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Introduction In the KarMMa-3 trial (NCT03651128), ide-cel, a BCMA-directed CAR T cell therapy (Tx), significantly improved median progression-free survival (13.3 vs 4.4 mo, HR 0.49, P < 0.001) and overall response rate (71% vs 42%, P < 0.001) vs std regimens in pts with RRMM who were TCE to immunomodulatory (IMiD ®) agents, proteasome inhibitors (PIs), and daratumumab (Rodríguez-Otero NEJM 2023). Early high-grade (gr) cytopenias and severe infections have been reported post-CAR T cell infusion (Logue Blood 2022, Thibaud Blood 2022), and persistent cytopenias and infections can pose clinical challenges in pt care. In this safety analysis of KarMMa-3, we report frequency, kinetics of occurrence, and management of cytopenias and infections post-Tx with ide-cel or std regimens. Methods This international, randomized, multicenter phase 3 trial enrolled pts with RRMM who received 2-4 prior Txs (an IMiD agent, a PI, and daratumumab) and were refractory to the last Tx. Pts were randomized 2:1 to ide-cel or a std regimen (DPd, DVd, IRd, Kd, or EPd) selected by investigator based on prior anti-MM Tx. In the ide-cel arm, pts could have ≤ 1 cycle of optional bridging Tx (BTx) for disease control. Treated population (pop; ide-cel: pts who received leukapheresis [LA], BTx, lymphodepleting chemotherapy, or ide-cel; std regimens: pts who received any dose of study Tx) was used to assess adverse events (AEs), gr 3/4 AEs, and serious AEs. Safety pop (pts who received ide-cel or any dose of std regimens) was used to assess treatment-emergent AEs, AEs of special interest, investigator-identified neurotoxicity/cytokine release syndrome and others. In pts who had documented disease progression on std regimens and then underwent LA to receive ide-cel, only AEs before LA were included. In this analysis, incidence of cytopenias and infections at various time intervals and management, types of infections, and incidence of hypogammaglobulinemia (HGG) were assessed. Results At data cutoff (Oct 3, 2022), median follow-up was 24.1 (range 5.9−41.0) mo in the 386 randomized pts. In the treated pop, 248/249 (99.6%) vs 124/126 (98.4%) pts had any-gr AEs, 234 (94.0%) vs 96 (76.2%) had gr 3/4, and 36 (14.5%) vs 9 (7.1%) had gr 5 in ide-cel vs std regimens arms, respectively. Of the gr 5 AEs, 18/36 and 3/9 had verbatim terms consistent with progressive disease. In the safety pop, incidence of gr 3/4 cytopenias with ide-cel were higher early after infusion but generally resolved over time (196 [87.1%] pts at < 3 mo, 52 [24.1%] pts at 3−< 6 mo, 30 [14.7%] pts at ≥ 6 mo; Table 1) vs std regimens, which showed lower rate of resolution over time. More pts in the ide-cel (16 [7.1%]) vs std regimens arms (3 [2.4%]) had any-gr febrile neutropenia. Cytopenias were mainly managed using colony-stimulating factor in both arms (55.5% and 58.7%, respectively); RBC (48%) and platelet transfusions (32%) were more common in the ide-cel arm. Overall, incidence of gr 3/4 infections was high at < 3 mo and remained consistent over time in both arms (ide-cel: 17 [7.6%] pts at < 3 mo, 18 [8.3%] pts at 3−< 6 mo, 13 [6.4%] pts at ≥ 6 mo; Table 2). Any-gr bacterial infections were more common in the ide-cel vs std regimens arms with higher incidence at < 3 mo (10% vs 6%) but lowered at later timepoints. Incidence of gr ≥ 3 viral infections remained low and consistent with time; fungal infections were uncommon. Deaths due to infections occurred in 3 (1.3%) vs 1 (0.8%) pts at < 3 mo, 0 pts at 3−< 6 mo, and 7 (3.4%) vs 2 (2.6%) pts at ≥ 6 mo in the ide-cel vs std regimens arms, respectively. Indence of any-gr new HGG was higher in the ide-cel vs std regimens arms but decreased over time: 15 (6.7%) vs 2 (1.6%) pts at < 3 mo, 3 (1.4%) vs 1 (0.9%) at 3−< 6 mo, and 5 (2.5%) vs 0 at ≥ 6 mo, respectively; of these, 13 (5.8%) vs 1 (0.8%), 2 (0.9%) vs 1 (0.9%), and 5 (2.5%) vs 0 pts received IV immunoglobulin replacement Tx at the respective time intervals. Incidence rate (% per 100 pt-years, 95% CI) of second primary malignancies remained low and similar between arms (ide-cel, 4.0 [2.4−6.7]; std regimens, 4.4 [1.9−10.7]). Conclusion In KarMMa-3, most severe cytopenias associated with ide-cel occurred early, with a low incidence of prolonged cytopenias; all were largely manageable. Any-gr bacterial infections decreased over time while viral infections remained the same. No new safety concerns were identified for ide-cel; safety profile was consistent with previous reports. Study support 2seventy bio and Celgene, a Bristol-Myers Squibb Company.

