Gonzalez, Rebecca

Abstract Introduction: Cilta-cel is a BCMA-directed CAR T-cell therapy that has shown remarkable efficacy in patients with RRMM. As real-world (RW) experience with cilta-cel continues to expand, and with the recent FDA guidance reducing the recommended proximity to the CAR T center from four to two weeks post-infusion, there is growing interest in identifying patients at low risk for severe early complications who may be safely managed in the outpatient setting and potentially ‘discharged’ home earlier. Methods Data were collected from 769 patients with RRMM treated with cilta-cel at 15 institutions in the U.S. via the Multiple Myeloma Immunotherapy Consortium.Logistic regression was used to identify predictors of patients who could be managed in the outpatient setting (low-risk group). Based on expert consensus within the Consortium, low-risk patients were defined as: grade ≤1 CRS, no ICANS, and no IEC-HS. The remaining patients were categorized as high-risk. We evaluated baseline characteristics with missingness < 20% as predictors, including age, sex, race, and ethnicity, ECOG performance status (PS) at time of lymphodepletion (LD), extramedullary disease, bone marrow plasma cell (BMPC) percentage, high-risk cytogenetics, bridging therapy including response, penta-refractory status, number of prior lines of therapy, prior anti-BCMA therapy, baseline C-reactive protein (CRP), and baseline ferritin. The cohort was restricted to patients with complete data on all predictors (n=455) and split into a training and testing cohort (80/20 split, n=364/91). Bidirectional stepwise regression was used to build the predictive model using variables with significance of p<0.15 selected for entry. The best model was selected based on the AIC (Akaike Information Criterion) and a significance level of p<0.05. Results Among the 455 patients with complete data included in the final model, 290 (64%) were categorized as low-risk and 165 (36%) as high-risk. Compared to the low-risk group, high-risk patients were more likely to have an ECOG PS ≥2 at time of LD (20% vs 9%, p<0.001), high-risk cytogenetics (47% vs 35%, p=0.009), and penta-refractory disease status (34% vs 24%, p=0.031). High-risk patients also had a higher median BMPC percentage (15% vs 5%, p<0.001), and higher baseline pre-LD CRP and ferritin. Overall response rates were high, at 95% vs 90% (p=0.047) for the low vs high risk groups, with complete response or better achieved in 73% vs 66% of patients, respectively (p=0.14). With a median follow-up of approximately 11 months, median progression-free survival was not reached (95% CI: 27-NA) in the low-risk group and 18.2 months (95% CI: 13.1-NA) in the high-risk group. In terms of safety, non-ICANS neurotoxicity (NINT) occurred less frequently in the low-risk group (6.6% vs 13%, p=0.015). Specifically, Parkinsonism was observed in 1.7% vs 6.1% (p=0.013), and cranial nerve palsy in 4.5% vs 5.5% (p=0.7), respectively. Non-relapse mortality (NRM) was lower in the low-risk group (4.2%) compared to the high-risk group (14%; p < 0.001). The most common causes of NRM in the low- and high-risk groups were acute toxicities (0% vs 36%, including CRS, IEC-HS, and ICANS), delayed toxicities (0% vs 8%, including colitis, NINT, and Parkinsonism), infections (50% vs 48%), and other unrelated causes (50% vs 8%). The best model to predict low-risk patients that could be managed in the outpatient settingincluded BMPC percentage and ECOG PS at LD. In the training cohort, patients with a higher pre-LD BMPC percentage and an ECOG PS ³2 were less likely to be in the low-risk group(OR per 1-unit change in BMPC percentage = 0.99, 95% CI=0.98-0.99, p<0.001 and OR for ECOG PS 2-4 = 0.38, 95% CI=0.20-0.72, p=0.003). The AUC for this model was 0.663 in the training cohort and 0.659 in the testing cohort. Conclusion In this large, multi-institutional cohort of patients with RRMM treated with cilta-cel, we identified clinical factors associated with lower risk for early severe toxicities, supporting outpatient administration and the potential for earlier discharge in selected patients, particularly those who are fit and have low disease burden. Our findings provide a practical framework to guide risk stratification and outpatient CAR T management strategies, particularly in light of evolving regulatory guidance and growing RW experience with cilta-cel.

