Dueck, Amylou C.

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 Background This secondary analysis of a phase I clinical trial illustrates integrated summary and visualization of Common Terminology Criteria for Adverse Events (CTCAE) data and Patient-Reported Outcomes version of the CTCAE (PRO-CTCAE) data at baseline and through the first cycle of treatment for tolerability review during dose-cohort evaluation in a phase I trial. Methods This study uses data from a phase I clinical trial of patients with relapsed or refractory acute myeloid leukemia. Through iterative feedback from clinicians and statisticians, we developed a summary of cycle 1 PRO-CTCAE and CTCAE data for the first dose-level cohort. This summary is intended to demonstrate reporting that would be reviewed to inform a decision about proceeding to the next dose level in a dose escalation trial. Results Cycle 1 CTCAE and PRO-CTCAE data for 4 patients enrolled in the first dose cohort are summarized as narrative and tabular summaries and visualized using swimmer and butterfly plots. In this cohort, 3/4 (75%) patients had at least one CTCAE grade 3 or higher adverse event, and all 4 (100%) patients had at least one PRO-CTCAE composite score of 3 during cycle 1. All 4 (100%) patients had at least one symptom for which PRO-CTCAE suggested greater symptom burden than was reflected in CTCAE. Conclusions In this illustrative summary of a dose cohort, PRO-CTCAE complemented CTCAE reporting by capturing patient-reported symptomatic burden that was not always fully reflected by clinician-graded adverse events. Reviewing PRO-CTCAE and CTCAE data together during dose-cohort evaluation may enrich discussions on safety and tolerability in phase I trials.

635 Background: Prospective data on efficacy, quality of life, and treatment-related toxicities in older adults with breast cancer are limited. The ATOP trial (NCT03587740) evaluated T-DM1 in older adults and demonstrated favorable 5-year invasive disease-free survival. Here, we report patient-reported adverse events (AEs) and health-related quality of life (HRQOL) findings from ATOP. Methods: ATOP was a single-arm, phase II, multicenter study of adjuvant T-DM1 for those aged 60 with stage I-III HER2+ breast cancer. Protocol therapy included postoperative administration of T-DM1 (3.6 mg/kg) every 21 days for one year (17 cycles). PRO-CTCAE (assessing specific symptoms) and EQ-5D (a measure of HRQOL) surveys were administered electronically or on paper at baseline (pre-treatment), on Day 1 of each treatment cycle, and at a single 6–12-month post-treatment time point. Participants who responded to the baseline and at least one follow-up survey were included in the PRO analysis. EQ-5D changes from baseline were assessed using general linear mixed models. Summary statistics were used to assess PRO-CTCAE scores to evaluate which symptoms developed between baseline and 1 subsequent survey(s) and their severity. Results: Among the 111 patients enrolled on ATOP (median age=71, range 60-88 years), 98 responded to the baseline survey and 1 subsequent survey(s). 1435 surveys were returned that included at least one PRO-CTCAE response, and 1661 surveys were returned that included EQ-5D. The Table displays the % of participants who reported PRO-CTCAE symptoms that worsened from baseline to any severity level (scores >0) or to a severe level (scores ≥3). More than 60% of survey respondents reported new or increased dry mouth, fatigue, muscle aches, decreased appetite, nausea, pain, and/or numbness/tingling at some point during or after treatment, but these were usually not severe. EQ-5D scores did not change significantly from baseline at any time point. Conclusions: In this adjuvant trial for patients aged >60, participation rates for PRO data collection were high. Reassuringly, global HRQOL was not impacted by T-DM1, and though frequently reported, the vast majority of patient-reported symptoms were mild. Future analyses of this trial will focus on duration and predictors (clinical and biomarker-based) of severe AEs, agreement between patient-reported and clinician-reported AEs, and whether sharing PRO reports with clinicians impacted clinician-reported AE grades. Clinical trial information: NCT03587740 . Most common new or worsening symptoms reported via PRO-CTCAE in ATOP (n=95). Symptom % with score >0 n (%) with score 3+ Dry mouth 79% 26% Fatigue 71% 29% Muscle aches 69% 20% Decreased appetite 69% 12% Nausea 67% 6% Pain 66% 21% Numbness/tingling 65% 9% Blurry vision 60% 4% Mouth or throat sores 60% 5%

