Symptoms Contributing to Mobility Limitations and Fear of Falls in Older Adults

Mobility limitations in older adults are associated with negative outcomes including fear of falls (FOF) and poorer quality of life. However, self-reported symptoms contributing to mobility difficulty have not been fully explored as an area for intervention. The study aimed to identify the prevalence of self-reported symptom causes of difficulty walking and stair-climbing. In addition, we examined associations between symptoms and FOF in a population-based cohort of community-dwelling older adults in the MOBILIZE Boston Study. Of the 243 older adults who reported difficulty with walking one quarter of a mile or climbing stairs, 67% were women, 72% were white, average age=79.4y (SD=5.7). FOF was measured with the Tinetti Falls Efficacy Scale. Pain was most commonly reported as the primary symptom responsible for mobility difficulty (38.4%) followed by endurance (21.1%), multiple symptoms (15.6%), weakness (13.2%), balance (8.7%), other symptoms (2.9%). Factorial ANCOVA determined gender differences in associations between symptoms and FOF, adjusting for age. In pairwise comparisons, women who identified balance as their primary symptom had higher FOF than women identifying endurance (p=.017), pain (p=.015), other (p=.017), or multiple (p=.050) symptoms. There were no FOF differences for women identifying balance compared to weakness as the primary issue (p=.395). Men who identified balance as their primary symptom had higher FOF than those who identified pain (p=.036); no other FOF differences were noted in men identifying balance compared to other symptoms. Understanding common symptoms experienced by older adults, and symptoms associated with greatest FOF, will assist in developing tailored interventions for mobility improvement.

Transcriptomic Correlates of Response to Selinexor in Multiple Myeloma Reveal a Predictive Signature

