Minimal residual disease assessment by multiparameter flow cytometry in transplant-eligible myeloma in the EMN02/HOVON 95 MM trial.

Minimal residual disease (MRD) by multiparameter flow cytometry (MFC) is the most effective tool to define a deep response in multiple myeloma (MM). We conducted an MRD correlative study of the EMN02/HO95 MM phase III trial in newly diagnosed MM patients achieving a suspected complete response before maintenance and every 6 months during maintenance. Patients received high-dose melphalan (HDM) versus bortezomib-melphalan-prednisone (VMP) intensification, followed by bortezomib-lenalidomide-dexamethasone (VRd) versus no consolidation, and lenalidomide maintenance. Bone marrow (BM) samples were processed in three European laboratories, applying EuroFlow-based MFC protocols (eight colors, two tubes) with 10-4-10-5 sensitivity. At enrollment in the MRD correlative study, 76% (244/321) of patients were MRD-negative. In the intention-to-treat analysis, after a median follow-up of 75 months, 5-year progression-free survival was 66% in MRD-negative versus 31% in MRD-positive patients (HR 0.39; p < 0.001), 5-year overall survival was 86% versus 69%, respectively (HR 0.41; p < 0.001). MRD negativity was associated with reduced risk of progression or death in all subgroups, including ISS-III (HR 0.37) and high-risk fluorescence in situ hybridization (FISH) patients (HR 0.38;). In the 1-year maintenance MRD population, 42% of MRD-positive patients at pre-maintenance became MRD-negative after lenalidomide exposure. In conclusion, MRD by MFC is a strong prognostic factor. Lenalidomide maintenance further improved MRD-negativity rate.

Burden of Treatment-Induced Peripheral Neuropathy in Patients with Multiple Myeloma in Sweden.

INTRODUCTION: Treatment-induced peripheral neuropathy (TIPN) is a complication of multiple myeloma (MM) treatment. OBJECTIVE: This real-world, retrospective study used electronic medical record (EMR) data from 3 Swedish clinics to assess the occurrence and economic burden of TIPN in patients with MM. METHODS: Eligible patients had an MM diagnosis in the Swedish Cancer Registry between 2006 and 2015 and initiated treatment during that period. Follow-up was until last EMR visit, death, or study end (April 2017). The current analyses included patients receiving bortezomib, lenalidomide, carfilzomib, or thalidomide at any treatment line. To discern healthcare resource utilization (HCRU) and costs associated with TIPN from other causes, patients with TIPN were matched with those without on baseline characteristics, treatment, and line of therapy. All analyses were descriptive. RESULTS: Overall, 457 patients were included; 102 (22%) experienced TIPN. Patients experiencing TIPN during first-line treatment mostly received bortezomib-based regimens (n = 48/57 [84%]); those with TIPN during second- and third/fourth-line treatment mostly received lenalidomide/thalidomide-based regimens (19/31 [61%], 8/14 [57%], respectively). Patients with TIPN had higher HCRU/costs than those without TIPN (mean differences in hospital outpatient visits: 5.2, p = 0.0031; total costs per patient-year: EUR 17,183, p = 0.0007). CONCLUSIONS: Effective MM treatments associated with a reduced incidence of TIPN could result in decreased healthcare expenditure.

Cost-Effectiveness of First-Line Versus Second-Line Use of Daratumumab in Older, Transplant-Ineligible Patients With Multiple Myeloma.

