A cautionary tale: an evaluation of the performance of treatment switching adjustment methods in a real world case study.

BACKGROUND: Treatment switching in randomised controlled trials (RCTs) is a problem for health technology assessment when substantial proportions of patients switch onto effective treatments that would not be available in standard clinical practice. Often statistical methods are used to adjust for switching: these can be applied in different ways, and performance has been assessed in simulation studies, but not in real-world case studies. We assessed the performance of adjustment methods described in National Institute for Health and Care Excellence Decision Support Unit Technical Support Document 16, applying them to an RCT comparing panitumumab to best supportive care (BSC) in colorectal cancer, in which 76% of patients randomised to BSC switched onto panitumumab. The RCT resulted in intention-to-treat hazard ratios (HR) for overall survival (OS) of 1.00 (95% confidence interval [CI] 0.82-1.22) for all patients, and 0.99 (95% CI 0.75-1.29) for patients with wild-type KRAS (Kirsten rat sarcoma virus). METHODS: We tested several applications of inverse probability of censoring weights (IPCW), rank preserving structural failure time models (RPSFTM) and simple and complex two-stage estimation (TSE) to estimate treatment effects that would have been observed if BSC patients had not switched onto panitumumab. To assess the performance of these analyses we ascertained the true effectiveness of panitumumab based on: (i) subsequent RCTs of panitumumab that disallowed treatment switching; (ii) studies of cetuximab that disallowed treatment switching, (iii) analyses demonstrating that only patients with wild-type KRAS benefit from panitumumab. These sources suggest the true OS HR for panitumumab is 0.76-0.77 (95% CI 0.60-0.98) for all patients, and 0.55-0.73 (95% CI 0.41-0.93) for patients with wild-type KRAS. RESULTS: Some applications of IPCW and TSE provided treatment effect estimates that closely matched the point-estimates and CIs of the expected truths. However, other applications produced estimates towards the boundaries of the expected truths, with some TSE applications producing estimates that lay outside the expected true confidence intervals. The RPSFTM performed relatively poorly, with all applications providing treatment effect estimates close to 1, often with extremely wide confidence intervals. CONCLUSIONS: Adjustment analyses may provide unreliable results. How each method is applied must be scrutinised to assess reliability.

Healthcare resource utilisation associated with skeletal-related events in European patients with multiple myeloma: Results from a prospective, multinational, observational study.

OBJECTIVES: Patients with multiple myeloma (MM) often experience debilitating skeletal-related events (SREs: pathologic fracture, radiation to bone [RB], surgery to bone [SB] or spinal cord compression [SCC]). This is the first comprehensive, prospective, observational analysis of healthcare resource utilisation (HRU), independently attributed to SREs by investigators, in patients with MM. METHODS: Eligible patients had lytic bone lesions, life expectancy ≥6 months, Eastern Cooperative Oncology Group performance status ≤2 and ≥1 SRE in the 97 days before enrolment. Data were collected retrospectively for 97 days before enrolment and prospectively for 18-21 months. RESULTS: Altogether, 153 patients were enrolled from Germany, Italy, Spain and the United Kingdom. Of the 281 observed SREs, 36.7% required inpatient stays (mean duration: 20.6 days per SRE [standard deviation (SD): 22.9]). SB and SCC were the SREs most likely to require stays (72.3% and 50.0% of SREs, respectively); SCC required the longest mean (SD) stay per event (40.5 [40.8] days). Overall, 179 SREs required outpatient visits; this was most likely for RB (74.8%) and least likely for non-vertebral fracture (50.0%). CONCLUSIONS: All SREs were associated with substantial HRU; therefore, preventing SREs in MM will reduce the economic and resource burden on healthcare systems.

Cost-effectiveness of once weekly carfilzomib 70 mg/m2 plus dexamethasone in patients with relapsed and refractory multiple myeloma in the United States.