Introduction: Patients with TCE RRMM have a high disease burden and often report worsening HRQoL with additional lines of therapy. The single-arm, phase 2 KarMMa study demonstrated that ide-cel, a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell therapy, improved HRQoL from baseline in patients with TCE RRMM who had received ≥ 3 prior regimens (Delforge M, et al. Blood Adv 2022;6:1309-1318). Furthermore, in the phase 3 KarMMa-3 clinical trial (NCT03651128), ide-cel significantly improved progression-free survival and response compared with standard regimens in patients with TCE RRMM who had received 2-4 prior regimens (Rodriguez-Otero P, et al. N Engl J Med 2023;388:1002-1014). Here we assessed the comparative effects of ide-cel versus standard regimens on HRQoL in patients with TCE RRMM who had received 3-4 prior regimens including an immunomodulatory agent, a proteasome inhibitor, and daratumumab (an anti-CD38 monoclonal antibody) using data from the KarMMa-3 study. Methods: Patient-reported outcomes (PROs) were assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire-Core 30 (QLQ-C30), EORTC Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY20), and EQ-5D-5L. The pre-specified primary domains of interest included EORTC QLQ-C30 global health status/QoL, physical functioning, cognitive functioning, fatigue, and pain; EORTC QLQ-MY20 disease symptoms and side effects of treatment; and the EQ-5D-5L visual analog scale (EQ-5D VAS). PROs were collected at screening (baseline), the day of ide-cel infusion (ide-cel) or first treatment dose (standard regimens), monthly from 2 to 28 months, and thereafter every 3 months. Comparisons were performed on least squares (LS) mean changes from baseline through 28 months between arms using constrained longitudinal data analysis (cLDA). Effect size was estimated by Hedges' g. The comparative effects of ide-cel versus standard regimens on time to confirmed improvement and time to confirmed deterioration (defined by prespecified change thresholds) were assessed via stratified Cox proportional hazards regression analyses. All P values are nominal and not adjusted for multiple testing. Statistical significance was set at P < 0.05. Results: Baseline characteristics were well balanced among the patients in the ide-cel arm (n = 167) and the standard regimen arm (n = 93), with a median age of 63 years and a median time of 4.7 years from RRMM diagnosis to study screening. Completion rates of HRQoL assessments were high over time for most visits (> 75%). At baseline, mean HRQoL domain scores were similar between arms. Overall LS mean changes from baseline to 28 months showed significant differences in favor of ide-cel versus standard regimens (nominal P < 0.05) for 11 domains (effect sizes of 0.26-0.82), and 7 (4 primary: global health status/QoL, cognitive functioning, pain, EQ-5D VAS; 3 secondary: dyspnea, insomnia, constipation) of them exceeded the prespecified MID thresholds (Table). Time to confirmed improvement was significantly shorter (nominal P < 0.05) in the ide-cel arm than in the standard regimen arm for 10 domains, including all primary domains except pain. Time to confirmed deterioration was longer in the ide-cel arm than the standard regimen arm for most domains, with significant differences in emotional functioning, cognitive functioning, and dyspnea (EORTC QLQ-C30). Finally, side effects of treatment favored the ide-cel versus standard regimen arm (EORTC QLQ-MY20) (Table). Conclusions: These patient-reported findings demonstrate that compared with standard regimens, treatment with ide-cel improved MM-relevant disease symptoms, functioning, and overall health status/HRQoL of patients with TCE RRMM in the KarMMa-3 trial. These data further substantiate the superior treatment outcomes of ide-cel over standard regimens in this patient population. Overall, treatment with ide-cel may help alleviate detriments to HRQoL in these patients with complex disease.

