Yee, Claire

Abstract Frailty influences treatment outcomes in older patients with multiple myeloma (MM), yet existing frailty tools capture limited geriatric domains and are incompletely studied in the context of contemporary therapies. We prospectively evaluated patient-reported comprehensive geriatric assessment (CGA) domains and their associations with treatment toxicity and patient-reported outcomes (PRO) in older adults with MM. Patients aged ≥60 years with newly diagnosed or relapsed/refractory MM initiating a new therapy completed electronic CGA and PRO questionnaires at baseline and 4 months. Outcomes included clinician- and patient-reported treatment toxicity, treatment adaptations, health care use, and health-related quality of life (HRQOL). A cumulative deficit frailty index (FI) was derived from CGA and HRQOL domains. Among 90 patients (mean age, 72 years), geriatric impairments were common, particularly physical function domains. High-grade nonhematologic toxicities were significantly associated with older age, comorbidities, patient-reported functional limitations, and anxiety. Toxicity rates on the PRO version of the Common Terminology Criteria for Adverse Events (CTCAE) were higher than on CTCAE, highlighting a discordance between physician- and patient-reported treatment toxicity. Frailty was present in 22% and associated with worse baseline HRQOL and increased high-grade nonhematologic toxicity but not treatment adaptations or health care use. Average CGA and HRQOL scores remained stable over 4 months, although individual trajectories varied. Patient-reported geriatric impairments are prevalent in older adults with MM and strongly associated with nonhematologic toxicities even in the contemporary treatment era. Physician-reported CTCAE may not fully reflect patients' symptom burden. Heterogeneity in individual geriatric trajectories during treatment emphasize the need for longitudinal assessment. This study was registered at www.clinicaltrials.gov as NCT05918185.

Abstract Frailty predicts adverse outcomes in multiple myeloma (MM), yet an objective frailty biomarker is lacking. Circulating senescence-associated secretory phenotype (SASP) factors correlate with frailty and adverse outcomes in chronic diseases, but their relevance in MM is unclear. In this study, we investigated the relationship between 36 plasma SASP factors, frailty, and clinical outcomes in: (1) a historical cohort using stored specimens from 59 patients with newly diagnosed MM, and (2) a prospective cohort of 36 patients initiating new MM treatment. Several SASP factors were significantly associated with frailty after adjusting for age, sex, and body mass index; GDF-15, TNF-RI, IL-6, and IL-8 showed positive correlations with both cumulative-deficit based and physical frailty indices. Additionally, significant age-adjusted associations were observed between SASP factors and treatment outcomes, including overall survival (OS), high-grade toxicity, and healthcare utilization. We developed a 5-factor SASP model that demonstrated superior predictive performance for OS compared to chronological age, R-ISS stage, and clinical frailty, and TNF-RI alone (5-year OS AUC: 0.90). These findings highlight the association between senescence biomarkers and frailty and OS, and support further investigation of SASP factors as objective frailty biomarkers in MM.