4513 Background: The AMBASSADOR trial (NCT03244381) showed that in patients with high-risk muscle-invasive urothelial carcinoma after radical surgery, adjuvant pembrolizumab for one year improved disease-free survival from 14.2 to 29.6 months (Apolo et al, NEJM 2024). Here we report the HRQOL results. Methods: HRQOL was completed by 560 randomized patients and included the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 plus the bladder cancer supplement BLM30, and the EQ-5D-5L, which assesses overall quality of life or health state. Published minimally important difference thresholds for EQ-5D-5L is 0.06, and for EORTC instruments is 5-10 points. For all reported HRQOL data, higher score is better except BLM30 urinary symptoms, where higher score indicates more symptoms. Results: Mean changes from baseline to 12 months (corresponding to end of treatment) for each HRQOL measure are summarized in the Table. No statistically significant difference was seen between the observation vs. pembrolizumab arms. Further, numerical differences between arms for these HRQOL measures do not meet (are lower than) the published minimally clinically important difference thresholds. Conclusions: Adjuvant pembrolizumab after radical surgery for patients with high-risk muscle-invasive urothelial carcinoma improved disease-free survival without negatively affecting HRQOL. These HRQOL results add further support to adjuvant immune checkpoint blockade therapy in these patients. Support: U10CA180821, U10CA180882, UG1CA189823 (https://acknowledgments.alliancefound.org). Clinical trial information: NCT03244381 . HRQOL mean change from baseline to 12 months and between-arm comparisons. A) Observation B) Pembrolizumab Difference A vs B P-value EQ-5D-5L Index Value -.029 -.012 -.02 .45 QLQ-C30 Global Health 0.07 1.45 -1.38 .55 QLQ-C30 Physical Functioning -.089 -.069 -0.02 .99 QLQ-C30 Role Functioning 3.22 -1.23 4.45 .15 BLM30 Urinary Symptoms -3.44 -3.02 -.42 .87 BLM30 Sexual Functioning -.53 4.15 -4.68 .07

3626 Background: For patients (pts) with dMMR stage III colon cancer, the addition of atezolizumab (atezo) to adjuvant 5-fluorouracil, leucovorin plus oxaliplatin (mFOLFOX6) significantly improved disease-free survival in ATOMIC (NCT02912559). Here we present HRQOL data. Methods: Pts with surgically resected stage III dMMR colon cancer were randomized (1:1) to receive mFOLFOX6 + atezo (840 mg IV q2 weeks) for 12 cycles (6 months [mo]) followed by atezo monotherapy for 13 cycles (12 mo total) versus mFOLFOX6 for 12 cycles. HRQOL was an exploratory endpoint measured using the FACT-C (includes FACT-G), FACT/GOG-NTX, EQ5D-5L, and PRO-CTCAE. Optional participation was by paper surveys at trial registration, prior to treatment cycles 4 and 7, and at 6, 12, and 36 mo after registration. Mean changes from baseline (BL) were compared between treatment arms using general linear mixed models (negative mean changes indicate worsening). At 6 mo, a two-sided 95% confidence interval excluding a difference of 1.9 points (FACT/GOG-NTX) and 6 points (FACT-C Trial Outcome Index [TOI]) favoring the mFOLFOX6 arm would indicate non-inferiority of the addition of atezo. Rates of side effect bother (FACT-G item GP5) and pt-reported adverse events (AEs) by PRO-CTCAE (composite scores, baseline adjusted) were compared using Fisher’s exact tests. Results: Of 712 randomized pts, 581 (285 atezo+mFOLFOX6; 296 mFOLFOX6) consented to participate in the survey. Pts completed 2398/3021 (79%) of expected surveys across all time points (1218/1489 [82%] atezo+mFOLFOX6; 1180/1532 [77%] mFOLFOX6). The difference in mean changes from BL between arms indicated non-inferiority of the addition of atezo at 6 mo (table); differences remained small at 12 and 36 mo. No significant differences in mean changes from BL between arms were found at 6, 12, or 36 mo for any scale. At 6 mo, 16% vs 20% of pts in each arm reported at least “quite a bit” of side effect bother (p=0.34), favoring atezo. Across cycles, atezo was associated with higher rates of pt-reported itchy skin (62% vs 48%), cough (53% vs 43%), and shortness of breath (51% vs 41%) [all p<0.05]. Conclusions: Addition of atezo to mFOLFOX6 slightly increases pt-reported AEs, but its effect on HRQOL is minimal and not clinically meaningful. Results support tolerability of atezo+mFOLFOX6 as standard of care adjuvant treatment for pts with dMMR stage III colon cancer. Support: UG1CA189823, U10CA180821, U10CA180882; Genentech, a member of the Roche group; https://acknowledgments.alliancefound.org. Clinical trial information: NCT02912559 . Scale Mo Mean change from BL – atezo+mFOLFOX6 Mean change from BL – mFOLFOX6 Diff (95% CI) FACT/GOG-NTX 6 -10.0 -10.6 0.6 (-0.8, 2.1) 12 -8.0 -9.4 1.4 (-0.2, 2.9) 36 -7.2 -6.9 -0.4 (-2.1, 1.4) FACT-C TOI 6 -4.1 -2.5 -1.6 (-3.7, 0.6) 12 2.1 1.8 0.3 (-1.9, 2.6) 36 0.7 1.8 -1.1 (-3.7, 1.5)