Background: An interim analysis (data cutoff date April 18, 2022) of the international, open-label, phase 3 KarMMa-3 trial (NCT03651128) showed the chimeric antigen receptor T cell therapy idecabtagene vicleucel (ide-cel) significantly improved progression-free survival and treatment response rates, as well as HRQoL, as compared with standard regimens, in patients with triple-class exposed (TCE) RRMM who had received 2-4 prior regimens (Rodriguez-Otero P, et al. N Engl J Med 2023;388:1002-1014; Delforge M, et al., HemaSphere, 2023;7(S3):P905). The aim of the present study was to analyze the effect of ide-cel versus standard regimens (daratumumab [DARA], pomalidomide, and dexamethasone [DEX]; DARA, bortezomib, and DEX; ixazomib, lenalidomide, and DEX; carfilzomib and DEX; or elotuzumab, pomalidomide, and DEX) on HRQoL in KarMMa-3 trial participants with an extended follow-up of patient-reported outcomes (PRO) data collection (data cutoff date April 28, 2023). Methods: In KarMMa-3, HRQoL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire-Core 30 (QLQ-C30), EORTC Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY20), and EQ-5D-5L. HRQoL assessments were completed at screening (baseline); the day of ide-cel infusion or the first dose of standard treatment; and monthly from 2 to 28 months; and every 3 months thereafter. The prespecified primary outcomes of interest were EORTC QLQ-C30 global health status/QoL, physical functioning, cognitive functioning, fatigue, and pain; EORTC QLQ-MY20 disease symptoms and side effects of treatment; and the EQ-5D visual analog scale (EQ-VAS). Least squares (LS) mean changes from baseline through month 25 for ide-cel and standard regimens were compared by constrained longitudinal data analysis (cLDA). Effect sizes were estimated by Hedges' g. The effect of ide-cel versus standard regimens on time to confirmed improvement and deterioration in HRQoL (defined by prespecified change thresholds and sustained duration) were compared by stratified Cox proportional hazards regression. There was no adjustment for multiple testing, and all P values reported are nominal. Results: Overall, 254 patients were randomized to the ide-cel arm and 132 to the standard regimens arm. Baseline characteristics were well balanced across treatment arms; both arms had a median age of 63 years, a median of 3 prior anti-myeloma regimens, and median time from MM diagnosis to screening was 4 years. The baseline HRQoL scores were generally comparable between treatment arms. Overall LS mean changes from baseline to month 25 showed significant differences (nominal P value < 0.05) in favor of ide-cel for 18 out of 21 HRQoL domains, with effect sizes (Hedges' g) of 0.27 to 0.82 (Table). For 13 of these domains (including 6 primary domains of interest), the difference in overall LS mean change from baseline exceeded the prespecified minimum important difference (MID) threshold. Time to confirmed improvement was significantly shorter in the ide-cel arm than the standard regimens arm for 19 domains, including all primary domains of interest (Table). Time to confirmed deterioration showed trends of being longer in the ide-cel arm than the standard regimens arm for most domains and was significantly longer for emotional functioning, cognitive functioning, social functioning, dyspnea, and constipation as measured by the EORTC QLQ-C30. The time to confirmed deterioration in side effects of treatment (based on the EORTC QLQ-MY20) was significantly longer for patients in the ide-cel arm and time to confirmed improvement was significantly faster, as compared with the standard regimens arm (Table). Conclusions: In the KarMMa-3 trial, patients with TCE RRMM who had received 2-4 prior regimens, ide-cel significantly and meaningfully improved MM-relevant symptoms, functioning, and overall health status/HRQoL compared with standard regimens. Confirmed HRQoL improvements in the ide-cel arm occurred sooner than standard regimens. PRO improvements were sustained over more than 2 years, which is notable after a single infusion treatment with ide-cel. These patient-reported findings further support the benefit of ide-cel in this patient population.

Introduction Patients (pts) with multiple myeloma (MM) have a higher risk of progression/death following an inadequate response to frontline ASCT (van de Velde Eur J Haematol 2017). Therapies (Tx) with novel mechanisms of action may further improve response outcomes. Ide-cel previously demonstrated frequent, deep, and durable responses in KarMMa (Munshi N Engl J Med 2021) and significantly improved median progression-free survival (PFS) and overall response rate (ORR) versus standard regimens in KarMMa-3 (Rodríguez-Otero N Engl J Med 2023) in pts with triple-class-exposed relapsed and refractory MM. KarMMa-2 (NCT03601078) is a multicohort, phase 2, multicenter trial evaluating the efficacy and safety of ide-cel in pts with MM; cohort 2c included pts with NDMM who had an inadequate response to frontline Tx with ASCT. In cohort 2c, with a median follow-up of 27.9 months, ide-cel demonstrated deep and durable responses; complete response (CR) rate was 74.2% (ORR, 87.1%), with a 24-month PFS rate of 83.1% (Dhodapkar Blood 2022). Here, we report results with an additional 11.5 months of median follow-up for updated efficacy and safety data, and health-related quality of