PURPOSE: The MAIA trial found that addition of daratumumab to lenalidomide and dexamethasone (DRd) significantly prolonged progression-free survival in transplant-ineligible patients with newly diagnosed multiple myeloma, compared with lenalidomide and dexamethasone alone (Rd). However, daratumumab is a costly treatment and is administered indefinitely until disease progression. Therefore, it is unclear whether it is cost-effective to use daratumumab in the first-line setting compared with reserving its use until later lines of therapy. METHODS: We created a Markov model to compare healthcare costs and clinical outcomes of transplant-ineligible patients treated with daratumumab in the first-line setting compared with a strategy of reserving daratumumab until the second-line. We estimated transition probabilities from randomized trials using parametric survival modeling. Lifetime direct healthcare costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated for first-line daratumumab versus second-line daratumumab from a US payer perspective. RESULTS: First-line daratumumab was associated with an improvement of 0.52 QALYs and 0.66 discounted life-years compared with second-line daratumumab. While both treatment strategies were associated with considerable lifetime expenditures ($1,434,937 v $1,112,101 in US dollars), an incremental cost of $322,836 for first-line daratumumab led to an ICER of $618,018 per QALY. The cost of daratumumab would need to be decreased by 67% for first-line daratumumab to be cost-effective at a willingness-to-pay threshold of $150,000 per QALY. CONCLUSION: Using daratumumab in the first-line setting for transplant-ineligible patients may not be cost-effective under current pricing. Delaying daratumumab until subsequent lines of therapy may be a reasonable strategy to limit healthcare costs without significantly compromising clinical outcomes. Mature overall survival data are necessary to more fully evaluate cost-effectiveness in this setting.

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.

Lenalidomide as maintenance treatment for patients with multiple myeloma after autologous stem cell transplantation: A pharmaco-economic assessment.

OBJECTIVE: Autologous stem cell transplantation (ASCT) has improved progression-free survival (PFS) and overall survival in eligible patients with newly diagnosed multiple myeloma (NDMM); however, relapse occurs. Maintenance therapy with lenalidomide (Len-Mt) extends survival and delays relapse and the subsequent initiation of costly second-line regimens. Here, we report the cost-effectiveness of Len-Mt following ASCT from a Dutch healthcare service perspective. METHODS: A partitioned survival model was developed to assess the lifetime costs and benefits for patients with NDMM. Efficacy was taken from a pooled meta-analysis of clinical trial data. Costs and subsequent therapy data were taken from sources appropriate for the Dutch market. RESULTS: Lenalidomide produced a quality-adjusted life year gain of 2.46 and a life year gain of 2.79 vs no maintenance treatment. The cost of lenalidomide was partially offset by savings of EUR 77 462 in subsequent treatment costs. The incremental cost-effectiveness ratio of Len-Mt vs no maintenance treatment was EUR 30 143. Key model drivers included subsequent therapies, dosing schedule, and time horizon. CONCLUSION: Lenalidomide is cost-effective after ASCT vs no maintenance therapy in the Netherlands. By extending PFS, lenalidomide delays the cost burdens associated with relapse and subsequent treatment lines.

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.

Lenalidomide maintenance post-transplantation in newly diagnosed multiple myeloma: real-world outcomes and costs.

Aim: To compare real-world outcomes and costs among patients with newly diagnosed multiple myeloma receiving lenalidomide-only maintenance (Len-Mt) versus no maintenance after autologous hematopoietic stem cell transplantation. Patients & methods: Time to next treatment (TTNT) was evaluated; costs were calculated for 0-12, 12-24 and 24-36 months postindex date. Results: Len-Mt cohort had longer TTNT (HR: 0.43; p < 0.0001). Per-patient per-month costs during months 0-12 were higher among patients, receiving Len-Mt (USD 13,095 vs USD 8910; p < 0.0001), due to higher pharmacy costs - outpatient costs were lower. During months 12-24 and 24-36, outpatient costs were similar in both cohorts; total and pharmacy costs remained elevated for patients receiving Len-Mt. Conclusion: Len-Mt improved TTNT, initially reduced outpatient costs, but resulted in higher overall and pharmacy costs.

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.

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.

Treatment Patterns and Clinical and Economic Outcomes in Patients With Newly Diagnosed Multiple Myeloma Treated With Lenalidomide- and/or Bortezomib-containing Regimens Without Stem Cell Transplant in a Real-world Setting.