BACKGROUND: In the US, carfilzomib 70 mg/m2 once-weekly plus dexamethasone (Kd70 QW) was recently indicated for relapsed and/or refractory multiple myeloma. In current US clinical practice, most patients treated with Kd receive carfilzomib at a previously approved dose of 27 mg/m2 twice-weekly (Kd27 BIW). This analysis assessed the cost-effectiveness (CE) of Kd70 QW vs Kd27 BIW regimens which were compared in the randomized phase 3 ARROW trial. METHODS: Based on clinical outcomes (overall survival and utilities) from ARROW, a partitioned survival model was developed to estimate life years (LYs) and quality-adjusted life years (QALYs). Long-term survival was extrapolated using SEER registry data matched to ARROW patients. Costs were estimated using a US healthcare payer perspective. RESULTS: The analysis estimated that treatment with Kd70 QW vs Kd27 BIW resulted in an increase of 1.10 LYs, 0.91 QALYs, and additional lifetime costs of $74,858, yielding an incremental CE ratio (ratio of incremental costs to QALYs) of $82,257 per QALY gained. Results were robust to sensitivity and subgroup analyses. CONCLUSIONS: When compared with Kd27 BIW, Kd70 QW is the optimal dose that represents a cost-effective utilization of health care budget with incremental CE ratios well below the accepted willingness-to-pay thresholds in the US.

Novel risk stratification algorithm for estimating the risk of death in patients with relapsed multiple myeloma: external validation in a retrospective chart review.

OBJECTIVES AND DESIGN: A novel risk stratification algorithm estimating risk of death in patients with relapsed multiple myeloma starting second-line treatment was recently developed using multivariable Cox regression of data from a Czech registry. It uses 16 parameters routinely collected in medical practice to stratify patients into four distinct risk groups in terms of survival expectation. To provide insight into generalisability of the risk stratification algorithm, the study aimed to validate the risk stratification algorithm using real-world data from specifically designed retrospective chart audits from three European countries. PARTICIPANTS AND SETTING: Physicians collected data from 998 patients (France, 386; Germany, 344; UK, 268) and applied the risk stratification algorithm. METHODS: The performance of the Cox regression model for predicting risk of death was assessed by Nagelkerke's R2, goodness of fit and the C-index. The risk stratification algorithm's ability to discriminate overall survival across four risk groups was evaluated using Kaplan-Meier curves and HRs. RESULTS: Consistent with the Czech registry, the stratification performance of the risk stratification algorithm demonstrated clear differentiation in risk of death between the four groups. As risk groups increased, risk of death doubled. The C-index was 0.715 (95% CI 0.690 to 0.734). CONCLUSIONS: Validation of the novel risk stratification algorithm in an independent 'real-world' dataset demonstrated that it stratifies patients in four subgroups according to survival expectation.

Carfilzomib and dexamethasone versus eight cycles of bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma: an indirect comparison using data from the phase 3 ENDEAVOR and CASTOR trials.

In ENDEAVOR, carfilzomib and dexamethasone (Kd56) demonstrated significant improvement in progression-free survival (PFS) compared with bortezomib and dexamethasone (Vd). Both agents were administered until disease progression; the EU label for Vd, however, stipulates a maximum of eight treatment cycles. Here, matching-adjusted treatment comparison was used to compare efficacy of Kd56 with Vd, if Vd was administered for 8 cycles (Vd-8). Data from ENDEAVOR and CASTOR trials (which compared daratumumab, bortezomib, and dexamethasone with Vd-8) were used. Hazard ratios of PFS were estimated for Vd vs. Vd-8 and Kd vs. Vd-8. For cycles 1-8, risk reduction in PFS for Kd56 vs. Vd-8 was equal to that estimated in ENDEAVOR (HR: 0.53; 95% CI 0.44-0.65). Beyond eight cycles, risk reduction in PFS for Kd56 and Vd-8 was estimated to be 60% (HR: 0.40; 95% CI 0.26-0.63). The analysis suggested that PFS benefit of Kd56 over Vd increases when Vd is given for eight cycles only.

A cost-effectiveness analysis of denosumab for the prevention of skeletal-related events in patients with multiple myeloma in four European countries: Austria, Belgium, Greece, and Italy.

