Once weekly selinexor, carfilzomib and dexamethasone in carfilzomib non-refractory multiple myeloma patients.

BACKGROUND: Proteasome inhibitors (PIs), including carfilzomib, potentiate the activity of selinexor, a novel, first-in-class, oral selective inhibitor of nuclear export (SINE) compound, in preclinical models of multiple myeloma (MM). METHODS: The safety, efficacy, maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of selinexor (80 or 100 mg) + carfilzomib (56 or 70 mg/m2) + dexamethasone (40 mg) (XKd) once weekly (QW) was evaluated in patients with relapsed refractory MM (RRMM) not refractory to carfilzomib. RESULTS: Thirty-two patients, median prior therapies 4 (range, 1-8), were enrolled. MM was triple-class refractory in 38% of patients and 53% of patients had high-risk cytogenetics del(17p), t(4;14), t(14;16) and/or gain 1q. Common treatment-related adverse events (all/Grade 3) were thrombocytopenia 72%/47% (G3 and G4), nausea 72%/6%, anaemia 53%/19% and fatigue 53%/9%, all expected and manageable with supportive care and dose modifications. MTD and RP2D were identified as selinexor 80 mg, carfilzomib 56 mg/m2, and dexamethasone 40 mg, all QW. The overall response rate was 78% including 14 (44%) ≥ very good partial responses. Median progression-free survival was 15 months. CONCLUSIONS: Weekly XKd is highly effective and well-tolerated. These data support further investigation of XKd in patients with MM.

Gamma models for estimating the odds ratio for a skewed biomarker measured in pools and subject to errors.

Measuring a biomarker in pooled samples from multiple cases or controls can lead to cost-effective estimation of a covariate-adjusted odds ratio, particularly for expensive assays. But pooled measurements may be affected by assay-related measurement error (ME) and/or pooling-related processing error (PE), which can induce bias if ignored. Building on recently developed methods for a normal biomarker subject to additive errors, we present two related estimators for a right-skewed biomarker subject to multiplicative errors: one based on logistic regression and the other based on a Gamma discriminant function model. Applied to a reproductive health dataset with a right-skewed cytokine measured in pools of size 1 and 2, both methods suggest no association with spontaneous abortion. The fitted models indicate little ME but fairly severe PE, the latter of which is much too large to ignore. Simulations mimicking these data with a non-unity odds ratio confirm validity of the estimators and illustrate how PE can detract from pooling-related gains in statistical efficiency. These methods address a key issue associated with the homogeneous pools study design and should facilitate valid odds ratio estimation at a lower cost in a wide range of scenarios.

A Note on Proposed Estimation Procedures for Claims-Based Frailty Indexes.

Two groups (Segal et al. Med Care. 2017;55(7):716-722; Segal et al. Am J Epidemiol. 2017;186(6):745-747; and Kim et al. J Gerontol A Biol Sci Med Sci. 2018;73(7):980-987) recently proposed methods for modeling frailty in studies where a reference standard frailty measure is not directly observed, but Medicare claims data are available. The groups use competing frailty measures, but the premise is similar: In a validation data set, model the frailty measure versus claims variables; in the primary data set, impute frailty status from claims variables, and conduct inference with those imputed values in place of the unobserved frailty measure. Potential use cases include risk prediction, confounding control, and prevalence estimation. In this commentary, we describe validity issues underlying these approaches, focusing mainly on risk prediction. Our main concern is that these approaches do not permit valid estimation of associations between the reference standard frailty measure (i.e., "frailty") and health outcomes. We argue that Segal's approach is akin to multiple imputation but with the outcome variable omitted from the imputation model, while Kim's is akin to regression calibration but with many variables improperly treated as surrogates. We discuss alternatives for risk prediction, including a secondary approach previously considered by Kim et al., and briefly comment on other use cases.

Formulas and Web Application for Designing a Biospecimen Pooling Study to Compare Group Means.