Abstract Introduction: Ciltacabtagene autoleucel (cilta-cel) is a highly effective BCMA-redirected CAR T-cell therapy for RRMM. While the pivotal CARTITUDE-1 trial established a target dose of 0.75 x 10^6 CAR+ viable T-cells/kg, the approved cell dose is 0.5-1.0 x 10^6 and the optimal dosing strategy to balance efficacy and toxicity remains unclear. This question is of interest given that a dose-response association has been demonstrated for idecabtagene vicleucel (a related BCMA-directed CAR T product). It has also been hypothesized that lower doses of cilta-cel may be associated with reduced toxicity. This study aims to evaluate the association between cilta-cel dose and key efficacy and toxicity outcomes using a large, real-world dataset from the US Multiple Myeloma Immunotherapy Consortium. Methods: We conducted a multicenter, retrospective analysis of 751 RRMM patients treated with commercial cilta-cel across 15 US academic centers. The administered cilta-cel dose (million cells/kg) was categorized into four groups: low (<0.5), standard-low (0.5 to <0.6), standard (0.6 to <0.8), and standard-high (0.8 to 1.0). We compared incidence rates of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), delayed neurotoxicity (DNT), and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) across these dose categories using logistic regression. Best response rates and progression-free survival (PFS), estimated using the Kaplan-Meier method, were also compared, with differences assessed using the log-rank test for the latter. Results presented are derived from multivariable models adjusting for extramedullary disease, ECOG status, penta-refractory disease and receipt of bridging therapy. Results: Among 751 infused patients, the dose distribution was: <0.5 (n=33), 0.5 to <0.6 (n=131), 0.6 to <0.8 (n=550), and 0.8 to 1.0 (n=37). The four dose groups were well-balanced in terms of baseline patient and disease characteristics, including age, high-risk cytogenetics, and extramedullary disease, with the exception of t(14;16), which was more common in the standard-low and standard dose groups (p=0.006). There were no statistically significant differences in the rates of any grade CRS (p=0.11), any grade ICANS (p=0.84), grade ≥3 ICANS (p=0.36), duration of CRS (p=0.18) or ICANS (p=0.64), or IEC-HS (p=0.16) across the four dose categories. Time to onset of CRS was shorter for the standard-high dose compared to the low dose (6 days vs. 8 days; p=0.08). Importantly, there was no significant difference in the rate of DNT (3.0%, 9.2%, 8.8%, 5.4%; p=0.24). Similarly, there was no significant difference in overall response rates (97%, 96%, 96%, 88%; p=0.50) or complete response rates (75%, 65%, 75%, 66%; p=0.10) by dose. The median follow-up was 12.3 months (IQR: 6.9, 20.5). For patients who received a standard-low dose (0.5, 0.6), the median PFS was 17.5 (IQR: 13.5, NR) months. For the standard dose range of (0.6, 0.8), the median PFS was 28.7 (95% CI: 19.8, NR) months, while the median PFS for the standard-high dose (0.8, 1.0) was not reached. For the low dose range of <0.5, the median follow up was only 8.7 months, which did not allow reliable estimation of the median PFS. While the overall difference in PFS among the groups did not reach statistical significance by the log rank test, there was a clear trend toward improved PFS with higher cell doses in the multivariable model, with outcomes clearly ordered in the same direction as the cell dose categories. A similar trend was also evident in the rates of 12-month PFS which showed an improvement with increasing dose (62% ,67%, 73%, 80%). Conclusions: In this large, real-world cohort of RRMM patients treated with cilta-cel, a lower cell dose was not associated with reduced incidence or severity of CRS, ICANS, DNT, or IEC-HS. Conversely, a dose-response correlation with PFS was observed, with higher doses trending toward longer median and 12-month PFS. It remains unknown if a lower cell dose in the commercial setting reflects poor T cell quality, yet these findings suggest that dose reduction of cilta-cel may not be an effective strategy to mitigate toxicities and might be associated with a trend toward lower efficacy. Therefore, the standard target dose should be utilized to maximize patient outcomes and further prospective dose exploration is warranted.

