Parrinello, Christina M.

e19025 Background: Recent studies suggest that patients with CLL/SLL (herein, CLL) relapsed/refractory (R/R) to both cBTKi and BCL2i (double R/R [DR]) may have poorer outcomes than the broader group of double-exposed (DE) patients. This study evaluated real-world response (rwR) and time-to-event (TTE) outcomes of a CLL DE cohort and DR subcohort in the US. Methods: This retrospective study used the nationwide Flatiron Health electronic health record-derived deidentified database to include patients with CLL treated with sequential or combination cBTKi and BCL2i in any line of therapy (LOT) on or after January 1, 2011, and a subsequent LOT (ie, index LOT) on or before November 30, 2022 (DE cohort). A subset with DR CLL (DR subcohort) was analyzed separately. Descriptive statistics were generated for demographic and clinical characteristics. Outcomes included clinician-confirmed rwR rate (rwRR) and median TTE outcomes (real-world duration of response [rwDOR], progression-free survival [rwPFS], time to next treatment [rwTTNT], and overall survival [rwOS]; Kaplan Meier, follow-up to May 31, 2023). Results: The DE cohort included 264 patients, 107 of whom were in the DR subcohort. Patients were mostly male (64%), White (75%), aged ≥65 years at first index LOT (72%) after prior cBTKi and BCL2i treatment, and treated in the community setting (71%). Approximately one-third of patients received a subsequent treatment after each index LOT. Most patients were re-treated with a cBTKi and/or BCL2i in the first index LOT (69% DE; 54% DR), and the percentage treated with chemotherapy increased with each subsequent index LOT. Confirmed rwRR was similar between DE and DR for all index LOTs (Table). More relevant are the median TTE outcomes, which were shorter for DR than DE, especially for the first index LOT, and shorter in subsequent index LOTs for both groups. Conclusions: The high percentage of patients re-treated with cBTKi and BCL2i therapies and increasing use of chemotherapy regimens with each subsequent index LOT indicate a lack of standard of care and options. Our results suggest a high unmet need in the DE CLL population, particularly in patients DR to cBTKi and BCL2i therapy, who have worse outcomes. Efficacious and durable therapy options are needed to address this unmet need. Double Exposed Index LOT Double R/R Index LOT 1st 2nd 3rd 1st 2nd 3rd N 264 90 35 107 41 12 rwRR, % (95% CI) 39(33-45) 42(32-53) 40(24-58) 36(27-45) 34(21-51) 42(16-71) Median TTE outcomes, months (95% CI) rwDOR 20.3 (13.5-32.6) 6.0(5.5-NR) 3.1(2.7-NR) 11.5 (7.9-23.5) 6.0(3.6-NR) 2.9(2.7-NR) rwPFS 8.8(7.5-10.6) 5.1(4.0-7.3) 4.3(2.9-6.3) 5.0 (4.0-7.3) 3.6(2.6-5.7) 4.7(2.7-NR) rwTTNT 13.8 (10.3-18.3) 7.9(5.7-11.3) 5.7(4.2-14.6) 8.0 (6.2-11.5) 5.9(4.4-11.4) 5.0(4.2-NR) rwOS 25.2 (22.1-37.1) 15.2(11.4-22.6) 6.6(5.7-NR) 14.7 (12.3-22.6) 11.4(5.9-NR) 6.6(5.0-NR)

