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Abstract Background: Infections account for over half of the non-relapse deaths among chimeric antigen receptor (CAR) T-cell recipients. Non-relapse mortality estimates are among the highest in patients with relapsed / refractory multiple myeloma (RRMM) receiving B-cell maturation antigen (BCMA)-directed CAR-T cell therapy. The current Center for International Blood and Marrow Transplantation Research (CIBMTR) study analyzed the burden, types, risk factors, and outcomes of infection and its impact on survival in 807 patients with RRMM receiving commercial idecabtagene vicleucel (ide-cel) CAR-T therapy from March 2021 to December 2023. Methods: The primary endpoint was infection density for overall infections and for organism type (bacterial, viral, or fungal) within 100 days post-CAR-T infusion. Infection density was estimated as the number of infections per 100 person days at risk, stratified into two distinct time intervals following CAR-T cell infusion: days 0-30 and days 31-100.Additional endpoints included the cumulative incidence of infections, infection-related mortality (IRM), and overall survival (OS). Multivariable Cox proportional hazards models were employed to identify factors associated with infectious complications within 100 days post-CAR-T cell infusion. Pre-specified risk factors were considered for the multivariable analysis (MVA) models. We further examined the impact of infections within 100 days of CAR-T on OS at any time beyond 100 days following CAR-T infusion. Results: Infections developed in 114 (14.1%) patients within 30 days and 226 (28%) patients within 100 days post-CAR-T infusion, resulting in an overall infection density of 0.49 per 100 patient-days and a 100-day cumulative incidence of 27.2%. Proportions of bacterial, viral, and fungal infections within 30 days of ide-cel infusion were 82 (10.2%), 50 (6.2%), and 5 (0.6%), respectively. Similarly, proportions of bacterial, viral, and fungal infections within 100 days of CAR T-cell infusion were 126 (15.6%), 125 (15.5%), and 8 (1%), respectively, with corresponding infection densities of 0.23, 0.22, and 0.012 per 100 patient-days. The 100-day cumulative incidence of bacterial, viral, and fungal infections were 14.1% (95% CI, 11.8-16.6%), 14.4% (95% CI, 12-16.9%), and 0.9% (95% CI, 0.3-1.6%) respectively. The 100-day IRM was 1.1% (95% CI, 0.5-2%). With a median follow-up of 11.6 months (1.1-26.7), 222 (27.5%) patients died, and infection was the primary cause of death in 17 cases (7.7%). In MVA, Karnofsky performance score ≤80 (p<0.001), infection prior to CAR-T cell infusion requiring with ongoing treatment after d+0 (p<0.001), cytokine release syndrome grade ³2 (p=0.002), and severe immune effector cell-associated neurotoxicity syndrome [ICANS] (grade ≥3) (p<0.001) were associated with an increased infection risk within 100 days post-infusion. Similarly, infection prior to CAR-T infusion requiring with continuing treatment after d+0 (p<0.001 for bacterial and p=0.003 for viral infections) and grade ≥3 ICANS (p<0.001 for bacterial and p=0.015 for viral infections) significantly conferred a heightened risk for bacterial and viral infections within 100 days of CAR-T infusion. Number of infections within 100 days (hazard ratio [HR], 2.36 for ≥2 vs. 0 infections; 95%CI, 1.48-3.77; p<0.001), extramedullary disease or plasma cell leukemia (HR, 1.8; 95%CI, 1.19-2.74; p=0.006), and prior BCMA-directed therapy (HR, 1.57; 95%CI, 1.06-2.33; p=0.025) were independent risk factors for inferior OS beyond day+100 after CAR-T therapy. Intravenous immunoglobulin (IVIG) replacement post-CAR-T therapy conferred a survival advantage (HR, 0.52; 95%CI, 0.38-0.72; p<0.001). Conclusion: In conclusion, study results demonstrate a significant incidence of infections for a prolonged duration (14.1% in the first 30 days and 28% in the first 100 days) in patients with RRMM undergoing ide-cel therapy. Notably, viral infections increased beyond d+30. Multiple infections (≥2 episodes) were associated with inferior OS. Results identify patients at an increased risk for infection and provide insights into risk-adapted interventions to mitigate infections and improve patient outcomes. Furthermore, continued surveillance for infection pre-emption and prevention beyond 3 months post-CAR T therapy may be necessary to reduce infection burden and IRM. Prophylactic strategies such as IVIG replacement could potentially modify infection risk in patients with RRMM receiving ide-cel.