Aim: The approved indication for denosumab (120 mg) was expanded in 2018 to include skeletal-related event (SRE) prevention in patients with multiple myeloma (MM). Therefore, a cost-effectiveness analysis was conducted comparing denosumab with zoledronic acid (ZA) for SRE prevention in patients with MM from the national healthcare system perspective in a representative sample of European countries: Austria, Belgium, Greece, and Italy. Methods: The XGEVA global economic model for patients with MM was used to calculate incremental cost-effectiveness ratios (ICERs) for denosumab vs ZA over a lifetime horizon. Clinical inputs were derived from the denosumab vs ZA randomized, phase 3 study ("20090482") in patients newly-diagnosed with MM, and comprised real-world adjusted SRE rates, serious adverse event (SAE) rates, treatment duration, dose intensity, progression-free survival (PFS), and overall survival (OS). Economic inputs comprised country-specific denosumab and ZA acquisition and administration costs, SRE and SAE management costs, and discount rates. Health utility decrements associated with MM disease progression, SRE and SAE occurrence, and route of administration were included. Results: Estimated ICERs (cost per quality-adjusted life-year [QALY] gained) for denosumab vs ZA in Austria, Belgium, Greece, and Italy were €26,294, €17,737, €6,982, and €27,228, respectively. Using 1-3 times gross domestic product (GDP) per capita per QALY as willingness to pay thresholds, denosumab was 69-94%, 84-96%, 79-96%, and 50-92% likely to be cost-effective vs ZA, respectively. Limitations: Economic inputs were derived from various sources, and time to event inputs were extrapolated from 20090482 study data. Conclusions: Denosumab is cost-effective vs ZA for SRE prevention in patients with MM in Austria, Belgium, Greece, and Italy, based on often-adopted World Health Organization thresholds. This conclusion is robust to changes in model parameters and assumptions. Cost-effectiveness estimates varied across the four countries, reflecting differences in healthcare costs and national economic evaluation guidelines.

Modeling Covariate-Adjusted Survival for Economic Evaluations in Oncology.

BACKGROUND AND OBJECTIVES: In economic evaluations in oncology, adjusted survival should be generated if imbalances in prognostic/predictive factors across treatment arms are present. To date, no formal guidance has been developed regarding how such adjustments should be made. We compared various covariate-adjusted survival modeling approaches, as applied to the ENDEAVOR trial in multiple myeloma that assessed carfilzomib plus dexamethasone (Cd) versus bortezomib plus dexamethasone (Vd). METHODS: Overall survival (OS) data and baseline characteristics were used for a subgroup (bortezomib-naïve/one prior therapy). Four adjusted survival modeling approaches were compared: propensity score weighting followed by fitting a Weibull model to the two arms of the balanced data (weighted data approach); fitting a multiple Weibull regression model including prognostic/predictive covariates to the two arms to predict survival using the mean value of each covariate and using the average of patient-specific survival predictions; and applying an adjusted hazard ratio (HR) derived from a Cox proportional hazard model to the baseline risk estimated for Vd. RESULTS: The mean OS estimated by the weighted data approach was 6.85 years (95% confidence interval [CI] 4.62-10.70) for Cd, 4.68 years (95% CI 3.46-6.74) for Vd, and 2.17 years (95% CI 0.18-5.06) for the difference. Although other approaches estimated similar differences, using the mean value of covariates appeared to yield skewed survival estimates (mean OS was 7.65 years for Cd and 5.40 years for Vd), using the average of individual predictions had limited external validity (implausible long-term OS predictions with > 10% of the Vd population alive after 30 years), and using the adjusted HR approach overestimated uncertainty (difference in mean OS was 2.03, 95% CI - 0.17 to 6.19). CONCLUSIONS: Adjusted survival modeling based on weighted or matched data approaches provides a flexible and robust method to correct for covariate imbalances in economic evaluations. The conclusions of our study may be generalizable to other settings. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01568866 (ENDEAVOR trial).

