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Abstract Introduction FD Ibr+Ven is approved as first-line (1L) treatment (tx) for CLL/SLL in 78 countries across Asia, Europe, the Middle East, and South America, plus Australia, Canada, and New Zealand. Clinical trials with up to 5.5 years (yrs) of follow-up have demonstrated progression-free and overall survival benefits of 1L FD Ibr+Ven in pts with CLL/SLL (Wierda WG, ASH 2024; Jacobs R, EHA 2024). Despite established clinical benefits, there is a lack of RW evidence on the effectiveness and tolerability of FD Ibr+Ven outside of clinical trial settings. Here we present pooled data from REALITY-WW and REALITY-2 to understand the usage, factors for therapy decision, clinical response, and safety of FD Ibr+Ven in routine clinical practice. Methods REALITY-WW and REALITY-2 are prospective observational cohort studies. REALITY-WW is an international study; REALITY-2 is conducted in Germany. Both included previously untreated pts with CLL/SLL from hospitals and medical institutions where Ibr+Ven was routinely used. The decision to start FD Ibr+Ven was made prior to and independent of pt enrollment. Pts aged ≥18 yrs with a confirmed diagnosis of CLL/SLL requiring 1L tx per iwCLL 2018 criteria received 3 cycles of Ibr, followed by 12 cycles of FD Ibr+Ven orally (Ibr, 420 mg/d; Ven, 5-week ramp-up to 400 mg/d). Primary end point was overall response rate (ORR) per iwCLL 2018 criteria. Secondary end points and outcomes of interest included tx-emergent adverse events (TEAEs), tumor lysis syndrome (TLS) risk, and factors associated with physician decision to initiate FD Ibr+Ven in routine clinical practice. Results At data cutoff (REALITY-WW: May 2025; REALITY-2: March 2025), 129 pts from both studies received FD Ibr+Ven (REALITY-WW, 81; REALITY-2, 48). The median (range) time on study was 6.4 (0.1-19.0) months (mo). Median (range) age was 65.0 (37.0-87.0) yrs, with 46.5% of pts aged <65 yrs and 53.5% of pts aged ≥65 yrs; 62.8% were male. Median (range) time from diagnosis to FD Ibr+Ven initiation was 38.1 mo (0.1-238.0) and median (range) duration of tx was 6.0 mo (0.1-15.9) for Ibr and 3.2 mo (0.1-8.4) for Ven. A Cumulative Illness Rating Scale score of >6 was observed in 12.6% of pts, with a higher score in pts aged ≥65 vs <65 yrs (18.0% vs 6.9%). TP53 mutations were seen in 7.4% of pts; 52.8% had an unmutated IGHV status. ORR was assessed in the 44 pts with ≥ 1 post-baseline assessment in REALITY-WW. Of these, 39 showed a response by the end of 6 tx cycles (3 cycles of Ibr + 3 cycles of FD Ibr+Ven) and 5 had stable disease. ORR at 6 mo per iwCLL 2018 criteria (partial response [PR] with lymphocytosis [PR-L] or better) was 88.6% (95% CI, 79.3-98.0), including complete responses in 29.5%, PR in 34.1%, and PR-L in 25.0% pts. Among 129 treated pts, TEAEs were reported in 61.2%; diarrhea was the most common TEAE (14.0%). Serious TEAEs and grade 3/4 TEAEs were reported in 12.4% and 8.5% of pts, respectively. The most common grade 3/4 TEAE was myocardial infarction (1.6%). Dose reduction was observed in 13.2% (Ibr) and 2.3% (Ven) of pts, mainly due to tx-associated TEAE/toxicity/TLS. Rates of TEAEs leading to discontinuation, dose reduction, and interruption of ≥1 study tx were 4.7%, 10.9%, and 20.9%, respectively. At baseline (n=129), 18.6%, 45.0%, and 14.7% of pts had high, intermediate, and low TLS risk, respectively, while 20.2% were not assessed and 1.6% had missing data. After the 3-cycle Ibr lead-in, the distribution shifted to 9.3%, 24.8%, and 24.0%, respectively, with 14.7% not assessed and 27.1% missing. There were no TEAEs of TLS and no hospitalizations due to TLS. Seven pts (6 aged ≥65 yrs and 1 <65 yrs) were hospitalized prophylactically for TLS. Prophylactic hospitalization was observed in 8.5% (11/129) of pts with high or medium TLS risk and impaired renal function for whom the Ven ramp-up was initiated; no pts were hospitalized due to laboratory/clinical TLS during the Ven ramp-up period. Physician questionnaire responses (n=126) indicated the most common factors associated with decision to initiate FD Ibr+Ven were administration route advantage (91.3%), overall health status (87.3%), anticipated superior efficacy of tx (84.1%), and general risk factors such as high tumor burden/genetic risk factors (81.0%). Conclusions Overall findings suggest that FD Ibr+Ven is an effective and safe tx for pts with CLL/SLL in a RW population, including those aged ≥65 yrs. Data with longer follow-up will be presented at the meeting.