BACKGROUND: When research focuses on biomarker assessment in settings where per-assay costs are high relative to per-subject costs, a biospecimen pooling study design can be extremely cost-effective. However, designing a study to maximize cost savings is complicated by the fact that pooled measurements are typically subject to processing error, inducing additional variability caused by combining biospecimens, and may also be affected by assay-related measurement error. METHODS: We provide formulas and an interactive web application (hereafter called app) for designing a pooling study to compare group means. Power and sample size formulas are justified by Central Limit Theorem arguments that make no distributional assumptions on the biomarker. Errors can be assumed mean-0 additive or mean-1 multiplicative, the latter being well-suited for skewed biomarkers. RESULTS: User inputs for the app include usual power parameters as well as per-assay and per-subject costs and information about the errors: which are present, whether they are additive or multiplicative, and their variances. The app generates plots revealing the optimal pool size, required number of assays, cost savings, and sensitivity to the hard-to-predict processing error variance. CONCLUSIONS: These tools should aid in the design and deployment of pooling studies powered to detect group mean differences while minimizing total study costs.

Dynamic sitting: Measurement and associations with metabolic health.

Dynamic sitting, such as fidgeting and desk work, might be associated with health, but remains difficult to identify out of accelerometry data. We examined, in a laboratory study, whether dynamic sitting can be identified out of triaxial activity counts. Among 18 participants (56% men, 27.3 ± 6.5 years), up to 236 counts per minute were recorded in the anteroposterior and mediolateral axes during dynamic sitting using a hip-worn accelerometer. Subsequently, we examined in 621 participants (38% men, 80.0 ± 4.7 years) from the AGES-Reykjavik Study whether dynamic sitting was associated with cardio-metabolic health. Compared to participants who recorded the fewest dynamic sitting minutes (Q1), those with more dynamic sitting minutes had a lower BMI (Q2 = -1.39 (95%CI = -2.33;-0.46); Q3 = -1.87 (-2.82;-0.92); Q4 = -3.38 (-4.32;-2.45)), a smaller waist circumference (Q2 = -2.95 (-5.44;-0.46); Q3 = -3.47 (-6.01;-0.93); Q4 = -8.21 (-10.72;-5.71)), and a lower odds for the metabolic syndrome (Q2 = 0.74 [0.45;1.20] Q3 = 0.58 [0.36;0.95]; Q4 = 0.36 [0.22;0.59]). Our findings suggest that dynamic sitting might be identified using accelerometry and that this behaviour was associated with health. This might be important given the large amounts of time people spend sitting. Future studies with a focus on validation, causation and physiological pathways are needed to further examine the possible relevance of dynamic sitting.

Logistic regression with a continuous exposure measured in pools and subject to errors.

In a multivariable logistic regression setting where measuring a continuous exposure requires an expensive assay, a design in which the biomarker is measured in pooled samples from multiple subjects can be very cost effective. A logistic regression model for poolwise data is available, but validity requires that the assay yields the precise mean exposure for members of each pool. To account for errors, we assume the assay returns the true mean exposure plus a measurement error (ME) and/or a processing error (PE). We pursue likelihood-based inference for a binary health-related outcome modeled by logistic regression coupled with a normal linear model relating individual-level exposure to covariates and assuming that the ME and PE components are independent and normally distributed regardless of pool size. We compare this approach with a discriminant function-based alternative, and we demonstrate the potential value of incorporating replicates into the study design. Applied to a reproductive health dataset with pools of size 2 along with individual samples and replicates, the model fit with both ME and PE had a lower AIC than a model accounting for ME only. Relative to ignoring errors, this model suggested a somewhat higher (though still nonsignificant) adjusted log-odds ratio associating the cytokine MCP-1 with risk of spontaneous abortion. Simulations modeled after these data confirm validity of the methods, demonstrate how ME and particularly PE can reduce the efficiency advantage of a pooling design, and highlight the value of replicates in improving stability when both errors are present.

Efficacy and safety of once weekly selinexor 40 mg versus 60 mg with pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma.

