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.

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.

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.

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.

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.

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.

Daily Patterns of Physical Activity by Type 2 Diabetes Definition: Comparing Diabetes, Prediabetes, and Participants with Normal Glucose Levels in NHANES 2003-2006.

OBJECTIVE: Diabetes is associated with low levels of physical activity (PA), but detailed objective information about how PA patterns vary by diabetes definition is lacking. METHODS: PA was measured with Actigraph accelerometers in older (60+) adults from the 2003-2006 National Health and Nutrition Examination Survey (n= 1,043) and analyzed in 2014. Diabetes definition (normal glucose levels, prediabetes, diabetes) was assessed (fasting glucose, hemoglobin A1C, and self-report). Accelerometer data were used to characterize total activity counts (TAC) per day and hour-by-hour activity counts by diabetes definition. Multiple linear regression models explored the relationship between diabetes definition and TAC. RESULTS: Despite similar patterns of PA, diabetes participants had significantly lower TAC compared to participants with normal glucose levels and prediabetes. Diabetes participants' activity counts per hour declined more rapidly after 12 pm, with the biggest differences between the groups occurring at 4 pm. Participants with normal glucose levels and prediabetes had similar TAC and daily PA profiles. CONCLUSION: Our novel methodology provides information about PA patterns by diabetes definition. Significantly lower TAC in the diabetes group, their significant drop in afternoon PA, and the similarity of PA between participants with normal glucose levels and prediabetes provide insight into potential targets for intervention.

Changes in daily activity patterns with age in U.S. men and women: National Health and Nutrition Examination Survey 2003-04 and 2005-06.

OBJECTIVES: To compare daily and hourly activity patterns according to sex and age. DESIGN: Cross-sectional, observational. SETTING: Nationally representative community sample: National Health and Nutrition Examination Survey (NHANES) 2003-04 and 2005-06. PARTICIPANTS: Individuals (n = 5,788) aged 20 and older with 4 or more valid days of monitor wear-time, no missing data on valid wear-time minutes, and covariates. MEASUREMENTS: Activity was examined as average counts per minute (CPM) during wear-time; percentage of time spent in nonsedentary activity; and time (minutes) spent in sedentary (<100 counts), light (100-759), and moderate to vigorous physical activity (MVPA (≥ 760)). Analyses accounted for survey design, adjusted for covariates, and were sex specific. RESULTS: In adjusted models, men spent slightly more time (~1-2%) in nonsedentary activity than women aged 20 to 34, with levels converging at age 35 to 59, although the difference was not significant. Women aged 60 and older spent significantly more time (~3-4%) in nonsedentary activity than men, despite similarly achieved average CPM. With increasing age, all nonsedentary activity decreased in men; light activity remained constant in women (~30%). Older men had fewer CPM at night (~20), more daytime sedentary minutes (~3), fewer daytime light physical activity minutes (~4), and more MVPA minutes (~1) until early evening than older women. CONCLUSION: Although sex differences in average CPM declined with age, differences in nonsedentary activity time emerged as men increased sedentary behavior and reduced MVPA time. Maintained levels of light-intensity activity suggest that women continue engaging in common daily activities into older age more than men. Findings may help inform the development of behavioral interventions to increase intensity and overall activity levels, particularly in older adults.

A variant of sparse partial least squares for variable selection and data exploration.

When data are sparse and/or predictors multicollinear, current implementation of sparse partial least squares (SPLS) does not give estimates for non-selected predictors nor provide a measure of inference. In response, an approach termed "all-possible" SPLS is proposed, which fits a SPLS model for all tuning parameter values across a set grid. Noted is the percentage of time a given predictor is chosen, as well as the average non-zero parameter estimate. Using a "large" number of multicollinear predictors, simulation confirmed variables not associated with the outcome were least likely to be chosen as sparsity increased across the grid of tuning parameters, while the opposite was true for those strongly associated. Lastly, variables with a weak association were chosen more often than those with no association, but less often than those with a strong relationship to the outcome. Similarly, predictors most strongly related to the outcome had the largest average parameter estimate magnitude, followed by those with a weak relationship, followed by those with no relationship. Across two independent studies regarding the relationship between volumetric MRI measures and a cognitive test score, this method confirmed a priori hypotheses about which brain regions would be selected most often and have the largest average parameter estimates. In conclusion, the percentage of time a predictor is chosen is a useful measure for ordering the strength of the relationship between the independent and dependent variables, serving as a form of inference. The average parameter estimates give further insight regarding the direction and strength of association. As a result, all-possible SPLS gives more information than the dichotomous output of traditional SPLS, making it useful when undertaking data exploration and hypothesis generation for a large number of potential predictors.

Association of chronic widespread pain with objectively measured physical activity in adults: findings from the National Health and Nutrition Examination survey.