703 Background: The association of circulating tumor DNA (ctDNA) reduction with treatment response has been investigated across multiple malignancies. This study aims to assess the impact of ctDNA response on survival outcomes in patients receiving enfortumab-pembrolizumab (EV-P). Methods: We identified 32 patients with advanced urothelial carcinoma who received EV-P and had ≥2 ctDNA assessments with ≥1 detectable level. Deep molecular response was defined as >2-log reduction from highest ctDNA detection. Radiographic progression was determined from radiology reports documenting progression by RECIST criteria. Kaplan Meier analyses were performed to compute Hazard Ratios (HR) with 95% confidence intervals (CI) for radiographic progression free survival (rPFS), defined as time from treatment start to radiographic progression or death and overall survival (OS) defined as time from treatment start to death were computed. Log-rank tests were performed to compare PFS and OS in patients with deep molecular response to those without response. A p-value <0.05 indicated a statistically significant association with response. Results: Thirty-two patients were included (median age 71 years; range 39–90). Median follow-up was 10.6 months. At cutoff (10/1/2025), 26 patients were alive and 6 had died. Seventeen (53%) achieved a ≥2-log ctDNA reduction (responders), while 15 (47%) did not (non-responders). Progression-free survival was significantly longer in responders (log-rank P < 0.001); median PFS was 5.9 months (95% CI 2.4–NR) in non-responders and not reached in responders (HR 0.09, 95% CI 0.02–0.44; P = 0.0026). Median overall survival was 12.7 months (95% CI 10.0–NR) in non-responders versus not reached in responders (log-rank P = 0.011; HR 0.11, 95% CI 0.01–0.88; P = 0.037). At cutoff, 94% of responders and 67% of non-responders were alive. Conclusions: Achieving a >2-log decrease in ctDNA during EV + Pembrolizumab therapy was significantly associated with improved progression free and overall survival. These findings support ctDNA kinetics as a potential early biomarker of response warranting prospective validation. Clinical outcomes by >2-log ctDNA reduction status. Endpoint > 2-log drop (n = 17 ≤ 2-log drop (n = 15) Log-rank p Median (mo) ≤ 2-log > 2-log HR (95% CI) P C-index PFS 2 events (12%) 10 events (67%) 0.0002 5.9 (2.4–NA) NR 0.09 (0.02–0.44) 0.0026 0.77 OS 1 event (6%) 6 events (40%) 0.011 12.7 (10.0–NA) NR 0.11 (0.01–0.88) 0.037 0.73

830 Background: Immune checkpoint inhibitors (ICIs) are standard therapy for MSI-H GI cancers. Lynch syndrome, caused by germline mutations in mismatch repair (MMR) genes, leads to MSI-H tumors and robust ICI responses, but its effect on irAEs remains poorly defined. Clarifying this risk may inform treatment selection and toxicity monitoring. Methods: We retrospectively reviewed MSI-H or MMR-deficient (dMMR) GI cancer patients (pts) treated with ICIs across Mayo Clinic (AZ, MN, FL) from January 2017 to June 2025. Eligible pts were identified using Mayo Data Explorer. Demographics, treatment, and irAEs (graded per CTCAE v5.0) were collected. Lynch status was determined by germline testing when available. Logistic regression estimated odds ratios (ORs) for any grade and grade ≥3 irAEs, adjusting for age, cancer type, prior chemotherapy, and treatment regimen. Results: A total of 209 pts with dMMR/MSI-H GI cancer were included: 61 with Lynch syndrome and 148 without. Lynch pts were younger (median 58 vs 76 years, p < 0.001) and more likely to have received prior chemotherapy (62% vs 43%, p = 0.009). Colorectal cancer was the predominant cancer type (74%), but Lynch pts had proportionally more non-colorectal GI cancers (15% vs 2.7%, p = 0.007). Overall, 29% of pts experienced an irAE, with rates significantly higher in Lynch vs non-Lynch pts (43% vs 24%, p = 0.005). The most frequent irAEs were gastrointestinal, endocrine, and dermatologic, followed by hepatic and pulmonary events. Grade ≥3 irAEs occurred in 16% overall, with no significant difference between groups (p = 0.124). In adjusted models, Lynch syndrome was independently associated with a higher risk of any grade irAE (OR 2.14, 95% CI 1.09 - 4.19, p = 0.026), while risk of severe irAEs was not increased (OR 1.55, 95% CI 0.64 - 3.59, p = 0.316). Lynch syndrome pts were more likely to have combination therapy (17% vs 6.8%, p = 0.029). However, there were no differences observed in any grade irAE between monotherapy and combination immunotherapy (OR 1.36, 95% CI 0.49 - 3.54, p = 0.535). Conclusions: Lynch syndrome is associated with a higher prevalence of any-grade irAEs among dMMR/MSI-H GI cancer pts treated with ICIs, though severe events were not increased. Incorporating Lynch status into immunotherapy planning may improve risk stratification and guide regimen selection.