Objective: To identify the optimal dose of selinexor in combination with pomalidomide and dexamethasone (SPd). Methods: An analysis of efficacy and safety of 2 once-weekly selinexor regimens (60 mg and 40 mg) with pomalidomide and dexamethasone (SPd-60 and SPd-40, respectively) given to patients with relapsed/refractory multiple myeloma (RRMM) in the STOMP (NCT02343042) and XPORT-MM-028 (NCT04414475) trials. Results: Twenty-eight patients (60.7% males, median age 67.5 years) and 20 patients (35.0% males, median age 65.5 years) were analyzed in the SPd-40 and SPd-60 cohorts, respectively. Overall response rate was 50% (95% confidence interval [CI] 30.6-69.4%) and 65% (95% CI 40.8-84.6%), respectively. Very good partial response or better was reported in 28.6% (95% CI 13.2-48.7%) and 30.0% (95% CI 11.9-54.3%) of patients, respectively. Among 27 responders in both cohorts, the 12-month sustained response rate was 83.3% (95% CI 64.7-100.0%) for SPd-40 and 28.1% (95% CI 8.9-88.8%) for SPd-60. Median progression-free survival was 18.4 months (95% CI 6.5 months, not evaluable [NE]) and 9.5 months (95% CI 7.6 months-NE) for SPd-40 and SPd-60, respectively. Twenty-four-month survival rates were 64.2% (95% CI 47.7-86.3%) for SPd-40 and 51.1% (95% CI 29.9-87.5%) for SPd-60. Treatment-emergent adverse events (TEAEs) included neutropenia (all grades: SPd-40 64.3% versus SPd-60 75.0%), anemia (46.4% versus 65.0%), thrombocytopenia (42.9% versus 45.0%), fatigue (46.4% versus 75.0%), nausea (32.1% versus 70.0%) and diarrhea (28.6% versus 35.0%). Conclusion: The all-oral combination of SPd exhibited preliminary signs of efficacy and was generally tolerable in patients with RRMM. The overall risk-benefit profile favored the SPd-40 regimen.

Objective measurements of daily physical activity patterns and sedentary behaviour in older adults: Age, Gene/Environment Susceptibility-Reykjavik Study.

BACKGROUND: objectively measured population physical activity (PA) data from older persons is lacking. The aim of this study was to describe free-living PA patterns and sedentary behaviours in Icelandic older men and women using accelerometer. METHODS: from April 2009 to June 2010, 579 AGESII-study participants aged 73-98 years wore an accelerometer (Actigraph GT3X) at the right hip for one complete week in the free-living settings. RESULTS: in all subjects, sedentary time was the largest component of the total wear time, 75%, followed by low-light PA, 21%. Moderate-vigorous PA (MVPA) was <1%. Men had slightly higher average total PA (counts × day(-1)) than women. The women spent more time in low-light PA but less time in sedentary PA and MVPA compared with men (P < 0.001). In persons <75 years of age, 60% of men and 34% of women had at least one bout ≥10 min of MVPA, which decreased with age, with only 25% of men and 9% of women 85 years and older reaching this. CONCLUSION: sedentary time is high in this Icelandic cohort, which has high life-expectancy and is living north of 60° northern latitude.

Association of Selinexor Dose Reductions With Clinical Outcomes in the BOSTON Study.

BACKGROUND: Dose modifications in response to adverse events (AEs) can maintain tumor response and improve therapy tolerability. We conducted a post-hoc analysis of the efficacy and safety of reduced selinexor doses in the BOSTON trial (NCT03110562). PATIENTS AND METHODS: Efficacy, safety, and quality of life (QoL) in 195 patients with relapsed/refractory multiple myeloma randomized to once-weekly (QW) selinexor (100 mg), QW subcutaneous bortezomib (1.3 mg/m2), and twice-weekly dexamethasone (20 mg) were compared between patients with dose reductions and those without. RESULTS: In total, 126 patients (65%) had selinexor dose reductions (median dose 71.4 mg/wk). In patients with dose reductions versus those without median progression-free survival was 16.6 months (95% CI 12.9-not evaluable [NE]) versus 9.2 months [95% CI 6.8-15.5]), overall response rate was 81.7% (95% CI 73.9-88.1%) versus 66.7% (95% CI 54.3-77.6%), ≥very good partial response was (51.6% [95% CI 42.5-60.6%] vs. 31.9% [95% CI 21.2-44.2]), median duration of response was not reached (95% CI 13.8-NE) versus 12.0 months (95% CI 8.3-NE), and time to next treatment was 22.6 months (95% CI 14.6-NE) versus 10.5 months (95% CI 6.3-18.2). Mean best change from baseline on the EORTC QLQ-C30 Global Health Status/QoL scale was 10.0 ± 20.5 versus 4.0 ± 20.9. Duration-adjusted AE rates that were lower after selinexor dose reduction included thrombocytopenia (62.5% before vs. 47.6% after), nausea (31.6% vs. 7.3%), fatigue (28.1% vs. 9.9%), decreased appetite (21.5% vs. 6.4%), anemia (17.9% vs. 10.3%), and diarrhea (12.9% vs. 5.2%). CONCLUSION: Appropriate dose reductions in response to AEs of the 100 mg selinexor starting dose in the BOSTON study were associated with improved efficacy, reduced AE rates and improved QoL.