Abstract Background: IEC-HS is a potentially life-threatening complication following CAR-T therapy in RRMM. Reliable diagnostic biomarkers are needed to help expeditiously identify cases to initiate prompt treatment and supportive care. Serum ferritin, a routinely available laboratory parameter, is commonly elevated in IEC-HS and has been used to identify cases. However, ferritin can also be elevated in cytokine release syndrome (CRS) or secondary to baseline tumor-related inflammation. The optimal diagnostic threshold for post-CAR-T ferritin in IEC-HS in RRMM has not been previously established. Methods: This study used data from 15 centers within the US Multiple Myeloma Immunotherapy Consortium to identify the optimal post-CAR-T ferritin threshold to distinguish RRMM patients (pts) with and without a diagnosis of IEC-HS. Receiver operating characteristic (ROC) analysis was used to determine the optimal threshold based on Youden's Index. The performance of the threshold was evaluated overall and stratified by CAR-T product (cilta-cel, ide-cel). Additional analyses included the temporal relationship of peak ferritin and IEC-HS diagnosis, the evaluation of IEC-HS criteria according to ferritin levels, comparison of IEC-HS criteria co-occurrence, and comprehensive baseline characteristic comparisons across ferritin strata. Results: Of 1502 RRMM CAR-T recipients (ide-cel, n=712; cilta-cel, n=790), 74 patients (4.9%) had a provider-determined diagnosis of IEC-HS. A post-CAR-T ferritin threshold of 7470 ng/mL was identified as optimal for distinguishing pts with and without IEC-HS (AUC 0.938). Sensitivity (0.904) and specificity (0.934) were both very high, indicating high discriminatory ability. Stratified ROC analyses showed near-identical optimal thresholds for cilta-cel (7450 ng/mL; sensitivity 0.885, specificity 0.936, AUC 0.94) and ide-cel (7470 ng/mL; sensitivity 0.952, specificity 0.933, AUC 0.95), indicating minimal impact of CAR-T product on ferritin's prognostic utility. Baseline pt characteristics (N=1,413) differed significantly by ferritin threshold. Pts above the ferritin threshold of 7470 (N=154) were younger (median 64 vs 67 years; p=0.004), more frequently male (65% vs 56%; p=0.043), had higher baseline ferritin (1,300 vs 187; p<0.001), higher ECOG at apheresis (p=0.001), more likely penta-refractory (p=0.016), had higher baseline bone marrow plasma cell burden (p<0.001), and had higher R-ISS scores (p<0.001). Evaluation of IEC-HS criteria (Hines et al, TCT 2023) demonstrated significantly higher rates of laboratory and clinical criteria, including hepatic transaminase elevation (43% vs 15%), hypofibrinogenemia (53% vs 0%), cytopenias (95% vs 81%), hypertriglyceridemia (43% vs 8%), ICANS (52% vs 23%), renal insufficiency (20% vs 0%), and soluble IL-2 receptor elevations (47% vs 4%), in pts with ferritin >7500 ng/mL compared to those with lower ferritin. Heatmap visualization revealed distinct patterns of co-occurring criteria in high- and low-ferritin groups. Assessment of the timing of peak ferritin and IEC-HS diagnosis among IEC-HS cases revealed a median difference of 0 days (IQR: -1, 0), suggesting simultaneous occurrence. Median time to max ferritin was 9 days (IQR 8,12) in IEC-HS pts compared to 8 days (IQR 5,10) in non-IEC-HS pts (Wilcoxon p<0.05). Conclusions: In this analysis of over 1500 patients, a post-CAR-T ferritin level of 7500 ng/mL robustly identifies RRMM pts with IEC-HS following either cilta-cel or ide-cel. Pts exceeding this threshold demonstrate marked enrichment in IEC-HS diagnostic criteria and significant differences in baseline characteristics, warranting further study of the role of ferritin in IEC-HS diagnosis and early intervention.

Abstract Introduction: IEC-HS is an emerging and potentially life-threatening complication in multiple myeloma (MM) patients (pts) treated with CAR-T therapies. We conducted a retrospective, multi-institutional analysis to define the features and outcomes of IEC-HS after ide-cel or cilta-cel in the real-world setting. Methods: This study used data from 15 centers within the US Multiple Myeloma Immunotherapy Consortium for patients with relapsed/refractory MM (RRMM) who received commercial cilta-cel or ide-cel. IEC-HS was defined by each center based on diagnostic criteria (Hines et al, TCT 2023). Kaplan-Meier and multivariable Cox models were used for time-to-event outcomes while logistic regression was used for categorical outcomes. Results: Of 1502 RRMM pts who received either ide-cel (n=712) or cilta-cel (n=790), 74 patients (4.9%) had a provider-determined diagnosis of IEC-HS. Product-specific incidences were 2.9% for ide-cel and 6.7% for cilta-cel. The median time from CAR-T infusion to IEC-HS onset was 9.5 days (range 2-37 days). IEC-HS-related clinical findings (Hines et al, 2024) included cytopenias (95%), elevated soluble IL-2R levels (79%), fever (76%), elevated LDH (71%, median 1,800 U/L), hypofibrinogenemia (70%), hypertriglyceridemia (65%), ICANS (63%), hepatic transaminase elevation (56%), pulmonary involvement (46%), renal insufficiency (29%), hyperbilirubinemia (22%), and hemophagocytosis in bone marrow (6%). The median interval from peak CRS