Abstract Introduction: Ciltacabtagene autoleucel (cilta-cel) has shown high efficacy in relapsed MM, but further efforts are needed to mitigate non-ICANS delayed neurotoxicity (DNT) and non-relapse mortality (NRM). Identifying risk factors associated with DNT and NRM may help with risk mitigation by aiding the development of interventions for potentially modifiable risk factors and also help with clinical decision making. Methods: In this multi-center retrospective study from the US MM Immunotherapy Consortium, we evaluated 761 patients treated at 15 centers receiving standard of care cilta-cel for relapsed MM between May 2022 to December 2024. Risk factors for DNT, particularly Parkinsonism and NRM were evaluated in by univariable and multivariable analysis. Any NRM events occurring after disease progression were censored for NRM evaluation. Results: The median age of the cohort was 65 years old (range: 30-88), median prior lines of therapy (pLoT) were 5 (range: 1-23). Cilta-cel was used in earlier relapse (1-3 pLOT) in 16% (n=120) patients. High-risk cytogenetics [del 17p, t(14;16) or t(4;14)] were present in 39%, with extramedullary disease (EMD) in 27% and R-ISS stage III in 18% of patients, respectively. Majority of patients (86%) received bridging therapy with response to bridging (≥ partial response, PR) seen in 33% of patients, respectively. Median follow up was 10.1 months, with response rate of 92% and CR rate of 70%. DNT was seen in 10% (n=75) of patients, with distribution as follows: Parkinsonism in 2.9% (n=22), cranial nerve palsy in 4.6% (n=35) and other DNT in 2.4% (n=18), with some patients manifesting more than one type of DNT. Risk of DNT was higher in patients who did not respond to bridging therapy (Any DNT: 12% vs 6%; Parkinsonism: 5% vs 0.5%, both p<0.05) Of the 22 cases of Parkinsonism, 21 patients (95%) did not respond to bridging, even though they achieved a post CAR-T response with ORR of 91% and ≥ CR in 68%. Absolute lymphocyte count (ALC), a surrogate measure of CAR expansion was higher in patients who developed DNT, particularly Parkinsonism, including ALC at days 7,14,21,28 and as peak ALC in the first month post cilta-cel (p<0.05 for all). Median peak ALC for patients with vs without Parkinsonism was: 5.88 vs 1.17/uL (p<0.001). We evaluated risk of Parkinsonism with various thresholds of peak ALC expansion. Amongst patients who developed Parkinsonism vs. not, peak ALC was as follows, > 1000/uL: 100% vs 57%, > 2500/uL: 73% vs 19% and > 3000/uL: 68% vs 14% (all p<0.001). The absolute risk of Parkinsonism with ALC > 3000 vs ≤ 3000/uL was 12% vs 1%, p<0.001; for ALC 2500 vs ≤ 2500uL was 9% vs 1%, p<0.001. On multivariable analysis, peak ALC > 3000/uL (OR: 12.7, p<0.001) and non-response to bridging therapy (OR: 9.9, p=0.03) were independent risk factors for developing Parkinsonism after cilta-cel. After cilta-cel, 1 and 2 year NRM estimates were 9% and 10%, respectively. Amongst 63 (8%) patients experiencing NRM events, the most common cause of NRM was infectious complications (35, 56%), followed by acute immune-mediated adverse events (AEs) like CRS, ICANS, IEC-HS in 14 (22%), delayed immune mediated AEs like DNT and colitis in 6 (9.5%), second cancers in 5 (8%) and other causes in 3 (5%) patients, respectively. When evaluating the timing of NRM events, the risk of infection related mortality remained relatively stable in the first year, though immune mediated toxicty deaths were uncommon after 6 months, while SPMs were uncommon within the first 6 months. On multivariable analysis, non-response to bridging (HR 2.41, p=0.046), poor performance status ≥ 2, high-risk cytogenetics and age ≥ 70 years were independent predictors for NRM. Conclusion: In a large cohort of over 750 patients receiving cilta-cel, we identified potentially modifiable risk factors for Parkinsonism and NRM. Non-response to bridging therapy and peak ALC > 3000/uL were independent predictors of developing Parkinsonism. Peak ALC of > 2500/uL and > 3000/uL were associated with 9% and 12% absolute risk of Parkinsonism. This indicates that peak ALC of 2500/uL or 3000/uL in the first month after cilta-cel may be a potential biomarker to identify patients for pre-emptive interventions such as steroids that can suppress rapid CAR expansion and perhaps decrease the risk of Parkinsonism. In addition, we need to focus on effective bridging strategies to further decrease the risk of Parkinsonism, as well as NRM with cilta-cel.