Methodology of a Novel Risk Stratification Algorithm for Patients with Multiple Myeloma in the Relapsed Setting.

INTRODUCTION: Risk stratification tools provide valuable information to inform treatment decisions. Existing algorithms for patients with multiple myeloma (MM) were based on patients with newly diagnosed disease, and these have not been validated in the relapsed setting or in routine clinical practice. We developed a risk stratification algorithm (RSA) for patients with MM at initiation of second-line (2L) treatment, based on data from the Czech Registry of Monoclonal Gammopathies. METHODS: Predictors of overall survival (OS) at 2L treatment were identified using Cox proportional hazards models and backward selection. Risk scores were obtained by multiplying the hazard ratios for each predictor. The K-adaptive partitioning for survival (KAPS) algorithm defined four groups of stratification based on individual risk scores. RESULTS: Performance of the RSA was assessed using Nagelkerke's R2 test and Harrell's concordance index through Kaplan-Meier analysis of OS data. Prognostic groups were successfully defined based on real-world data. Use of a multiplicative score based on Cox modeling and KAPS to define cut-off values was effective. CONCLUSION: Through innovative methods of risk assessment and collaboration between physicians and statisticians, the RSA was capable of stratifying patients at 2L treatment by survival expectations. This approach can be used to develop clinical decision-making tools in other disease areas to improve patient management. FUNDING: Amgen Europe GmbH.

Cost Effectiveness of Blinatumomab Versus Inotuzumab Ozogamicin in Adult Patients with Relapsed or Refractory B-Cell Precursor Acute Lymphoblastic Leukemia in the United States.

BACKGROUND AND OBJECTIVE: The TOWER and INO-VATE-ALL trials demonstrated the efficacy and safety of blinatumomab and inotuzumab ozogamicin (inotuzumab), respectively, versus standard-of-care (SOC) chemotherapy in adults with relapsed or refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL). The cost effectiveness of blinatumomab versus inotuzumab has not previously been examined. METHODS: Cost effectiveness of blinatumomab versus inotuzumab in R/R B-cell precursor ALL patients with one or no prior salvage therapy from a United States (US) payer perspective was estimated using a partitioned survival model. Health outcomes were estimated based on published aggregate data from INO-VATE-ALL and individual patient data from TOWER weighted to match patients in INO-VATE-ALL using matching adjusted indirect comparison (MAIC). Analyses were conducted using five approaches relating to use of anchored versus unanchored comparisons of health outcomes and, for the anchored comparisons, the reference treatment to which treatment effects on health outcomes were applied. Estimates from TOWER including the probabilities of complete remission and allogeneic stem-cell transplant (allo-SCT), overall and event-free survival, utilities, duration of therapy, and use of subsequent therapies were MAIC adjusted to match INO-VATE-ALL. Costs of treatment, adverse events, allo-SCT, subsequent therapies, and terminal care were from published sources. A 50-year time horizon and 3% annual discount rate were used. RESULTS: Incremental costs for blinatumomab versus inotuzumab ranged from US$7023 to US$36,244, depending on the approach used for estimating relative effectiveness. Incremental quality-adjusted life-years (QALYs) ranged from 0.54 to 1.78. Cost effectiveness for blinatumomab versus inotuzumab ranged from US$4006 to US$20,737 per QALY gained. CONCLUSIONS: Blinatumomab is estimated to be cost effective versus inotuzumab in R/R B-cell precursor ALL adults who have received one or no prior salvage therapy from a US payer perspective.

Development of an Initial Conceptual Model of Multiple Myeloma to Support Clinical and Health Economics Decision Making.