life (HRQoL) outcomes in cohort 2c. Methods Eligible pts had NDMM, received ≥ 3 cycles of induction Tx (including a proteasome inhibitor, an immunomodulatory agent, and dexamethasone), had < very good partial response (VGPR) 70-110 days after ASCT (single/tandem), and had Eastern Cooperative Oncology Group performance status ≤ 1. Pts received a single infusion of ide-cel (dose range: 150-450 × 10 6 CAR+ T cells) after lymphodepletion and could receive maintenance Tx post-infusion at investigator's discretion. The primary endpoint CR rate and secondary endpoints ORR, duration of response (DOR), PFS, overall survival (OS), safety, and patient-reported outcomes on HRQoL, assessed via European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 Questionnaire (QLQ-C30) and EORTC Quality of Life Multiple Myeloma Module 20 Questionnaire (QLQ-MY20), are reported. The exploratory endpoint of minimal residual disease (MRD) negativity (sensitivity, 10 -5) is also reported. Results At data cutoff (May 3, 2023), with a median follow-up of 39.4 (range, 31.6-44.7) months, all 31 pts who were infused with ide-cel were alive; 28 (90.3%) remained in follow-up, with 3 (9.7%) having discontinued due to disease progression. The ORR and CR rates were 87.1% and 77.4%, respectively ( Table); best overall response in 1 pt improved from VGPR to stringent CR. The median DOR was not reached (NR; 95% CI, NR-NR), neither was median PFS (95% CI, 38.0-NR) or median OS (95% CI, NR-NR); the 36-month event-free rates were 80.9%, 76.8%, and 100.0%, respectively. In pts who did not receive lenalidomide (LEN) maintenance, 9 (29.0%) had disease progression; of the 8 pts who received LEN maintenance post ide-cel infusion, none experienced disease progression. At 36 months, MRD negativity was confirmed in 9/14 (64.3%) evaluable pts; all 9 achieved ≥ CR. In this extended follow-up, safety results were generally consistent with the previous data cutoff. All pts experienced ≥ 1 any-grade adverse event (AE), most commonly hematologic, including neutropenia (80.6%), anemia (38.7%), leukopenia (32.3%), and thrombocytopenia (29.0%); infection and infestation AEs occurred in 74.2% of pts. No grade 5 AEs were reported. Incidence of any-grade cytokine release syndrome (58.1%; no grade ≥ 3) was unchanged and there were no additional reports of parkinsonism since the previous report. Overall, HRQoL improved ( Figure) and MM disease symptoms were stable over time based on the EORTC QLQ-C30 and QLQ-MY20, respectively, following ide-cel treatment; by month 3, > 75% of pts had improved or stable global health status/QoL. Conclusions Ide-cel continued to demonstrate deep, durable responses in pts with an inadequate response to frontline ASCT, no new safety signals were observed with extended follow-up, and no deaths were reported. No pts who received LEN maintenance post ide-cel experienced disease progression. Ide-cel treatment resulted in stable or improved HRQoL. Overall, ide-cel continued to demonstrate a favorable clinical benefit-risk profile in NDMM after ASCT. Study support 2seventy bio and Celgene, a Bristol-Myers Squibb Company.

Background:Patients with R/R CLL/SLL who experience intolerance to or disease progression after Bruton tyrosine kinase inhibitor (BTKi) and venetoclax treatment have no established standard of care and poor outcomes, indicating a critical unmet need. Liso-cel, an autologous, CD19-directed, 4-1BB CAR T cell product, has demonstrated efficacy in large B-cell lymphoma and CLL/SLL. In the primary analysis of the phase 1/2, single-arm, multicenter TRANSCEND CLL 004 (NCT03331198) study, a single administration of liso-cel demonstrated rapid, deep, and durable responses and a manageable safety profile in patients with R/R CLL/SLL, including those with progression on previous BTKi and venetoclax failure (Siddiqi T, et al. Lancet 2023). The primary endpoint was met in the prespecified subset of efficacy-evaluable patients with disease progression on BTKi and venetoclax failure (primary efficacy analysis set [PEAS]) at a target dose of 100 × 10 6 CAR + T cells (null hypothesis: ≤ 5%) with the rate of complete response/remission (CR) and CR with incomplete marrow recovery (CRi) by an independent review committee (IRC) per 2018 International Workshop on CLL (iwCLL) criteria at 18.4% ( P = 0.0006). Here we report results from TRANSCEND CLL 004 with a median follow-up of 23.5 months. Methods: Patients must have received ≥ 2 prior lines of therapy, including a BTKi. Eligible patients received liso-cel at a target dose of either 50 × 10 6 (dose level [DL] 1) or 100 × 10 6 (DL2) CAR + T cells after lymphodepleting chemotherapy. The primary endpoint was CR/CRi in the PEAS at DL2. Key secondary endpoints were ORR and rate of undetectable MRD (uMRD; 10 −4 by next-generation sequencing) in blood. All null hypotheses were tested at the primary analysis and not retested in this analysis. Results:Of 137 leukapheresed patients, 118 received liso-cel (safety set), 97 (DL1 = 9; DL2 = 88) were efficacy evaluable, and 54 (DL1 = 4; DL2 = 50) were in the PEAS. In the safety set, median (range) age was 65 years (49-82), 83% had high-risk cytogenetics (del[17p], 42%; TP53 mutation, 47%; unmuted immunoglobulin heavy-chain variable gene, 47%; ≥ 3 chromosomal aberrations, 61%), median (range) lines of prior therapy was 5 (2-14), and all patients had