Selinexor acts by inhibiting the nuclear export protein XPO1; however, its mRNA expression does not correlate with response, and the biological mechanisms underlying treatment response for different patients remain unclear. There is a critically unmet need for validated genomic biomarkers to help guide treatment recommendations to selinexor based therapy. Here, we characterized the transcriptomic correlates of response to selinexor in data from 189 patients from multiple studies of selinexor-based therapy and identified and validated a 3-gene expression signature predictive of treatment response. We performed RNA sequencing on CD138+ cells from 103 patients who participated in the BOSTON study, a phase III, open-label clinical trial of patients with multiple myeloma (MM) who were treated with selinexor, bortezomib and dexamethasone (XVd) after 1-3 lines of standard therapy versus a bortezomib and dexamethasone (Vd) regimen (Grosicki et al 2020 Lancet; Fig 1A-B). Then, we performed differential expression, followed by pathway analysis, to compare patients with long and short progression-free survival (PFS) in the XVd arm of the BOSTON dataset across various PFS and overall depth-of-response (OR) cutoffs. Here, we identified a total of 24 unique downregulated genes and 33 unique upregulated genes that were associated with longer PFS or better depth of response in the XVd arm (FDR < 0.05). Pathway analyses revealed downregulation of apoptosis and MYC targets in patients with selinexor-associated longer PFS or better depth of response (FDR < 0.05), consistent with the known relationship between depth and duration of response in MM. Using the differentially expressed genes, we employed time-to-event univariate Cox proportional hazard models (CPH) with repeated 4-fold cross validation, log-rank testing, and spearman correlations to identify a novel signature that predicts PFS in the BOSTON dataset. This analysis revealed a GSVA score composed of three genes, WNT10A, DUSP1, and ETV7, that were upregulated in XVd patients with PFS > 120 days. Further, this signature accurately distinguished patients with long term PFS in the XVd arm of the BOSTON study (Fig 1C; log rank P = 0.017; spearman Rho = 0.46, P = 0.0007; CPH, FDR=0.047, HR=0.36 [95% CI = 0.14-0.84]). We also found that the signature significantly tracks with a depth of response of VGPR or better (Fig 1D, Wilcoxon P = 0.025). Finally, we validated the accuracy of our signature using transcriptomic data from two external cohorts: the STORM trial of penta-refractory MM (N = 64; Chari et al., NEJM), and a cohort of patients treated with selinexor-based regimens at Mount Sinai who were not part of a clinical trial (N = 21). This signature validated successfully in the STORM study (Fig 1E, log-rank P = 0.02; spearman Rho = 0.18, P = 0.14; CPH P = 0.08, HR=0.63 [95% CI = 0.47-1.03 ]) and in the non-trial Mount Sinai cohort (Fig 1G, log-rank P = 0.0033; spearman Rho = 0.6, P = 0.0043; CPH P = 0.004, HR = 0.215 [95% = 0.15-0.72]). Additionally, the association of the signature expression with depth-of-response validated in the STORM cohort (Fig 1F; Wilcoxon P = 0.021), further supporting the robustness of our signature. We used the MMRF-COMMPASS dataset (N=700) as a negative control and found that the signature is not predictive of PFS in patients who were treated with non-selinexor based, standard of care therapies. Together, these results support the conclusion that our signature is specific to selinexor treatment response and is not reflective of overall prognosis. We are currently performing experimental validation of the three genes in cell line experiments to better understand the mechanisms underlying their predictive power. We are also evaluating the utility of augmenting gene-expression based biomarkers with an ex-vivo mass-based biomarker assay to more accurately predict response to selinexor. In summary, we report a novel gene expression signature for response to selinexor-based therapy in patients with MM. We have validated our findings in several external transcriptomic datasets of MM patients treated with selinexor-based regimens. This signature has important clinical significance as it could identify patients most likely to benefit from treatment with selinexor-based therapy, especially in earlier lines of therapy. Figure 1 Figure 1. Disclosures Stevens: Travera: Current Employment. Richter: Adaptive Biotechnologies: Speakers Bureau; Celgene: Consultancy; Janssen: Consultancy; BMS: Consultancy; Karyopharm: Consultancy; Antengene: Consultancy; Sanofi: Consultancy; X4 Pharmaceuticals: Consultancy; Oncopeptides: Consultancy; Adaptive Biotechnologies: Consultancy; Celgene: Speakers Bureau; Janssen: Speakers Bureau; Secura Bio: Consultancy; Astra Zeneca: Consultancy. Richard: Karyopharm, Janssen: Honoraria. Chari: Takeda: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Millenium/Takeda: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jagannath: Bristol Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Sanofi: Consultancy; Legend Biotech: Consultancy; Takeda: Consultancy. Walker: Karyopharm Therapeutics Inc.: Current Employment. Landesman: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Parekh: Foundation Medicine Inc: Consultancy; Amgen: Research Funding; PFIZER: Research Funding; CELGENE: Research Funding; Karyopharm Inv: Research Funding.

Impact of One-Way Streets and Contraflow on Low-Stress Bicycle Network Connectivity

One-way restrictions on local streets, which tend to have low traffic stress, can create a significant barrier to low-stress cycling. Contraflow, a treatment that undoes one-way restrictions on bike travel, has the potential to improve low-stress connectivity. Although contraflow is applied routinely in the Netherlands and Belgium, it has been sparingly applied in the United States. We propose refined measures of connectivity and accessibility that account for one-way restrictions by requiring a low-stress round trip path between origins and destinations. Different methods of associating origin–destination demand from polygons with a street network were analyzed. These methods are particularly important where there are one-way restrictions and irregular street networks because of the assumptions they entail in relation to first- and last-segment travel. In a case study of Greater Boston, we found that with the current bike network, low-stress connectivity between homes and jobs would increase from 1.2% to 8.7% if one-way restrictions on local streets were eliminated. We also found that even with a dense mesh of low-stress main bike routes, connectivity would still be 16% lower without contraflow on local streets than with. These results suggest that creating a network of main bike routes is not always enough; it is also important to provide contraflow on local streets. The Boston study also found that providing contraflow on selected links representing only 3% of local one-way street mileage delivered 40% of the connectivity impact of universal contraflow. Based on this finding, a method is proposed for prioritizing streets for contraflow conversion.