Background. We aimed to develop and validate a conceptual model of multiple myeloma (MM) that characterizes the attributes affecting disease progression and patient outcomes, and the relationships between them. Methods. Systematic and targeted literature reviews identified disease- and patient-specific attributes of MM that affect disease progression and outcomes. These attributes were validated by a Delphi panel of four international MM experts, and a physician-validated model was constructed. Real-world clinical data from the Czech Registry of Monoclonal Gammopathies (RMG) was used to confirm the relationships between attributes using pairwise correlations and multiple Cox regression analysis. Results. The Delphi panel reached consensus that most cytogenetic abnormalities influenced disease activity, which results in symptoms and complications and affects overall survival (OS). Comorbidities and complications also affect OS. The entire panel agreed that quality of life was influenced by comorbidities, age, complications, and symptoms. Consensus was not reached in some cases, in particular, the influence of del(17p) on complications. The relationships between attributes were confirmed using pairwise analysis of real-world data from the Czech RMG; most of the correlations identified were statistically significant and the strength of the correlations changed with successive relapses. Czech RMG data were also used to confirm significant predictors of OS included in the model, such as age, Eastern Cooperative Oncology Group performance status, and extramedullary disease. Conclusions. This validated conceptual model can be used for economic modeling and clinical decision making. It could also inform the development of disease-based models to explore the impact of disease progression and treatment on outcomes in patients with MM.

Effects of nonglucose nutrients on insulin secretion and action in people with pre-diabetes.

To determine whether nonglucose nutrient-induced insulin secretion is impaired in pre-diabetes, subjects with impaired or normal fasting glucose were studied after ingesting either a mixed meal containing 75 g glucose or 75 g glucose alone. Despite comparable glucose areas above basal, glucose-induced insulin secretion was higher (P < 0.05) and insulin action lower (P < 0.05) during the meal than the oral glucose tolerance test (OGTT) in all subgroups regardless of whether they had abnormal or normal glucose tolerance (NGT). However, the nutrient-induced delta (meal minus OGTT) in insulin secretion and glucagon concentrations did not differ among groups. Furthermore, the decrease in insulin action after meal ingestion was compensated in all groups by an appropriate increase in insulin secretion resulting in disposition indexes during meals that were equal to or greater than those present during the OGTT. In contrast, disposition indexes were reduced (P < 0.01) during the OGTT in the impaired glucose tolerance groups, indicating that reduced glucose induced insulin secretion. We conclude that, whereas glucose-induced insulin secretion is impaired in people with abnormal glucose tolerance, nonglucose nutrient-induced secretion is intact, suggesting that a glucose-specific defect in the insulin secretory pathway is an early event in the evolution of type 2 diabetes.

Two years of treatment with dehydroepiandrosterone does not improve insulin secretion, insulin action, or postprandial glucose turnover in elderly men or women.

To determine if dehydroepiandrosterone (DHEA) replacement improves insulin secretion, insulin action, and/or postprandial glucose metabolism, 112 elderly subjects with relative DHEA deficiency ingested a labeled mixed meal and underwent a frequently sampled intravenous glucose tolerance test before and after 2 years of either DHEA or placebo. Despite restoring DHEA sulphate concentrations to values observed in young men and women, the changes over time in fasting and postprandial glucose concentrations, meal appearance, glucose disposal, and endogenous glucose production were identical to those observed after 2 years of placebo. The change over time in postmeal and intravenous glucose tolerance test insulin and C-peptide concentrations did not differ in men treated with DHEA or placebo. In contrast, postmeal and intravenous glucose tolerance test change over time in insulin and C-peptide concentrations were greater (P < 0.05) in women after DHEA than after placebo. However, since DHEA tended to decrease insulin action, the change over time in disposition indexes did not differ between DHEA- and placebo-treated women, indicating that the slight increase in insulin secretion was a compensatory response to a slight decrease in insulin action. We conclude that 2 years of replacement of DHEA in elderly men and women does not improve insulin secretion, insulin action, or the pattern of postprandial glucose metabolism.

Short-term high dietary fructose intake had no effects on insulin sensitivity and secretion or glucose and lipid metabolism in healthy, obese adolescents.