prior BTKi. As of data cutoff (February 28, 2023), median (range) on-study follow-up was 23.5 months (0.4-59.6) for the safety set. In the PEAS at DL2, CR/CRi rate was 20% (95% CI, 10.0-33.7; Table 1). ORR was 44% (95% CI, 30.0-58.7). One patient who had best overall response (BOR) of partial response/remission (PR) at primary analysis had deepened to CR/CRi at 18 months without any additional therapy. Of 9 patients who had BOR of CR/CRi at the primary analysis, 8 had ongoing CR/CRi and 1 completed the study with the last assessment as CR/CRi. The uMRD rate was 64% (95% CI, 49.2-77.1) in blood and 60% (95% CI, 45.2-73.6) in marrow. Median (95% CI) duration of response was 35.3 months (12.4-not reached [NR]) and median duration of CR/CRi was NR. Median (95% CI) PFS was 11.9 months (5.7-26.2). Median (95% CI) OS was 30.3 months (15.0-NR). The efficacy outcomes were similar in the full population at DL2. Of 16 patients who had BOR of CR/CRi at primary analysis, 10 had ongoing CR/CRi. In the safety set, rates of any-grade and grade ≥ 3 treatment-emergent AEs were similar across age groups (Table 2). The rate of any-grade cytokine release syndrome (CRS) was 85% (grade 3, 8%; no grade 4/5) and neurological events (NE) was 45% (grade 3, 18%; grade 4, 1%; no grade 5); 69% received tocilizumab and/or corticosteroids for CRS/NEs. Median (range) time to onset and resolution was 4 days (1-18) and 6 days (2-37) for CRS and 7 days (1-21) and 7 days (1-83) for NEs, respectively. Prolonged cytopenia (grade ≥ 3 at Day 30 after liso-cel infusion), grade ≥ 3 infections, hypogammaglobulinemia, tumor lysis syndrome, second primary malignancy, and macrophage activation syndrome occurred in 54%, 18%, 15%, 11%, 9%, and 3%, respectively. Forty-five (33%) of 137 leukapheresed patients died after liso-cel infusion (disease progression, n = 27 [20%]; AE, n = 6 [4%]; other reasons, n = 12 [9%]). Conclusions: With longer follow-up, liso-cel continued to demonstrate durable CR/CRi, high uMRD rates, and a manageable safety profile in patients with heavily pretreated, high-risk R/R CLL/SLL. The safety results from longer follow-up were similar to those reported in the primary analysis with no new safety signals and were consistent across age groups.

Introduction Golcadomide (GOLCA, CC-99282) is an orally available cereblon E3 ligase modulator (CELMoD ®) that potently degrades target proteins Ikaros and Aiolos, enhancing antiproliferative, apoptotic, and immunomodulatory activity and preferentially distributing to lymphoid organs. In a phase 1 study, GOLCA monotherapy previously demonstrated a manageable safety profile with promising clinical activity in relapsed/refractory non-Hodgkin lymphoma (Michot Blood 2021). In the ongoing CC-220-DLBCL-001 study (NCT04884035), GOLCA dose finding is underway in patients with previously untreated aggressive B-cell lymphoma (BCL), in combination with R-CHOP in 21-day (D) cycles (C), at a variety of GOLCA dose levels (DLs) and schedules: DL-1 = 0.2 mg D1-7, DL1 = 0.4 mg D1-7, and DL2 = 0.4 mg D1-10. Here, we report Ikaros degradation, immune modulation, circulating tumor DNA (ctDNA) assessment, and baseline tumor genomics. Methods Peripheral blood was collected to analyze Ikaros and Aiolos levels in T cells by flow cytometry (C1D1, C1D7, and C2D1). Immune phenotyping of T and natural killer (NK) cells was performed by flow cytometry (C1D1, C1D15, C2D1, and C3D1). ctDNA levels were analyzed by the PhasED-Seq assay (timepoints C1D1, C2D1, C3D1, and end of treatment [EOT]; Kurtz Nat Biotechnol 2021); somatic variants were filtered by performing PhasED-seq on buffy coats. Pretreatment biopsies were analyzed by whole genome sequencing and whole transcriptome sequencing. DL1 (0.4 mg D1-7) and DL2 (0.4 mg D1-10) data were pooled. Results Ikaros levels in T cells at 5 hours after the first dose had a 1.1% median increase with 0.2 mg and 44% median decrease with 0.4 mg; by C1D7 pretreatment, Ikaros substantially decreased with both DLs (median: 0.2 mg, 87% decrease; 0.4 mg, 83% decrease). Ikaros differences between 0.2 mg and 0.4 mg were not substantial. By C2D1, Ikaros levels recovered to baseline. Based on preclinical benchmarks, steady-state Ikaros degradation in T cells suggested that direct tumor cell killing by GOLCA was achieved. Changes in T and NK cell phenotypes in peripheral blood included activation, increased proliferation, increased T effector memory and regulatory cell levels, and decrease in naive T cells. Changes were seen by C1D15 and maintained at C2D1 and C3D1. Overall, immune changes between 0.2 mg and 0.4 mg dose levels were not substantially different. Phased variant data from ctDNA and buffy coats were evaluable for 34 patients (0.2 mg, n =15; 0.4 mg, n = 19). Baseline ctDNA levels were similar between the 0.2 mg and 0.4 mg cohorts and, consistent with prior studies, correlated with International Prognostic Index and cell of origin. Previously reported landmarks such as early molecular response (EMR; ≥ 2 log decrease) at C2D1 and major molecular response (MMR; ≥ 2.5 log decrease) at C3D1 were assessed (Kurtz J Clin Oncol 2018) . A high fraction of patients designated high risk by pretreatment ctDNA (≥ 2.5 log haploid genome equivalents [HGE]/mL; Kurtz J Clin Oncol 2018) were clinical responders. Patients who achieved minimal residual disease (MRD) negativity on treatment generally