Selinexor-Based Triplet Regimens in Patients With Multiple Myeloma Previously Treated With Anti-CD38 Monoclonal Antibodies.

BACKGROUND: The increasing use of anti-CD38 monoclonal antibodies (αCD38 mAbs) for newly diagnosed or early relapsed multiple myeloma (MM), especially in non-transplant eligible patients, may lead to more patients developing αCD38 mAb-refractory disease earlier in the treatment course with fewer treatment options. PATIENTS AND METHODS: We analyzed the efficacy and safety of selinexor-based triplets (selinexor+dexamethasone [Sd] plus pomalidomide [SPd, n = 23], bortezomib [SVd, n = 16] or carfilzomib (SKd, n = 23]) in a subset of STOMP (NCT02343042) and BOSTON (NCT03110562) study patients treated previously with αCD38 mAbs. RESULTS: Sixty-two patients (median 4 prior therapies, range 1 to 11, 90.3% refractory to αCD38 mAb) were included. Overall response rates (ORR) in the SPd, SVd and SKd cohorts were 52.2%, 56.3%, and 65.2%, respectively. Overall response rate was 47.4% among patients who had MM refractory to the third drug reintroduced in the Sd-based triplet. Median progression-free survival in the SPd, SVd, and SKd cohorts was 8.7, 6.7, and 15.0 months, respectively, and median overall survival was 9.6, 16.9, and 33.0 months, respectively. Median time to discontinuation in the SPd, SVd, and SKd cohorts was 4.4, 5.9, and 10.6 months, respectively. The most common hematological adverse events were thrombocytopenia, anemia, and neutropenia. Nausea, fatigue, and diarrhea were primarily grade 1/2. Adverse events were generally manageable with standard supportive care and dose modifications. CONCLUSION: Selinexor-based regimens may offer effective and well-tolerated therapy to patients with relapsed and/or refractory MM who had disease previously exposed or refractory to αCD38 mAb therapy and could help address the unmet clinical need in these high-risk patients.

Selinexor-based regimens in patients with multiple myeloma after prior anti-B-cell maturation antigen treatment.

There is a lack of consensus on therapy sequencing in previously treated multiple myeloma, particularly after anti-B-cell maturation antigen (BCMA) therapy. Earlier reports on selinexor (X) regimens demonstrated considerable efficacy in early treatment, and after anti-BCMA-targeted chimeric antigen receptor-T cell therapy. Here, we present data from 11 heavily pretreated patients who predominantly received BCMA-antibody-drug conjugate therapy. We observe that X-containing regimens are potent and achieve durable responses with numerically higher overall response and clinical benefit rates, as well as median progression free survival compared to patients' prior anti-BCMA therapies, despite being used later in the treatment course. In an area of evolving unmet need, these data reaffirm the efficacy of X-based regimens following broader anti-BCMA therapy.

Selinexor, daratumumab, and dexamethasone in patients with relapsed or refractory multiple myeloma.

We assessed the safety, efficacy, maximum tolerated dose (MTD), and the recommended phase 2 dose (RP2D) of selinexor, a first in class oral selective inhibitor of nuclear export (100 mg once weekly [QW] or 60 mg twice weekly), in combination with daratumumab (16 mg/kg per label) and dexamethasone (40 mg QW) (SDd) in patients with relapsed refractory multiple myeloma (RRMM). Thirty-four patients (median prior therapies, 3 [range, 2-10]) were enrolled; MM was refractory to proteasome inhibitor (PI) in 85%, immunomodulatory agent (IMiD) in 76%, both in 74%, and daratumumab in 6% of patients. Two dose-limiting toxicities (DLTs) were reported in the selinexor 60 mg twice-weekly cohort with no DLTs in the 100 mg QW cohort, making 100 mg QW the MTD and RP2D. Common treatment-related adverse events included thrombocytopenia (70.6%), nausea (70.6%), fatigue (61.8%), anemia (61.8%), and neutropenia (50.0%). Overall response rate was 73% and median progression-free survival 12.5 months in daratumumab-naïve patients. SDd was well tolerated and its promising efficacy suggests that further study of this PI- and IMiD-free regimen in RRMM patients who had at least one prior line of therapy including a PI and an IMiD but whose disease is naïve to daratumumab is warranted.