UNLABELLED: There is virtually no information on the metabolic impact of dietary fructose intake in adolescents despite their high fructose consumption, particularly via sweetened beverages. AIM: To determine the short-term metabolic effects of dietary fructose intake in obese adolescents. METHODS: Six volunteers (3 M/3 F; 15.2 +/- 0.5 yr; 35 +/- 2 kg/m2; 39 +/- 2% body fat) were studied twice following 7 d of isocaloric, isonitrogenous high carbohydrate (60% CHO; 25% fat) diets with fructose accounting for 6% and 24% of total energy intake, respectively (random order). Insulin sensitivity and secretion were analyzed by the stable labeled intravenous glucose tolerance test and glucose and lipid kinetics using GCMS. RESULTS: A fourfold increase in dietary fructose intake did not affect insulin sensitivity or secretion, glucose kinetics, lipolysis or glucose, insulin, C-peptide, triglycerides, HDL- and LDL-cholesterol concentrations. CONCLUSIONS: In the short term, when energy intake is constant, dietary fructose per se is not a contributor to insulin resistance and hypersecretion in obese adolescents.

Reframing the Value of Treatments for Relapsed/Refractory Multiple Myeloma.

DISCLOSURES: Ailawadhi reports research support from Pharmacyclics and consulting relationships with Takeda, Amgen, and Celgene. Jakubowiak reports consulting and advisory board relationships with AbbVie, Amgen, BMS, Celgene, Karyopharm, SkylineDX, and Takeda. Panjabi, Campioni, and Majer are employees of and stockholders in Amgen.

Healthcare resource utilization among patients with relapsed multiple myeloma in the UK, France, and Italy.

AIMS: To assess the real-world healthcare resource utilization (HRU) and costs associated with different treatment regimens used in the management of patients with relapsed multiple myeloma in the UK, France, and Italy. METHODS: Retrospective medical chart review of characteristics, time to progression, level of response, HRU during treatment, and adverse events (AEs). Data collection started on June 1, 2015 and was completed on July 15, 2015. In the 3 months before record abstraction, eligible patients had either disease progression after receiving one of their country's most commonly prescribed regimens or had received the best supportive care and died. Costs were calculated based on HRU and country-specific diagnosis-related group and/or unit reference costs, amongst other standard resources. RESULTS: Physicians provided data for 1,282 patients (387 in the UK, 502 in France, 393 in Italy) who met the inclusion criteria. Mean [median] total healthcare costs associated with a single line of treatment were €51,717 [35,951] in the UK, €37,009 [32,538] for France, and €34,496 [42,342] for Italy, driven largely by anti-myeloma medications costs (contributing 95.0%, 90.0%, and 94.2% of total cost, respectively). During active treatment, the highest costs were associated with lenalidomide- and pomalidomide-based regimens. Mean cost per month was lowest for patients achieving a very good partial response or better. Unscheduled events (i.e. not considered part of routine management, whether or not related to multiple myeloma, such as unscheduled hospitalization, AEs, fractures) accounted for 1-9% of total costs and were highest for bendamustine. LIMITATIONS: The use of retrospective data means that clinical practice (e.g. use of medical procedures, evaluation of treatment response) is not standardized across participating countries/centers, and some data (e.g. low-grade AEs) may be incomplete or differently adjudicated/reported. The centers involved may not be fully representative of national practice. CONCLUSIONS: Drug costs are the main contributor to total HRU costs associated with multiple myeloma. The duration of active treatment may influence the average total costs, as well as response, associated with a single line of therapy. Improved treatment outcomes, and reductions in unscheduled events and concomitant medication use may, therefore, reduce the overall HRU and related costs of care in multiple myeloma.

Cost per response analysis of strategies for chronic immune thrombocytopenia.