PURPOSE There is growing scientific interest in incorporating patient-reported outcomes (PROs) in early phase dose-finding oncology trials (DFOTs) to assess tolerability, inform dose selection, and guide later stage trial design. However, research indicates that PRO objectives in DFOTs are often unclear. The Incorporating Patient-Reported Outcomes in Dose-Finding Trials-Research Objectives Recommendations (OPTIMISE-ROR) project was established to support trialists to effectively incorporate PROs into DFOTs. METHODS Using the Enhancing Quality and Transparency of Health Research (EQUATOR) Network's methodological framework, guideline development included the following: (1) a methodological review of published DFOTs incorporating PROs; (2) candidate item generation, refined through expert consultation; (3) a two-round international multistakeholder Delphi survey (N = 109 in Round 1 [October 2024]; N = 96 in Round 2 [December 2024]); and (4) an independently chaired virtual consensus meeting (N = 31; January 2025) where multidisciplinary, international experts reviewed and voted to finalize items for inclusion. RESULTS Consensus was reached on six recommendations emphasizing three core PRO tolerability concepts: overall side effect impact, symptomatic adverse events, and overall health-related quality of life. The integration of PROs to inform final dose recommendations in dose escalation and optimization trials should be considered, regardless of trial design. The recommendations highlight the importance of PRO data analysis over time and across dose levels, defining PRO research objectives as descriptive or statistically powered, and assessing PRO-related end points to guide end point selection for subsequent studies. CONCLUSION This foundational guidance outlines key PRO research objectives in DFOTs. By facilitating the systematic integration of PROs, this guidance supports the utilization of patient-centered evidence for the tolerability and efficacy assessment of therapies to inform dose escalation, optimization, and regulatory evaluation—ultimately contributing to the development of safer, more effective therapies.

Abstract Background: The functional importance of bone marrow adipocytes (BMA) is frequently overlooked even though they are critical components of the BM (bone marrow) microenvironment. BMA have been proposed to play a supportive role within the hematopoietic niche and to directly sustain hematopoietic stem cell (HSC) survival as well as to preferentially support leukemia cell survival and proliferation (Sabbah Cell Commun Signal 2023). Although significant ex-vivo data implicates direct and indirect crosstalk between BMA and neoplastic HSCs (Venti Front Endocrinol 2022), the possible role of BMA in myeloproliferative neoplasms and their dynamics following therapy have yet to be characterized. Adiponectin, an anti- inflammatory adipokine that maintains metabolic homeostasis through regulation of insulin sensitivity, lipid metabolism and pro-inflammatory signaling is low in MPN patients and increases with IFN-α therapy (Avcu Int J Hematol. 2006). IFN-α has also been implicated in inhibiting adipogenesis via JAK-STAT1 signaling (Lee Biochim Biophys Act. 2016). A single institutional study of IFN-α in patients with essential thrombocythemia (ET) and polycythemia vera (PV) confirmed the potential for BM histopathologic responses and a correlation with molecular responses (Masarova Exp Hematol Oncol 2017). The aim of this analysis was to characterize the change in BM cellularity and fat composition with pegylated IFN α-2a (Pegasys; PEG) and the relationship with both hematologic and molecular response from tissue collected in prospective, global clinical trials of PEG in patients with ET/PV. Methods: A total of 24 subjects from the phase 2 MPN-RC 111 (Yacoub Blood 2019) salvage PEG study and 16 subjects from the MPN-RC 112 (Mascarenhas Blood 2022) phase 3 study comparing PEG to HU with available clinical, BM H&E slides, laboratory