to IEC-HS onset was 4 days (IQR 1–6). Some variables, such as splenomegaly and coagulopathy, were not systematically collected. Nearly all pts received pharmacologic intervention: corticosteroids (94%, n=59), anakinra (76%, n=48), tocilizumab (71%, n=45), emapalumab (13%, n=8), ruxolitinib (16%, n=10), or etoposide (3%, n=2). Only one pt (2%) did not receive any IEC-HS therapy. Among those evaluable for outcomes, 58% (n=35) improved, 12% (n=7) developed further CAR-T-related complications (e.g., recurrent IEC-HS, delayed neurotoxicity), and 30% (n=18) had no therapeutic response and died. Compared to non-IEC-HS pts (n=1,428), those with IEC-HS were younger (median age 63 vs 66), male (61% vs 57%), and more frequently received cilta-cel (72% vs 52%, all p<0.01). They had higher rates of triple-class (81%) and penta-refractory (43%) disease, greater pre-treatment bone marrow plasma cell burden (40% vs 6%), and higher baseline ferritin (1058 vs 208 ng/mL). Prior autologous SCT was less common, and advanced R-ISS stage was more prevalent. IEC-HS was associated with dramatically worse PFS and OS: with cilta-cel, median PFS was 6.5 months (mo) with IEC-HS (vs 33.1 without); for ide-cel, 8.9 vs 11.4 mo. Median OS for cilta-cel IEC-HS pts was 9.6 mo (not reached in non-IEC-HS pts); for ide-cel IEC-HS, 19.6 mo (vs 40.8 mo). Multivariable analysis confirmed IEC-HS as an independent predictor of shorter PFS (HR 1.88, 95% CI 1.29–2.74, p=0.0011) and OS (HR 2.30, 95% CI 1.39–3.83, p=0.0013). Notably, IEC-HS was not associated with lower response rates – either best CR (63.9% vs 64.0%, p=0.71) or ORR (91.8% vs 90.9%, p=0.97). Cilta-cel pts had a higher probability of achieving a deep (CR) response, regardless of IEC-HS status. Grade > 3 CRS occurred in 14% (n=3/21) of ide-cel and 15% (n=8/52) of cilta-cel IEC-HS pts, versus 2% (n=12/691) and 2% (n=13/737) in non-IEC-HS pts, respectively. Any-grade ICANS was observed in 67% (n=14/21) of ide-cel and 55% (n=29/52) of cilta-cel IEC-HS cases, compared to 26% (n=179/690) and 20% (n=148/738) in non-IEC-HS. Grade ≥3 ICANS occurred in 29% (n=6/21) of ide-cel and 26% (n=14/52) of cilta-cel IEC-HS cases, relative to 4% (n=25/690) and 4% (n=27/738) in pts without IEC-HS. Severe infections were also more common: 71% (n=15/21) of ide-cel and 53% (n=28/52) of cilta-cel IEC-HS pts experienced at least one infection, compared to 31% (n=214/691) and 29% (n=217/737) in non-IEC-HS groups. Conclusions: IEC-HS is an uncommon but severe and early complication after CAR T-cell therapy for RRMM. Despite similar ORRs with or without IEC-HS, IEC-HS was associated with significantly worse PFS and OS for both ide-cel and cilta-cel. These findings support the need for vigilant monitoring and potential preemptive treatment strategies to better manage this syndrome.

Abstract Background: Real-world data suggest that safety and efficacy of ide-cel and cilta-cel mirror data from pivotal trials, yet older adults remain underrepresented. We report outcomes of the largest cohort of RRMM patients aged ≥75 years receiving CAR-T and compare them with propensity-matched younger patients. Methods: We retrospectively analyzed RRMM patients receiving standard-of-care BCMA CAR-T at 15 centers from the US Myeloma Immunotherapy Consortium between May 2021 and December 2024. Patients ≥ 75 years were 2:1 propensity-matched to patients < 75 based on CAR-T product, sex, performance status, extramedullary disease, baseline ferritin, penta-refractory status, bridging therapy, prior autologous SCT and lines of therapy. Continuous outcomes were analyzed with multivariable linear regression, binary outcomes with logistic regression, and time-to-event endpoints with Cox proportional-hazards models. We estimated average treatment effects via G-computation, using cluster-robust standard errors to account for the matched sets. Results: After 2:1 propensity matching, the cohort included 194 patients ≥ 75 years (cilta-cel: 64 and ide-cel: 130) and 388 patients < 75 years (cilta-cel: 128, ide-cel: 260). Median ages were 78 (range: 75-90) for the older cohort vs 65 (range: 35-74) for the younger cohort. The older cohort had a higher frequency of t(14;16) (9% vs. 3%, p = 0.005), lower baseline ferritin (151 vs. 196 ng/mL, P = 0.046), and lower likelihood of prior ASCT (57% vs. 71%, P = 0.001). Median prior lines of therapy were 5. Median follow-up time for ≥ 75 and < 75 groups for cilta-cel was 11.5 and 11 months and for ide-cel was 16 and 24.3 months, respectively. ORR did not differ amongst the older vs younger patients: cilta-cel (97% vs. 97%) and ide-cel (90% vs. 88%).For patients ≥ 75 years, median PFS with cilta-cel was 28.7 months (95% CI: 13.3–NR) and with ide-cel was 16.4 months (95% CI: 12.1–22.4). In patients < 75 years, median PFS was not reached for cilta-cel but was 11.5 months (95% CI: 9.6–12.7) for ide-cel, reflecting inferior PFS with ide-cel in the younger group (HR 0.4, 95% CI 0.3–0.6). On sensitivity analysis by Cox proportional hazards model, we did not observe any statistically significant differences in PFS in older vs younger patients receiving cilta-cel, although older patients paradoxically had better PFS with ide-cel compared to