Multiple myeloma refractory to lenalidomide: A systematic literature review of trials and real-world evidence.

The growing use of frontline lenalidomide treatment in multiple myeloma (MM) is increasing the proportion of lenalidomide-refractory patients, which may limit the efficacy of subsequent lines of treatment (LOT). This systematic literature review (January 2008-October 2023) of clinical trials (CT) and real-world studies (RW) assessed treatment outcomes in adults with relapsed/refractory MM (RRMM) who were previously treated with ≥1 LOT, progressed and were lenalidomide-refractory. Medline, EMBASE and additional electronic databases were searched for articles published in English. Primary outcomes included progression-free survival (PFS), overall survival (OS) and overall/objective response rate (ORR); 24 CT and 19 RW were included. For CT, the population-weighted mean of median PFS (CT = 14) and OS (CT = 6) were shorter in the lenalidomide-refractory cohort (months: 8.8 [n = 2699] and 21.7 [n = 1066], respectively) than the intent-to-treat population (months: 13.8 [n = 5380] and 35.9 [n = 2264], respectively); the population-weighted (N = 2142) mean ORR for lenalidomide-refractory patients (CT = 18) was 56.0%. RW reported considerable variation in PFS (RW = 7), OS (RW = 8) and ORR (RW = 8); and median PFS (RW = 2; months) was lower in lenalidomide/bortezomib-refractory (5.5/5.5; n = 81/n = 25) versus lenalidomide-refractory (7.3/8.0; n = 81/n = 61) patients. These data provide evidence that clinical trials and real-world outcomes are suboptimal in lenalidomide-refractory patients with RRMM, highlighting the need to improve treatment options for this population.

A disease progression model estimating the benefit of tolvaptan on time to end-stage renal disease for patients with rapidly progressing autosomal dominant polycystic kidney disease.

BACKGROUND: Tolvaptan was approved in the United States in 2018 for patients with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression as assessed in a 3-year phase 3 clinical trial (TEMPO 3:4). An extension study (TEMPO 4:4) showed continued delay in progression at 2 years, and a trial in patients with later-stage disease (REPRISE) provided confirmatory evidence of efficacy. Given the relatively shorter-term duration of the clinical trials, estimating the longer-term benefit associated with tolvaptan via extrapolation of the treatment effect is an important undertaking. METHODS: A model was developed to simulate a cohort of patients with ADPKD at risk of rapid progression and predict their long-term outcomes using an algorithm organized around the Mayo Risk Classification system, which has five subclasses (1A through 1E) based on estimated kidney growth rates. The model base-case population represents 1280 patients enrolled in TEMPO 3:4 beginning in chronic kidney disease (CKD) stages G1, G2, and G3 across Mayo subclasses 1C, 1D, and 1E. The algorithm was used to predict longer-term natural history health outcomes. The estimated treatment effect of tolvaptan from TEMPO 3:4 was applied to the natural history to predict the longer-term treatment benefit of tolvaptan. For the cohort, analyzed once reflecting natural history and once assuming treatment with tolvaptan, the model estimated lifetime progression through CKD stages, end-stage renal disease (ESRD), and death. RESULTS: When treated with tolvaptan, the model cohort was predicted to experience a 3.1-year delay of ESRD (95% confidence interval: 1.8 to 4.4), approximately a 23% improvement over the estimated 13.7 years for patients not receiving tolvaptan. Patients beginning tolvaptan treatment in CKD stages G1, G2, and G3 were predicted to experience estimated delays of ESRD, compared with patients not receiving tolvaptan, of 3.8 years (21% improvement), 3.0 years (24% improvement), and 2.1 years (28% improvement), respectively. CONCLUSIONS: The model estimated that patients treated with tolvaptan versus no treatment spent more time in earlier CKD stages and had later onset of ESRD. Findings highlight the potential long-term value of early intervention with tolvaptan in patients at risk of rapid ADPKD progression.

Clinical and economic impacts of large volume delayed sampling and pathogen reduction technology platelet processing strategies in the United States.