Survival among older patients with previously treated multiple myeloma treated with selinexor, bortezomib, and dexamethasone (XVd) in the BOSTON study.

8019 Background: Multiple myeloma (MM) typically affects older populations, which are more vulnerable to toxicity with anti-MM treatments. These patients (pts) have significant morbidity and mortality, resulting in a need for dose modifications or alternative suboptimal treatment options. Significant improvements were observed in the BOSTON study with XVd vs Vd in median progression-free survival (PFS), overall response rate (ORR), and rates of peripheral neuropathy (PN); median overall survival (OS) trended in favor of XVd. Methods: The phase 3 randomized BOSTON trial (NCT03110562) is a controlled, open-label study of once weekly XVd vs. twice weekly standard Vd in pts with MM and 1-3 prior treatment regimens. We performed post-hoc analyses to compare survival benefits in pts ≥65 vs < 65 years of age. Results: The BOSTON study enrolled a total of 402 pts between June 2017 and February 2019 that were randomized into XVd or Vd arms. The numbers of pts treated with XVd or Vd who were ≥65 were 109/132 and 86/75 who were < 65, respectively. Baseline characteristics were similar by age although pts ≥65 years were less likely to have received ASCT than those < 65 years (48.4% vs. 25.3%). Median PFS was prolonged with XVd compared with Vd, across both age groups: ≥65 (HR, 0.55 [95% CI, 0.37-0.83] P = 0.002) and < 65, (HR, 0. 74 [95% CI, 0.49-1.11], P = 0.07). Vd was associated with a lower ORR (64.4%) than treatment with XVd (76.1%) (OR, 1.77 [95% CI, 1.00-3.11], P = 0.024) in pts ≥65, while the ORR in those < 65 was 76.7% with XVd and 58.7% (OR, 2.33 [95% CI, 1.18-4.59], P = 0.007) with Vd. As of Jan 2021, the median OS for the overall population was not reached for both arms (HR = 0.86; p = 0.193), with 61 and 75 deaths in the XVd and Vd arms, respectively. Median OS was not reached in pts ≥65 with XVd and was 28.6 months with Vd (HR = 0.60; 95% CI, 0.38-0.94; p = 0.012), while there was no difference in the OS for pts < 65 (HR = 1.52; 95% CI, 0.86-2.68; p = 0.926). Pts ≥65 had a lower incidence of death with XVd as compared to Vd (29 vs 56) and there were 32 deaths with XVd and 19 with Vd in pts < 65. Grade ≥3 treatment-emergent adverse events were not observed more often in older compared to younger pts. Amongst pts ≥65, PN of any grade was lower with XVd (32.1%) compared to Vd (46.5%); (OR 0.57 [95% CI 0.34-0.97], p = 0.017), including a lower incidence of grade ≥3 PN (XVd 4.6% vs. Vd 11.6%). Pts < 65 followed a similar trend of PN AEs of any grade: XVd, 32.6%; Vd, 48.0% (OR 0.42 [95% CI 0.21-0.82], p = 0.006). Conclusions: In an older patient population with a poor prognosis, XVd was associated with a significant survival benefit, improved PFS and OR with reduced PN, and requires relatively short and infrequent clinic visits. XVd may be a simple, effective regimen for pts ≥65 years of age. Clinical trial information: NCT03110562.

Effects of weekly selinexor, bortezomib, dexamethasone (XVd) versus standard twice weekly bortezomib and dexamethasone (Vd) on RAS-mutated previously treated multiple myeloma (MM).