remained MRD negative at subsequent timepoints. At C2D1, the EMR and MRD negativity rates for 0.2 mg were 73% (11/15) and 20% (3/15), respectively; for 0.4 mg these rates were 83% (15/18) and 44% (8/18). At C3D1, the MMR and MRD negativity rates for 0.2 mg were 83% (10/12) and 42% (5/12), respectively; for 0.4 mg these were 83% (10/12) and 58% (7/12). Although ctDNA differences between 0.2 mg and 0.4 mg were not substantial, numerically greater ctDNA changes were seen with 0.4 mg GOLCA + R-CHOP vs 0.2 mg GOLCA + R-CHOP and vs R-CHOP and R-CHOP-like regimens from other cohorts ( Figure). Insufficient samples were available to draw conclusions about EOT, but additional ctDNA data will be presented. Whole genome and transcriptome sequencing data from GOLCA + R-CHOP-treated patients will be shown. Conclusions Pharmacodynamic biomarkers and ctDNA levels indicate that both tumor-intrinsic and immune-modulating mechanisms of action of GOLCA remain relevant in combination with R-CHOP in previously untreated aggressive BCL. ctDNA data during treatment are consistent with the efficacy noted on clinical restaging. Translational data demonstrate the potency of GOLCA and will support future frontline clinical trial designs in patients with untreated aggressive BCL. Study support: Celgene, a Bristol-Myers Squibb Company

Background Diffuse large B cell lymphoma (DLBCL) is the most common aggressive lymphoid malignancy in adults. Though standard immunochemotherapy regimens can result in clinical remission and cure in a majority of patients, approximately 30% of patients are primary treatment resistant or eventually relapse (rrDLBCL), and their prognosis is very poor. Recent molecular classification by large scale genomic and transcriptomic profiling of newly diagnosed DLBCL tumors has resulted in a deeper understanding of disease drivers, however, the molecular heterogeneity of rrDLBCL is yet to be fully explored. Therefore, in this study, we used an unsupervised approach to better define transcriptional and genetic programs in rrDLBCL samples hypothesizing that molecular stratification within this high-risk group may lead to a better understanding of this disease, which remains an unmet need, and a more personalized therapeutic approach. Methods Data used in this study included RNA (n=143) and whole exome (n=126) sequencing data from available FFPE tumor samples at the time of a relapse (any line of treatment, r1-r10 relapse timepoints included in analysis, one per patient), consented to the Molecular Epidemiology Resource (n=61), banked in the Mayo Lymphoma Biobank (n=50), or consented to the CC-122-ST-001 clinical trial (n=32, NCT01421524). Unsupervised clustering was performed on protein coding gene expression values using the non-negative matrix factorization (NMF) approach. NMF was carried out by performing 200 runs on cluster sizes from 2 to 6. Cell of origin (COO) was determined using the method described by Reddy et al. The tumor microenvironment was analyzed using CIBERSORTx and Lymphoma Microenvironment Classification (LME). Genetic classification was done using LymphGen. Results In order to identify unique transcriptional programs in rrDLBCL, we implemented NMF and consensus clustering to define an ideal quantity of stable patient clusters. We identified 4 rrDLBCL patient clusters (rrC1-rrC4) as the most stable solution, based on consensus clustering selection criteria of iterative NMF runs. While relapse timepoint was not associated with individual clusters, we did observe significant differences in tumor characteristics between the clusters. COO classification found that rrC1 and rrC4 were enriched for GCB-DLBCL while rrC3 was enriched for ABC-DLBCL classification (P < .001). To explore the biologic programs in each cluster, we used pathFindR, which leverages protein-protein interaction networks to identify disease related pathways, rrC1 and rrC4 were defined by pathways involved in cell cycle and mismatch repair; oxidative phosphorylation in rrC2; and MAPK and NF-kB in rrC3. Next, LME classification was done to define patterns in the tumor microenvironment and we found a significant difference between groups (P < .001), with rrC2 and rrC4 tumors enriched for a depleted TME, while rrC1 and rrC3 had a more immune rich or inflammatory TME. This was supported by CIBERSORTx analysis identifying significant differences (P > .001) in abundance of CD8 T cells, memory CD4 T cells, and M1 macrophages between clusters, with rrC4 having the lowest abundance. We then explored genetic patterns in each cluster. Gene level mutation enrichment analysis showed BCL7A mutation exclusively in C4 (6/6, P = .03). The clusters were not associated with LymphGen classification. Lastly, our recently published high risk signature classification that is associated with early clinical failure and is characterized by metabolic dysregulation, a depleted TME, T53 alterations, and poor outcome, was significantly different between the groups (P = .03) with enrichment for high-risk cases in rrC4. In summary, we show for the first time that rrDLBCL patients can be classified into four gene expression clusters that are associated with distinct pathway, TME, and genetic programs. These clusters should now be tested to learn if they can help select patients for newer therapies for rrDLBCL such as CAR-T and bispecific antibodies.

