Persistent challenges with treating multiple myeloma early.

Over the past decade, 2 strategies have advanced the treatment of patients with multiple myeloma and its precursor diseases. First, the definition has changed to include patients without end organ damage, who previously would not have been treated. Second, there is widespread enthusiasm for treating high-risk, smoldering multiple myeloma. In this commentary, we explore the evidence supporting these therapeutic expansions. Although early treatment adds cost and therapeutic burden, it remains unknown whether survival and health-related quality of life are improved by early treatment. Herein, we consider the implications of diagnostic expansion in multiple myeloma.

Association of adverse events and associated cost with efficacy for approved relapsed and/or refractory multiple myeloma regimens: A Bayesian network meta-analysis of phase 3 randomized controlled trials.

BACKGROUND: Several new treatment options have been approved for relapsed and/or refractory multiple myeloma (RRMM). In this systematic review, associations of the efficacy of each approved regimen with adverse events (AEs) and the total cost per cycle were compared with a Bayesian network meta-analysis (NMA) of phase 3 randomized controlled trials (RCTs). METHODS: Scopus, Cochrane, PubMed Publisher, and Web of Science were searched from January 1999 to July 2018 for phase 3 RCTs of regimens (approved by the US Food and Drug Administration) used in RRMM. The relative ranking of agents was assessed with surface under the cumulative ranking (SUCRA) probabilities. The primary efficacy, safety, and cost outcomes were progression-free survival with the regimen, grade 3 to 4 AEs, and the total cost per cycle (regimen cost plus average cost of managing AEs). RESULTS: Fifteen studies including 7718 patients and evaluating 14 different regimens were identified. Daratumumab, lenalidomide, and dexamethasone were ranked highest for reducing progression (hazard ratio, 0.13; 95% credible interval, 0.09-0.19; SUCRA, 1) but carried the highest probability of total cost per cycle ($41,420; 95% Credible Interval [CrCl], $58,665-$78,041; SUCRA, 0.02). Panobinostat, bortezomib, and dexamethasone were the least effective and least safe (SUCRA, 0.24), whereas bortezomib, thalidomide, and dexamethasone emerged as least effective with the highest total cost per cycle (SUCRA, 0.33). Carfilzomib and dexamethasone emerged as the winner when this regimen was considered in terms of efficacy and safety (SUCRA, 0.61) and efficacy and total cost per cycle (SUCRA, 0.60). CONCLUSIONS: The results of this NMA can provide additional guidance for the decision-making process when one is choosing the most appropriate regimen for RRMM.

Real-world treatment patterns, resource use and cost burden of multiple myeloma in Portugal.

OBJECTIVE: We provide a real-world overview of multiple myeloma (MM) treatment patterns, outcomes and healthcare resource use (HRU) in Portugal. METHODS: Data were collected retrospectively from consecutive patients diagnosed/treated at the Portuguese Oncology Institute of Porto (IPO-Porto) between 2012 and 2015. Primary objectives were progression-free survival (PFS) and overall survival (OS), with treatment patterns and HRU secondary. Analysis was by line of therapy (LOT), and post hoc by age (<65/≥65 years). RESULTS: 165, 73 and 32 patients received first, second and third LOTs respectively (N = 187). OS probabilities were 91.5%, 83.2% (<65 years) and 86.6%, 65.3% (≥65 years) at 12, 24 months respectively. PFS decreased from the start of each LOT for both age groups and was less for patients ≥65 years. Younger patients received more combination treatment (immunomodulatory drugs + proteasome inhibitors) and stem cell transplants, and had higher mean costs than older patients (€81,213 vs. €36,864 where three LOTs were received). Cost drivers were medications, transplantations and hospitalisations. CONCLUSION: Our results suggest divergence between younger and older MM patients. Older patients had lower OS and PFS probabilities, HRU costs and fewer stem cell transplantations. The treatment patterns in each LOT may differ from other countries' findings, suggesting treatment heterogeneity.

Cost-effectiveness of adding daratumumab or bortezomib to lenalidomide plus dexamethasone for newly diagnosed multiple myeloma.