OBJECTIVES: This analysis estimated the cost per response and the incremental cost per additional responder of romplostim, eltrombopag, and the "watch-and-rescue" (monitoring until rescue therapies are required) strategy in adults with chronic immune thrombocytopenia (ITP). STUDY DESIGN: The decision tree is designed to estimate the total cost per response for romiplostim, eltrombopag, and watch and rescue over a 24-week time horizon; cost-effectiveness was evaluated in terms of incremental cost per additional responder. METHODS: Model inputs including response rates, bleeding-related episode (BRE) rates, and costs were estimated from registrational trial data, an independent Bayesian indirect comparison, database analyses, and peer-reviewed publications. Costs were applied to the proportions of patients with treatment response and nonresponse (based on platelet count). The total cost per response and the incremental cost per additional responder for each treatment were calculated. Sensitivity analyses and alternative analyses were performed. RESULTS: With higher total costs and greater treatment efficacy, romiplostim and eltrombopag had a lower 24-week cost per response and a lower average number of BREs than watch and rescue. Eltrombopag was weakly dominated by romiplostim. The incremental cost-effectiveness ratio of romiplostim versus watch and rescue was $46,000 per additional responder. The model results are most sensitive to response rates of romiplostim and watch and rescue and the BRE rate for splenectomized nonresponders. Alternative analyses results were similar to the base case. CONCLUSIONS: In adults with chronic ITP, romiplostim represents an efficient way to achieve response, with lower costs per response than eltrombopag; both romiplostim and eltrombopag had lower costs per response than watch and rescue.

Real-world Outcomes of Multiple Myeloma: Retrospective Analysis of the Czech Registry of Monoclonal Gammopathies.

INTRODUCTION: Real-world data on patient outcomes and treatment patterns in multiple myeloma (MM) are limited. MATERIALS AND METHODS: The present noninterventional, observational, retrospective analysis of prospectively collected Czech patient medical record data from the Registry of Monoclonal Gammopathies estimated real-world outcomes in adults with a diagnosis of symptomatic MM made between May 2007 and June 2014. RESULTS: In total, 2446 patients had initiated first-line treatment. The median overall survival since the diagnosis (primary endpoint) was 50.3 months (95% confidence interval, 46.1-54.5 months) and decreased with each successive treatment line. A similar trend was observed for progression-free survival and the depth of response. In line with European guidelines and clinical practice, bortezomib-, thalidomide-, and lenalidomide-based regimens were most commonly used across all treatment lines (42.3%, 28.9%, and 18.4%, respectively). In the first line, bortezomib and thalidomide were used most often, with lenalidomide the most commonly used agent in the relapse setting (second to fourth lines). Exploratory analyses revealed that younger age (≤ 65 years), lower international staging system stage, and previous stem cell transplantation were associated with significant improvements in overall and progression-free survival, especially in the early treatment lines. CONCLUSION: The present study is the first analysis of Czech data from the Registry of Monoclonal Gammopathies, and it provides important insights into the real-world management of MM for physicians and healthcare providers.

Pathogenesis of pre-diabetes: mechanisms of fasting and postprandial hyperglycemia in people with impaired fasting glucose and/or impaired glucose tolerance.

Thirty-two subjects with impaired fasting glucose (IFG) and 28 subjects with normal fasting glucose (NFG) ingested a labeled meal and 75 g glucose (oral glucose tolerance test) on separate occasions. Fasting glucose, insulin, and C-peptide were higher (P < 0.05) in subjects with IFG than in those with NFG, whereas endogenous glucose production (EGP) did not differ, indicating hepatic insulin resistance. EGP was promptly suppressed, and meal glucose appearance comparably increased following meal ingestion in both groups. In contrast, glucose disappearance (R(d)) immediately after meal ingestion was lower (P < 0.001) in subjects with IFG/impaired glucose tolerance (IGT) and IFG/diabetes but did not differ in subjects with IFG/normal glucose tolerance (NGT) or NFG/NGT. Net insulin action (S(i)) and insulin-stimulated glucose disposal (S(i)*) were reduced (P < 0.001, ANOVA) in subjects with NFG/IGT, IFG/IGT, and IFG/diabetes but did not differ in subjects with NFG/NGT or IFG/NGT. Defective insulin secretion also contributed to lower postprandial R(d) since disposition indexes were lower (P < 0.001, ANOVA) in subjects with NFG/IGT, IFG/IGT, and IFG/diabetes but did not differ in subjects with NFG/NGT and IFG/NGT. We conclude that postprandial hyperglycemia in individuals with early diabetes is due to lower rates of glucose disappearance rather than increased meal appearance or impaired suppression of EGP, regardless of their fasting glucose. In contrast, insulin secretion, action, and the pattern of postprandial turnover are essentially normal in individuals with isolated IFG.