Introduction: Adverse events (AE), such as cytokine release syndrome (CRS) and neurological toxicity (NT), have been associated with chimeric antigen receptor (CAR) T cell therapies. Idecabtagene vicleucel (ide-cel, bb2121), a B-cell maturation antigen-directed CAR T cell therapy, demonstrated deep and durable responses in triple-class exposed (TCE) patients (pts) with RRMM in the pivotal, single-arm, open-label phase 2 KarMMa (3 prior lines of therapy [LOTs]; NCT03361748) (Munshi NC, et al. NEJM 2021;384:705-716) and superior progression-free survival with ide-cel vs standard regimens in the phase 3 KarMMa-3 trial (2-4 prior LOTS; NCT03651128) (Rodríguez-Otero P, et al. NEJM 2023;388:1002-1014). Healthcare resource utilization (HCRU) and costs associated with CRS/NT management were estimated previously for pts receiving ide-cel in the KarMMa trial (McGarvey N, et al. Value Health 2023;26:S89) and suggested low rates of severe (grade ≥ 3) CRS/NT following ide-cel infusion and higher HCRU and costs with increasing AE severity. To further assess resource and economic burden associated with care of treatment-emergent AEs, this analysis evaluated HCRU and estimated cost of CRS/NT management among pts treated with ide-cel in earlier-line settings in the KarMMa-3 study. Methods: In this retrospective study, case report forms from the KarMMa-3 clinical trial database among pts experiencing a CRS and/or NT event that initiated within 90 days post ide-cel infusion were assessed. Pt-level HCRU data, including hospitalizations and length of hospital stay (LOS) (standard inpatient [IP], intensive care unit [ICU] days), diagnostics (eg, lab work, imaging), procedures (eg, dialysis, intubation), and medications (eg, oncology supportive care, prophylactics, other AE management) were identified from CRS/NT onset through resolution. AE management costs were estimated using a micro-costing methodology in which unit costs sourced from public databases or literature (eg, United States Centers for Medicare and Medicaid Services, Healthcare Cost and Utilization Project, IBM ® Micromedex ® RED BOOK ®) were adjusted to 2022 US dollars (USD) using the Consumer Price Index and applied to each HCRU identified. Results: Of 225 pts treated with ide-cel in the KarMMa-3 trial, 203 (90.2%) experienced any grade CRS and/or NT event. Pts experiencing a CRS/NT event had a mean (standard deviation [SD]) age of 61.9 (8.9) years and most were male (123/203 [60.6%]), White (138/203 [68.0%]), and non-Hispanic or Latino (138/203 [68.0%]). The majority (187/203 [92.1%]) of pts experienced less severe CRS/NT events (grade ≤ 2), which resolved quicker and relatively few pts (16/203 [7.9%]) had a more severe (grade ≥ 3) event, which took longer to resolve. Among pts who received ide-cel, the estimated median cost of AE management ranged from USD 17,124 (CRS only grade 1) to USD 181,552 (nonconcurrent CRS or NT grade ≥ 3) (Figure 1). Additional median costs for a pt with a grade ≥ 3 CRS/NT event was USD 31,045 higher than a grade ≤ 2 CRS/NT event. Across AE categories, the main contributors to CRS/NT management were facility costs, namely standard IP hospitalizations and ICU stays. Almost all pts (202/203 [99.5%]) had a standard IP hospitalization; 3.9% (8/203) had an ICU stay (Table 1). The trial protocol required a stay of ≥ 15 days post infusion unless admitted to the ICU; some hospitalization days recorded during the AE overlapped with the protocol-required stay. ICU admissions were more common among pts with CRS/NT grade ≥ 3 (7/16 [43.8%]) than those with grade ≤ 2 (1/187 [0.5%]). Median (range) total LOS was 10 days longer among pts with grade ≥ 3 (14.5 [2-84] days) than those with grade ≤ 2 (4 [1-34] days) CRS/NT. Pts with grade ≥ 3 CRS/NT had higher rates of HCRU than those with grade ≤ 2 for several interventions, such as medications (eg, tocilizumab + corticosteroids: 13/16 [81.3%] vs 63/187 [33.7%]), diagnostics (eg, imaging: 14/16 [87.5%] vs 48/187 [25.7%]), and procedures (eg, dialysis:3/16 [18.8%] vs 0/187 [0%]). Conclusions: Most pts with RRMM treated with ide-cel in the KarMMa-3 trial experienced a CRS and/or NT event, however, few were of high severity (grade ≥ 3). HCRU and costs for CRS/NT increased with AE severity and management. CAR T cell therapies associated with lower-severity AEs and planned interventions to prevent higher-grade AEs may provide an opportunity to better manage HCRU and costs.

