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Abstract Introduction: Liso-cel is an autologous, CD19-directed, 4-1BB CAR T cell product. TRANSFORM (NCT03575351) is a global, randomized, open-label, phase 3 study of liso-cel versus SOC as second-line therapy in adults with R/R LBCL. In the TRANSFORM study, liso-cel showed superior, more durable efficacy versus SOC, with a potential long-term survival benefit and a favorable safety profile, highlighting the curative potential of liso-cel for second-line R/R LBCL. Upon completion of TRANSFORM, patients who received liso-cel could enroll into a separate, long-term follow-up (LTFU) study (NCT03435796). Here, we report results after approximately 4 years of follow-up in patients from TRANSFORM who consented to the LTFU study. Methods The TRANSFORM study compared liso-cel versus SOC (chemotherapy [R-DHAP, R-ICE, or R-GDP] followed by high-dose chemotherapy [HDCT] + ASCT) in adults aged ≤ 75 years with LBCL primary refractory to or relapsed within 12 months of first-line therapy and eligible for ASCT. Patients in the liso-cel arm underwent lymphodepletion followed by liso-cel (100 × 106 CAR+ T cells). Crossover to receive liso-cel was allowed for patients in the SOC arm. The LTFU study enrolled patients who received liso-cel and discontinued early or completed TRANSFORM; liso-cel was not administered during the LTFU study and subsequent therapies were administered at investigator discretion. Selected AEs considered related to liso-cel (malignancies, neurologic, hematologic, or rheumatologic/autoimmune disorders) and OS would be assessed at each visit (month 3 and then every 6 months from years 1 to 5, and then annually) for up to 15 years from liso-cel infusion until study withdrawal or death, whichever occurred first. OS for the combined study was defined as the time from randomization to death due to any cause. PFS for the combined TRANSFORM and LTFU studies incorporated data from TRANSFORM, assessed by an independent review committee, and from LTFU, assessed by investigators, and was defined as the time from randomization to disease progression or death from any cause. For LTFU only, OS and PFS were measured from LTFU consent to event or censoring. In cases where the patient was censored at last assessment date (without receiving new therapy) in TRANSFORM and enrolled in LTFU, LTFU data were used. For patients from the liso-cel arm of TRANSFORM who did not enroll in the LTFU study, the data from TRANSFORM were considered (ie, either an event or censored) at their last adequate assessment date or before starting new therapy. Results are reported descriptively. Results In total, 184 patients were randomized in TRANSFORM (92 per arm); key demographics and baseline characteristics were previously reported (Abramson, et al. Blood 2023). The LTFU study enrolled 67 patients who received liso-cel (liso-cel arm, n = 43; crossover from SOC arm, n = 24). The median follow-up (range) for the liso-cel arm was 16.9 months (1.3–29.7) in the LTFU study and 40.1 months (2.2–61.9) combining the TRANSFORM and LTFU studies. The median follow-ups for OS and PFS for the liso-cel arm in the LTFU study were 17.1 (16.1–21.9) and 16.9 months (16.0–21.8), respectively. In patients from the LTFU study in the liso-cel arm (n = 43), median PFS and OS were both not reached (NR) with 95% CIs of NR–NR. The 24-month rates (95% CI) of PFS and OS were 94.7% (87.4–100.0) and 95.1% (88.4–100.0), respectively. In the 92 patients randomized to the liso-cel arm, using combined data from the TRANSFORM and LTFU studies, median (95% CI) PFS was NR (12.6–NR); 48-month PFS rate was 52.2% (41.5–62.8). Median (95% CI) OS was NR (NR–NR); 48-month OS rate was 61.5% (51.2–71.7). Safety results from the LTFU study in the liso-cel arm showed no new signals compared with previous reports from TRANSFORM. AEs of any grade occurred in 2 patients (hypogammaglobulinemia and dyspnea; n = 1 each), with no second primary malignancies or serious infections. AEs of grade 3 or 4 occurred in 1 patient (dyspnea). No AEs led to death.Conclusions: After a median follow-up of approximately 4 years combining data from the TRANSFORM and LTFU studies, liso-cel continued to demonstrate long-term clinical benefit with high PFS and OS rates in patients with second-line R/R LBCL. The safety profile of liso-cel continued to be manageable with no new safety signals observed during LTFU. These results further support liso-cel as an effective second-line treatment with curative potential for R/R LBCL.