BACKGROUND: Large volume delayed sampling (LVDS) and pathogen reduction technology (PRT) are strategies for platelet processing to minimize transfusion of contaminated platelet components (PCs). This study holistically compares the economic and clinical impact of LVDS and PRT in the United States. STUDY DESIGN AND METHODS: A decision model was constructed to simulate collection, processing, and use of PCs and to compare processing strategies: PRT with 5-day shelf life, LVDS with 7-day shelf life (LVDS7), and LVDS with 5-day shelf life extended to 7 days with secondary testing (LVDS5/2). Target population was adults requiring two or more transfusions. Collection, processing, storage, and distribution data were obtained from the National Blood Collection and Utilization Survey and published literature. Patient outcomes associated with transfusions were obtained from AABB guidelines, meta-analyses, and other published clinical studies. Costs were obtained from reimbursement schedules and other published sources. RESULTS: Given 10,000 donated units, 9512, 9511, and 9651 units of PRT, LVDS5/2, and LVDS7 PCs were available for transfusion, respectively. With these units, 1502, 2172, and 2329 transfusions can be performed with similar levels of adverse events. Assuming 30 transfusions a day, a hospital would require 69,325, 47,940, and 45,383 units of PRT, LVDS5/2, and LVDS7 platelets to perform these transfusions. The mean costs to perform transfusions were significantly higher with PRT units. CONCLUSIONS: Compared with PRT, LVDS strategies were associated with lower costs and higher PC availability while patients experienced similar levels of adverse events. Increased utilization of LVDS has the potential to improve efficiency, expand patient access to platelets, and reduce health care costs.

Cost-Effectiveness of Blood-Based Brain Biomarkers for Screening Adults with Mild Traumatic Brain Injury in the French Health Care Setting.

Two blood-based brain biomarker tests such as the combination of glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 (GFAP+UCH-L1) or S100B have potential to reduce the need for head computed tomography (CT) scanning in patients with mild traumatic brain injury (mTBI). We assessed the clinical and economic impact of using GFAP+UCH-L1 versus CT scan and GFAP+UCH-L1 versus S100B to screen adults with suspected mTBI presenting to an emergency department (ED). A decision model was developed to estimate costs and health outcomes of GFAP+UCH-L1, CT scan, and S100B associated with these screening protocols. Model parameters were extracted from peer-reviewed articles, clinical guidelines, and expert opinion. Analysis was performed from a French health care system perspective (costs in 2020 euros). In the model, patients with a positive biomarker receive a CT scan to confirm the presence of intracranial lesions (ICLs). Depending on clinical state and biomarker and CT results, patients were discharged immediately, kept for observation in the ED, admitted for in-hospital stay and observation, or admitted for surgical management. Incorrect test results may lead to delayed treatment and poor outcomes or overtreatment. GFAP+UCH-L1 use was associated with an overall decrease in CT scans when compared with CT screening or S100B use (325.42 and 46.43 CTs per 1000 patients, respectively). The use of GFAP+UCH-L1 resulted in modest cost savings when compared with CT scanning and with S100B. In all cases, use of GFAP+UCH-L1 marginally improved quality-adjusted life-years (QALYs) and outcomes. Thus, screening with GFAP+UCH-L1 reduced the need for CT scans when compared with systematic CT scan screening or use of S100B while maintaining similar costs and health outcomes.

Budget impact analysis of darolutamide for treatment of nonmetastatic castration-resistant prostate cancer.