8027 Background: Activating mutations of the RAS genes NRAS, KRAS, and HRAS ( RASmut) occur in up to 50% of MM and portend poor survival and high recurrence rates. MM cells with RASmut are susceptible to inhibition of germinal center kinase (GCK), resulting in IKAROS degradation independent of cereblon (CRBN). Selinexor is a selective inhibitor of nuclear export (SINE) compound that can induce IKAROS degradation through CRBN-independent pathways to overcome immunomodulatory drug resistance. We explored the benefit of selinexor treatment for pts with RASmut MM. Methods: In the randomized BOSTON study, pts with MM after 1-3 therapies received weekly XVd or twice weekly Vd. In the single-arm STORM study pts with penta-treated, triple class refractory MM were treated with twice weekly Xd. Both treatment regimens are now FDA approved. Mutations were assessed post-hoc by exome sequencing of 119 and 52 pts from BOSTON and STORM, respectively. Pts were considered RASmut if their MM had NRAS, KRAS or HRAS mutations in codons 12, 13 or 61. Results: There were 54 pts (45%) with RASmut in BOSTON (XVd = 26, Vd = 28), and 17 (33%) in STORM. In BOSTON, pts with RASmut MM treated with XVd had significantly longer progression-free survival (PFS) than those treated with Vd (median [med] = 12.9 vs 6.7 months [mo], hazard ratio [HR] = 0.48 [95% CI 0.24-0.97], p = 0.039). For pts treated with Vd, those with RASmut had significantly shorter overall survival (OS) compared to RASwild-type (WT) (med = 16.8 mo vs not reached [NR], HR = 2.87 [95% CI 1.03-7.99], p = 0.035). PFS was not significantly different (med = 6.74 vs 9.82 mo, HR = 1.64 [95% CI 0.88-3.07], p = 0.122). Amongst pts on XVd, there was no difference in survival between RASmut and RASWT pts (PFS: med = 12.8 vs 12.9 mo, HR = 1.08 [95% CI 0.52-2.26], p = 0.83; OS: med = NR vs NR, HR = 0.94 [95% CI 0.36-2.45], p = 0.91). In STORM, pts with RASmut had shorter OS compared to RASwt pts (med = 6.1 vs NR, HR = 2.05 [95% CI 1.22-5.19], p = 0.010). Preliminary studies to explore the mechanisms of action related to RASmut MM sensitivity to XVd demonstrated that selinexor treatment in vitro leads to downregulation of GCK. Conclusions: Despite typically having the worst outcomes, pts with RASmut MM had a similar benefit from XVd as RASWT MM, showing that the XVd combination can overcome RASmut. Mechanistically, selinexor induced down regulation of GCK and enhanced killing of RASmut MM cells. With a manageable safety profile, the XVd regimen could provide a viable treatment option to improve survival of pts with MM with RAS mutations. Clinical trial information: NCT03110562. [Table: see text]

Effects of refractory status to lenalidomide on safety and efficacy of selinexor, bortezomib, and dexamethasone (XVd) versus bortezomib and dexamethasone (Vd) in patients with previously treated multiple myeloma.