BACKGROUND: Multiple myeloma survival rates are steadily increasing due to availability of new drug classes used in combination with corticosteroids and chemotherapy. The latest treatments are daratumumab or bortezomib in combination therapy with lenalidomide and dexamethasone (Rd). Daratumumab, a CD38-targeted, human IgG1k monoclonal antibody, and bortezomib, a proteasome inhibitor, are both approved as regimens for transplant-ineligible relapsed/refractory multiple myeloma (RRMM). There have been cost-effectiveness analyses for daratumumab and bortezomib use in RRMM, but there are limited data regarding cost-effectiveness for daratumumab or bortezomib use in newly diagnosed multiple myeloma patients who are ineligible for stem cell transplantation. OBJECTIVE: To compare the cost-effectiveness of 3 separate regimens-(1) daratumumab, lenalidomide, and dexamethasone triple therapy (DRd); (2) bortezomib and lenalidomide plus dexamethasone triple therapy (VRd); and (3) lenalidomide plus dexamethasone (Rd)-in patients with multiple myeloma ineligible for autologous stem cell transplant. METHODS: A 2-state Markov model was developed using a US health system perspective and lifetime time horizon. Transition probabilities were calculated from the latest progression-free survival data reported in two phase 3 randomized controlled trials-MAIA and SWOG S0777-and extrapolated using a Weibull distribution based on the Hoyle Henley method. National data sources were used to obtain costs in 2019 US dollars, discounted by 3%. Health state utilities from available literature were applied to each health state. Utility decrements for adverse events were individualized in each choice branch with utility decrement weighted by the percentage of patients who experienced the adverse event in the MAIA and SWOG S0777 trials. We assumed a treatment would be cost-effective at a willingness to pay (WTP) of $150,000 per progression-free quality-adjusted life-year ($/PFQALY). One-way and probabilistic sensitivity analyses were conducted. RESULTS: Rd standard therapy had the lowest overall cost at $329,867, followed by VRd at $385,434 and DRd with the highest overall total cost at $626,900. Rd was estimated to result in the least amount (1.24) of PFQALYs, followed by VRd at 1.35 PFQALYs and DRd at 1.52 PFQALYs. With a WTP threshold of $150,000 per PFQALY, VRd was not cost-effective compared with Rd standard therapy, with an incremental cost-effectiveness ratio (ICER) of $530,256 per PFQALY. DRd was not cost-effective compared with VRd (ICER = $1,396,318 per PFQALY), nor as compared with Rd standard therapy (ICER = $1060,832). One-way sensitivity analysis showed that our model was sensitive to cost of DRd, VRd, and Rd drugs. Probabilistic sensitivity analysis showed that only at a WTP threshold of $550,000 was VRd cost-effective for 40% of iterations. There were no reasonable WTP thresholds, up to $800,00, where DRd became more cost-effective than VRd. CONCLUSIONS: This study is the first analysis to directly compare the cost-effectiveness of 3 acceptable chemotherapy treatment regimens for patients with multiple myeloma ineligible for autologous stem cell transplant. Neither DRd nor VRd triple therapy were found to be cost-effective vs Rd. Further cost-effectiveness analyses that include overall survival data for daratumumab and bortezomib triple therapies are needed to demonstrate an ICER in QALYs. DISCLOSURES: No funding was received for this study. At the time of this study, Narsipur was a UCSF-Actelion Clinical Research and Medical Communications Fellow, unrelated to this study. The other authors have nothing to disclose.

Lenalidomide plus rituximab Vs rituximab alone in relapsed or refractory indolent lymphoma: A cost-effectiveness analysis.

BACKGROUND: The aim of the study was to evaluate the cost-effectiveness of lenalidomide plus rituximab vs rituximab alone in patients with relapsed or refractory indolent lymphoma. METHODS: A Markov decision model was established to carry out the cost-effectiveness analysis. Three discrete health states, progression-free survival (PFS), progressive disease (PD), and death, were included. Cycle length was set at 1 month, and utility scores were derived from previously published literature. The incremental cost-effectiveness ratio (ICER) was defined as the primary endpoint, and the willingness-to-pay (WTP) threshold was set at $29,306.43 per quality-adjusted life year (QALY). Both cost and effectiveness were determined using a 3% annual discount rate. Furthermore, one-way and probabilistic sensitivity analyses were performed to check the robustness of the model. RESULTS: Lenalidomide plus rituximab gained 6.08 QALYs at a cost of $120,979.62 while rituximab alone gained 4.84 QALYs at a cost of $48,052.11. The ICER of lenalidomide plus rituximab vs rituximab alone was $58,812.51/QALY. The parameters most significantly influenced the model were the utility values for the PFS state, the duration of the PFS state in the lenalidomide plus rituximab group, and the cost of lenalidomide. The probability of lenalidomide plus rituximab or rituximab alone being the most cost-effective option was 0% and 100%, respectively, at a WTP threshold of $29,306.43/QALY. CONCLUSIONS: Lenalidomide plus rituximab is not a cost-effective strategy compared with rituximab monotherapy for relapsed or refractory indolent lymphoma from a Chinese societal perspective.