BACKGROUND: Darolutamide, a structurally distinct androgen receptor inhibitor approved for the treatment of men with nonmetastatic castration-resistant prostate cancer (nmCRPC), has been shown to increase metastasis-free survival among men with nmCRPC compared with placebo. This treatment has a novel chemical structure that may also have safety, tolerability, and efficacy advantages for men with nmCRPC. OBJECTIVE: To estimate the projected budget impact of including darolutamide on a U.S. payer formulary as a treatment option for men with nmCRPC. METHODS: A budget impact model was developed to evaluate darolutamide for nmCRPC for a hypothetical 1-million-member plan over a 5-year period. Costs (drug acquisition, drug administration, and treatment-related adverse events [AEs]) were estimated for 2 scenarios: with and without darolutamide treatment for nmCRPC. The budget impact of darolutamide was calculated as the difference in costs for these 2 scenarios. An analysis for high-risk nmCRPC also was conducted. The model included treatments recommended by the National Comprehensive Cancer Network (e.g., apalutamide and enzalutamide) and potential comparators that are used but are not specifically indicated for nmCRPC. All treatments were assumed to be administered in combination with a weighted average androgen deprivation therapy comparator (consisting of luteinizing hormone-releasing hormone [LHRH] agonists, LHRH antagonists, and first-generation antiandrogens). Market share estimates were derived from interviews with physicians treating men with nmCRPC. The model includes grade 3-4 AEs, and the rates were obtained from clinical trial data. Costs were taken from publicly available sources and varied in a one-way sensitivity analysis. RESULTS: For a plan with 1 million lives, there were approximately 90 incident cases of nmCRPC (46 high risk) each year, with 332 (109 high risk) treatment-eligible cases by year 5. Darolutamide's market share increased from 3.6% in year 1 to 18% in year 5. Given the utilization of other agents, introducing darolutamide along with other targeted therapies was predicted to increase the total budget by $158,640 ($0.0132 per member per month [PMPM]) in year 1, which decreased over time to a cost savings of $149,240 ($0.0124 PMPM) by year 5. The scenario with darolutamide showed reduced AE costs each year. Similar results were observed for the high-risk nmCRPC population. CONCLUSIONS: Adding darolutamide to a U.S. payer formulary for the treatment of nmCRPC can result in a manageable increase in the budget that is partly offset by AE costs in the first 4 years, followed by a cost savings by year 5. DISCLOSURES: This study was conducted by RTI Health Solutions under the direction of Bayer U.S. and was funded by Bayer U.S., which was involved in the design of the study; collection, analysis, and interpretation of the data; writing of the report; and the decision to submit the report for publication. Miles and Purser (and/or their institutions) are employees of RTI Health Solutions and received research funding from Bayer U.S. to develop the budget impact model. Appukkuttan and Farej are employees of Bayer U.S. Wen was an employee of Bayer U.S. at the time of the study. This study was presented as a poster at the AMCP Virtual Learning Event, April 20-24, 2020.

The Humanistic and Economic Burden of Chronic Idiopathic Constipation in the USA: A Systematic Literature Review.

BACKGROUND: Chronic idiopathic constipation (CIC) is a functional gastrointestinal disorder with an estimated prevalence of 16% in the USA; however, the humanistic and economic burden of CIC is poorly characterized. AIM: This systematic literature review aimed to assess the humanistic and economic burden of CIC in adults in the USA. METHODS: Two systematic literature searches of English-language publications on the humanistic and economic burden of CIC in adults in the USA were conducted using electronic databases and other resources. Both searches included the terms "chronic idiopathic constipation" and "functional constipation". Specific terms used in the search on humanistic burden included "quality of life", "SF-36", "SF-12", and "PAC-QOL"; search terms for economic burden included "cost", "resource use", "absenteeism", and "productivity". RESULTS: Overall, 16 relevant articles were identified. Health-related quality of life (HRQoL) appeared to be reduced in patients with CIC compared with controls and the general US population. Abdominal (r=0.33-0.49), stool (r=0.23-0.33), and rectal symptoms (r=0.53) appeared to be associated with reduced HRQoL. Younger age and female sex were associated with reduced overall HRQoL and greater symptom severity. Direct outpatient costs were higher in patients with CIC than those without CIC (US$6284 vs US$5254). Patients with CIC and abdominal symptoms reported more days of disrupted productivity per month than those without abdominal symptoms (3.2 days vs 1.2 days). The overall prevalence of complementary and alternative medicine use by patients with CIC was similar to that in the general US population. CONCLUSION: The reduced HRQoL and increased costs associated with CIC indicate unmet therapeutic need in this disorder. Further research is required to better understand the humanistic and economic burden of CIC in the USA.

Expected Budget Impact and Health Outcomes of Expanded Use of Vagus Nerve Stimulation Therapy for Drug-Resistant Epilepsy.