Abstract Background: The addition of the CD19/CD3 bispecific T-cell engager, blinatumomab, to standard consolidation chemotherapy in adults with ALL who achieved a measurable residual disease negative (MRDneg) remission (CR), demonstrated an improvement in 3-year overall survival (OS, 85% vs 68%, HR 0.41, P=0.002) and 3-year relapse-free survival (RFS, 80% vs 64%, HR 0.53) compared to conventional chemotherapy in the ECOG-ACRIN E1910 study (Litzow et al, NEJM 2024). Given the complex therapy in this study, treatment delays and modifications are expected. We herein explored the impact of such delays on patient outcomes. Methods: In the phase 3 ECOG-ACRIN E1910 trial (NCT02003222), adults aged 30-70 years with newly diagnosedALL who had achieved MRDneg CR following induction and intensification were randomized to consolidation chemotherapy with blinatumomab (blina arm) or chemotherapy alone (chemo arm). We examined the association between the timing of the initiation of maintenance therapy and OS and RFS. The expected duration of consolidation was 252 days vs 126 days for patients on the blina and chemo arms, respectively. For this analysis, participants were classified into two groups (no/short delay or long delay) depending on whether they started on time/before or after the median time between the beginning of consolidation and start of maintenance therapy for their treatment group (medians: 335 days, range, 181-457 days vs 176 days, range, 139-265 days for blina and chemo arms, respectively). Multivariate analyses of OS and RFS were performed to examine the effect of no/short delay vs. long delay in starting maintenance. Patients were stratified according to their assigned consolidation treatment arm, and the models were further adjusted for age, sex, white blood cell count, platelets, hemoglobin, peripheral blood blasts, bone marrow blasts, performance status and genetic-genomic risk at diagnosis. Results: Of the 488 patients enrolled, 224 MRDneg patients were randomized to consolidation chemotherapy with or without blinatumomab and 135 of the 224 went on to maintenance therapy on study (N= 66 on blina arm and 69 on chemo arm, respectively). The median follow-up from the time of maintenance registration was 43.4 months. There were no significant differences in baseline characteristics between patients in either arm who experienced no/short delay or long delay. In the blina group, 60 of 66 patients (90.9%) received all 8 cycles of consolidation therapy of which 31 (45.6%) had long delays. Sixty-eight of 69 patients on the chemo arm (98.5%) received all cycles of consolidation therapy, of which 34 (50%) had a long delay. Strikingly, patients who had a long delay before initiation of maintenance had a significant improvement in OS in multivariate analysis compared to patients who had no/short delay (HR 0.31, 95% CI: 0.11-0.91; P =0.03). However, within each treatment group, OS benefit did not reach statistical significance (blina arm: HR 0.04, 95% CI: 0.001-1.64; P =0.09; chemo arm: HR 0.32, 95% CI: 0.08-1.38; P =0.13). Similar results were observed for RFS in multivariate analysis (HR 0.40, 95% CI: 0.16-1.01; P =0.05), though this impact on improved RFS was noted in the chemo arm but not in blinatumomab treated patients (blina arm: HR 0.56, 95% CI: 0.10-3.24; P =0.52; chemo arm: HR 0.19, 95% CI: 0.04-0.83; P=0.03). Additionally, patients who had no/short delay before starting maintenance experienced a longer median duration of maintenance treatment (blina arm, 548 days; chemo arm, 708 days) compared to patients who had a long delay (blina arm 488 days; chemo arm 598 days) before initiation of maintenance (P=0.0008). Conclusion: In the phase 3 randomized ECOG-ACRIN E1910 clinical trial, long delays between initiation of consolidation therapy and start of maintenance therapy were associated with improved OS compared to no/short delays. However, within each treatment group (blina or chemo), no significant difference of OS was observed. We postulate that these longer delays allowed more patients to receive all of the recommended protocol-assigned therapy thereby resulting in improved survival. Furthermore, patients who had no/short delays had a significantly longer duration of maintenance therapy. These data indicate that treatment delays during consolidation do not worsen survival. Further studies are being done to better understand why patients with long delays had better overall survival.

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.

Abstract Introduction: The attainment of rapid and deep hematologic responses is key to restoring organ function and reducing mortality in AL amyloidosis. Despite the introduction of anti-CD38 monoclonal antibodies, ~50% of AL patients will respond sub optimally to 1st-line therapy, and many will relapse. Bispecific T-cell engagers (TCEs) have produced unprecedented outcomes in relapsed myeloma, and whether they can be safely applied to AL amyloidosis is a key clinical question. Methods: A multicenter retrospective study involving 9 US academic medical centers within the US Multiple Myeloma Immunotherapy Consortium. We included patients with systemic AL amyloidosis who received bispecific TCE therapy targeting either BCMA or GPRC5D to investigate the safety, and efficacy of this approach. Results: Between February 2023 and March 2025, we identified 29 patients with AL amyloidosis treated with TCEs (n=19 teclistamab, n=6 elranatamab, n=4 talquetamab). The