Abstract Caregivers for people with neurodegenerative disease (PWNDs) often experience mental and physical health problems, especially when caring for PWNDs who have deficits in emotional functioning. We studied 65 PWNDs and their caregivers both during active caregiving and after caregiving had ended to determine: (a) how caregiver health changes after caregiving ends; and (b) whether PWNDs’ emotional functioning predicts these changes. PWND emotional functioning was assessed in the laboratory by measuring their generation of preparatory physiological activity (e.g., increased heart rate) to an upcoming emotional event (i.e., emotion eliciting films). Caregiver mental and physical health were measured using the Short-Form Health Survey (SF36) during active caregiving and again after caregiving had ended. Results indicated that, overall, caregivers reported increases in mental health, (t(36) = 2.58, p = .014, 95% CI [1.31, 10.93]) but decreases in physical health (t(36) = -2.35, p = .025, 95% CI [-7.26, -0.53]) across the two measurement periods. Using latent change score models, PWNDs’ preparatory physiological response impairments were associated with better caregiver mental health trajectories (β = -0.37, SE = 0.04, p = .003) such that smaller PWND preparatory responses predicted greater improvements in caregiver mental health (β = 9.92, SE = 2.84, p &lt; .001). There was no association with changes in caregiver physical health. Smaller preparatory physiological responses in PWNDs may indicate diminished emotional responding, which is linked with lower caregiver mental health during active caregiving. Once caregiving ends, these caregivers may be most likely to “rebound” and show improvements in mental health.

Abstract As a group, family caregivers of people with dementia (PWDs) have substantially elevated levels of depression and anxiety, compared to same-aged non-caregiving adults. However, there is striking variation in mental health among individual caregivers. Previous research on predictors of the sources of these individual differences has focused on characteristics of individual caregivers and PWDs (rather than on the caregiver-PWD relationship), self-report measures (rather than behavioral measures), and negative emotion (rather than positive emotion). We examined 185 caregiver-PWD dyads who had an unrehearsed 10-minute conversation about an area of conflict in the laboratory. Video recordings were coded for Behavioral Indicators of Positivity Resonance (BIPR), which derives from Positivity Resonance Theory and assesses dyad-level behavioral expressions of positive affect, mutual warmth, and synchrony. Caregivers reported their level of depression, anxiety, and emotional well-being and PWDs underwent a comprehensive neurological and neuropsychological evaluation. Pearson’s correlations revealed that greater dyad-level BIPR was associated with caregivers’ higher emotional well-being (r(181) = .19, p = .008), lower depression (r(179) = -.17, p = .025), and lower anxiety (r(180) = -.15, p = .045). Regression analyses revealed that these associations were still obtained after controlling for caregiver age and sex and PWD dementia severity, cognitive impairment, and neuropsychiatric behavior (emotional well-being ß = .18, p = .012; depression ß = -.15, p = .039; anxiety ß = -.15, p = .044). Future studies should determine whether interventions that increase co-experienced positive emotions among caregiver-PWD dyads help buffer caregivers from adverse mental health consequences.

Abstract Objectives There are striking differences among caregivers of people with dementia in their health and well-being during active caregiving and after caregiving has ended. A key factor influencing caregiver health is the emotional quality of the caregiver–care recipient relationship, which may be reflected in the emotional language caregivers use when describing this relationship. The present study assessed whether caregivers’ positive and negative language is associated with their current and future depression trajectories. Methods Active caregivers responded to an open-ended question about a recent time they felt connected to the care recipient. We summed the number of positive and negative emotion words and divided them by the total words in the response. We evaluated whether caregivers’ emotional language (a proxy for the emotional quality of the caregiver–care recipient relationship) was associated with their depression assessed both concurrently (N = 347 active caregivers) and longitudinally (N = 224 former caregivers). Results Neither positive nor negative emotional language significantly correlated with caregiver depression during active caregiving. Structural equation modeling revealed caregivers’ greater positive emotional language (accounting for baseline depression) was associated with less steep increases in depression after the care recipient’s death. Results were robust when accounting for negative emotional language and covariates. Negative emotional language was not significantly associated with changes in caregiver depression. Discussion Caregivers who use more positive words when describing their connection with the care recipient may be more resilient, underscoring the potential role of positive emotional qualities of the caregiving relationship in preserving caregivers’ mental health after caregiving ends.