UNLABELLED: Chronic widespread pain (CWP) is a common and potentially debilitating disorder. Patterns of physical activity (PA) in adults with CWP have primarily been investigated using subjective, self-report measures. The current study sought to characterize PA among community-dwelling individuals with CWP, chronic regional pain, or no chronic pain using objective measurements obtained via accelerometry in the 2003 to 2004 National Health and Nutrition Examination Survey. Data from 3,952 participants ages 20 and older were analyzed to assess relationships between pain status and objective measurements of PA. Prevalence of CWP was 3.3% and 5.4% in men and women, respectively. In men and women, the average activity counts per minute and time spent in moderate-to-vigorous PA were significantly lower for the CWP group than for the no chronic pain group. Interestingly, time spent in sedentary, light, and lifestyle activities was not associated with pain status. Statistical interaction tests indicated that the effects of chronic pain on counts per minute were stronger in men than in women. Despite recommendations for increased moderate-to-vigorous PA as a pain management strategy for CWP, results from this nationally representative study indicate that adults with CWP participate in less moderate-to-vigorous PA than individuals without chronic pain. PERSPECTIVE: Using objective measurement of PA in a nationally representative sample, this study demonstrates that adults with CWP participate in reduced daily and moderate-to-vigorous PA in comparison to people with no chronic pain. Findings indicate that clinicians should emphasize the importance of increasing PA in patients with CWP.

Is there a sex difference in accelerometer counts during walking in older adults?

BACKGROUND: Accelerometers have emerged as a useful tool for measuring free-living physical activity in epidemiological studies. Validity of activity estimates depends on the assumption that measurements are equivalent for males and females while performing activities of the same intensity. The primary purpose of this study was to compare accelerometer count values in males and females undergoing a standardized 6-minute walk test. METHODS: The study population was older adults (78.6 ± 4.1 years) from the AGES-Reykjavik Study (N = 319). Participants performed a 6-minute walk test at a self-selected fast pace while wearing an ActiGraph GT3X at the hip. Vertical axis counts · s(-1) was the primary outcome. Covariates included walking speed, height, weight, BMI, waist circumference, femur length, and step length. RESULTS: On average, males walked 7.2% faster than females (1.31 vs. 1.22 m · s(-1), P < .001) and had 32.3% greater vertical axis counts · s(-1) (54.6 vs. 39.4 counts · s(-1), P < .001). Accounting for walking speed reduced the sex difference to 19.2% and accounting for step length further reduced the difference to 13.4% (P < .001). CONCLUSION: Vertical axis counts · s(-1) were disproportionally greater in males even after adjustment for walking speed. This difference could confound free-living activity estimates.

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 sedentary time with mortality independent of moderate to vigorous physical activity.

BACKGROUND: Sedentary behavior has emerged as a novel health risk factor independent of moderate to vigorous physical activity (MVPA). Previous studies have shown self-reported sedentary time to be associated with mortality; however, no studies have investigated the effect of objectively measured sedentary time on mortality independent of MVPA. The objective our study was to examine the association between objectively measured sedentary time and all-cause mortality. METHODS: 7-day accelerometry data of 1906 participants aged 50 and over from the U.S. nationally representative National Health and Nutrition Examination Survey (NHANES) 2003-2004 were analyzed. All-cause mortality was assessed from the date of examination through December 31, 2006. RESULTS: Over an average follow-up of 2.8 years, there were 145 deaths reported. In a model adjusted for sociodemographic factors, lifestyle factors, multiple morbidities, mobility limitation, and MVPA, participants in third quartile (hazard ratio (HR):4.05; 95%CI:1.55-10.60) and fourth quartile (HR:5.94; 95%CI: 2.49-14.15) of having higher percent sedentary time had a significantly increased risk of death compared to those in the lowest quartile. CONCLUSIONS: Our study suggests that sedentary behavior is a risk factor for mortality independent of MVPA. Further investigation, including studies with longer follow-up, is needed to address the health consequences of sedentary behavior.

Employment and physical activity in the U.S.

BACKGROUND: Physical inactivity is a risk factor for obesity, cardiovascular disease, hypertension, and other chronic diseases that are increasingly prevalent in the U.S. and worldwide. Time at work represents a major portion of the day for employed people. PURPOSE: To determine how employment status (full-time, part-time, or not employed) and job type (active or sedentary) are related to daily physical activity levels in American adults. METHODS: Cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) were collected in 2003-2004 and analyzed in 2010. Physical activity was measured using Actigraph uniaxial accelerometers, and participants aged 20-60 years with ≥4 days of monitoring were included (N=1826). Accelerometer variables included mean counts/minute during wear time and proportion of wear time spent in various intensity levels. RESULTS: In men, full-time workers were more active than healthy nonworkers (p=0.004), and in weekday-only analyses, even workers with sedentary jobs were more active (p=0.03) and spent less time sedentary (p<0.001) than nonworkers. In contrast with men, women with full-time sedentary jobs spent more time sedentary (p=0.008) and had less light and lifestyle intensity activity than healthy nonworkers on weekdays. Within full-time workers, those with active jobs had greater weekday activity than those with sedentary jobs (22% greater in men, 30% greater in women). CONCLUSIONS: In men, full-time employment, even in sedentary occupations, is positively associated with physical activity compared to not working, and in both genders job type has a major bearing on daily activity levels.