median age was 72-years (IQR: 66, 75), with a female predominance (59%, n=17). Most patients had lambda light-chain isotype (59%, n=17), 31% (n=9) had t(11;14). Diagnostic bone marrow plasma cell (BMPC) burden was unknown in 6 cases, of the remaining cases 74% had ≥10% and 65% had ≥20% BMPCs. Ten patients (34%) had either ≥60% BMPCs at diagnosis or an involved FLC ratio >100 prior to TCE. The median number of prior lines was 5 (IQR: 4, 6), all patients had previous anti-CD38 monoclonal antibody exposure, 55% (n=16) had received an autologous stem cell transplant, and 28% (n=8) had received prior BCMA-directed therapy (n=4 antibody drug conjugates [ADCs], n=3 CAR T, n=1 ADC + TCE). Immediately prior to TCE therapy, 8% (n=2) were stage 3A and 19% (n=5) were stage 3B according to the European modification of the Mayo 2004 prognostic score. Staging was unknown in n=3 cases. Regarding organ involvement, 66% (n=19) had cardiac, 59% (n=17) had renal, 24% (n=7) had gastrointestinal (biopsy-proven), 10% (n=3) had peripheral nerve and 3% (n=1) had autonomic nerve involvement. The rate of cytokine release syndrome (CRS) was 45% (Grade 1, G1: n=8, Grade 2, G2: n=5, Grade ≥3,G3+: n=0), and immune cell associated neurological syndrome (ICANS) was 14% (G1: n=3, G2: n=1, G3+: n=0). Seven patients (24%) received tocilizumab as treatment, a further one patient received prophylactic tocilizumab. One-third of the cohort experienced at least one infection (n=10), and 20 (n=6) experienced a ≥grade 3 infection. The overall response rate was 76% (n=22) by AL amyloidosis response criteria, including a 66% (n=19) complete response (CR), 7% (n=2) very good partial response (VGPR), and 3% (n=1) partial response (PR) rate. Two patients did not undergo disease reassessment; one due to an early treatment-emergent death, and one who was lost to follow-up before cycle 2. Among responders, the median time to a VGPR or better was 29 days (IQR: 18, 56). At a median follow up of 8.8 months, the 1-year overall survival rate was 77% (95%CI: 62%-95%). Of the 6 deaths which occurred, 3 occurred while on TCE therapy (VF arrest during step up not associated with CRS, cardiac failure, and infectious complication), and 3 deaths occurred off therapy (unknown, progressive disease, and as a complication of surgery). Of 14 patients eligible for cardiac response assessment at the time of TCE therapy (NTproBNP>650 OR BNP>150), 9 (64%) obtained a response (CarPR=4, CarVGPR=2, CarCR=3). Of 4 patients eligible for renal response assessment at the time of TCE initiation (>1g proteinuria/day), all 4 patients obtained a response (RenPR=1, RenVGPR=2, RenCR=1). Conclusion: This is the largest cohort of TCE therapy in AL amyloidosis. TCE therapy produced a high rate of rapid and deep haematological responses. Despite a high prevalence of cardiac and renal involvement, rates of CRS were low with no grade ≥3 events, however, infectious complications were frequent. Non-relapse mortality reflected our cohort's advanced disease and prior treatment, including 2 deaths (7%) unequivocally related to cardiac causes. Although follow-up was limited, there was a high rate of early organ responses, consistent with the deep hematological response rates observed. Although our cohort exhibited overlapping features with multiple myeloma, such as a high baseline plasma cell burden, the pattern of organ involvement was consistent with typical AL amyloid populations, supporting the broader application of this therapy in AL amyloidosis.

Abstract Introduction: Liso-cel, an autologous, CD19-directed CAR T cell product, has demonstrated consistent efficacy in a broad population of pts with B-cell malignancies, including R/R LBCL. Its well-established safety profile has made OP delivery commonplace. This, combined with recent changes to postinfusion monitoring requirements, offers pts the potential for greater access to care. Here, we describe real-world safety and effectiveness outcomes for pts with R/R LBCL who received liso-cel as standard of care (SOC) therapy in the inpatient (IP) or OP setting. Methods: This was an observational study of pts in the US with R/R LBCL who received commercial liso-cel as second-line (2L) or later treatment (tx) in the IP or OP setting between 02/2021 and 02/2025 and had ≥1 postinfusion assessment reported in the Center for International Blood & Marrow Transplant Research (CIBMTR). Safety outcomes included rates of AEs of special interest and nonrelapse mortality (NRM). Postinfusion hospitalizations in the OP group were also assessed. Effectiveness outcomes included ORR, CR rate, duration of response (DOR), PFS, and OS. All results are reported descriptively. Results: Of 1116 eligible pts, 34% (n=375) were intended for OP tx, as reported to the CIBMTR, including 82 of 195 (42%) pts who received liso-cel as 2L tx. Among pts treated in the IP vs OP setting, median (range) age was 71.5 y (21.5–91.2) and 69.8 y (25.0–86.1), respectively, and most pts were male (59% and 61%). Proportions of pts with high-grade B-cell lymphoma (16% and 12%), ≥2 extranodal involvement sites (26% and 26%), and secondary CNS involvement (5% and 4%) were similar for the IP and OP groups, respectively. In contrast, 48% vs 37% of pts in the IP vs OP groups, respectively, had elevated LDH before infusion and 10% vs 3% had ECOG PS ≥2. One or more comorbidities were reported for 72% and 65% (including cardiac, 36% and 32%; pulmonary, 30% and 26%; active infections requiring