Abstract Introduction: Multiple myeloma (MM) predominantly affects older adults who vary widely in physiological status and treatment outcomes. Comprehensive Geriatric Assessment (CGA) is considered the gold standard for frailty assessment in older cancer patients (pts), but clinical useis limited. Current frailty tools for MM include only select GCA domains, rely on trial datasets, and do not incorporate pt-reported outcomes (PROs). Since their development, treatment strategies have evolved with the use of anti-CD38 MAbs and quadruplets in older pts. The impact of geriatric impairments on treatment tolerance in the era of modern therapy remains unclear and changes in geriatric domains during treatment are not well characterized. Aim: This prospective study evaluates the association between pt-reported CGA and treatment outcomes in older MM pts.Methods: We included MM pts ≥60 years initiating a new treatment at Mayo Clinic from March 2023-June 2024. Pts completed the CARG GCA (Hurria et al 2005) electronically prior to and after 4 treatment cycles. We collected data on toxicity using CTCAE and PRO-CTCAE and quality of life using the PROMIS10-GH SF.Results: Ninety pts were enrolled. Median age was 72 (range: 63-86), 42% female, and &gt;90% non-Hispanic white. Over half (59%) were newly diagnosed with 41% and 56% receiving quadruplets and triplets, respectively. Among newly diagnosed pts, 34% had early stem cell transplant. Baseline median self- and physician- reported KPS were 80% and 90%, respectively, with high correlation (r=0.657). The median number of meds per pt was 9 (range:0-30), 39% had ≥3 comorbidities, 21% reported ≥1 fall in the past 6 months, and 40% reported ≥1 IADL limitation. On the Hospital Anxiety and Depression Scale, 3% and 7% had anxiety and depression, respectively. On the Blessed Orientation-Memory-Concentration test, 19% had mild cognitive impairment, and 1% had severe cognitive impairment. While only 19% had grade (G) ≥3 non-hematologic toxicity by CTCAE, 71% had ≥1 treatment delay, dose reduction, or discontinuation, and 39% had ≥1 ED visit or unplanned hospitalization within the first 4 cycles. This suggests physician grading of non-hem toxicities may inadequately capture toxicity burden from MM therapy. Notably, the rate of G≥3 toxicity by PRO-CTCAE was 49%, highlighting the discrepancy between physician- and pt-reported symptom burden. CGA domains significantly associated with G≥3 non-hem toxicity were: age (74 v 71.5, p=0.032), ≥3 comorbidities (65% v 33%, p=0.015), anxiety (18% v 0%, p=0.006), ≥1 IADL limitation (65% v 33%, p=0.018), physician KPS ≤80 (53% v 27%, p=0.042), limitations in vigorous activities (100% v 78%, p=0.023) and limitations in climbing several flights of stairs (88% v 56%, p&lt;0.001). Predictors of PRO-CTCAE G≥3 toxicity were ≥1 falls (30% v 11%, p=0.030), ≥3 comorbidities (52% v 26%, p=0.011), polypharmacy (≥9 meds) (67% v 43%, p=0.023), and physician KPS ≤80 (43% v 22%, p=0.030). CGA domains associated with ≥1 treatment adjustments were polypharmacy (62% v 33%, p=0.017) and unintentional weight loss (35% v 12%, p=0.028). Polypharmacy was the only domain associated with healthcare utilization (68% v 45%, p = 0.040), which may reflect underlying multimorbidity and greater pain burden. On multivariable logistic regression, any level of limitation in climbing several flights of stairs (OR: 6.0, 95% CI 1.2-30.3; p= 0.030) and older age (OR: 1.1, 95% CI 1.0-1.1; p=0.032) were independently associated with G≥3 non-hem toxicity, reflecting impaired functional status and reduced physiologic reserve, while ≥3 comorbidities only trended toward significance (OR:1.9, 95% CI 1.1-3.9, p=0.051).Compared to baseline, there were no significant changes in CGA domains or PROMIS10 scores after 4 cycles. While there was no significant difference in the proportion of pts reporting limitations in IADLs or physical function, we observed heterogeneity among individual pts, with changes in all 3 directions (improvement, stability, and decline). Conclusions: Geriatric impairments are prevalent in older pts with MM; pt-reported impairments are significantly associated with G≥3 non-hem toxicities, need for treatment modifications, and increased healthcare utilization, even in the era of novel therapies. Physical functional trajectories during treatment are variable among individual pts, underscoring the need for personalized treatment strategies and reassessment of geriatric domains throughout treatment.