8024 Background: Lenalidomide (LEN) is typically a frontline therapy for newly diagnosed MM. Patients (pts) with MM refractory to LEN are less likely to repond to other IMiDs and represent a signification area of unmet medical need. In the BOSTON study in the ITT population, XVd was associated with significant improvements in median progression-free survival (PFS), overall response rate (ORR), and rates of peripheral neuropathy, with trends in overall survival (OS) favoring XVd. Methods: The BOSTON trial (NCT03110562) is a Phase 3 randomized, controlled, open-label study of once weekly XVd vs twice weekly Vd in pts with MM and 1-3 prior therapies. We performed post-hoc analyses on two different subgroups to compare outcomes based on refractory status to LEN and immunomodulatory drug (IMiD) therapy. These post hoc analyses evaluated if PFS, overall response rate (ORR), time to next treatment (TTNT) and safety was influenced by prior treatment with LEN when comparing XVd with Vd. Results: Amongst the 402 pts in BOSTON, 160 had MM refractory to any IMiD (XVd = 74, Vd = 86). Of those, 106 were documented to be refractory to LEN (XVd = 53, Vd = 53) and 296 were not refractory to LEN (XVd = 142, Vd = 154). Baseline characteristics were generally well balanced between subgroups. In these subgroups based on refractory status to IMiD or LEN, median PFS was significantly longer in the XVd arm as compared to Vd (IMiD refractory, 13.9 vs. 8.4 months (mo), p = 0.005; LEN refractory, 10.2 vs. 7.1 mo, p = 0.012; not LEN refractory, 15.4 vs 9.6 mo, p = 0.014). Significant increases in TTNT were observed with XVd treatment in pts that were IMiD refractory (14.8 vs. 10.2 mo, p = 0.003), LEN refractory (13.0 vs. 7.6 mo, p = 0.015), and not refractory to LEN (19.1 vs 12.9 mo, p = 0.005). ORR was improved with XVd compared to Vd regardless of refractory status (IMiD refractory, 68.9% vs 55.8%, p = 0.045; LEN refractory, 67.9% vs. 47.2%, p = 0.016; and not refractory to LEN, 79.6% vs 67.5%, p = 0.010). The most common treatment-emergent AEs for the XVd/Vd arms for all subgroups were thrombocytopenia (66.2/30.6%; 71.7/40.4%; 55.6/22.4%), nausea (48.6/11.8%; 50.9/11.5%; 50.0/9.2%), and fatigue (40.5/20.0%; 45.3/21.2%; 40.8/17.1%) for IMiD, LEN, and not LEN refractory, respectively. Incidence of PN AEs of any grade were reduced compared to pts treated with Vd (IMiD refractory, 27% vs. 42.4%; LEN refractory, 30.2% vs 36.5%; not refractory, LEN 33.1% vs 50.7%). Conclusions: In pts with previously treated MM, PFS, ORR, and TTNT were significantly improved regardless of documented refractory status to any IMiD or to LEN-specifically. These analyses support the use of the XVd combination for pts with disease refractory to LEN and likely to any IMiD. Clinical trial information: NCT03110562.

Effect of prior treatments on selinexor, bortezomib, and dexamethasone in previously treated multiple myeloma

Therapeutic regimens for previously treated multiple myeloma (MM) may not provide prolonged disease control and are often complicated by significant adverse events, including peripheral neuropathy. In patients with previously treated MM in the Phase 3 BOSTON study, once weekly selinexor, once weekly bortezomib, and 40 mg dexamethasone (XVd) demonstrated a significantly longer median progression-free survival (PFS), higher response rates, deeper responses, a trend to improved survival, and reduced incidence and severity of bortezomib-induced peripheral neuropathy when compared with standard twice weekly bortezomib and 80 mg dexamethasone (Vd). The pre-specified analyses described here evaluated the influence of the number of prior lines of therapy, prior treatment with lenalidomide, prior proteasome inhibitor (PI) therapy, prior immunomodulatory drug therapy, and prior autologous stem cell transplant (ASCT) on the efficacy and safety of XVd compared with Vd. In this 1:1 randomized study, enrolled patients were assigned to receive once weekly oral selinexor (100 mg) with once weekly subcutaneous bortezomib (1.3 mg/m2) and 40 mg per week dexamethasone (XVd) versus standard twice weekly bortezomib and 80 mg per week dexamethasone (Vd). XVd significantly improved PFS, overall response rate, time-to-next-treatment, and showed reduced all grade and grade ≥ 2 peripheral neuropathy compared with Vd regardless of prior treatments, but the benefits of XVd over Vd were more pronounced in patients treated earlier in their disease course who had either received only one prior therapy, had never been treated with a PI, or had prior ASCT. Treatment with XVd improved outcomes as compared to Vd regardless of prior therapies as well as manageable and generally reversible adverse events. XVd was associated with clinical benefit and reduced peripheral neuropathy compared to standard Vd in previously treated MM. These results suggest that the once weekly XVd regimen may be optimally administered to patients earlier in their course of disease, as their first bortezomib-containing regimen, and in those relapsing after ASCT.Trial registration: ClinicalTrials.gov (NCT03110562). Registered 12 April 2017. https://clinicaltrials.gov/ct2/show/NCT03110562.