and molecular data were included in this retrospective analysis of prospective clinical trial data. We assigned a semi-quantitative score for changes in cellularity, fat distribution, and megakaryocyte (MK) histo-topography for changes from baseline, at 12, 24 and 36 months when available. Changes in BMA content and para-trabecular distribution were assessed on whole slide digital images with machine learning models. BMA content was quantified with a QuPath pixel classifier that distinguished adipocytes from other marrow components (Bankhead Scientific Reports 2017). Para-trabecular adipocyte distribution was assessed by leveraging UNI2-h, a self-supervised Vision Transformer (ViT-H/14) model and successor to UNI (Mahmood Nature 2024). UNI2-h was pre-trained on 200 million image tiles from over 300,000 H&E and IHC slides. In this study, UNI2-h was adapted to distinguish between high and low para-trabecular adiposity using image tiles centered on trabeculae. Trabeculae with a surrounding layer of adipocytes were labeled as ‘high’ adiposity, while ‘low’ para-trabecular fat distribution was defined by the direct contact of cellular marrow with trabeculae, lacking surrounding adipocytes. Results: A total of 40 PEG-treated ET (n=18) and PV (n=22) patients were included in this analysis with a median age of 64 years (26-85), 77% JAK2V617F+, 23% CALRmut+, and 40% treatment-naïve. The median JAK2V617F variant allele fraction (VAF) was 26% (range 3-96%). A complete hematologic response (CHR) was obtained with PEG in 58%, 61% attained &gt;20% reduction in driver VAF and 48% attained a &gt;50% reduction in VAF (MR) within 24 months of baseline. We observed an increase in BMA content and notable increase in para-trabecular distribution (confirmed by morphology and ML, independently) in 93% and 53% of PEG treated patients attaining a MR versus only 31% and 6% who did not attain MR, respectively (P Value=0.0004). There was more notable improvement towards normalization of MK histo-topography and orderly erythropoiesis in MR (86.6%) than in non-MR (31.2%) (P value=0.001). Increase in BMA content, BMA para-trabecular distribution, or improvement in MK histo-topography were not associated with achievement of CHR or changes in CALR VAF in this small cohort. Cytokine correlation with BMA dynamics is currently ongoing and will be reported at the meeting. Conclusion: Treatment of MPN patients with IFN-α resulted in reproducible changes in BM cellularity including MK histo-topography, erythropoiesis, BMA number and distribution. Changes in BMA were closely associated with reduction in JAK2V617F VAF following PEG treatment.

Abstract Background/rationale Primary myelofibrosis (PMF) and post-polycythemia vera/essential thrombocythemia (Post-PV/ET MF) (collectively termed MF) are chronic hematopoietic malignancies with progressive bone marrow collagen fibrosis, peripheral cytopenias, extramedullary hematopoiesis, splenomegaly, debilitating constitutional symptoms and heightened risk of transformation to acute leukemia. The only currently approved therapies for MF are JAK inhibitors (JAKi) which can provide significant improvements in splenomegaly and systemic symptoms but do not fundamentally change the pathogenesis of the disease. As a result, additional non-JAKi therapies for patients with MF after JAKi failure represent an important translational focus. Reparixin is a novel, potent and specific inhibitor of the chemokine CXCL8 (IL)-8. IL-8 is a member of a class of cytokines involved in leukocyte recruitment and activation in tissues. There are two known types of CXCL8 receptors – CXCR1 and CXCR2, which are expressed in neutrophils (Baggiolini M, Adv Immunol 1994). IL-8/CXCR1/2 signaling has been shown to be a key mediator of inflammatory signaling in MF patients. Hematopoietic stem/progenitor cells from patients with MF are enriched for a CXCL8/CXCR2 gene signature and display enhanced proliferation and fitness in response to an exogenous CXCL8 ligand in vitro. Genetic deletion or a small molecule inhibitor of CXCR2 in MF mouse adoptive transfer models ameliorates fibrosis, extends overall survival and improves hematologic parameters (Dunbar A, Blood 2023). This pre-clinical data validates targeting this pathway in clinical investigations. Study design This is an open-label, phase II study assessing the efficacy, safety, and tolerability of reparixin in patients with Dynamic International Prognostic Scoring System (DIPSS) intermediate-2, or