BACKGROUND: Real-world data in patients with newly diagnosed multiple myeloma (NDMM) are sparse. Using United States claims databases, we analyzed treatment patterns, clinical outcomes, and health care utilization and costs in patients receiving lenalidomide- and/or bortezomib-containing therapy. MATERIALS AND METHODS: Patient claims were obtained from a large commercial and Medicare database (October 2009 to May 2015). Patients with NDMM who received lenalidomide- and/or bortezomib-containing therapy and did not receive stem cell transplant (SCT) were analyzed. Duration of treatment (DOT), time to next treatment (TTNT), and health care utilization and costs were evaluated. RESULTS: Of 3075 patients, 1767 received doublet therapy (814 lenalidomide-dexamethasone [Rd], 953 bortezomib-dexamethasone [Vd]) and 464 received triplet therapy (318 lenalidomide-bortezomib-dexamethasone [RVd], 146 cyclophosphamide-bortezomib-dexamethasone [CyBord]). Rd versus Vd resulted in longer median DOT (12.0 vs. 5.9 months; P < .0001) and median TTNT (36.7 vs. 24.4 months; P = .0005). Year 1 costs were greater with Rd versus Vd (Δ = $14,964; P = .0009), primarily owing to higher pharmacy costs; outpatient physician visits and chemotherapy administration costs were lower. Median DOT (14.8 vs. 9.0 months; P < .0001) and median TTNT (35.7 vs. 22.3 months; P = .0007) were longer with RVd versus CyBord; year 1 costs were comparable. CONCLUSIONS: In this study of patients with NDMM ineligible for transplant, the median duration of therapy was approximately 70% of that in clinical trial observations. Lenalidomide therapy versus Vd and CyBord resulted in longer DOT, which correlated with longer TTNT, and higher pharmacy costs, which were partially offset by lower outpatient and chemotherapy administration costs.

Response to First Cycle Is the Major Predictor of Long-Term Response to Lenalidomide and Dexamethasone Therapy in Relapsed and Refractory Multiple Myeloma: Can We Spare Patients the Toxicity and Costs of Additional Agents?

BACKGROUND: Lenalidomide plus dexamethasone (Ld) is still considered an option of care for some selected patients with relapsed or refractory multiple myeloma (RRMM), despite the proven superiority of lenalidomide-based triplet therapy. Up to 20% of patients obtain long-term benefit from Ld alone. The aim of this multicenter retrospective study was to identify and characterize those with good response to Ld salvage therapy, defined as progression-free survival lasting more than 24 months. PATIENTS AND METHODS: Patients treated with Ld in a consortium of 3 tertiary-care hospitals (Institut Català d'Oncologia) between 2009 and 2016 were prospectively registered; 227 patients had evaluable data. RESULTS: In multivariate analysis, obtaining partial response after the first therapy cycle was the main independent factor associated with progression-free survival lasting more than 24 months. Together with standard risk cytogenetics, partial response after first cycle was also independently associated with a higher rate of complete response. Previous plasma-cell dyscrasia remained as the only baseline characteristic independently associated with long-lasting responses. High-risk cytogenetics and no history of monoclonal gammopathy of undetermined significance were the only statistically significant negative prognostic factors for overall survival. Patients who had received only one prior therapy showed a trend toward higher overall survival. CONCLUSION: If Ld is to be considered a treatment choice, at least a partial response should be obtained after the first therapy cycle to maintain double-agent therapy safely.

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.

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.

Assessment of Safety and Immunogenicity of PVX-410 Vaccine With or Without Lenalidomide in Patients With Smoldering Multiple Myeloma: A Nonrandomized Clinical Trial.