their matched younger cohort. In the cilta-cel cohort, HR for PFS for older vs younger patients was 1.48 (95% CI:0.77-2.84; p=0.2) and in the ide-cel cohort it was 0.7 (95% CI: 0.5, 0.98; p=0.04). Median OS was reached only in the < 75-year ide-cel cohort at 40 months (95% CI: 32.5–43.5). Rates of CRS were similar, with any-grade (grade ≥3) CRS seen in 74% vs 78% (0% vs. 0.8%) of cilta-cel recipients and 86% vs. 87% (3.1% vs. 1.5%) of ide-cel recipients in the older vs younger groups, respectively. ICANS rates were 21% vs. 20% for cilta-cel (p = 0.79) and 29% vs 20% for ide-cel (p = 0.07), with similar rates of grade ≥ 3 ICANS. In the cilta-cel cohort, Parkinsonian delayed neurotoxicity (DNT) occurred in 3/62 (4.8%) older patients and 6/128 (4.7%) younger patients. Similarly, other non-Parkinsonian DNT rates were similar across age groups, with 6.4% vs 5.5% in older vs younger cilta-cel cohort and 0% vs 1% in the older vs younger ide-cel cohort. Rates of IEC-HS, and infections were comparable across the cohorts. There was no difference in hospital length of stay and ICU admission rate between products within either age cohort. The overall non-relapse mortality (NRM) was 6.7% for patients ≥ 75 years and 6.2% in patients < 75 years. For cilta-cel, NRM in older vs younger cohort was 9.4% vs 4.7% (p= 0.96) and for ide-cel it was 5.4% vs 6.9%, respectively (p= 0.65). Conclusion: Appropriately selected older adults (≥75 years) receiving CAR-T therapy for RRMM can derive a similar efficacy benefit with CAR-T as a propensity-matched younger cohort, without any increased signal of toxicity including CRS, ICANS or delayed NT. NRM was numerically greater, but not statistically significant, in older adults receiving cilta-cel. Median PFS with cilta-cel and ide-cel in older adults were 28.7 months and 16.4 months with median OS not reached and 40 months, respectively. Older adults, ≥75 years old, should not be excluded from CAR-T therapy solely due to advanced age. Overall, cilta-cel was not associated with worsened toxicities in older adults and may offer better PFS.

Abstract Background: Undetectable minimal residual disease (uMRD) at the end of first-line (1L) treatment (tx) with 12-cycles (C) of venetoclax (ven) + obinutuzumab (obin) is associated with prolonged survival for patients (pts) with chronic lymphocytic leukemia (CLL, Al Sawaf et al. Blood 2024). We hypothesized that MRD may be used to guide ven tx duration for CLL pts treated with 1L ven + obin. Methods In this ongoing phase II, multicenter investigator-initiated study, pts receive ven + obin for 1L tx of CLL/small lymphocytic lymphoma (NCT04447768). Eligible pts have a CIRS score of ≤ 6 and require 1L tx per iwCLL 2018 criteria. Pts receive 6 x 28-day C of obin and initiate ven on C1D22. Ven duration is dependent on peripheral blood (PB) MRD status measured by ClonoSeq next generation sequencing. At C7, pts undergo MRD testing. Pts uMRD6 (<10-6 sensitivity) at both C7 and C9 dc ven after 9C and enter treatment free observation (TFO). Pts with detectable MRD6 (dMRD6) at C7 undergo repeat testing at C12; if uMRD5 (<10-5) pts dc ven after 12C. Pts dMRD5 at C12 continue ven for an additional 12C (24C total) prior to TFO. The primary study endpoint is 36-month PFS; the unpromising rate is set at 82% and will be tested by a nonparametric survival estimate (Kaplan-Meier) along with Greenwood's formula. RNA sequencing (RNAseq) was performed pre-tx on patient bone marrow (or PB if inaspirable) samples. Unsupervised clustering using machine learning (ML) based on consensus nonnegative matrix factorization was applied to the most variable genes to identify patient clusters. Clusters were then biologically characterized by gene signature scoring using xCell algorithm and assessed for association with uMRD6 at C7 using a Fisher exact test. Results Baseline characteristics of the 100 pts who initiated tx include: median age 58 (range 34-81); 71% male, 90% White, 3% Black and 2% Asian, 5% unknown; 49% IGHV unmutated, 16% TP53 mutation, 8% del17p (previously reported, Roeker et al. ASH 2024). 3 pts stopped tx prior to C7. 51 pts were uMRD6 at C7 and C9 and completed 9C ven. 46 pts were dMRD6 at C7; 6 pts stopped tx outside of meeting protocol requirements and are included in intention-to-treat (IIT) analyses. 32 pts were uMRD5 at C12 and dc ven after 12C. 8 pts were dMRD5 at C12: 5 continued ven per protocol (3 completed 24C ven, 2 ongoing tx as of 15 May 2025 data cut-off), 2 stopped ven outside of protocol requirements (included in ITT analyses), and 1 pt withdrew consent. At a median follow-up of 35 months, the 36-month PFS rate is 90% (95% CI: 84%, 97%). 