Presence of deletion17p (del17p) in frontline (1L) and relapsed/refractory (R/R) CLL has been associated with shorter time to treatment initiation, early relapse after therapy and inferior overall survival (OS) (Mato et.al., Haemotologica 2022). However, there exists notable clinical heterogeneity in terms of outcome within this group (Tam et.al., Blood 2009, Stephens et.al; AJH 2015). Previous reports in 1L and R/R CLL have identified percentage of del17p nuclei by fluorescence in situ hybridization (FISH), having TP53 mutations on the second allele, copy number alterations and complex karyotype (CK) as additional risk factors within the del17p population (Yu et al., CCR 2017; Baliakas et al., Blood 2019). Here we profile a cohort of wait and watch (W&W, n=14), 1L treated (n=36) and R/R CLL (n=3) patients by whole genome sequencing (WGS) and RNA sequencing (RNAseq) to gain insights into genomic factors and gene expression pathways contributing to the high-risk nature of del17p across the spectrum of CLL patients. Using the Mayo Clinic CLL Database, we identified 53 patients with del17p (identified by FISH testing in routine clinical practice at diagnosis) who had stored peripheral blood mononuclear cells (PBMCs) available. RNA and DNA from matched peripheral blood (tumor) and DNA from CD19- (germline) samples at diagnosis (n=50) and relapse (n=3) was extracted using Qiagen RNeasy (RNA) and Purene (DNA) kits and subjected to RNAseq and WGS respectively. Additional FISH assays (del11q, trisomy 12, del13q) and CK by chromosomal banding analysis (CBA) were performed. Baseline clinical characteristics, time to first treatment, types of treatment, and survival were abstracted from the CLL Database. The Mayo Clinic IRB approved this study. Copy number analysis identified deletions in 3p, 4p, 8p, 9p, 9q and gains in 2p, 8q, 15q and 17q chromosomal lesions occurring in patients. We explored the association of clinical and genetic factors, and genomic instability signatures with survival to identify high-risk features in del17p patients. Both total number of deletions by WGS and number of chromosomal aberrations by CBA as a continuous variable were significantly associated with unfavorable OS in the entire cohort (n=53) in a univariate analysis (Hazard ratio, HR= 2.29, p= 0.00054 and HR= 2.33, p=0.0054 respectively). However, there was no significant association of number of gained genes by WGS or aneuploidy scores with survival (HR=0.74, p=0.37). In patients with CK data (n=41), deletion burden, but not gains, were highly correlated to chromosomal aberrations by CBA. Using cutpointr package for identifying deletion threshold corresponding to CK≥ 3, we defined patients with deletion burden ≥ 514 as enhanced-high risk (EHR; median OS = 4.83 years) compared to the group with high-risk (HR; median OS=9.94 years) (p=0.025). There was no significant difference in number of deleted genes between WW and treated patients. The EHR group is enriched in patients with high clonal cell fraction of del17p by FISH, unmutated IGHV and CK≥ 3. The EHR group remains significant in a multi-variable analysis with IGHV-mutation status, ZAP70, and age (HR: 5.16, 95% CI: 1.04 - 25.6, p=0.04). Mutational analysis identified 35 known CLL driver mutations with TP53 (86%), ATM (15%), NOTCH1(13%), MGA (13%), CHD2 and MED12(11%) as the top mutated genes. Total number of driver genes mutated was not significantly different between EHR and HR subgroups, but the EHR subset was significantly enriched with mutations in NOTCH1 (21%), and MGA (21%) as compared to no mutations in the HR group in these genes. Deleted genes (≥ 514) was prognostic in bi-allelic TP53 aberration patients as well (p=0.021) Differential expression gene-set enrichment analysis indicated a significant enrichment of DNA repair, cellular response to DNA damage and downregulation of inflammatory responses in the EHR group. CK is a known prognostic marker which includes both chromosomal losses and gains. In this small cohort of del17p we were able to show the prognostic value of deletions only, but not gains, as captured by WGS. Using genome wide sequencing, we identify increasing genomic deletions as a feature of enhanced-high risk del17p. While deletion burden cut-offs identified here are specific to our research method and require further validation in additional independent cohorts, EHR subgroup remained significant after adjusting for other known prognostic variables .