Background: Patients with low gradient non-severe aortic stenosis (AS) at rest, in the context of reduced left ventricular ejection fraction (LVEF) (less than 50%), occasionally undergo dobutamine stress echocardiogram (DSE). However, limited data is available in the literature regarding the utility of DSE in this context. Methods: We conducted a retrospective study on patients with non-severe AS and LVEF less than 50% at rest who underwent DSE after Institutional Review Board approval. Retrospective data was extracted including rest and DSE parameters using an internal database. Only patients greater than 18 years old, who had an LVEF less than 50%, mean gradient (MG) less than 40 mmHg, and valve area greater than or equal to 1 cm 2 at rest were included in the study. Univariate and multivariate regression methods were used to identify which resting variables were associated with severe AS (MG greater than 40 mm Hg and valve area less than 1 cm 2 ) with DSE. Results: A total of 124 patients were included in the study. The mean age of patients was 78 years (±9) and 84% were male. The mean resting LVEF was 34% (±8%) while it was 40% (±12%) with DSE, mean stroke volume index at rest was 39 mL/m2 (±9) while it was 45 mL/m2 (±10) with DSE, MG at rest was 20 mmHg (±7) while it was 31 mmHg (±10) with DSE, and mean aortic valve area at rest was 1.27 cm 2 (±0.27) while it was 1.24 cm 2 (±0.29) with DSE. Of the 124 patients with non-severe AS at rest, 13 (10.5%) patients had severe AS with DSE. MG at rest was associated with severe AS (OR 1.3; 95% Cl: 1.1 - 1.5; p < 0.001) in a multivariate logistic regression model after adjusting for age, sex, LVEF at rest, SV index at rest. Resting aortic valve mean gradient also showed the highest AUC in relation to likelihood of having severe AS (0.87) (figure 1). Conclusion: Our study indicated that DSE remains useful in identifying severe AS in certain patients (up to 10%) who exhibit non-severe AS at rest in the setting of reduced LVEF. Additionally, MG at rest is the most reliable parameter to determine those who may benefit from undergoing DSE. This is one of the first studies to our knowledge in the literature suggesting that DSE may still be useful in identifying severe AS patients despite non-severe AS (i.e., valve area greater than or equal to 1 cm 2 ) at rest with reduced LVEF. Further research is warranted to validate our findings.

Abstract The Patient‐Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO‐CTCAE) was developed by the US National Cancer Institute to allow patients to directly report their side effects, enhancing the accuracy and patient‐centeredness of cancer clinical trial adverse event reporting. Clinician‐based reporting often misses the full range of patient symptoms, resulting in underreporting of side effects. The selection of adverse events for patient reporting must be defined in advance and consistently applied across all study arms. Investigators can use core symptom sets, including diarrhea, fatigue, and nausea, alongside tailored items specific to the treatments being studied. PRO‐CTCAE has demonstrated similar scores across electronic, paper‐based, and automated telephone administration methods. PRO‐CTCAE administration typically occurs before start of treatment and regularly throughout treatment, with the administration frequency tailored to the expected trajectory of side effects. Ensuring high survey completion rates is essential for PRO‐CTCAE success. Standard reporting can include tabular reporting of the proportion of patients with any (score ≥1) and high (score ≥3) levels of symptoms at the individual item level. A baseline‐adjustment approach should be applied to account for symptoms before start of treatment to isolate treatment‐emergent adverse events. The distribution of PRO‐CTCAE scores at each time point can be visualized using stacked bar charts. PRO‐CTCAE integration into cancer clinical trials is crucial for capturing a comprehensive range of treatment‐related symptomatic adverse events and improving the evaluation of therapy tolerability. Ongoing research continues to refine its implementation, supported by regulatory guidance.