Physical activity patterns and multimorbidity burden of older adults with different levels of functional status: NHANES 2003-2006.

BACKGROUND: Physical function and physical activity decrease with age, but differences in physical activity patterns within different physical functioning groups are unknown. OBJECTIVES: To describe physical activity patterns and multimorbidity burden by physical function group and age. METHODS: Actigraph accelerometer-derived physical activity patterns were compared by physical function (high functioning, activity limitations, activity of daily living disabled) determined by questionnaire and age among 2174 older adults (mean age = 70.9, sd = 0.2 years) from the cross-sectional 2003-2006 National Health and Nutrition Examination Survey. Associations between physical function, physical activity, and multimorbidity were examined. RESULTS: Reduced physical function and increased age were associated with lower physical activity, increased sedentary time and a compressed activity profile. During the most active hour of the day (11:00 a.m.), the oldest, lowest physical functioning group was 82% less active than the youngest, highest physical functioning group. High functioning had over 30% more total activity counts, over 56% more time in moderate-to-vigorous activity, about 8% less time sedentary and took approximately one more sedentary break/hour than lower physical functioning groups. Gender differences in physical activity variables were prevalent for high functioning, but limited within reduced physical functioning groups. Physical function, age, total activity counts/day, and breaks in sedentary time/day were independently associated with multimorbidity (p < 0.005). CONCLUSIONS: Reduced physical function and increased age are associated with physical activity levels, and all three are associated with multimorbidity. Understanding physical activity differences by physical function is important for designing interventions for older individuals at increased risk for mobility disability.

Daily Physical Activity by Occupational Classification in US Adults: NHANES 2005-2006.

BACKGROUND: Little is known about the daily physical activity (PA) levels of people employed in different occupational categories. METHODS: Nine ActiGraph accelerometer-derived daily PA variables are presented and ranked for adults (N = 1465, 20-60 y) working in the 22 occupational categories assessed by NHANES 2005-2006. A composite score was generated for each occupational category by summing the rankings of 3 accelerometer-derived daily PA variables known to have strong associations with health outcomes (total activity counts [TAC], moderate to vigorous PA minutes per week in modified 10-minute bouts [MVPA 10], and percentage of time spent in sedentary activity [SB%]). RESULTS: Classified as high-activity occupational categories, "farming, fishing, forestry," and "building & grounds cleaning, maintenance" occupations had the greatest TAC (461 996 and 449 452), most MVPA 10 (149.6 and 97.8), most steps per day (10 464 and 11 602), and near the lowest SB% (45.2% and 45.4%). "Community, social services" occupations, classified as low-activity occupational categories, had the second lowest TAC (242 085), least MVPA 10 (12.1), fewest steps per day (5684), and near the highest SB% (64.2%). CONCLUSIONS: There is a strong association between occupational category and daily activity levels. Objectively measured daily PA permitted the classification of the 22 different occupational categories into 3 activity groupings.

Comparison of Summer and Winter Objectively Measured Physical Activity and Sedentary Behavior in Older Adults: Age, Gene/Environment Susceptibility Reykjavik Study.

In Iceland, there is a large variation in daylight between summer and winter. The aim of the study was to identify how this large variation influences physical activity (PA) and sedentary behavior (SB). Free living PA was measured by a waist-worn accelerometer for one week during waking hours in 138 community-dwelling older adults (61.1% women, 80.3 ± 4.9 years) during summer and winter months. In general, SB occupied about 75% of the registered wear-time and was highly correlated with age (ß = 0.36). Although the differences were small, more time was spent during the summer in all PA categories, except for the moderate-to-vigorous PA (MVPA), and SB was reduced. More lifestyle PA (LSPA) was accumulated in ≥5-min bouts during summer than winter, especially among highly active participants. This information could be important for policy makers and health professionals working with older adults. Accounting for seasonal difference is necessary in analyzing SB and PA data.