Importance: Increasing evidence suggests the significance of the role of the immune system in the progression of smoldering multiple myeloma (SMM) to symptomatic multiple myeloma (MM). Boosting the immune system via vaccination in the earlier, asymptomatic SMM stage may provide a novel strategy to prevent or slow progression to active MM. Objective: To determine the safety, tolerability, immunogenicity, and anti-MM activity of the PVX-410 multipeptide vaccine with or without lenalidomide. Design, Setting, and Participants: This 3-cohort phase 1/2a multicenter dose-escalation study accrued 22 adults (≥18 years) with SMM with normal organ/marrow function who were human leukocyte antigen A2-positive and at moderate or high risk of progression to MM. Interventions: Patients received 6 doses of PVX-410 emulsified in Montanide ISA 720 VG, 0.4 mg total (0.1 mg/peptide) (n = 3) or 0.8 mg total (0.2 mg/peptide) (n = 9), biweekly via subcutaneous injection. In the combination cohort (n = 10), patients also received three 21-day cycles of lenalidomide, 25 mg, orally daily every 28 days. All patients received 0.5 mL (1 mg) poly-ICLC (2 mg/mL) via intramuscular injection with each PVX-410 dose. Main Outcomes and Measures: Adverse events (AEs) were evaluated using the Common Terminology Criteria for Adverse Events, version 4.03. PVX-410-specific T lymphocytes by flow cytometry to assess tetramer and interferon (IFN)-γ response. Disease response was assessed by investigators using the International Myeloma Working Group (IMWG) and modified European Group for Bone Marrow Transplantation (EBMT) criteria. Results: Overall, 14 (64%) patients were men and the median age at enrollment was 56 years in the monotherapy and 57 years in the combination cohorts (overall range, 39-82 years). Six of 12 patients in the monotherapy and 9 of 10 in the combination cohorts were at moderate risk. The PVX-410 vaccine was well tolerated. The most common AEs were mild-to-moderate injection site reactions and constitutional symptoms. Of note, PVX-410 was immunogenic as monotherapy (10 of 11 patients) and in combination with lenalidomide (9 of 9 patients), as demonstrated by an increase in percentage of tetramer-positive cells and IFN-γ cells in the CD3+CD8+ cell population. The combination resulted in greater mean fold increases in proportions of CD3+CD8+ T cells that were tetramer-positive and IFN-γ-positive, statistically significant for IFN-γ-positive cells after 2 and 4 vaccinations. An increase and persistence of vaccine-specific effector memory cells was noted. In total, 7 of 12 patients in the PVX-410-alone cohort had stable disease with 2 of 3 (low-dose cohort) and 1 of 9 of the target-dose cohort progressing (median TTP, 36 weeks), whereas 5 of 12 patients in the combination cohort showed, clinical response, with 1 patient progressing (median TTP not reached). Conclusions and Relevance: Overall, these results suggest that the vaccine is safe and immunogenic in this patient population and support continued study of PVX-410 in SMM. Trial Registration: ClinicalTrials.gov identifier: NCT01718899.

Cost-effectiveness of Daratumumab-based Triplet Therapies in Patients With Relapsed or Refractory Multiple Myeloma.

PURPOSE: The prominent efficacy of the addition of daratumumab to lenalidomide and dexamethasone (DRd) or the addition to bortezomib and dexamethasone (DVd) was proven previously for patients with relapsed or refractory multiple myeloma (RRMM). However, the cost-effectiveness of adding daratumumab to traditional doublet regimens versus doublet regimens alone (DRd vs Rd; DVd vs Vd) was unknown. METHODS: We developed a semi-Markov model by using a US payer perspective and 10-year time horizon to estimate the cost and quality-adjusted life years (QALYs) for treatments. Clinical data were obtained from the POLLUX (Phase 3 Study Comparing DRd Versus Rd in Subjects with Relapsed or Refractory Multiple Myeloma [RRMM]) and CASTOR (Phase 3 Study Comparing DVd Versus Vd in Subjects with RRMM) trials. Deterministic and probabilistic sensitivity analyses were conducted to evaluate model uncertainty. FINDINGS: The incremental cost-effectiveness ratio (ICER) for DVd compared with Vd was $284,180 per QALY; the ICER for DRd compared with Rd was $1,369,062 per QALY. Only when the price of daratumumab was reduced to 37% (US $702/vial) of the current price could the addition of daratumumab to Vd be cost-effective under the US willingness-to-pay (WTP) of $50,000/QALY. However, under no discount level of the daratumumab price is the addition of daratumumab to Rd acceptable. When the WTP increased to $300,000/QALY, the addition of DVd had a 56.7% probability of being cost-effective compared with the Vd regimen. IMPLICATIONS: Due to the high price of daratumumab, neither the addition of daratumumab to Rd nor Vd proved to be cost-effective under US WTP. However, if the daratumumab price fell to a certain discount level, the DVd regimen might be cost-effective.