ongoing tx, 6% and 3%) of pts in the IP and OP groups, respectively. Median (range) number of prior lines of therapy was 3 (1–13) in the IP group and 3 (1–16) in the OP group. Use of bridging therapy was reported in 65% of the IP group and 62% of the OP group. Median (95% CI) follow-up for this study was 12.7 mo (12.5–13) in the IP group and 12.6 mo (12.4–12.8) in the OP group. Safety was similar in both settings; any-grade CRS was reported in 52% of IP vs 49% of OP setting pts, with low rates of grade 2 CRS (15% vs 11%) and grade ≥3 CRS (3% vs 2%) in both groups. Any-grade immune effector cell–associated neurotoxicity syndrome (ICANS) rates were also similar in pts in the IP vs OP setting (28% vs 23%), with low rates of grade 2 ICANS (5% vs 4%) and grade ≥3 ICANS (10% vs 8%). Prolonged cytopenia (grade 4 thrombocytopenia and/or neutropenia at 30 d after infusion) was reported in 12% and 14% in the IP and OP groups; clinically significant infections at any time after infusion occurred in 48% of IP and 42% of OP setting pts. In the IP and OP groups, 37% and 30% of pts died, most commonly due to PD (25% and 21%) and the NRM rates at 12 mo were 7.1 (95% CI, 5.2–9.4) and 4.1 (95% CI, 2.2–6.8). Among OP setting pts, 46% were not hospitalized after infusion; of those hospitalized after OP infusion, median (IQR) time to hospitalization was 5 d (3-8) and duration of stay was 5 d (3-9). Response rates were high in both the IP (ORR, 80% [95% CI, 77–83]; CR rate, 70% [95% CI, 66–73]) and OP setting (ORR, 83% [95% CI, 79–87]; CR rate, 74% [95% CI, 69–79]). At ~12 mo follow-up, median (95% CI) DOR was not reached (NR; NR–NR) in either group with 12-mo DOR rates of 59% (95% CI, 54–63) and 63% (95% CI, 56–69), respectively. Median (95% CI) PFS was 11.8 mo (8.8–NR) in the IP group vs NR (NR–NR) in the OP group, with 12-mo PFS rates of 49% (95% CI, 45–53) and 56% (95% CI, 50–61), respectively. Median (95% CI) OS was NR (NR–NR) in both groups with 12-mo OS rates of 65% (95% CI, 61–68) in the IP group and 74% (95% CI, 68–78) in the OP group. Conclusions: These results continue to demonstrate that one-time tx with liso-cel results in deep, clinically meaningful efficacy in the SOC setting across a broad population of pts with R/R LBCL. Despite the few differences reported in baseline characteristics, outcomes were consistent among pts treated in the IP and OP care settings. The well-established safety profile of liso-cel is conducive to OP tx, allowing ~50% of pts to remain out of the hospital postinfusion.

Abstract Background: Hypomethylating agent (HMA) with venetoclax (VEN) is used in clinical practice for frontline management of patients with myelodysplastic syndrome (MDS) based on encouraging data from phase 1 clinical trial (Garcia JS et al. Blood 2025). While the randomized clinical trial (VERONA-NCT04401748) did not show a survival benefit of azacitidine-VEN, the study had important differences such as exclusion of therapy related MDS and being conducted in several non-academic US centers. To better understand the impact of this regimen and its effects in subgroups, we conducted a real-world analysis of frontline MDS patients treated mainly at academic medical centers with HMA-VEN and compared to HMA monotherapy. Methods: This is a multicenter retrospective study of 19 US academic medical centers. We included contemporary cohorts of adults (age≥18 years) with MDS (intermediate, high or very high risk by IPSS-R) who were treated outside of clinical trials with either upfront combination of HMA-VEN or HMA monotherapy. Data on patient-related, disease-related and treatment-related variables were collected through chart review. Descriptive statistics were used for baseline characteristics. Overall survival (OS) and event free survival (EFS: progression, leukemic transformation, death as events) analysis was conducted using Kaplan-Meier method. Determinants of outcomes were analyzed using multivariable regression models. All analyses were conducted at a significance level of p<0.05. Results: Among 1198 patients with intermediate, high or very-high risk MDS, 313 patients received upfront VEN in combination with HMA [HMA-VEN] and 885 patients received HMA monotherapy. Median age was 70 (63-76) years and majority of patients had MDS with excess blasts-1 (34% overall, HMA-VEN=26%, HMA=37%) or MDS with excess-blasts-2 (41% overall, HMA-VEN=60%, HMA=34%). Disease risk by IPSS-R was intermediate (29% overall, HMA-VEN=18%, HMA=33%), high (30% overall, HMA-VEN=31%, HMA=30%) or very-high risk (41% overall, HMA-VEN=51%, HMA=37%, p<0.001). Therapy related MDS (t-MDS) was seen in 27% of patients (HMA-VEN=33%, HMA=25%, p=0.004), 34% had TP53 mutation (HMA-VEN=40%, HMA=32%, p=0.005) and 33% underwent allogeneic hematopoietic stem cell transplantation (AHSCT) (HMA-VEN=42%, HMA=30%, p<0.001). The most common mutations detected at baseline included TP53 (34%), ASXL1 (22%), DNMT3A (16%), RUNX1 (16%), TET2 (14%), SRSF2 (13%), and U2AF1 (11%). The response rate by IWG 2006 criteria was significantly higher with HMA-VEN than HMA monotherapy (overall 81% vs 39%, CR: 17% vs 9.6%; marrow CR: 56% vs 14%, p<0.001). In multivariable analysis accounting for upfront treatment, AHSCT, genomic mutations, baseline bone marrow blasts and t-MDS, patients treated with HMA-VEN in the upfront setting had significantly improved EFS (median EFS 10.7 vs. 7.8 mon, HR 0.83, 95%CI 0.72-0.96, p=0.01) and OS (median OS 22.4 vs. 18.1 mon, HR 0.79, 95%CI 