CONCLUSION The most widely used multiple myeloma (MM) staging system, the Revised International Staging System (R-ISS), is based on lactate dehydrogenase (LDH), albumin, high-risk genetic markers by FISH, and beta-2 microglobulin (B2M). However, it does not account for additional risk impacted by multiple genetic abnormalities, or the risk imparted by presence of gain of chromosome 1q, and most patients are staged as R-ISS Stage 2. Two new staging systems, the Mayo Additive Staging System (MASS), and the Second Revision of the International Staging System (R2-ISS) have been recently proposed. A comparison of the performance of these two systems has not previously been done. We aimed to externally demonstrate the application of these staging systems and compare their performances in a large, contemporary cohort of patients in the United States. We conducted a retrospective cohort study using the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database, comprising de-identified patient-level structured and unstructured data, curated via technology-enabled abstraction and originating from approximately 280 US cancer clinics (~800 sites of care). The study included newly diagnosed MM patients initiating treatment between January 1, 2016 and October 1, 2022. We used the Kaplan-Meier method to evaluate real-world overall survival (rwOS) and patients were followed from first-line treatment initiation (index date) until the first of death, end of the study period or last recorded activity. The log-rank test to compare survival curves across derived stages. Multivariable analysis was conducted using stratified Cox models to account for non-proportional hazards by age with covariate adjustment for race/ethnicity, sex, practice type (academic or community) and diagnosis year (2016-2019 vs 2020-2022). Discrimination and calibration were evaluated in crude models using Harrell's c-index and the Hosmer-Lemeshow goodness-of-fit test, respectively. There were 497 patients with MM included. Patient characteristics are listed in Panel A. The distribution of patients across R-ISS stages were as follows, 24%, 63% and 13% for Stage 1, 2 and 3 respectively. rwOS differed across R-ISS stage (log-rank p = 0.0006) and the median OS (OS) was not reached (NR), 63, and 37 months for R-ISS stage 1, 2, and 3, respectively. 34%, 35% and 31% for MASS 1, 2, and 3, respectively. The corresponding survival curves were significantly different (p < 0.0001), with associated mOS of 77, 61 and 45 months for MASS stages 1, 2, and 3, respectively. R2-ISS includes four risk categories (stages I-IV) and in our cohort, 20% (n = 100) were stage I (low), 126 (25%) were stage II (low-intermediate), 229 (46%) were stage III (intermediate), and 42 (9%) were stage IV (high). Survival across stages were significantly different (p<0.0001), though the survival curves for low and low-intermediate, and intermediate-high and high, were clustered, suggesting comparable outcomes in stages I-II and stages III-IV. mOS for R2-ISS stages I, II, III, and IV was NR, 69, 50 and 51 months respectively (Panel B). In fully adjusted analyses, as compared to MASS I, the hazards of death were 2.0 (95% CI 1.3-3.2) for MASS II and 2.7 (1.7-4.2) for MASS III. The hazards of death were similar for R2-ISS low and low-int (HR for low-int vs low: 1.2 [0.7, 2.3]). As compared to R2-ISS low, the hazards of death were similarly higher for int-high and high (HRs: 2.4 [1.4, 4.1] and 2.6 [1.3, 5.2], respectively). Discrimination and calibration were similar across all staging systems (c = 0.6, and Hosmer-Lemeshow p>0.05 for all three staging systems). Application of contemporary MM staging systems in a large cohort of US patients shows that they are prognostic for OS in MM. MASS demonstrated a greater separation for OS across stages, whereas R2-ISS intermediate-high and high were largely overlapping. Although our results demonstrate similar accuracy and reliability of MASS and R2-ISS, the discrimination of patients across different stages seen with the newer staging systems, as opposed to R-ISS, calls for greater use of these newer staging systems in routine clinical practice.

Introduction: Among older adults with diabetes, cognitive dysfunction is of particular concern as it has implications for treatment adherence and diabetes self-management. The prevalence of cognitive dysfunction has not been well characterized in this population. Methods: We conducted a cross-sectional analysis of 5509 participants (1815 with diabetes) from visit 5 (2011-2013) of the ARIC Study. Diabetes was defined based on self-reported physician diagnosis, diabetes medication use, or HbA1c ≥ 6.5%. Cognitive function was measured using 8 neuropsychological tests, which were grouped into three cognitive domains representing memory, executive function, and language. Participants were categorized as having cognitive dysfunction if test scores were more than 1.5 standard deviations below age-, race-, and education-adjusted scores derived from a cognitively healthy population. We calculated crude prevalence estimates and used Poisson regression to estimate adjusted prevalence ratios (PRs), comparing cognitive dysfunction in persons with and without diabetes. We adjusted for demographic and clinical characteristics. Results: The mean age of participants was 75 years, 59% were female, 79% were white, and 33% had diabetes. In each domain, the prevalence of cognitive dysfunction among persons with diabetes ranged from 14% to 27%. Persons with diabetes were more likely than persons without diabetes to have dysfunction in multiple domains (PR = 1.29, 95% CI: 1.12, 1.49). Prevalence of cognitive dysfunction was significantly higher in persons with versus without diabetes for memory (PR=1.13, 95% CI: 1.02, 1.25), language (PR=1.24, 95% CI: 1.09, 1.45), and executive function (PR=1.10, 95% CI: 1.00, 1.22)(Figure). PRs were similar in crude models. Conclusions: The prevalence of cognitive dysfunction among older adults with diabetes is high. These results have implications for how physicians educate patients in appropriate self-management practices and for the prevention of diabetes-related complications.