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.

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.

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.

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.

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.

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.

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.

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.