INTRODUCTION: The objective was to estimate, from the perspective of a managed care organization in the United States, the budget impact and effect on health outcomes of expanded use of vagus nerve stimulation [VNS (VNS Therapy®)] among patients aged ≥ 12 years with drug-resistant epilepsy (DRE) with partial-onset seizures. METHODS: An Excel model was developed to compare the costs of continued anti-epileptic drug (AED) treatment with the costs of VNS plus AED treatment. The number of people eligible for VNS was estimated using published prevalence data and an estimate of the percentage of eligible patients currently without VNS. Costs included VNS device, placement, programming, and battery changes; adverse events associated with VNS (cough, voice alteration, device removal resulting from surgical site infection); AEDs; and seizure-related costs affected by seizure frequency, which affects resource utilization (i.e., hospitalizations, emergency department visits, neurologist visits). To estimate the potential savings with VNS due to a reduction in seizure frequency, the budget impact model uses the results of an underlying Markov model to estimate seizure-related costs by seizure frequency. Transitions occurred among four health states, defined by number of seizures per month (i.e., seizure-free, ≤ 1, > 1 to < 10, ≥ 10) on a 3-month cycle based on published clinical trials and registry data. RESULTS: VNS resulted in an estimated net cost savings, on average, over 5 years, due to the expected reduction in seizure frequency. The initial cost of the VNS device, placement, and programming was estimated to be offset 1.7 years after VNS device placement. Reductions in hospitalizations were the main contributor to the cost savings with VNS. CONCLUSIONS: VNS is a proven intervention that offers a long-term solution for patients with DRE by reducing seizure frequency, which leads to lower resource utilization and lower costs. FUNDING: LivaNova PLC.

Correction to: Expected Budget Impact and Health Outcomes of Expanded Use of Vagus Nerve Stimulation Therapy for Drug-Resistant Epilepsy.

The article "Expected Budget Impact and Health Outcomes of Expanded Use of Vagus Nerve Stimulation Therapy for Drug-Resistant Epilepsy", written by Molly F. Purser, Deirdre M. Mladsi, Alan Beckman, Francesca Barion, John Forsey was originally published electronically on the publisher's internet portal (currently SpringerLink) on August 24, 2018 without open access.

Improved Chondrogenic Potential and Proteomic Phenotype of Porcine Chondrocytes Grown in Optimized Culture Conditions.

For successful cartilage tissue engineering, the ability to generate a high number of chondrocytes in vitro while avoiding terminal differentiation or de-differentiation is critical. The ability to accomplish this by using the abundant and easily sampled costal cartilage could provide a practical alternative to the use of articular cartilage and mesenchymal stem cells. Chondrocytes isolated from pig costal cartilage were expanded in either serum-free medium with FGF2 (SFM) or fetal bovine serum-containing medium (SCM), under either high (21%) or low (5%) oxygen conditions. Overall, chondrocytes cultured in SFM and low oxygen (Low-SFM) demonstrated the highest cell growth rate (p < 0.05). The effect of passage number on the differentiation status of the chondrocytes was analyzed by alkaline phosphatase (AP) staining and real-time PCR for known chondrocyte quality markers. AP staining indicated that chondrocytes grown in SCM had a higher proportion of terminally differentiated (hypertrophic) chondrocytes (p < 0.05). At the mRNA level, expression ratios of ACAN/VCAN and COL2/COL1 were significantly higher (p < 0.05) in cells expanded in Low-SFM, indicating reduced de-differentiation. In vitro re-differentiation capacity was assessed after a 6-week induction, and chondrocytes grown in Low-SFM showed similar expression ratios of COL2/COL1 and ACAN/VCAN to native cartilage. Proteomic analysis of in vitro produced cartilage indicated that the Low-SFM condition most closely matched the proteomic profile of native costal and articular cartilage. In conclusion, Low-SFM culture conditions resulted in improved cell growth rates, reduced levels of de-differentiation during expansion, greater ability to re-differentiate into cartilage on induction, and an improved proteomic profile that resembles that of in vivo cartilage.

A Matching-Adjusted Indirect Comparison of Sonidegib and Vismodegib in Advanced Basal Cell Carcinoma.

OBJECTIVES: Based on single-arm trial data (BOLT), sonidegib was approved in the US and EU to treat locally advanced basal cell carcinomas (BCCs) ineligible for curative surgery or radiotherapy. Vismodegib, the other approved targeted therapy, also was assessed in a single-arm trial (ERIVANCE). We examined the comparative effectiveness of the two drugs using a matching-adjusted indirect comparison (MAIC) versus an unadjusted indirect comparison. METHODS: After comparing trials and identifying potential prognostic factors, an MAIC was conducted to adjust for differences in key patient baseline characteristics. Due to BOLT's small sample size, the number of matching variables was restricted to two. Efficacy results for sonidegib were generated so that selected baseline characteristics matched those from ERIVANCE and were compared with published ERIVANCE results. RESULTS: Matching variables were baseline percentages of patients receiving prior radiotherapy and surgery. After weighting, sonidegib objective response rate (ORR) and median progression-free survival (PFS) were effectively unchanged (prematched versus postmatched ORR and PFS, 56.1% versus 56.7% and 22.1 versus 22.1 months, resp.). Vismodegib's ORR and PFS were 47.6% and 9.5 months. CONCLUSIONS: Comparative effectiveness of sonidegib versus vismodegib remains unchanged after adjusting BOLT patient-level data to match published ERIVANCE baseline percentages of patients receiving prior surgery and radiotherapy.