0.64-0.97, p=0.02). In addition, TP53 mutation status (OS: HR 1.88, 95% CI 1.57-2.26, p<0.001, EFS: HR 1.43, 95% CI 1.23-1.65, p<0.001), subsequent AHSCT (OS: HR 0.34, 95% CI 0.27-0.41, p<0.001; EFS: HR 0.47, 95% CI 0.40-0.54, p<0.001), and therapy related MDS (OS: HR 1.20, 95% CI 1.00-1.44, p=0.04, EFS: HR 1.10, 95% CI 0.96-1.27, p=0.2) were significant predictors on multivariable analysis. When separately investigated in subgroups, an OS benefit of HMA-VEN over HMA was seen in patients undergoing subsequent AHSCT (median OS 40.6 vs. 30 mon, p=0.05), bone marrow blast 10-19% (median OS 25.1 vs. 17.4 mon, P=0.01), de novo MDS (median OS 30 vs. 20.1 mon, P=0.003) and absence of TP53 mutation (median OS 34.9 mon vs. 23.1 mon, p=0.004). The benefit of HMA-VEN over HMA was also seen across molecular mutations including presence of ASXL1 mutation (median OS 35.2 vs 20.9 mon, p=0.03). Conclusions: In this large multicenter retrospective analysis from US academic medical centers, we found that HMA-VEN therapy significantly improved OS in certain subsets of high risk MDS including patients with 10-19% blasts, denovo MDS, subsequent AHSCT and those without TP53 mutation. While our analysis is limited by its retrospective design, prospectively exploring subgroups of MDS patients who could benefit from HMA-VEN therapy is needed.

Abstract Introduction: Multiple myeloma (MM) is an incurable plasma cell (PC) malignancy, in which nearly all patients are expected to relapse and undergo multiple lines of treatment over the course of their disease. By the time patients receive CAR-T cell therapy, they have typically been exposed to numerous prior therapies, including high-dose melphalan (HDM). Chemotherapeutic agents that cause genotoxic stress, such as HDM, can induce cellular senescence in normal cells. More recently, it has been demonstrated that tumor cells can also exhibit features of therapy-induced senescence (TIS). TIS in tumor cells is associated with distinct gene expression patterns that have been implicated in resistance to therapy and relapse. To investigate whether TIS is activated in MM cells following exposure to chemotherapies, particularly in the context of late-stage disease, we performed an integrated analysis of single-cell RNA sequencing (scRNA-seq) datasets. Methods: We integrated scRNA-seq data from bone marrow plasma cells and MM cells using the following three sources: 1) Boiarsky, et al. (GSE193531, dbGaP: phs001323.v3.p1), which includes healthy donors, MGUS, SMM, and newly diagnosed MM (NDMM) patients; 2) Dhodapkar, et al. (GSE210079), which includes late-stage MM patients pre- and post-CAR-T cell therapy; and 3) newly generated scRNA-seq data from healthy donor (N=3) and late-stage MM patients pre- (N=10) and post- (N=2) CAR-T cell therapy. Non-plasma cells were excluded based on canonical plasma cell markers. We used Seurat v4.3 for data integration, employing canonical correlation analysis (CCA) to define anchors using the FindIntegrationAnchors and IntegrateData functions. Integration quality across datasets was validated by the consistent clustering of healthy plasma cells and expected expression patterns of chromosomal translocation markers CCND1 in t(11;14) cases and FGFR3 in t(4;14) cases, as previously described (PMID: 36396631). To evaluate senescence, we applied single-cell gene set enrichment analysis (scGSEA) using previously published gene sets (PMID: 40164720): SenUp (Senescence Upregulated), SenGA (Senescence Growth Arrest), and SCAPs (Senescent Cell Anti-apoptosis Pathways). We also curated a Plasma Cell Senescence (PCSen) gene set, composed of senescence-related genes that were differentially upregulated in pre-malignant plasma cells across two independent datasets (GSE5900, GSE47552).A normal plasma cell gene set was also generated, comprising genes differentially expressed between healthy and abnormal plasma cells in GSE193531. Results:In the integrated dataset, scGSEA revealed significantly higher enrichment of PCSen, SenUp, SenGA, and SCAPs in late-stage MM cells (both pre- and post-CAR-T cell therapy) compared to NDMM and healthy donors (p<0.05, Kruskal-Wallis with Dunn's posttest). Conversely, the Normal gene set was significantly enriched in healthy plasma cells relative to MM (p<0.05). Expression of CDKN2A, which encodes the senescence marker p16, was also increased in late-stage MM relative to NDMM or healthy plasma cells. Notably, in our newly generated scRNA-seq samples collected within 6 months before CAR-T therapy, we observed a significant inverse correlation between senescence marker expression and progression free survival (PFS) post-CAR-T, suggesting that MM cells exhibiting TIS may be more resistant to T cell mediated cytotoxicity. Supporting this, preliminary in vitro experiments showed that MM cells treated with HDM displayed reduced sensitivity to T cell-mediated cytotoxicity, consistent with a senescence-associated resistant phenotype. Conclusion: Our findings demonstrate that late-stage MM cells exhibit transcriptional signatures consistent with therapy-induced senescence, potentially driven by prior exposure to chemotherapy. This senescent phenotype may contribute to resistance to immunotherapies, including CAR-T cells. These data highlight senescence as a mechanism of resistance and a potential biomarker for predicting CAR-T outcomes. Further studies are needed to explore senescence-targeted strategies to enhance immunotherapeutic efficacy in MM.