36-month OS is 94% (95% CI: 89%, 99%). Landmark PFS analyses from EOT were performed for pts who dc ven after 9C due to uMRD6 (24-month PFS 92%, 95% CI: 85, 100%, n=51) and pts who dc ven after 12C due to uMRD5 (24-month PFS 96%, 95% CI: 89%, 100%, n=32). For pts dc ven after 9C due to uMRD6 (n=51), PB MRD at 12C after EOT was: 59% uMRD6, 12% uMRD5, 4% uMRD4, 8% dMRD4 and 18% unknown. For pts dc ven after 12C due to uMRD5 status (n=32), PB MRD at 12C following EOT was: 9% uMRD6, 31% uMRD5, 9% uMRD4, 25% dMRD4 and 25% unknown. Of the 5 pts with PD, 3 pts have had Richter Transformation to diffuse large B-cell lymphoma (all uMRD6 at C7 / 9). Two pts with PD have not met iwCLL tx criteria and remain in TFO. Five pts have died (suicide, West Nile encephalitis, COVID-19, complications of glioblastoma and RT DLBCL). Five C12 dMRD5 pts who continued ven have reached C18, with only 1 of 5 converting to uMRD5 in PB. However, all 5 maintained uMRD4 (<10-4). Of 3 pts that completed 24C ven (2 ongoing tx), 1 pt had deepening of response to uMRD5 at C24, and 2 pts had rising MRD on ven (dMRD4 at C24). To investigate patient heterogeneity at baseline and its relationship to uMRD, we clustered patient RNAseq samples into two clusters using artificial intelligence/ML based unsupervised clustering. The clusters associated with uMRD6 at C7 (Fisher exact test p=0.038), and patients in the cluster with significantly higher immunosuppressive cells such as T-regulatory cells and M2 macrophages were less likely to be uMRD6 at C7. Conclusions At a median follow-up of 35 months, the estimated 36-month PFS rate is 90%. RNAseq transcriptomic analyses identified that patients with enriched immunosuppressive cells were less likely to be uMRD6 at C7. Additional follow-up is required to confirm the durability of this MRD-guided ven + obin tx strategy.

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.

Abstract Introduction: Telomere biology disorders (TBDs) are caused by germline pathogenic or likely pathogenic variants in telomere maintenance genes and result in multisystem manifestations, including impaired bone health. Patients with TBDs experience reduced bone mineral density (BMD), avascular necrosis, and increased rates of fragility fractures. However, the underlying mechanisms of these bone complications remain poorly understood, and no TBD-specific treatments for bone health currently exist. Our objective was to characterize the clinical features, management, and outcomes of TBD-related bone health issues, including fractures and reduced BMD. Methods: We conducted a retrospective, multicenter, international cohort study using data from 232 patients with TBDs enrolled across 12 centers participating in the Clinical Care Consortium of Telomere-Associated Ailments. Medical records were reviewed for fracture history and BMD assessments by dual-energy X-ray absorptiometry (DXA). The primary endpoint was fracture incidence; secondary endpoints included BMD assessment and fracture management. Data were stratified by pediatric (≤18 years) and adult (>18 years) age groups. Analyses were based on data availability; specific denominators are provided where applicable. Result: Data were available for 53 (23%) pediatric and 179 (77%) adult patients. TERT mutations were the most frequently identified variants in both groups (28% pediatric, 23% adult). Fractures occurred in 25% (13/53) of pediatric patients and 35% (62/178) of adults. In contrast, fractures are estimated to occur in 10-15% of the general pediatric population. The median age at first fracture was 8.2 years (range 2.5–17) in children and 29.2 years (range 18.3–66.9) in adults. Among those with fracture data (n=20 pediatric, n=22 adult), fragility fractures were more common in adults (57%) versus predominantly traumatic fractures in children (61%). Multiple fractures occurred in 65% of affected pediatric patients and 45% of affected adults. Fracture management also differed: non-surgical treatments were used in 60% of pediatric fractures (n=12/20) versus 36% (n=8/22) of adult fractures; surgical interventions were more common in adults (36%). The inheritance pattern (autosomal dominant versus recessive or X-linked) was not associated with fracture risk but the subset of patients with CTC1 mutations were associated with increased fracture risk (n=5 of 124 patients with fracture history, 4% vs n=2 of 247 patients with no fracture history, 0.8%; p=0.04). We also assessed whether vascular manifestations were associated with fracture risk comparing patients with and without fractures. Pulmonary arteriovenous malformations (AVMs) were significantly more common in patients with fractures (17%, 7/42) versus those without (5.4%, 6/112; p=0.04). No significant differences were found in rates of retinal vasculopathy or hemorrhage (13% vs 7.2%, p=0.23) or gastrointestinal bleeding (22% vs 16%, p=0.35). DXA data were available for 171 patients (22 pediatric, 149 adult). The median age at first DXA was 11.4 years (range 4–17.7) for children and 58.2 years (range 20.8–79.4) for adults. Among pediatric patients, the median lumbar spine Z-score was –1.2 (IQR –3.0 to –0.2, n=18), with 39% (7/18) showing a Z-score < –2. Among adults, the median femoral neck T-score was –1.1 (IQR –1.7 to –0.5, n=118), with 21% (29/138) demonstrating T-scores < –2, indicating low BMD. Conclusions: Fractures and reduced BMD are common in both pediatric and adult patients with TBDs, with a substantial burden of early-onset and recurrent fractures. Our findings underscore the importance of early bone health screening and surveillance in TBDs and suggest a possible link between vascular abnormalities and skeletal fragility in this population that requires further study.