Cost-effectiveness of lenalidomide in combination with dexamethasone compared to bortezomib in combination with dexamethasone for the second-line treatment of multiple myeloma in Chile. / Análisis costo-efectividad de lenalidomida en combinación con dexametasona frente a bortezomib combinado con dexametasona en el tratamiento en segunda línea del mieloma múltiple en Chile.

BACKGROUND: Multiple myeloma is a hematologic malignancy affecting bone marrow derived plasma cells. Current therapies are not able to eradicate the disease and most patients become refractory to the treatment. Lenalidomide and bortezomib have proved effective in the second-line treatment of these patients. OBJECTIVE: To evaluate the cost-effectiveness of lenalidomide in combination with dexamethasone compared to bortezomib in combination with dexamethasone in patients with multiple myeloma previously treated with bortezomib, from the perspective of the Chilean National Health Service. METHODOLOGY: A four-state Markov model (preprogression on treatment; preprogression off treatment, progression and death) was used to simulate the evolution of a cohort of multiple myeloma patients over a 25-year time horizon. Efficacy data, resource use and frequency of adverse events were extracted from MM009/010 studies and a retrospective analysis of retreatment with bortezomib. All inputs were validated by experts. A 3% annual discount rate was used for costs and health outcomes. The robustness of the results was evaluated through univariate and probabilistic sensitivity analyses. RESULTS: Lenalidomide in combination with dexamethasone treatment provided 1.41 incremental life years and 0.83 incremental quality-adjusted life years in comparison with bortezomib in combination with dexamethasone, with an incremental cost of 11 864 597.86 CLP (19 589.86 US$). The incremental cost-effectiveness and cost-utility ratio were estimated at 8 410 266.92 CLP (13 886,35 US$) / incremental life year and 14 271 896.16 CLP (23 564,59 US$)/incremental quality-adjusted life years, respectively. CONCLUSIONS: Lenalidomide in combination with dexamethasone represents a potentially cost-effective alternative for the second-line treatment of patients with multiple myeloma who are not eligible for transplantation, from the perspective of the Chilean National Health Service.

CONTEXTO: El mieloma múltiple es una neoplasia de las células plasmáticas de la medula ósea. Las terapias disponibles no son curativas y la mayoría de los pacientes se vuelve refractario al tratamiento. Agentes como lenalidomida y bortezomib han demostrado su eficacia en el tratamien-to en segunda línea de estos pacientes. OBJETIVO: Evaluar el costo-efectividad de la combinación lenalidomida/dexametasona frente a bortezomib/dexametasona en pacientes con mieloma múltiple, no candidatos a trasplante, previamente tratados con bortezomib, desde la perspectiva del sistema nacional de salud chileno. METODOLOGÍA: Se empleó un modelo de Markov que simula la evolución de una cohorte de pacientes a través de cuatro estados de salud (preprogresión en tratamiento, preprogresión sin tratamiento, progresión o muerte) en un horizonte temporal de 25 años. Los datos de eficacia, uso de recursos y frecuencia de efectos adversos fueron extraídos de los ensayos sobre mieloma múltiple MM-009 y MM-010 y de un estudio retrospectivo de retratamiento con bortezomib. Todos los parámetros fueron validados por expertos. Se aplicó una tasa de descuento en costos y beneficios de 3%. La robustez de los resultados fue evaluada mediante un análisis de sensibilidad univariante y probabilístico. RESULTADOS: El tratamiento con lenalidomida/dexametasona proporciona 1,41 años de vida y 0,83 años de vida ajustados por calidad incrementales respecto a bortezomib/dexametasona, con un costo incremental de 11 864 597,86 pesos chilenos (19 589,86 dólares). La ratio de cos-to-efectividad y costo-utilidad incremental se cifró en 8 410 266,92 pesos chilenos (13 886,35 dólares) por año de vida ganado y 14 271 896,16 pesos chilenos (23 564,59 dólares) por año de vida ajustado por calidad respectivamente. CONCLUSIÓN: La lenalidomida/dexametasona representa una alternativa potencialmente costo-efectiva, desde la perspectiva del sistema nacional de salud chileno, para el tratamiento en segunda línea de pacientes con mieloma múltiple no candidatos a trasplante.