Abstract Introduction: Chimeric Antigen Receptor T-cell (CAR-T) therapy has revolutionized the treatment landscape for many types of non-Hodgkin's lymphoma (NHL), offering the potential for prolonged remission and even cure in relapsed/refractory disease. Despite being a one-time treatment, patients spend a significant number of days in contact with the healthcare system in the preparation, monitoring and follow-up required for safe administration. Time toxicity describes the burden on patients' time required to receive all care associated with treatment. This study seeks to characterize the number of healthcare contact days (the so-called time toxicity) associated with CAR-T cell therapy for NHL. Methods: We conducted a claims database analysis of healthcare contact days using the OptumLabs platform. Patients who received CAR-T were identified using a combination of ICD-10-Procedure Coding System (PCS) codes, Current Procedural Terminology (CPT)/revenue codes and Healthcare Common Procedure Coding System (HCPCS) codes. NHL diagnosis was confirmed using ICD-10 codes (C82.X, C83.X and C85.X) to include diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL) or other NHL subtype. All claims indicating a healthcare contact day were captured in the time between apheresis and administration and at 1 month, 3 months and 1 year following CAR-T administration. Patients were excluded from analysis if they did not have continuous coverage with available claims data within the periods of interest. Negative binomial regression was used to estimate incident rate ratios (IRR), adjusting for demographic and clinical factors. Results: A total of 813 patients received CAR-T cell therapy for NHL between October 2017 and December 2024. The mean age of patients was 64.4 (range 18-87 years); 64.7% of patients were male, and 79.3% of patients received CAR-T inpatient. Median length of follow-up from CAR-T administration to coverage end or death was 340 days (IQR 164-639 days). Eleven patients (1.4%), 54 patients (6.6%), and 205 patients (25.2%) died in the 1 month, 3 months, and 1 year following CAR-T, respectively. DLBCL was the most common NHL subtype (86.0%) followed by MCL (6.8%), other NHL subtype (4.1%) and FL (3.2%). Patients received axi-cel (32.1%), liso-cel (21.2%), brexu-cel (9.7%), tisa-cel (4.7%) or unspecified CAR-T product (32.4%). Between apheresis and CAR-T administration, patients spent a median of 7 days (IQR 5-11 days) or 23.7% of days with healthcare contact (n=470). At 1 month after CAR-T, patients spent a median of 20 days (IQR 16-25 days) or 67.2% of days with healthcare contact (n=806). At 3 months, patients spent a median of 28 days (IQR 22-38 days) or 31.5% of days with healthcare contact (n=773). At 1 year, patients spent a median of 52 days (IQR 37-72 days) or 18.9% of days with healthcare contact (n=591). Outpatient CAR-T administration was associated with lower time toxicity at all timepoints compared to inpatient administration (p<0.05). FL and MCL had lower time toxicity only at the 1-year mark compared to DLBCL (FL IRR 0.72, 95% CI 0.57-0.90, p<0.01, MCL IRR 0.74, 95% CI 0.57-0.97, p=0.03). Brexu-cel was associated with higher time toxicity at all timepoints compared to liso-cel (p<0.05). Axi-cel was associated with higher time toxicity at 1 month (IRR 1.08, 95% CI 1.01-1.15, p=0.03) and 3 months (IRR 1.20, 95% CI 1.08-1.34, p<0.01), but not at 1 year when compared to liso-cel (IRR 1.09, 95% CI 0.91-1.30, p=0.35). Conclusions: Patients receiving CAR-T cell therapy for NHL spent a significant number of days in contact with the healthcare system, particularly in the first month following administration. Time toxicity lessened over time but patients still spent nearly 20% of their days with healthcare contact in the year following CAR-T. Outpatient administration was associated with significantly lower time toxicity. FL and MCL had lower time toxicity at 1 year compared to DLBCL, likely due to selection for surviving patients. Axi-cel and brexu-cel were associated with higher time toxicity when compared to liso-cel, reflecting the increased toxicity profiles of these products. These findings help clinicians and patients understand their true time commitment beyond the first month and can potentially inform future innovations for patient-centered delivery of cellular therapy that decrease time toxicity and improve patient quality of life.