Effects of age and sex on postprandial glucose metabolism: differences in glucose turnover, insulin secretion, insulin action, and hepatic insulin extraction.

To determine the effects of age and sex on the regulation of postprandial glucose metabolism, glucose turnover, insulin secretion, insulin action, and hepatic insulin extraction were concurrently measured in 145 healthy elderly (aged 70 +/- 1 years) and in 58 young (aged 28 +/- 1 years) men and women before and after ingestion of a mixed meal containing [1-(13)C]glucose. At the time of meal ingestion, [6-(3)H]glucose and [6,6-(2)H(2)]glucose were infused intravenously to enable concurrent measurement of the rates of postprandial endogenous glucose production (EGP), meal appearance, and glucose disappearance. Fasting and postprandial glucose concentrations were higher (P < 0.001) in both elderly women and elderly men compared with young individuals of the same sex. The higher postprandial glucose concentrations in the elderly than young women were caused by higher rates of meal appearance (P < 0.01) and slightly lower (P < 0.05) rates of glucose disappearance immediately after eating. In contrast, higher glucose concentrations in the elderly than young men were solely due to decreased (P < 0.001) glucose disappearance. Although postprandial glucose concentrations did not differ in elderly women and elderly men, rates of meal appearance and glucose disappearance rates both were higher (P < 0.001) in the women. Fasting EGP was higher (P < 0.05) in elderly than young subjects of both sexes and in women than men regardless of age. On the other hand, postprandial suppression of EGP was rapid all groups. Insulin action and secretion were lower (P < 0.001) in the elderly than young men but did not differ in the elderly and young women. This resulted in lower (P < 0.001) meal disposition indexes in elderly than young men but no difference in elderly and young women. Total meal disposition indexes were lower (P < 0.05) in elderly men than elderly women, indicating impaired insulin secretion, whereas disposition indexes were higher (P < 0.05) in young men than young women. Hepatic insulin clearance was greater (P < 0.001) in the elderly than young subjects of both sexes but did not differ between men and women regardless of age. In contrast, the ability of glucose to facilitate its own uptake (glucose effectiveness) was higher (P < 0.001) in women than men but did not differ in elderly and young subjects. Thus, age and sex impact on insulin secretion, insulin action, hepatic insulin extraction, and glucose effectiveness, resulting in substantial differences in the regulation of postprandial glucose metabolism in men and women and in elderly and young subjects.

Prediction of postprandial glycemic exposure: utility of fasting and 2-h glucose measurements alone and in combination with assessment of body composition, fitness, and strength.

OBJECTIVE: To determine the best predictors of total postprandial glycemic exposure and peak glucose concentrations in nondiabetic humans. RESEARCH DESIGN AND METHODS: Data from 203 nondiabetic volunteers who ingested a carbohydrate-containing mixed meal were analyzed. RESULTS: Fasting glucose and insulin concentrations were poor predictors of postprandial glucose area above basal (R2 = approximately 0.07, P < 0.001). The correlation was stronger for 2-h glucose concentration (R2 = 0.55, P < 0.001) and improved slightly but significantly (P < 0.001) with the addition of fasting glucose, insulin, age, sex, and body weight to the model (r2 = 0.58). The 2-h glucose concentration also predicted the peak glucose concentration (R2 = 0.37, P < 0.001) with strength of the prediction increasing (P < 0.001) modestly with the addition of fasting glucose, insulin, age, sex, and body weight to the model (R2 = 0.48, P < 0.001). On the other hand, addition of measures of body function and composition did not improve prediction of total glycemic exposure or peak glucose concentration. CONCLUSIONS: Isolated measures of fasting or 2-h glucose concentrations alone or in combination with more complex measures of body composition and function are poor predictors of postprandial glycemic exposure or peak glucose concentration. This may explain, at least in part, the weak and at times inconsistent relationship between these parameters and cardiovascular risk.