimopoulos MA, San-Miguel J, Belch A, et al. Daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of POLLUX. Haematologica. 2018;103(12):2088-96. doi: 10.3324/haematol.2018.194282 PMid:30237262 PMCid:PMC6269302
  19. Spencer A, Lentzsch S, Weisel K, et al. Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR. Haematologica. 2018;103(12): 2079-2087. doi: 10.3324/haematol.2018.194118 PMid:30237264 PMCid:PMC6269293
  20. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carlfizomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 2015;372(2):142-152. doi: 10.1056/NEJMoa1411321 PMid:25482145  
  21. Dimopoulos MA, Moreau P, Palumbo A, et al. Carlfizomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOUR): a randomized, phase 3, open-label, multicenter study. Lancet Oncol. 2016;17(1):27-38. doi: 10.1016/S1470-2045(15)00464-7
  22. Richardson PG, Oriol A, Beksac M, et al. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomized, open-label, phase 3 trial. Lancet Oncol. 2019;20(6):781-94. doi: 10.1016/S1470-2045(19)30152-4  
  23. Moreau P, Joshua D, Chng W-J, et al. impact of prior treatment on patients with relapsed multiple myeloma treated with carfilzomib and dexamethasone vs bortezomib and dexamethasone in the phase 2 ENDEAVOR study. Leukemia. 2017;31(1):115-122. doi: 0.1038/leu.2016.186 PMid:27491641 PMCid:PMC5220137
  24. Felix J, Aragao F, Almeida JM, et al. Time-dependent endpoints as predictors of overall survival in multiple myeloma. BMC Cancer. 2013;13:122. 10.1186/1471-2407-13-122. PMid:23497363 PMCid:PMC3607860
  25. Proskorovsky I, Lewis P, Williams CD, et al. Mapping EORTC QLQ-C30 and QLQ-MY20 to EQ-5D in patients with multiple myeloma. Health Qual Life Outcomes. 2014;12:1-9. doi: 10.1186/1477-7525-12-35. PMid:24618388 PMCid:PMC4007827
  26. Acaster S, Gaugris S, Velikova G, Yong K, Lloyd A. Impact of the treatment-free interval on health-related quality of life in patients with multiple myeloma: a UK cross-sectional survey. Supportive Care Cancer. 2013;21(2):599-607. doi: 10.1007/s00520-012-1548-y PMid:22886429
  27. Carlson JJ, Guzauskas GF, Chapman RH, et al. Cost-effectiveness of drugs to treat relapsed/refractory multiple myeloma in the United States. J Manag Care Spec Pharm. 2018;24(1):29-38. doi: 10.18553/jmcp.2018.24.1.29. PMid:29290170
  28. Hollmann S, Moldaver D, Goyert N, Grima D, Maiese EM. A US cost analysis of triplet regimens for patients with previously treated multiple myeloma. J Manag Care Spec Pharm. 2019;25(4):449-59. doi: 10.18553/jmcp.2019.25.4.449. PMid:30917078  
  29. Zhang TT, Wang S, Wan N, et al. Cost-effectiveness of daratumumab-based triplet therapies in patients with relapsed or refractory multiple myeloma. Clin Ther. 2018;40(7):1122-1139. doi: 10.1016/j.clinthera.2018.05.012 PMid:30006069
  30. Jakubowiak AJ, Houisse I, Majer I, et al. Cost-effectiveness of carlfizomib plus dexamethasone compared with bortezomib plus dexamethasone for patients with relapsed or refractory multiple myeloma in the United States. Expert Rev Hematol. 2017;10(2):1107-1119. doi: 10.1080/17474086.2017.1391088. PMid:29027825
  31. Gonzalez-McQuire S, Young K, Leleu H, et al. Healthcare resource utilization among patients with relapsed multiple myeloma in the UK, France, and Italy. J Med Econ. 2018;21(5):450-467. doi: 10.1080/13696998.2017.1421546 PMid:29278014
  32. Ashcroft J, Judge D, Dhanasiri S, Taylor-Stokes G, Middleton C. Chart review across EU5 in MM post-ASCT patients. Int J Hematol Oncol. 2018;7:IJH05 PMid:30302236 PMCid:PMC6176952
  33. Pelligra CG, Parikh K, Abouzaid S, Ailawadi S. Cost-effectiveness of pomalidomide, carlfizomib, and daratumumab for the treatment of patients with heavily pretreated relapsed-refractory multiple myeloma in the United States. Clin Ther. 2017;398(10):1986-2005. Doi: 10.1016/j.clinthera.2017.08.010 PMid:28967482
  34. Goldschmidt H, Mai EK, Durig J, et al. Response-adapted lenalidomide maintenance in newly diagnosed myeloma: results from the phase III GMMG-MM5 trial. Leukemia 2020 (in press PMid:32034285
  35. Olry de Labry Lima A, Gimeno-Ballester V, Rios 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. 2019;54(11):1908-1919. doi: 10.1038/s41409-019-0574-5 PMid:31150015
  36. Zhou Z-Y, Parikh K, Chai X, et al. cost-effectiveness analysis of lenalidomide for maintenance therapy after autologous stem cell transplant (ASCT) in newly diagnosed multiple myeloma (NDMM) patients: a United States payer perspective. Blood. 2018;132 (suppl 1).
  37. Uyl-de Groot CA, Ramsen R, Boersma J, et al. Lenalidomide as maintenance treatment for patients with newly diagnosed multiple myeloma post-autologous stem cell transplantation: a pharmacoeconomic assessment in the Netherlands. Blood. 2018;132 (suppl 1).  
  38. Lehners N, Becker N, Benner A, Pritsh M, Lopprich M, Mai EK. Analysis of long-term survival in multiple myeloma after first-line autologous stem cell transplantation: impact of clinical risk factors and sustained response. Cancer Med. 2018;7(2): 307-316. doi: 10.1002/cam4.1283. PMid:29282899 PMCid:PMC5806105
  39. Bonello F, Pulini S, Ballanti S, et al. Lenalidomide maintenance with or without prednisone in newly diagnosed myeloma patients: a pooled analysis. Cancers (Basel). 2019;11(11):E1735. doi: 10.3390/cancers11111735. PMid:31694338 PMCid:PMC6896192
  40. Usmani SZ, Hoering A, Cavo M, et al. Clinical predictors of long-term survival in newly diagnosed transplant eligible multiple myeloma - an IMWG Research project. Blood Cancer J. 2018;8(12): 123. Doi: 10.1038/s41408-018-0155-7. PMid:30470751 PMCid:PMC6251924
  41. Boccadoro M, Usmani SZ, Chari A, et al. A global treatment standard in multiple myeloma (MM) remains elusive despite advances in care over 15 years first results from insight mm, the largest global perspective, observational MM study. HemaSphere. 2018;2; supplement 2 (591-)  
  42. Hewitt C, Foxon G, Craddy P, Chunara F. ICERs are not all the same. How cost-effectiveness estimates differ beween the UK and US. Value in Health. 2018; 21; supplement 1 (S20-)  
  43. Marchetti M. Value of innovation for haematologic malignancies. J Med Econ. 2016;19(5):487-489. doi: 10.3111/13696998.2015.1133429 PMid:26706602
  44. Jackson G, Galinsky J, Alderson DEC, et al. Productivity losses in patients with newly diagnosed multiple myeloma following stem cell transplantation and the impact of maintenance therapy. Eur J Haematol. 2019;103(4):393-401. doi: 10.1111/ejh.13298 PMid:31325331 PMCid:PMC6899492
  45. Kristinsson SY, Anderson WF, Landgren O. Improved long-term survival in multiple myeloma up to the age of 80 years. Leukemia. 2014; 28: 1346-1348. doi: doi:10.1038/leu.2014.23 PMid:24418994