Abstract Introduction: Teclistamab is the first FDA approved BCMA-directed bispecific antibody for the treatment of relapsed and refractory multiple myeloma (RRMM). With BCMA-targeting CAR-T therapies, cytokine release syndrome (CRS) is a risk factor for cardiotoxicity. Teclistamab was associated with fatal cardiovascular adverse events (CVAEs) in a recent US pharmacovigilance database analysis, but this analysis was limited by reporting bias. Therefore, the aim of our study is to conduct a multicenter study to define the real-world incidence of CVAEs in RRMM patients treated with teclistamab. Method We performed a retrospective multi-center cohort study of patients receiving teclistamab at 5 medical centers. Baseline oncologic and cardiovascular characteristics (including vital sign and echocardiographic data) were collected. Baseline cardiovascular disease (CVD) was defined as presence of coronary artery disease, congestive heart failure, severe or symptomatic valvular heart disease, or stroke at baseline. CVAE was collected and categorized based on CTCAE v5.0 by each institution. Major adverse cardiovascular event (MACE) was a composite outcome with any of the following: congestive heart failure, asymptomatic cardiomyopathy (interval LVEF drop >10% to resultant LVEF less than 50%), coronary artery disease requiring intervention, stroke or cardiovascular death. Arrhythmia was a composite outcome with any of the following: atrial tachyarrhythmia, ventricular tachyarrhythmia or bradyarrhythmia. Median follow-up was calculated through reverse Kaplan-Meier method. Multivariable Cox regression analysis was used to define the relation between MACE and survival. Cause of death was categorized as myeloma-related death or non-myeloma-related deaths (i.e. CRS, infection or cardiovascular death). Cause-specific Cox regression was performed to define relationship between MACE and cause of death. Results In a cohort of 219 patients treated with teclistamab with median follow-up of 20.1 months, 7.3% (N=16) developed MACE, 7.3% (N=16) developed arrhythmia and 12.8% (N=28) developing any MACE or arrhythmia. MACE occurred at a median of 4.5 days (IQR 2.25-15.75 days) after teclistamab step-up. The incidence of MACE was 16.4% in patients with baseline CVD versus 2.7% in those without baseline CVD (p<0.001). Patients who developed MACE had inferior ECOG performance status (PS) (PS >=2: 62.5% vs. 27.7%; p=0.008). Additionally, baseline hemoglobin level (9 vs 10g/dL; p=0.072) was numerically lower in MACE, compared to no MACE. There was no difference in age, sex, bone marrow (BM) plasma cell burden, ferritin, C-reactive protein or LDH levels between MACE vs. no MACE group. Patients who developed MACE had lower baseline diastolic blood pressure (67.7 vs 73.8mmHg; p=0.041) and numerically lower LVEF (51.4 vs 59.3%; p=0.059; baseline echocardiogram performed in 86% of all cohort). Patients who developed MACE had similar incidences of CRS (Grade >=2: 25.0 vs 16.7%; p=0.620) and immune effector cell-associated neurotoxicity (ICANS) grade 2 or higher (12.5 vs 7.5%; p=0.812). In multivariable Cox regression analysis, MACE was independently associated with inferior overall survival (HR 2.72; 95% CI 1.41-5.25; p=0.003), after adjusting for baseline CVD, age, high BM burden, extramedullary disease, and plasma cell leukemia. In cause-specific multivariable Cox regression analysis, MACE was independently associated with non-myeloma-related death (HR: 10.77 95% CI 4.39- 26.41; p<0.001) but not with myeloma-related death (1.54; 95% CI 0.64- 3.70; p=0.336). Conclusion In conclusion, in this large, real-world multicenter study, we observed that MACE occurred in over 7% of patients following teclistamab for RRMM, typically within 2 weeks of initiation. MACE was significantly associated with increased non-myeloma-related mortality. In contrast to CAR-T therapy, CRS or ICANS were not associated with MACE, whereas majority of patients who developed MACE had ECOG PS >=2 or baseline cardiovascular disease. More studies are necessary to define mechanisms and strategies to reduce these MACE and improve survival. Patients with baseline cardiovascular disease or poor performance status may benefit from cardiovascular optimization before and during teclistamab therapy.