Abstract Introduction Ciltacabtagene autoleucel (cilta-cel) has demonstrated unprecedented response rates and progression-free survival (PFS) in relapsed/refractory multiple myeloma (RRMM), but a proportion of patients experience early relapse. Identifying these patients is essential to guide future therapeutic strategies, such as enhanced bridging therapy or consolidation, while avoiding overtreatment in those likely to achieve durable disease control. Methods We conducted a multi-center study of patients treated with cilta-cel at 15 U.S. academic centers. Outcomes were evaluated based on high-risk (HR) features, including functional HR disease (FHR; relapse within 18 months of first-line therapy initiation), true extramedullary disease (EMD), traditional HR cytogenetics as defined in CARTITUDE-1 [deletion 17p, t(4;14), t(14;16)], and a 2024 IMS-IMWG-adapted HR definition (deletion 17p; t(4;14) or t(14;16) with gain 1q or deletion 1p; and gain 1q with deletion 1p). Multivariable Cox regression was used to examine the association of HR features (FHR, adapted IMS-IMWG HR, and EMD, individually and collectively) with PFS while adjusting for baseline ferritin, prior BCMA, and ECOG performance status (PS ≥2). Among patients with ≥18 months of follow-up, we evaluated predictors of early relapse (≤18 months post infusion) using logistic regression. Results Our cohort included 598 patients treated with cilta-cel between 5/2022 and 12/2024 who had available data on all HR features. The median age was 65 years (range 33-83), and the median prior lines of therapy (pLOT) was 5 (range: 1-18, 84% with >3 pLOT); 8% had received prior BCMA-directed therapy, and 27% were penta-refractory. Most patients (88%) received bridging therapy and 30% achieved ≥ partial response. In our cohort, 33% (n=195) had FHR, 43% (n=258) had traditional HR cytogenetics, 42% (n=253) had adapted IMS-IMWG HR disease, and 11% (n=64) had EMD. Median follow up was 10.6 months (range 0.4-34.1). Overall response rate (ORR) and complete response (CR) rates were lower in patients with vs without HR features: FHR (ORR: 89% vs 94%, CR: 61% vs 75%), traditional HR (ORR: 90% vs 94%, CR: 65% vs 74%), adapted IMS-IMWG HR (ORR: 91% vs 94%, CR: 64% vs 75%) and EMD (ORR: 77% vs 94%, CR: 61% vs 71%). Corresponding 12-month PFS was also lower in patients with vs without HR features: FHR (55% vs 79%), traditional HR (63% vs 78%), adapted IMS-IMWG HR (61% vs 80%) and EMD (59% vs 73%). ORR, CR rate, and 12-month PFS in patients without any HR features compared to those with ≥1 HR feature were 96% vs 90%, 81% vs 64%, and 83% vs 65%, respectively. In multivariable models, each HR feature (FHR, adapted IMS-IMWG HR, and EMD) was independently associated with inferior PFS after adjusting for baseline ferritin, prior BCMA, and ECOG PS ≥ 2. However, because early relapse cannot always be identified a priori based on traditional risk factors, we sought to identify predictors of relapse within 18 months of cilta-cel in a subset of patients with ≥18 months of follow-up (N=247; infused by 