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.

Pomalidomide with Dexamethasone for Treating Relapsed and Refractory Multiple Myeloma Previously Treated with Lenalidomide and Bortezomib: An Evidence Review Group Perspective of an NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE), as part of the institute's single technology appraisal (STA) process, invited the manufacturer of pomalidomide (POM; Imnovid®, Celgene) to submit evidence regarding the clinical and cost effectiveness of the drug in combination with dexamethasone (POM + LoDEX) for the treatment of relapsed and refractory multiple myeloma (RRMM) after at least two regimens including lenalidomide (LEN) and bortezomib (BOR). Kleijnen Systematic Reviews Ltd (KSR) and Erasmus University Rotterdam were commissioned as the Evidence Review Group (ERG) for this submission. The ERG reviewed the evidence submitted by the manufacturer, validated the manufacturer's decision analytic model, and conducted exploratory analyses in order to assess the robustness and validity of the presented clinical and cost-effectiveness results. This paper describes the company submission, the ERG assessment, and NICE's subsequent decisions. The company conducted a systematic review to identify studies comparing POM with comparators outlined in the NICE scope: panobinostat with bortezomib and dexamethasone (PANO + BOR + DEX), bendamustine with thalidomide and dexamethasone (BTD) and conventional chemotherapy (CC). The main clinical effectiveness evidence was obtained from MM-003, a randomized controlled trial (RCT) comparing POM + LoDEX with high-dose dexamethasone (HiDEX; used as a proxy for CC). Additional data from other studies were also used as nonrandomized observational data sources for the indirect treatment comparison of POM + LoDEX with BTD and PANO + BOR + DEX. Covariate or treatment switching adjustment methods were used for each comparison. The model developed in Microsoft® Excel 2010 using a semi-Markov partitioned survival structure, submitted in the original submission to NICE for TA338, was adapted for the present assessment of the cost effectiveness of POM + LoDEX. Updated evidence from the clinical-effectiveness part was used for the survival modelling of progression-free survival and overall survival. For POM + LoDEX, the patient access scheme (PAS) discount was applied to the POM price. Three separate comparisons were conducted for each comparator, each comparison using a different dataset and adjustment methods. The ERG identified and corrected some errors, and the corrected incremental cost-effectiveness ratios (ICERs) for POM + LoDEX versus each comparator were presented: approximately £45,000 per quality-adjusted life-year (QALY) gained versus BTD, savings of approximately £143,000 per QALY lost versus PANO + BOR + DEX, and approximately £49,000 per QALY gained versus CC. The ERG also conducted full incremental analyses, which revealed that CC, POM + LoDEX and PANO + BOR + DEX were on the cost-effectiveness frontier. The committee's decision on the technology under analysis deemed that POM + LoDEX should be recommended as an option for treating multiple myeloma in adults at third or subsequent relapse of treatments including both LEN and BOR, contingent on the company providing POM with the discount agreed in the PAS.