Abstract Introduction: The first-generation BCL2 inhibitor,venetoclax, is an effective treatment for CLL/SLL, but its usage may be limited by toxicity. Sonrotoclax, a next-generation BCL2 inhibitor, is a more selective and pharmacologically potent inhibitor of BCL2 than venetoclax, with a shorter half-life and no drug accumulation. BGB-11417-101 (NCT04277637) is an ongoing, phase 1/1b, dose-escalation/expansion study in patients with B-cell malignancies. Presented here are preliminary data for sonrotoclax + obinutuzumab in patients with treatment-naive (TN) CLL/SLL in BGB-11417-101. Methods: Obinutuzumab is administered intravenously at 100 mg on day (D) 1, 900 mg on D2, 1,000 mg on D8 and D15 of cycle (C) 1, and then 1,000 mg on D1 of C2-6 of each 28-day cycle. Beginning on C2D1, sonrotoclax is administered orally once daily with ramp-up to the target doses, 160 or 320 mg. Patients can continue treatment until progressive disease (PD), unacceptable toxicity, or undetectable minimal residual disease (uMRD4; <1 CLL cell per 10,000 leukocytes [<0.01%]) in peripheral blood (PB) by next-generation sequencing (NGS; ClonoSEQ) after 15 treatment cycles. Study endpoints include safety per NCI-CTCAE v5.0, overall response rate (ORR) per iwCLL guidelines, and MRD status in PB per modified ERIC flow cytometry (FC) assay or NGS, depending on the timepoint. Tumor lysis syndrome (TLS) is assessed per Howard (2011) criteria. Results: As of May 16, 2025, 55 patients with TN CLL/SLL were enrolled (160 mg, n=20; 320 mg, n=35), and 21 patients (all 320 mg) have discontinued sonrotoclax + obinutuzumab (due to uMRD4 per NGS as protocol-mandated [n=17], PI decision uMRD4 per FC [n=2], and PD [n=2]). Four patients discontinued obinutuzumab only per PI decision (160 mg, n=1), thrombocytopenia (320 mg, n=2), and prostate cancer prior to starting sonrotoclax (160 mg, n=1). For all patients, the median age was 62 y, 65% were male, and 89% were White. At baseline, 14% of patients (8/55) had high tumor burden and 58% (31/53) had unmutated IGHV. Median study follow-up was 8.9 months (range, 0.4-25.4 months) for all patients; 6.4 months (range, 0.4-9.0 months) for 160 mg; and 16.0 months (range, 2.9-25.4 months) for 320 mg. Maximum tolerated dose was not reached. The most common any-grade treatment-emergent AEs (TEAEs) were thrombocytopenia (56%), infusion-related reaction (56%), and neutropenia (49%). Neutropenia was the most common grade ≥3 TEAE (38%). No deaths due to TEAEs occurred, and no TEAEs led to sonrotoclax discontinuation. Two cases of laboratory TLS occurred after C1D1 of obinutuzumab prior to starting sonrotoclax; no clinical or laboratory TLS occurred during sonrotoclax ramp up. No meaningful safety differences were observed among sonrotoclax dose cohorts. In 37 efficacy-evaluable patients (160 mg, n=7; 320 mg, n=30), the ORR was 89%; for the 320-mg cohort, ORR was 93% (28/30). Complete response (CR) rates (CR + CR with incomplete marrow recovery [CRi]) were 46% (all patients) and 43% (320 mg). For 23 patients in the 320 mg cohort who reached the C15 MRD assessment, the best C15 uMRD4 rate per FC was 87% (20/23; 2 not evaluable; 1 missing); per NGS, the uMRD4 rate at C15 was 78% (18/23; 5 missing). All patients with an available C15 MRD assessment achieved uMRD4 and remain in remission as of the data cutoff date. The median time from reaching sonrotoclax target dose to uMRD4 was 2.3 months (range, 1.4-5.6 months) in the 320-mg cohort. Three patients experienced PFS events: 1 died from an indeterminate cause (160 mg, discontinued treatment after C1D9 of obinutuzumab) and 2 had PD (320 mg; both Richter's transformation at C6 and C2). Conclusions: Sonrotoclax + obinutuzumab was generally well tolerated in patients with TN CLL/SLL, with no sonrotoclax discontinuations or deaths due to TEAEs. No laboratory or clinical TLS events occurred during sonrotoclax ramp-up. Encouraging antitumor activity was observed with sonrotoclax 320 mg. High rates of blood uMRD4 occurred early and deepened over time. All patients with an available C15 MRD assessment by NGS or FC achieved uMRD4 and remain in remission. A registrational phase 3 study (CELESTIAL-RRCLL, BGB-11417-303) assessing this combination with sonrotoclax 320 mg is currently recruiting.