12/2023). Notably, while FHR (OR=3.04, 95% CI=1.59-5.89) and adapted IMS-IMWG HR (OR=2.07, 95% CI=1.10-3.89) were independently associated with odds of relapse within 18 months, EMD was not (OR=0.90, 95% CI=0.32, 2.40) when accounting for prior BCMA, ECOG PS ≥ 2, and baseline ferritin. We also used a time-varying Cox model to examine each HR feature associated with PFS at two time periods, <18 and ≥18 months, while adjusting for baseline ferritin, ECOG PS, and prior BCMA. We confirmed that FHR and adapted IMS-IMWG HR were both associated with relapse <18 months (HR=2.05, 95% CI=1.48-2.83 and HR=1.56, 95% CI=1.11-2.19) but not in the ≥18-month time period (HR=0.70, 95% CI=0.19-2.59 and HR=0.76, 95% CI=0.24-2.40). The magnitude of the association for EMD with PFS was similar across both time periods (<18 months HR=1.67, 95% CI=1.09-2.57 and ≥18 months HR=2.17, 95% CI=0.45-10.40). Conclusion While cilta-cel leads to high response rates and durable PFS in RRMM, a subset of patients with FHR and adapted IMS-IMWG HR remains at increased risk for early relapse. In this large multi-center cohort, we describe PFS outcomes across high-risk subgroups and identify key predictors of relapse within 18 months of cilta-cel. These findings inform risk-adapted therapeutic strategies and interventional trials, including bridging, consolidation, or maintenance approaches, to improve outcomes in the highest-risk RRMM patients.

Abstract Outcomes of bispecific antibodies in patients with renal impairment (RI) are not well characterized, given the exclusion of these patients from clinical trials. Herein, we evaluated patients with relapsed/refractory multiple myeloma and RI treated with standard-of-care teclistamab. RI was defined as creatinine clearance (CrCl) <40 mL/min. CrCl <30 mL/min or dialysis dependence was defined as severe RI. Of the 384 included patients, 81 (21%) had RI, including 45 (18%) with severe RI, and 18 (5%) on dialysis. Patients with RI were more likely to be older (median age, 71 vs 67 years; P = .002) and have a higher median number of previous lines of therapy (7 vs 6; P = .04). Rates and severity of cytokine release syndrome (51% vs 59%; grade ≥3: 1.2% vs 1%) and immune effector cell–associated neurotoxicity syndrome (16% vs 13%; grade ≥3: 2.5% vs 2.6%) were similar in patients with and without RI, respectively. Patients with RI had higher baseline and day 30 post-teclistamab grade ≥3 anemia and grade ≥3 thrombocytopenia. Renal function did not worsen after teclistamab initiation in most patients with RI outside of the context of disease progression. Overall response rate (52% vs 56%; P = .61) and survival outcomes (median progression-free survival, 4.6 vs 6.5 months; P = .62) were comparable in patients with and without RI, respectively, after a median follow-up of 9.9 months. No differences in overall survival or non-relapse mortality were noted. Our findings suggest that treatment with teclistamab is feasible in patients with RI, including those on dialysis, with a similar safety and efficacy profile to patients without RI.