A budget impact analysis of lenalidomide in multiple myeloma Egyptian patients.

INTRODUCTION: The aim of this study was to estimate the budget impact of lenalidomide and dexamethasone (RD) versus bortezomib, cyclophosphamide and dexamethasone (VCD) in newly diagnosed multiple myeloma (NDMM) and relapsed refractory (RR) MM patients, from the perspective of the Egyptian Ministry of health (MoH). METHODS: Two budget impact dynamic models were conducted to assess the budget impact of RD entry over a 3-year period. The clinical data for the modeled cohorts were based on published articles. Total annual medical costs associated with non-progression and progression disease states included the sum of estimated costs for adverse effects management, concomitant treatments, hospitalization and the follow up were measured. Deterministic sensitivity analyses were performed. RESULTS: The target population in a given year was estimated to include 245 patients with RRMM and 291 patients with NDMM receiving RD versus VCD. In RRMM, the annual budget savings of lenalidomide entry were estimated at EGP -1,103,969, -3,362,793 and -5,949,228 at year 1, year 2 and year 3, respectively. In NDMM, the annual budget savings of lenalidomide entry were estimated at EGP869,415, -1,779,776 and -2,139,311 at year 1, year 2 and year 3, respectively, to the payer after lenalidomide entry. The model results in RRMM were most sensitive to variations in patients eligible to transplantation in RRMM. In NDMM, the model results were most sensitive to the market share of VCD in the first year. CONCLUSION: The results of our BI models suggest that not only does RD treatment have an effect on the budget, but also has major cost savings in other areas which are very important while considering the total costs of MM treatment. This study results provided evidence-based information to the MoH that will help in decision making of whether to implement RD as a treatment intervention or not.

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

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.

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

Aim: To assess the cost-effectiveness of lenalidomide plus low dose dexamethasone (Rd) relative to bortezomib-contained therapy (BCT) for newly diagnosed multiple myeloma patients ineligible for stem cell transplantation (ndMM) in China. Materials & methods: A literature review was conducted to identify appropriate evidence for developing a cost-effectiveness model comparing Rd with BCT for lifetime health outcomes and direct medical costs in Chinese ndMM patients. Results: The estimated incremental cost-effectiveness ratio per gained quality-adjusted life years for Rd versus BCT was ¥49,793. The chance for Rd to be cost effective, under the cost-effectiveness thresholds of three-times the 2018 Chinese gross domestic goods per capita, was 90.8%. Conclusion: The cost-effectiveness of Rd relative to BCT for ndMM in Chinese patients is highly attractive.

How patent law reform can improve affordability and accessibility of medicines in South Africa: Four medicine case studies.

South Africa (SA) is in the process of amending its patent laws. Since its 2011 inception, Fix the Patent Laws, a coalition of 40 patient groups, has advocated for reform of SA's patent laws to improve affordability of medicines in the country. Building on two draft policies (2013, 2017) and a consultative framework (2016) for reform of SA's patent laws, Cabinet approved phase 1 of the Intellectual Property Policy of the Republic of South Africa on 23 May 2018. Fix the Patent Laws welcomed the policy, but highlighted concerns regarding the absence of important technical details, as well as the urgent need for government to develop bills, regulations and guidelines to provide technical detail and to codify and implement patent law reform in the country. In this article, we explore how reforms proposed in SA's new intellectual property policy could improve access to medicine through four medicine case studies.

The tale of lenalidomide clinical superiority over thalidomide and regulatory and cost-effectiveness issues.

In April 2017, the National Sanitary Surveillance Agency (ANVISA-Brazil) approved lenalidomide (LEN) for multiple myeloma (MM) and myelodysplastic syndrome. ANVISA had rejected the first application in 2010, and denied a request for reconsideration in 2012. The reason for rejection was the lack of comparative effectiveness studies proving that LEN was more effective than thalidomide (THAL), a strictly controlled drug regulated by Federal law 10.651/2003 and dispensed to patients (at no costs) through public health system units and hospitals. ANVISA unexplained retreat on the LEN approval for marketing was an unquestionable triumph of the lobbying that ensued the denial, at the forefront of which were politicians, Congress members, patient organizations and medical societies. Two randomized (phase III) trials and three observational (case-control and population-based cohort) compared the effectiveness of THAL- versus LEN-based therapies in MM. Overall, these studies showed no difference in efficacy between LEN- and THAL-based therapies. LEN caused less neuropathy, and more severe hematologic adverse effects. It is much costlier than THAL, and substitution of THAL by LEN shall raise considerably public healthcare costs in Brazil.