Abstract Introduction AL amyloidosis is a rare disorder caused by amyloid fibrils produced by clonal plasma cells, leading to serious organ dysfunction. Cardiac involvement is a major risk factor for poor survival. CD38-binding Daratumumab (D) targets plasma cells and, with bortezomib, cyclophosphamide and dexamethasone (VCd) is the only approved regimen for newly diagnosed AL amyloidosis. The ANDROMEDA phase 3 study showed significant improvements in hematologic responses, major organ deterioration progression free survival and overall survival, compared with VCd alone. The AQUARIUS study (NCT05250973) evaluated cardiac safety of different D-VCd schedules and potential cardiac toxicity mitigation strategies. Methods This multicenter, open-label, phase 2 study enrolled 151 newly diagnosed AL amyloidosis patients at 37 sites in 10 countries. Patients enrolled in either Cohort 1 (n=120, cardiac involvement [Mayo 2004 stage II/IIIA], randomized 2:1 to receive D + immediate VCd or D + deferred VCd) or Cohort 2 (n=31, racial or ethnic minorities with ≥1 any organ involvement, treated with D + immediate VCd). Immediate VCd began on Cycle 1, deferred VCd on Cycle 4. The primary safety endpoint was the incidence of cardiac treatment emergent adverse events (TEAEs). Cardiac assessments included HS TroponinT, NT-proBNP, echocardiogram (ECHO), ECG, NYHA, and the 6-minute walk test (6MWT). Clinical cardiac signs and symptoms (S&S) were assessed at baseline and monthly. Selected, clinically relevant grade ≥3 and/or serious cardiac TEAEs were defined as Major Cardiac TEAE and were assessed by an independent adjudication committee for causality. Patients were followed for 12 treatment cycles or 12 months from first dose (if treatment discontinued prior to 12 cycles). Results 142 patients from both cohorts had cardiac involvement and received at least one dose of D + immediate VCd (n=103) or D + deferred VCd (n=39). Baseline characteristics were balanced between the two groups, including Mayo 2004 stage (IIIa: immediate VCd, 35.0%; deferred VCd, 35.9%; II: immediate VCd, 62.1%; deferred VCd, 53.8%). Treatment duration (median: 10.4 months) and proportion completing ≥10 cycles (79% vs 85%) were similar. Serious cardiac TEAEs occurred at similar rates across groups (immediate VCd, 7.8%; deferred VCd, 7.7%). The most common serious cardiac TEAE (MedDRA term) was cardiac failure (immediate VCd, 5.8%; deferred VCd, 2.6%). Two deaths occurred within 60 days of first study treatment, both were in the immediate VCd group, cardiac-related and unrelated to treatment. The immediate VCd group had fewer cardiac TEAEs overall (48.5% vs 61.5%) but experienced them more frequently during Cycles 1-3 than deferred VCd (35.9% vs 28.2%). This trend reversed for Cycles 4-6 (immediate VCd, 17.7%; deferred VCd, 28.9%). Cardiac TEAEs were low for both groups for Cycles 7-9 (immediate VCd, 9.3%; deferred VCd, 12.1%) and Cycles 10-12 (immediate VCd, 7.4%; deferred VCd, 12.1%). Levels of NT-proBNP, HS troponin T, the 6MWT, and overall cardiac S&S improved similarly for both treatment groups. Rate of cardiac TEAEs of any grade was similar for Mayo stage III patients in the two groups (immediate VCd, 73.0%; deferred VCd, 68.8%) whereas for Mayo stage II patients the incidence was higher in the deferred group (35.9% vs 57.1%). Twenty patients (Immediate VCd, 13; deferred VCd, 7) experienced 30 Major Cardiac TEAEs (selected grade ≥3 and/or serious). Adjudicators attributed 28 events primarily to amyloid cardiomyopathy and 2 events primarily to treatment. These 20 patients had higher baseline Mayo stage (IIIa: 70% vs 29.5%) than the remaining patients (n=122), higher baseline median NT-proBNP (4862 ng/L vs 1723 ng/L) and overall S&S score (7.5 vs 4.0). Several ECHO measures were worse at baseline in these 20 patients (notably, median GLS: -8.8% vs -13.7% and E prime lateral: 4.4 cm/s vs 6.1 cm/s) as was 6MWT (median distance: 319 m vs 363 m). Complete Response (CR) rates were similar in both groups: immediate VCd, 62.1%; deferred VCd, 59.0%. Median time to CR was 64 days for the immediate VCd group and 113 days for the deferred VCd group. Conclusion The D-VCd regimen (immediate or deferred) had a manageable safety profile consistent with previous studies. Cardiac TEAEs were similar between regimens, and their emergence correlated with the start of VCd. Major cardiac events were associated with underlying disease and baseline risk factors that are quantifiable and monitorable.