Pain Interference: A Barrier for Daily Living Activities in Older Adults with Multisite Musculoskeletal Pain

Almost half of older adults experience multisite musculoskeletal pain (MMP) contributing to difficulty in daily activities but little is known about specific domains by which pain interferes in daily living. This study aims to determine domains of pain interference (PI) related to MMP in a cohort of older adults living in the community. The MOBILIZE Boston Study (MBS) is a cohort study of 749 adults aged ≥70y. Musculoskeletal (MSK) pain was assessed using the joint pain questionnaire and grouped as: no pain, single site, and multisite pain. The Brief Pain Inventory PI sub-scale assessed level of interference (0-10 rating) in 7 categories in the previous week including general activity, mood, walking, work, relationships with people, sleep, and enjoyment of life. Interference items were grouped as: none (0 rating), mild (&gt;0, ≤2), moderate ( ≥2, ≤5), and severe (≥5) PI. There was a strong gradient of PI according to pain groups with severe walking interference in 36.5% of those with MMP compared to 3.8% of those with no MSK pain. The least PI was in relationships with others (9.1% of MMP vs 1.1% of no MSK pain). Reports of interference in other domains were intermediate (20-26% of MMP vs 3-4% of no MSK pain). Women and those with Less education reported the most PI in every domain but no differences were observed by age. Greater attention to specific domains of pain interference such as walking could have substantial benefits for reducing the overall impact of MMP among older adults.

Weekly selinexor, bortezomib, and dexamethasone (SVd) versus twice weekly bortezomib and dexamethasone (Vd) in patients with multiple myeloma (MM) after one to three prior therapies: Initial results of the phase III BOSTON study.

8501 Background: Selinexor is an oral, selective inhibitor of XPO1-mediated nuclear export, leading to the reactivation of tumor suppressor proteins. In a phase 1b/2 study, the combination of once weekly (QW) selinexor with bortezomib and dexamethasone (SVd) was well tolerated with anti-MM activity in patients (pts) with PI-sensitive and PI-refractory disease. While twice weekly (BIW) bortezomib in combination therapy is efficacious, prolonged use is limited due to peripheral neuropathy (PN, 50-60%). The BOSTON study was designed to determine if SVd improves progression free survival (PFS), overall response rates (ORR) and reduces the rate of PN vs Vd. Methods: BOSTON is a global, phase 3, randomized study of QW SVd vs BIW Vd after 1-3 prior anti-MM regimens. The primary endpoint is PFS. Secondary endpoints include ORR, overall survival (OS) and PN (rates and EORTC QLQ-CIPN20 outcomes). Randomization is stratified by treatment with prior PI therapies, number of prior anti-MM regimens (1 vs > 1), and Revised International Staging System (R-ISS; Stage III vs I or II). Following confirmation of progressive disease, pts on Vd could cross over to either: 1) SVd for pts able to tolerate continued bortezomib or 2) selinexor and dexamethasone for pts with bortezomib intolerance. Results:402 pts were enrolled; 195 and 207 to SVd and Vd, respectively. Median age was 67 (range: 38-90). Most (59.6%) pts were > 65 years and 57.1% were male. R-ISS stage at the time of MM diagnosis was III for 18.5% of pts. Baseline characteristics were balanced across the 2 arms. SVd significantly prolonged PFS vs Vd (median 13.93 vs 9.46 months, HR = 0.70, P = 0.0066). SVd was associated with a significantly higher ORR (76.4% vs 62.3%, P = 0.0012). Median OS was not reached on SVd vs 25 months on Vd (P = 0.28). Most frequent treatment-related adverse events (grade ≥3) for SVd vs Vd were thrombocytopenia (35.9% vs 15.2%), fatigue (11.3% vs 0.5%) and nausea (7.7% vs 0%). Clinically important differences were reported on the motor, autonomic and sensory scales on CIPN20. PN rates (grade ≥2) were significantly lower with SVd vs Vd (21.0% vs 34.3%, P = 0.0013). Conclusions: BOSTON is the first phase 3 study to evaluate the clinical benefit of SVd for relapsed/refractory MM. The study met the primary endpoint: once weekly SVd significantly improved PFS and ORR compared to twice weekly Vd. Rates of PN were significantly reduced with numerically fewer deaths on SVd vs Vd. Full dataset will be presented at the meeting. Clinical trial information: NCT03110562 .