high-risk PMF, post ET/PV MF either after prior treatment with, or those who are ineligible for treatment with a JAKi. Patients will receive oral reparixin 1200 mg three times daily on a four-week cycle for a core study period of 24 weeks. Patients who achieve at least clinical improvement (CI) or stable disease (SD) with one grade improvement in bone marrow fibrosis by International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria at the Cycle 7 response assessment may continue receiving reparixin until loss of response, disease progression, unacceptable toxicity, patients/physician withdrawal, or termination of study by sponsor. The study monitors both efficacy and toxicity using a Bayesian Optimal Phase 2 (BOP2) design. If response is observed in at least one patient out of 10 and safety is confirmed at the interim analysis, the trial will proceed to full enrollment of 26 patients. If more than three responses are observed in the total cohort, then a signal of activity is confirmed. Primary Objective: To estimate the efficacy of reparixin treatment in DIPSS intermediate-2 or high-risk subjects with PMF, post PV-MF, or post ET-MF. Secondary Objectives: To assess the efficacy of reparixin as determined by response assessment using IWG-MRT/ELN criteria at the end of Cycle 6 and Cycle 12. To assess the change in bone marrow fibrosis grade at the end of Cycle 6 and Cycle 12 with reparixin. To assess the safety of reparixin as measured by the adverse event profile of Common Terminology Criteria for Adverse Events v5.0. To assess spleen volume reduction by imaging after Cycle 6 and Cycle 12 as compared to baseline spleen volume. Key Exploratory Objectives: To evaluate changes in quality of life and patient-reported outcomes To conduct correlative studies to measure biomarkers of reparixin activity, such as Vascular Endothelial Growth Factor (VEGF) levels, bone marrow microvessel density, megakaryocyte number and peripheral blood CD34+ cell number, and patients with and without IL-8 secretion. Key inclusion criteria: Have a pathologically confirmed diagnosis of PMF, post-ET-MF, or post-PV-MF as per the WHO diagnostic criteria with intermediate-2 or higher risk disease by DIPSS Be refractory/resistant to or intolerant of/inappropriate for JAKi therapy Have adequate liver and kidney function Platelet count ≥ 25 x 109/L Bone marrow and peripheral blood blast count &lt; 10% ANC ≥ 1000 mm3. MPN Research Consortium (MPN-RC) 120 is currently enrolling patients through the MPN-RC clinical sites throughout the United States. Clinical Trial Identifier NCT05835466

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: The PRO-CTCAE provides patient-reported data on symptomatic AEs. A summary metric—the ACS—reflecting total AE burden can be calculated by averaging AE-level composite scores at a given timepoint for each participant. This study investigated the psychometric properties and interpretability of this PRO-CTCAE ACS in patients with breast, lung, or head/neck cancers. Methods: We conducted a secondary analysis of a PRO-CTCAE validation dataset comprising 940 adults undergoing chemotherapy or radiation therapy (clinicaltrials.gov: NCT02158637). We focused on empirically recommended symptom terms for three cancer sites. Analyses included Spearman’s correlations, coefficient alpha, and eigenvalues from the correlation matrices, confirmatory factor analysis (CFA), and principal component analysis (PCA). Latent profile analysis (LPA) was used to assess ACS interpretability in the lung cohort. Results: Mean composite score inter-correlations were moderate (0.30–0.35), and coefficient alphas were high (0.81–0.91). Eigenvalue ratios and CFA supported retention of a single factor/component, with suitable model fit indices. ACS correlated highly with factor scores and the first principal component from the PCA. Reduced sets of terms produced reliable scores that closely approximated the full set scores and aligned with external criteria. LPA in the lung subgroup identified four latent classes; ACS differentiated high vs. low symptom burden groups but did not distinguish the two groups expressing distinct symptom profiles. Conclusion: The ACS demonstrated structural validity through adequately fitting linear factor models and effectively summarized symptomatic AE burden. However, similar ACS values may mask clinically distinct symptomatic AE profiles, underscoring the value of both summary metrics and profile-based approaches.