Ixazomib for Relapsed or Refractory Multiple Myeloma: Review from an Evidence Review Group on a NICE Single Technology Appraisal.

Ixazomib is an oral proteasome inhibitor used in combination with lenalidomide plus dexamethasone (IXA-LEN-DEX) and licensed for relapsed or refractory multiple myeloma. As part of a single technology appraisal (ID807) undertaken by the National Institute of Health and Care Excellence, the Evidence Review Group, Warwick Evidence was invited to independently review the evidence submitted by the manufacturer of ixazomib, Takeda UK Ltd. The main source of clinical effectiveness data about IXA-LEN-DEX came from the Tourmaline-MM1 randomized controlled trial in which 771 patients with relapsed or refractory multiple myeloma received either IXA-LEN-DEX or placebo-LEN-DEX as their second-, third-, or fourth-line treatment. Takeda estimated the cost effectiveness of IXA-LEN-DEX using a de-novo partitioned-survival model with three health states (pre-progression, post-progression, and dead). In their first submission, this model was used to estimate the cost effectiveness of IXA-LEN-DEX vs. bortezomib plus dexamethasone (BORT-DEX) in second-line treatment, and of IXA-LEN-DEX vs. LEN-DEX in third-line treatment. To estimate the relative clinical performance of IXA-LEN-DEX vs. BORT-DEX, Takeda conducted network meta-analyses for important outcomes. The network meta-analysis for overall survival was found to be flawed in several respects, but mainly because a hazard ratio input for one of the studies in the network had been inverted, resulting in a large inflation of the claimed superiority of IXA-LEN-DEX over BORT-DEX and a considerable overestimation of its cost effectiveness. In subsequent submissions, Takeda withdrew second-line treatment as an option for IXA-LEN-DEX. The manufacturer's first submission comparing IXA-LEN-DEX with LEN-DEX for third-line therapy employed Tourmaline-MM1 data from third- and fourth-line patients as proxy for a third-line population. The appraisal committee did not consider this reasonable because randomization in Tourmaline-MM1 was stratified according to one previous treatment and two or more previous treatments. A further deficiency was considered to be the manufacturer's use of interim survival data rather than the most mature data available. A second submission from the company focussed on IXA-LEN-DEX vs. LEN-DEX as third- or fourth-line treatment (the two or more previous lines population) and a new patient access scheme was introduced. Covariate modeling of survival outcomes was proposed using the most mature survival data. The Evidence Review Group's main criticisms of the new evidence included: the utility associated with the pre-progression health state was overestimated, treatment costs of ixazomib were underestimated, survival models were still associated with great uncertainty, leading to clinically implausible anomalies and highly variable incremental cost-effectiveness ratio estimates, and the company had not explored a strong assumption that the survival benefit of IXA-LEN-DEX over LEN-DEX would be fully maintained for a further 22 years beyond the observed data, which encompassed only approximately 2.5 years of observation. The appraisal committee remained unconvinced that ixazomib represented a cost-effective use of National Health Service resources. Takeda's third submission offered new base-case parametric models for survival outcomes, a new analysis of utilities, and proposed a commercial access agreement. In a brief critique of the third submission, the Evidence Review Group agreed that the selection of appropriate survival models was problematic and at the request of the National Institute for Health Care and Excellence investigated external sources of evidence regarding survival outcomes. The Evidence Review Group considered that some cost and utility estimates in the submission may have remained biased in favor of ixazomib. As a result of their third appraisal meeting, the committee judged that for the two to three prior therapies population, and at the price agreed in a commercial access agreement, ixazomib had the potential to be cost effective. It was referred to the Cancer Drugs Fund so that further data could accrue with the aim of diminishing the clinical uncertainties.

Healthcare resource utilization with ixazomib or placebo plus lenalidomide-dexamethasone in the randomized, double-blind, phase 3 TOURMALINE-MM1 study in relapsed/refractory multiple myeloma.