Introduction: Recent efforts have shed light on the clinical and laboratory factors associated with toxicity and response to BCMA-directed CAR-T therapy in patients with relapsed/refractory multiple myeloma (RRMM). However, a major limitation of current scoring systems lies in their assessment at time of lymphodepletion. Because they are not determined before apheresis, they are ill-equipped to guide patient selection, anticipate level-of-care, or plan pre-emptive toxicity management strategies. We therefore aimed to characterize early predictors of CAR-T toxicity and response. Study Design: In this multicenter observational study, we examined demographic, clinical, and laboratory data across three distinct timepoints: indication (e.g., treatment decision), apheresis, and pre-lymphodepletion (LD). CRS and ICANS were graded according to ASTCT criteria. Hematotoxicity (ICAHT) was graded using EHA/EBMT criteria. Early infections (day 0-100) were defined based on microbiologic data or as a clinical infection syndrome, and graded per Hill et al, Blood 2018. Kaplan-Meier estimates of progression-free (PFS) and overall survival (OS) were compared by log-rank test. Cox proportional hazard models were applied to explore associations between pre-apheresis risk factors and key toxicity and survival outcomes. The CAR-HEMATOTOX (HT) score - encompassing markers of inflammation (e.g., CRP, ferritin) and marrow reserve (e.g., hemoglobin, ANC, platelet count) - was determined at each timepoint (Rejeski et al, Blood 2021). Results: We included 530 RRMM patients treated with standard-of-care cilta-cel (n=184) or ide-cel (n=346) across nine centers. Median age was 65 (range 31-88), median ECOG was 1 (IQR 0-1), and patients received a median of 5 prior lines of therapy (IQR 4-7). The median time from indication to apheresis was 16 days (IQR 7-52), while the median time from apheresis to infusion was 56 days (IQR 46-69). The proportion of high-risk patients by HT score did not change between the pre-apheresis and LD timepoints (19% vs. 20%, p=0.82). Most patients stayed either low-risk (n=388, 73.2%) or high-risk (n=68, 12.8%). However, 35 patients (6.6%) shifted from high-to-low risk, while 39 patients (7.4%) progressed from low-to-high risk - reflecting their response to bridging therapies. We noted considerable differences in morbidity and mortality based on the pre-apheresis HT score. Compared to their low-risk counterparts (score 0-2, n=427), high-risk patients (score ≥3, n=103) were hospitalized longer (12 vs. 15 days, p=0.009) and required more frequent ICU admissions (6% vs. 12%, p=0.05). They exhibited more severe early cytopenias (G3+: 8% vs. 25%, p<0.001) and late cytopenias (G3+: 7% vs. 21%, p<0.001), resulting in increased use of TPO agonists and stem cell boosts. Grade 3 or higher ICANS was also more common in HThigh patients (3% vs. 11%, p=0.006), as were severe infections (14% vs. 27%, p=0.007). We found increased non-relapsed mortality in HThigh patients (1-yr NRM 4.6% vs. 16.1%, p<0.001), but no significant difference in the occurrence of secondary malignancies (p>0.9). With a median follow-up of 12.4 months, HThigh patients showed inferior PFS (1-yr PFS 29% vs. 63%, p<0.0001) and OS (1-yr OS 49% vs. 83%, p<0.0001). Transitioning from a low-to-high score was linked to poor survival (1-yr PFS 26%), while the shift from high-to-low risk was associated with favorable outcomes (1-yr PFS 51%). In a multivariable Cox regression model of pre-apheresis features, a high HT score (aHR 2.52, p<0.0001), prior anti-BCMA therapy (aHR 1.55, p=0.04), history of extramedullary disease (aHR 1.42, p=0.02), and penta-refractoriness (aHR 1.45, p=0.02) were independently associated with PFS. Notably, the presence of more than 3 of these high-risk features defined an ultra-high-risk cohort of 28 patients (5.3%) with particularly dismal survival (1-year PFS 15%). Conclusions: Leveraging granular pre-apheresis data from a large international cohort, we identify early markers of toxicity and response in CAR-T-treated RRMM patients. The HT score - reflecting baseline inflammation and hematopoietic reserve - identified high-risk patients likely to benefit from pre-emptive toxicity mitigation strategies such as prophylactic stem cell collection. Most importantly, we characterize a small yet ultra-high-risk group of RRMM patients in need of more effective bridging and therapeutic options.