Cost Effectiveness of Ofatumumab Plus Chlorambucil in First-Line Chronic Lymphocytic Leukaemia in Canada.

OBJECTIVE: Our objective was to estimate the cost effectiveness of ofatumumab plus chlorambucil (OChl) versus chlorambucil in patients with chronic lymphocytic leukaemia for whom fludarabine-based therapies are considered inappropriate from the perspective of the publicly funded healthcare system in Canada. METHODS: A semi-Markov model (3-month cycle length) used survival curves to govern progression-free survival (PFS) and overall survival (OS). Efficacy and safety data and health-state utility values were estimated from the COMPLEMENT-1 trial. Post-progression treatment patterns were based on clinical guidelines, Canadian treatment practices and published literature. Total and incremental expected lifetime costs (in Canadian dollars [$Can], year 2013 values), life-years and quality-adjusted life-years (QALYs) were computed. Uncertainty was assessed via deterministic and probabilistic sensitivity analyses. RESULTS: The discounted lifetime health and economic outcomes estimated by the model showed that, compared with chlorambucil, first-line treatment with OChl led to an increase in QALYs (0.41) and total costs ($Can27,866) and to an incremental cost-effectiveness ratio (ICER) of $Can68,647 per QALY gained. In deterministic sensitivity analyses, the ICER was most sensitive to the modelling time horizon and to the extrapolation of OS treatment effects beyond the trial duration. In probabilistic sensitivity analysis, the probability of cost effectiveness at a willingness-to-pay threshold of $Can100,000 per QALY gained was 59 %. CONCLUSIONS: Base-case results indicated that improved overall response and PFS for OChl compared with chlorambucil translated to improved quality-adjusted life expectancy. Sensitivity analysis suggested that OChl is likely to be cost effective subject to uncertainty associated with the presence of any long-term OS benefit and the model time horizon.

A novel shape memory alloy annuloplasty ring for minimally invasive surgery: design, fabrication, and evaluation.

A novel annuloplasty ring with a shape memory alloy core has been developed to facilitate minimally invasive mitral valve repair. In its activated (austenitic) phase, this prototype ring has comparable mechanical properties to commercial semi-rigid rings. In its pre-activated (martensitic) phase, this ring is flexible enough to be introduced through an 8-mm trocar and easily manipulated with robotic instruments within the confines of a left atrial model. The core is constructed of 0.50 mm diameter NiTi, which is maintained below its martensitic transition temperature (24 °C) during deployment and suturing. After suturing, the ring is heated above its austenitic transition temperature (37 °C, normal human body temperature) enabling the NiTi core to attain its optimal geometry and stiffness characteristics indefinitely. This article summarizes the design, fabrication, and evaluation of this prototype ring. Experimental results suggest that the NiTi core ring could be a viable alternative to flexible bands in robot-assisted minimally invasive mitral valve repair.

Evaluation of a shape memory alloy reinforced annuloplasty band for minimally invasive mitral valve repair.

PURPOSE: An in vitro study using explanted porcine hearts was conducted to evaluate a novel annuloplasty band, reinforced with a two-phase, shape memory alloy, designed specifically for minimally invasive mitral valve repair. DESCRIPTION: In its rigid (austenitic) phase, this band provides the same mechanical properties as the commercial semi-rigid bands. In its compliant (martensitic) phase, this band is flexible enough to be introduced through an 8-mm trocar and is easily manipulated within the heart. EVALUATION: In its rigid phase, the prototype band displayed similar mechanical properties to commercially available semi-rigid rings. Dynamic flow testing demonstrated no statistical differences in the reduction of mitral valve regurgitation. In its flexible phase, the band was easily deployed through an 8-mm trocar, robotically manipulated and sutured into place. CONCLUSIONS: Experimental results suggest that the shape memory alloy reinforced band could be a viable alternative to flexible and semi-rigid bands in minimally invasive mitral valve repair.