Análisis costo-efectividad de lenalidomida en combinación con dexametasona frente a bortezomib combinado con dexametasona en el tratamiento en segunda línea del mieloma múltiple en Chile / Cost-effectiveness of lenalidomide in combination with dexamethasone compared to bortezomib in combination with dexamethasone for the second-line treatment of multiple myeloma in Chile

CONTEXTO: El mieloma múltiple es una neoplasia de las células plasmáticas de la medula ósea. Las terapias disponibles no son curativas y la mayoría de los pacientes se vuelve refractario al tratamiento. Agentes como lenalidomida y bortezomib han demostrado su eficacia en el tratamien-to en segunda línea de estos pacientes. OBJETIVO: Evaluar el costo-efectividad de la combinación lenalidomida/dexametasona frente a bortezomib/dexametasona en pacientes con mieloma múltiple, no candidatos a trasplante, previamente tratados con bortezomib, desde la perspectiva del sistema nacional de salud chileno. METODOLOGÍA: Se empleó un modelo de Markov que simula la evolución de una cohorte de pacientes a través de cuatro estados de salud (preprogresión en tratamiento, preprogresión sin tratamiento, progresión o muerte) en un horizonte temporal de 25 años. Los datos de eficacia, uso de recursos y frecuencia de efectos adversos fueron extraídos de los ensayos sobre mieloma múltiple MM-009 y MM-010 y de un estudio retrospectivo de retratamiento con bortezomib. Todos los parámetros fueron validados por expertos. Se aplicó una tasa de descuento en costos y beneficios de 3%. La robustez de los resultados fue evaluada mediante un análisis de sensibilidad univariante y probabilístico. RESULTADOS: El tratamiento con lenalidomida/dexametasona proporciona 1,41 años de vida y 0,83 años de vida ajustados por calidad incrementales respecto a bortezomib/dexametasona, con un costo incremental de 11 864 597,86 pesos chilenos (19 589,86 dólares). La ratio de cos-to-efectividad y costo-utilidad incremental se cifró en 8 410 266,92 pesos chilenos (13 886,35 dólares) por año de vida ganado y 14 271 896,16 pesos chilenos (23 564,59 dólares) por año de vida ajustado por calidad respectivamente. CONCLUSIÓN: La lenalidomida/dexametasona representa una alternativa potencialmente costo-efectiva, desde la perspectiva del sistema nacional de salud chileno, para el tratamiento en segunda línea de pacientes con mieloma múltiple no candidatos a trasplante.

BACKGROUND: Multiple myeloma is a hematologic malignancy affecting bone marrow derived plasma cells. Current therapies are not able to eradicate the disease and most patients become refractory to the treatment. Lenalidomide and bortezomib have proved effective in the second-line treatment of these patients. OBJECTIVE: To evaluate the cost-effectiveness of lenalidomide in combination with dexamethasone compared to bortezomib in combination with dexamethasone in patients with multiple myeloma previously treated with bortezomib, from the perspective of the Chilean National Health Service. METHODOLOGY: A four-state Markov model (preprogression on treatment; preprogression off treatment, progression and death) was used to simulate the evolution of a cohort of multiple myeloma patients over a 25-year time horizon. Efficacy data, resource use and frequency of adverse events were extracted from MM009/010 studies and a retrospective analysis of retreatment with bortezomib. All inputs were validated by experts. A 3% annual discount rate was used for costs and health outcomes. The robustness of the results was evaluated through univariate and probabilistic sensitivity analyses. RESULTS: Lenalidomide in combination with dexamethasone treatment provided 1.41 incremental life years and 0.83 incremental quality-adjusted life years in comparison with bortezomib in combination with dexamethasone, with an incremental cost of 11 864 597.86 CLP (19 589.86 US$). The incremental cost-effectiveness and cost-utility ratio were estimated at 8 410 266.92 CLP (13 886,35 US$) / incremental life year and 14 271 896.16 CLP (23 564,59 US$)/incremental quality-adjusted life years, respectively. CONCLUSIONS: Lenalidomide in combination with dexamethasone represents a potentially cost-effective alternative for the second-line treatment of patients with multiple myeloma who are not eligible for transplantation, from the perspective of the Chilean National Health Service.