Background Maintenance therapy improves PFS in NDMM pts. Additional active, well-tolerated treatment options that are suitable for long-term administration are required. The international, multicenter, double-blind, placebo-controlled, phase 3 TOURMALINE-MM4 trial (NCT02312258) of the oral PI ixazomib as maintenance therapy post-induction in non-transplant NDMM pts met its primary endpoint of PFS. Ixazomib demonstrated a significant and clinically meaningful benefit vs placebo, with a manageable and well-tolerated toxicity profile. Feasible, tolerable options for long-term therapy are particularly important in this setting, as pts are often elderly and/or frail. We report herein a subgroup analysis of TOURMALINE-MM4 according to age and frailty status. Methods Pts who achieved ≥partial response (PR) after 6-12 months of standard-of-care induction therapy were randomized 3:2 to ixazomib or placebo maintenance for up to 24 months. The sum of 4 components - age (<75 vs 75-80 vs >80 years; score 0 vs 1 vs 2), the Katz Index of Independence in Activities of Daily Living (ADL; >4 vs ≤4, score 0 vs 1), the Lawton Instrumental ADL Scale (>5 vs ≤5, score 0 vs 1), and the Charlson Comorbidity Index (≤1 vs ≥2, score 0 vs 1) - was used to classify pts as fit (total score: 0), unfit (score: 1), or frail (score: ≥2). Analyses of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and MY20 modules were conducted to evaluate the effects of treatment on QoL within subgroups defined by frailty status and age. Results In the ixazomib (n=425) vs placebo (n=281) arms, there were similar proportions of pts aged <65, 65-74, and ≥75 years and of pts classified as fit, unfit, and frail (Table 1). Baseline disease and treatment characteristics were generally balanced in ixazomib vs placebo pts across the different age and frailty groups, with some numerical differences observed. In pts aged <65 years, higher rates of International Staging System (ISS) stage III disease and fit pts and a lower rate of complete (CR) or very good partial (VGPR) response post-induction were seen (Table 1). Across frailty groups, a higher rate of CR or VGPR was seen in fit pts, a lower rate of ISS stage III disease was seen in unfit pts, and a higher rate of ISS stage III disease and a lower rate of CR or VGPR were seen in frail pts (Table 1). PFS benefit with ixazomib vs placebo was seen across age groups, with hazard ratios (HRs) of 0.576 (95% confidence interval [CI] 0.299-1.108, p=0.095, median 11.0 vs 9.3 months) in pts aged <65 years, 0.615 (95% CI 0.467-0.810, p<0.001, median 17.9 vs 9.3 months) in pts aged 65-74, and 0.740 (95% CI 0.537-1.019, p=0.064, median 16.7 vs 10.2 months) in pts aged ≥75 years. HRs for time to progression (TTP) were similar to those for PFS. PFS benefit with ixazomib vs placebo was also seen across frailty groups (Figure), with similar HRs for TTP. Rates of grade ≥3 treatment-emergent adverse events (TEAEs), serious TEAEs, and discontinuation due to TEAEs were higher or similar with ixazomib vs placebo across age and frailty subgroups (Table 2). Rates were generally somewhat higher in older age groups and in unfit/frail pts in both arms; nevertheless, rates of discontinuation due to TEAEs across groups were <20%, even in pts aged ≥75 years and frail pts (Table 2). With ixazomib, rates of common gastrointestinal TEAEs were similar across age groups; rash and liver impairment appeared less common and peripheral neuropathy more common in older pts (Table 2). Covariate-adjusted changes in QoL subscales from baseline were estimated at each cycle using repeated measures linear mixed models stratified by frailty status. In all frailty groups, the mean changes in each treatment arm were small over time (<10 points on a 0-100 scale) and similar between arms, indicating that continued treatment with ixazomib vs placebo maintenance did not adversely affect pts' QoL. Analyses by age were generally consistent with the results by frailty. Conclusions Ixazomib as post-induction maintenance therapy in non-transplant NDMM pts results in PFS benefits vs placebo regardless of age or frailty status. Ixazomib appeared generally well tolerated across groups, with TEAE rates in both arms generally elevated in elderly/frail vs younger/fit pts. Ixazomib is a feasible and effective maintenance option for prolonging PFS across this heterogeneous pt population. Disclosures Bringhen: Takeda: Consultancy; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Vorog:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Labotka:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Wang:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Cherepanov:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Cain:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Manne:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Dimopoulos:Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Beigene: Honoraria; Amgen: Honoraria. OffLabel Disclosure: Use of the oral proteasome inhibitor ixazomib as maintenance therapy in patients with newly diagnosed multiple myeloma not undergoing stem cell transplantation