Supplementary Data

Suppl Tab 1 Supplementary Table 1. Distribution of therapy choices for second and third line: carlfizomib, lenalidomide, dexamethasone (KRD), daratumumab, lenalidomide, dexamatheasone (DaraRD), daratumumab, bortezomib, dexamethasone (DaraVD), carlfizomib, dexamethasone (KD), pomalidomide, bortezomib, dexamethasone (pomVD), pomalidomide, cyclophosphamide, dexamethasone (PomCD).

Suppl Table 2 Supplementary Table 2. Literature search strategy.

Suppl Table 3 Supplementary Table 3. Retrieved studies.

Suppl Figure 1 Supplementary Figure 1. Breakdown of costs in the EU setting (panel A) and in the US setting (panel B). X-axis shows thousand euros in panel A and thousand dollars in panel B.
Abbreviations: continuous lenalidomide maintenance: “cont”; 2-year fixed-duration lenalidomide maintenance: “fixed”; no post-transplant maintenance: “no maint”.

Suppl Figure 2 Supplementary Figure 2. Monte Carlo simulation of the decision model outputs. Incremental cost and incremental effectiveness (quality-adjusted months) of continuous or fixed-duration lenalidomide maintenance versus no maintenance are reported: each simulation is represented by a dot. Continuous lenalidomide maintenance versus no maintenance is reported in panels A (US setting) and B (EU setting). Two-year fixed duration maintenance versus no maintenance is reported in panels C (US setting) and D (EU setting). Willingness to pay (WTP) for an additional QALY in thousand dollars or thousand euros is plotted. The higher is the number of dots plotted above the WTP line, the less cost-effective was the maintenance strategy assessed.

Suppl Figure 3 Supplementary Figure 3. PRIMSA flow-chart.