Examining differences in physical activity levels by employment status and/or job activity level: Gender-specific comparisons between the United States and Sweden.

OBJECTIVES: The aim of the study was to examine the relationship between employment status and job activity level with physical activity (PA) and sedentary time, stratified by gender and country. DESIGN: Cross-sectional study design. METHODS: Data from working age adults (18-65 years) from two cross-sectional studies, the Swedish 2001-2002 and 2007-2008 Attitude Behavior and Change Study (ABC; n=1165) and the 2003-2006 US National Health and Nutrition Examination Survey (NHANES; n=4201), were stratified by employment status (employed and not employed) and job activity level (active, sedentary and mixed). PA in counts×min(-1) and time spent in sedentary, low and moderate or higher intensity were measured with accelerometers. Analyses were conducted in 2012-2013. RESULTS: In NHANES, the employed had significantly higher counts×min(-1) and spent more time in moderate or higher intensity PA than those not employed. In ABC, no significant differences were observed between employed and unemployed. Adults with active versus sedentary occupations had higher counts×min(-1) and less sedentary time in both the USA and Sweden and in both men and women. For example, counts×min(-1) were 20-40% greater in active versus sedentary jobs. CONCLUSIONS: Employment status is related to PA and sedentary time among men and women in the USA but not in Sweden. Among the employed, occupational PA is associated with total PA and sedentary time for both genders and in both countries. Comparisons of PA levels based on objective measurements can refine understanding of country differences in activity.

Accelerometer-measured dose-response for physical activity, sedentary time, and mortality in US adults.

BACKGROUND: Moderate-to-vigorous-intensity physical activity is recommended to maintain and improve health, but the mortality benefits of light activity and risk for sedentary time remain uncertain. OBJECTIVES: Using accelerometer-based measures, we 1) described the mortality dose-response for sedentary time and light- and moderate-to-vigorous-intensity activity using restricted cubic splines, and 2) estimated the mortality benefits associated with replacing sedentary time with physical activity, accounting for total activity. DESIGN: US adults (n = 4840) from NHANES (2003-2006) wore an accelerometer for ≤7 d and were followed prospectively for mortality. Proportional hazards models were used to estimate adjusted HRs and 95% CIs for mortality associations with time spent sedentary and in light- and moderate-to-vigorous-intensity physical activity. Splines were used to graphically present behavior-mortality relation. Isotemporal models estimated replacement associations for sedentary time, and separate models were fit for low- (<5.8 h total activity/d) and high-active participants to account for nonlinear associations. RESULTS: Over a mean of 6.6 y, 700 deaths occurred. Compared with less-sedentary adults (6 sedentary h/d), those who spent 10 sedentary h/d had 29% greater risk (HR: 1.29; 95% CI: 1.1, 1.5). Compared with those who did less light activity (3 h/d), those who did 5 h of light activity/d had 23% lower risk (HR: 0.77; 95% CI: 0.6, 1.0). There was no association with mortality for sedentary time or light or moderate-to-vigorous activity in highly active adults. In less-active adults, replacing 1 h of sedentary time with either light- or moderate-to-vigorous-intensity activity was associated with 18% and 42% lower mortality, respectively. CONCLUSIONS: Health promotion efforts for physical activity have mostly focused on moderate-to-vigorous activity. However, our findings derived from accelerometer-based measurements suggest that increasing light-intensity activity and reducing sedentary time are also important, particularly for inactive adults.

Part-Time Work and Physical Activity in American High School Students.

OBJECTIVE: To compare physical activity (PA) in American high school students who work part-time with those who do not work. METHODS: Data were obtained from the National Health and Nutrition Examination Survey 2003 to 2006 (n = 791). Work status was self-reported and PA was measured using accelerometers. RESULTS: In males, adjusted for age, race, and poverty-income ratio, workers averaged greater counts per minute, less sedentary time, and greater moderate-to-vigorous PA compared with nonworkers. In females, workers and nonworkers had similar counts per minute, whereas nonworkers had somewhat greater moderate-to-vigorous PA. There was a work-by-school status interaction on sedentary time (P = 0.021), whereby work was associated with less sedentary time among students not on break from school. CONCLUSIONS: In American high school students, work is associated with greater PA in males and a different composition of PA in females.