Abstract Introduction: Bispecific T-cell engagers (TCE) targeting BCMA (teclistamab, elranatamab) and GPRC5D (talquetamab) are important therapeutic options in relapsed/refractory MM (RRMM). However, data on the independent prognostic impact of individual cytogenetic abnormalities and functional high-risk MM on outcomes with TCEs remains limited. Methods We included RRMM patients treated with BCMA TCEs (teclistamab, elranatamab) and talquetamab across 15 centers in the US. Patients where TCEs were used only as bridging therapy to CAR-T were excluded. High-risk cytogenetic abnormalities (HRCA) included del(17p), t(4;14), t(14;16), 1q gain/amplification (1q21+), del(1p) before initiation of TCE. Functional high-risk disease (FHRMM) was defined as PFS <18 months with frontline therapy. Extramedullary disease (EMD) included visceral or soft tissue disease and excluded paraskeletal disease. Progression-free survival (PFS) was estimated from TCE initiation using the Kaplan–Meier method and compared using the log-rank test. Univariate and multivariable Cox proportional hazards models were used to identify predictors of PFS in the entire cohort and the subcohorts of BCMA TCEs and talquetamab (Talq). Results We analyzed 943 treatment initiations with TCEs in RRMM, comprising 577 BCMA-directed TCEs [teclistamab (n=436) and elranatamab (n=141)] and 366 talquetamab initiations. The median follow-up from TCE initiation was 13.4 months (95% CI: 12.5–14.2) and median age was 68 years (interquartile range 61-75 years). Two ore more HRCAs were noted in 30% of the cohort (34% in Talq vs. 28% in BCMA TCEs, p=0.04), EMD was present in 21% of patients (26% in Talq vs. 18% in BCMA TCEs, p=0.002), and 45.5% of patients had FHRMM (47% in Talq vs. 45% in BCMA TCE, p=0.54). The median prior lines of therapy was 6 (interquartile range: 5-8), with 92% being triple-class refractory (TCR); 60% received prior BCMA-directed therapy (85% in Talq vs. 45% in BCMA TCE, p<0.0001) and 45% had prior CAR-T in 45% (57% in Talq vs. 37% in BCMA TCE, p<0.001). The best overall response rate (ORR) was 67.1 % for the entire cohort (66.4% for BCMA cohort and 68.2% for Talq), with 32.5% patients achieving a ≥ complete response. The median PFS was 7.7 months (95% CI: 6.7–8.6) for the entire cohort, with a median PFS of 10.1 months (95% CI: 7.5-13.4) for teclistamab and 10.1 months (95% CI: 3.9-NR) for elranatamab. In the more heavily pretreated talq cohort, the median PFS was 6.4 months (95% CI: 5.1-7.5). In a univariate analysis (UVA), several HRCAs were associated with inferior PFS−del(17p) (HR 1.59), t(4;14) (HR 1.43), del(1p) (HR 1.54), and ≥2 HRCAs (HR 1.64), all p<0.01. Apart from HRCAs, adverse disease characteristics included FHRMM (HR 1.20) and EMD (HR 1.46); all p<0.05. Among laboratory markers, hemoglobin <9 g/dL (HR 2.10), platelet count <75 ×10⁹/L (HR 1.96), and elevated ferritin (≥600 ng/mL; HR 2.17) (all p<0.01) were prognostic for PFS. ECOG ≥2 (HR 1.62), prior BCMA-directed therapy (HR 1.56), and prior CAR-T (HR 1.44) (all p<0.001) were also associated with inferior PFS. In a multivariable analysis (MVA), prior BCMA therapy (HR 1.72, p<0.0001), ferritin >600 ng/mL (HR 1.68, p<0.0001), hemoglobin <9 g/dL (HR 1.53, p=0.001), ECOG PS ≥2 (HR 1.52, p=0.0009), del(17p) (HR 1.44, p=0.0034) and FHRMM (HR 1.26, p=0.047), were associated with inferior PFS. Within the talq cohort (n=366), EMD (HR 1.64), del(17p) (HR 1.42), del(1p) (HR 1.54), FHRMM (HR 1.34), ECOG ≥2 (HR 1.56), ferritin >600 (HR 1.88), hemoglobin <9 g/dL (HR 1.6), platelet count <75 ×10⁹/L (HR 1.36) and leukopenia <0.25 x 10⁹/L (HR 1.52) were adverse prognostic markers on UVA. A MVA confirmed the independent impact of ferritin >600 ng/mL (HR: 1.77), ECOG ≥2 (HR 1.61) and functional high-risk status (HR 1.52) on PFS, whereas del(17p) and EMD were trending toward significance. Within the BCMA TCE cohort (n=577), prior BCMA therapy (HR 1.9), ferritin >600 (HR 1.79), ECOG ≥2 (HR 1.55), Hb <9 g/dL (HR 1.54), and del(17p) (HR 1.52) were independently associated with inferior PFS on a MVA.Conclusions: In this large real-world cohort of TCE, outcomes varied by fitness, disease biology, and treatment history. The ECOG PS, elevated ferritin, functional high-risk status and del(17p) were consistently associated with inferior PFS. Prior BCMA exposure was an independent risk factor for inferior PFS in the BCMA TCE cohort, but not with talquetamab.