Abstract Introduction: Achieving rapid and deep hematological responses is essential for improving organ function and reducing early mortality in AL amyloidosis. While daratumumab has transformed the management of newly diagnosed disease, many daratumumab-treated patients will not clear amyloidogenic serum free light chains or will relapse. Chimeric antigen receptor (CAR) T-cell therapy is a highly active modality in multiple myeloma, capable of inducing deep and durable remissions. Whether this strategy can be safely and effectively adopted in AL amyloidosis remains an important unanswered question. Methods: This multicenter retrospective study involved 8 US academic medical centers within the US Multiple Myeloma Immunotherapy Consortium. We included patients with systemic AL amyloidosis who received BCMA-targeted CAR T therapy to treat AL amyloidosis with concurrent myeloma to investigate the safety, and efficacy of this approach. Results: Between September 2021 and March 2025, we identified 33 patients with AL amyloidosis treated with CAR T (n=9 ide-cel, n=24 cilta-cel). The median age was 69-years (IQR: 60, 72); 48% were female. Most patients were kappa light-chain isotype (61%, n=20), 4 patients (13%) had the t(11;14) translocation. Although baseline plasma cell burden was unknown in 2 cases, all patients had a concurrent diagnosis of myeloma, and 88% of patients had ≥20% bone marrow plasma cells (BPMC) at diagnosis. The median number of prior lines was 6 (range: 3-13), all patients had previous anti-CD38 exposure, and 27 patients (82%) had received previous autologous stem cell transplant. Regarding organ involvement, 11 patients (33%) had cardiac, 9 (27%) renal, 8 (24%) gastrointestinal, 3 (9%) peripheral nerve and 1 (3%) autonomic nerve involvement. Five patients had AL amyloid deposition without known organ involvement. Prior to CAR T, cardiac staging was unavailable or unknown in 19 cases. Of the remaining 14 cases, 6 cases were European Modification of Mayo 2004 stage 3A with no stage 3B cases. Prior to lymphodepletion the median BMPC was 6% (IQR: 1, 20). The overall rate of cytokine release syndrome (CRS) was 64% (Grade 1, G1: n=15, Grade 2, G2: n=4, Grade 3, G3: n=2), and immune cell associated neurological syndrome (ICANS) was 15% (G1: n=3, G3: n=2). The rate of CRS was 56% for ide-cel (G1: 33%, G2: 22%) and 67% for cilta-cel (G1: 50%, G2: 8%, G3: 8%). The median time to CRS onset was 1 day for ide-cel and 6 days for cilta-cel. The median duration of CRS was 1 day for ide-cel and 2 days for cilta-cel. The rate of ICANS was 11% for ide-cel (G1: n=1), and 16% for cilta-cel (G1: n=2, G3: n=2). There were no cases of non-ICANS neurotoxicity. Ten patients (30%) experienced infections (≥Grade 3 = 9%). The overall response rate (ORR) by AL amyloidosis response criteria (Palladini et al. 2012) was 91%, including n=5 very good partial responses (VGPRs) and n=24 complete responses (CRs). The ORR for ide-cel was 78% (n=6 CRs, n=1 VGPR), and for cilta-cel was 96% (n=18 CRs, n=4 VGPRs). Among responders, the median time to VGPR or better was 30 days (IQR: 29, 32). One cilta-cel recipient died of infection on day 17 prior to disease reassessment. At a median follow up of 17.8 months, the 12 and 18-month overall survival rates were 88% (95%CI: 76%-100%) and 83% (95%CI: 68%-100%), respectively. There were 5 deaths; 3 were related to underlying disease, 1 related to infection, and 1 unrelated. Seven patients were eligible for cardiac response assessment (NTproBNP>650 OR BNP>150) at the time of CAR T, and of those, three obtained a cardiac response (2 Cardiac PR, 1 Cardiac VGPR). Three patients were eligible for renal response assessment (>1g proteinuria/day) at the time of CAR T; of those, two obtained a renal PR. Conclusion: We demonstrate that commercial BCMA-targeted CAR T-cell therapy induces deep and rapid hematological responses in a cohort of heavily pretreated patients with AL amyloidosis. Although all patients exhibited overlapping features with concurrent multiple myeloma (≥10% plasma cells at diagnosis), CAR T-cell therapy was feasible to administer, with modest rates of CRS and only isolated cases of severe CRS or ICANS. Nearly all patients achieved a deep hematological response, which appeared to translate into meaningful organ improvement among those who were evaluable.