AIMS: The aim of this analysis was to assess healthcare resource utilization in the pivotal phase 3 TOURMALINE-MM1 study of the oral proteasome inhibitor ixazomib or placebo plus lenalidomide and dexamethasone (Rd) in relapsed and/or refractory multiple myeloma (RRMM). METHODS: In this double-blind, placebo-controlled, randomized study (NCT01564537), 722 patients with RRMM following 1-3 prior lines of therapy received Rd plus ixazomib (ixazomib-Rd; n = 360) or matching placebo (placebo-Rd; n = 362) until disease progression or unacceptable toxicity. Healthcare resource utilization data were captured on Day 1 of each 28-day cycle, every 4 weeks during follow-up for progression-free survival, and every 12 weeks during subsequent follow-up, and included medical encounters (length of stay, inpatient, outpatient, and reason) and number of missing days from work or other activities for patients and caregivers. RESULTS: Exposure-adjusted rates of hospitalization were similar between the ixazomib-Rd and placebo-Rd arms, at 0.530 and 0.564 per patient year (ppy), respectively, as were outpatient visit rates (3.305 and 3.355 ppy). Mean length of hospitalization per patient was 10.0 and 10.8 days, respectively. In both arms, hospitalization and outpatient visit rates were higher in patients with two or three prior lines of treatment (ixazomib-Rd: 0.632 and 3.909 ppy; placebo-Rd: 0.774 and 3.539 ppy) compared with patients with one prior line (ixazomib-Rd: 0.460 and 2.888 ppy; placebo-Rd: 0.436 and 3.243 ppy). Patients and their caregivers who missed any work or other activity missed a median of 7 and 5 days in the ixazomib-Rd arm, respectively, vs 8 and 4 days with placebo-Rd. LIMITATIONS: The study was not powered for a statistical comparison of healthcare resource utilization between treatment arms, nor did it capture costs associated with utilization of the identified healthcare resources. CONCLUSIONS: This pre-specified analysis demonstrated that the all-oral triplet regimen of ixazomib added to Rd did not increase healthcare resource utilization compared with placebo-Rd.

The tale of lenalidomide clinical superiority over thalidomide and regulatory and cost-effectiveness issues / A narrativa de que a lenalidomida é clinicamente superior à talidomida, e questões regulatórias e de custo-efetividade

Abstract In April 2017, the National Sanitary Surveillance Agency (ANVISA-Brazil) approved lenalidomide (LEN) for multiple myeloma (MM) and myelodysplastic syndrome. ANVISA had rejected the first application in 2010, and denied a request for reconsideration in 2012. The reason for rejection was the lack of comparative effectiveness studies proving that LEN was more effective than thalidomide (THAL), a strictly controlled drug regulated by Federal law 10.651/2003 and dispensed to patients (at no costs) through public health system units and hospitals. ANVISA unexplained retreat on the LEN approval for marketing was an unquestionable triumph of the lobbying that ensued the denial, at the forefront of which were politicians, Congress members, patient organizations and medical societies. Two randomized (phase III) trials and three observational (case-control and population-based cohort) compared the effectiveness of THAL- versus LEN-based therapies in MM. Overall, these studies showed no difference in efficacy between LEN- and THAL-based therapies. LEN caused less neuropathy, and more severe hematologic adverse effects. It is much costlier than THAL, and substitution of THAL by LEN shall raise considerably public healthcare costs in Brazil.

Resumo A Agência Nacional de Vigilância Sanitária (ANVISA) aprovou em abril de 2017 a lenalidomida (LEN) para o mieloma múltiplo (MM) e síndrome mielodisplásica. A ANVISA havia negado o registro em 2010, e indeferido um recurso apresentado em 2012. O motivo do indeferimento foi a falta de estudos comparativos de efetividade demonstrando que LEN era mais eficaz do que a talidomida (TAL), um medicamento rigorosamente controlado pela lei federal 10.651/2003 e dispensado gratuitamente a pacientes através de unidades de saúde e hospitais públicos. O recuo não explicado da ANVISA em relação ao registro da LEN foi um inquestionável triunfo do lobby que sucedeu a recusa inicial do registro, a frente do qual estavam políticos, membros do Congresso, associações de pacientes e sociedades médicas. Dois ensaios randomizados (fase III) e três estudos observacionais (caso-controle e coorte de base populacional) compararam a efetividade de terapias para o MM com TAL- e com LEN. Em conjunto, esses estudos mostraram que não havia diferenças quanto a eficácia de tratamentos com LEN- e aqueles com TAL. A LEN causou menos neuropatias, e efeitos adversos hematológicos mais graves. Ela é muito mais cara do que a TAL, e a substituição da TAL pela LEN aumentará muito os custos da assistência pública à saúde no Brasil.