7508 Background: Idecabtagene vicleucel (Ide-cel) has demonstrated excellent efficacy in patients with relapsed/refractory multiple myeloma (RRMM). However, outcomes in patients with extramedullary disease (EMD) remain to be better characterized. Methods: We included patients from 11 US academic centers, who were evaluated for EMD and were infused with ide-cel between May 2021 and April 2023. Patients with soft tissue or visceral lesions non-contiguous from bony lesions were classified as having true EMD, with paraskeletal disease classified as non-EMD. Disease responses were evaluated using the IMWG criteria. Time-to-event analyses were performed from the date of ide-cel infusion. Results: Among 351 patients with RRMM treated with ide-cel, 84 (24%) had EMD prior to infusion. Median follow-up for the entire cohort was 18.2 months (95% CI: 17-19.3). Baseline characteristics at ide-cel infusion for EMD and non-EMD cohorts are depicted in the table. For the EMD and non-EMD cohorts, the Day 30 objective response rates (ORR) were 58% vs. 69% (p=0.1), Day 30 ≥complete response rates were 16% vs 24% (p=0.11), the Day 90 ORR were 52% vs 82% (p<0.001), and best ORR were 58% vs 82%, respectively. The median progression-free survival (PFS) was 5.3 months (95% CI: 4.1-6.9) for the EMD cohort vs. 11.1 months (95% CI: 9.2-12.6; p<0.0001) for the non-EMD cohort. The median duration of response for EMD among day 30 responders was 6.4 months (95% CI: 5.1-8.4). In a multivariable analysis, EMD was an independent predictor of inferior PFS [hazard ratio 1.8 (95% CI: 1.2-2.5), p<0.001] after adjusting for ECOG status, revised ISS stage, penta-drug refractoriness, elevated ferritin, prior BCMA-directed therapy and use of bridging therapy. Pattern of progression in the EMD cohort (n=68/84) included EMD site only (21%), hematologic only (22%), or both (57%), with comparable PFS for type of progression (p=0.19). The median overall survival (OS) was 14.8 months [95% CI: 9-Not reached (NR)] for EMD and 26.9 months [95% CI: 26.3 vs NR, p=0.006)] for the non-EMD group. Rates of Grade ≥2 cytokine release syndrome or neurotoxicity syndrome were comparable between the two cohorts. Conclusions: Patients with EMD demonstrate significantly inferior Day 90 ORR and presence of EMD is an independent risk factor for inferior PFS. [Table: see text]

Introduction: Lymphodepletion (LD) chemotherapy is critical for the efficacy of CAR-T therapy by eradicating immunosuppressive cells, inducing costimulatory molecules, and promoting expansion and persistence of CAR-T cells. It also can contribute to an increased risk of infections, cytopenia, and other toxicities. We evaluated the utilization of varying LD regimens used in standard-of-care (SOC) autologous B-cell maturation antigen-directed (BCMA) CAR-T therapy with ide-cel or cilta-cel for relapsed/refractory multiple myeloma (RRMM) and the effect on outcomes and toxicity. Methods: Data were retrospectively collected from patients with RRMM who underwent LD and CAR-T cell infusion by December 31, 2022, from 13 US academic institutions with SOC ide-cel or cilta-cel. Response rates and other categorical variables, specifically LD regimen, were tested for association using Wilcoxon rank-sum (or Kruskal-Wallis for three or more groups) or Fisher's exact tests, respectively. Results: A total of 523 patients were infused at the time of data cut-off with 489 patients evaluable for safety and survival analyses; 368 (75%) were infused with ide-cel and 121 (25%) with cilta-cel. The median age was 65 years old (range 30-90) with 206 females (42%) and 283 males (58%), and 13% with ECOG performance status ≥ 2 at time of LD. Fludarabine and cyclophosphamide (Flu/Cy) LD was used in 422 patients while 67 patients received other LD regimens including bendamustine-based (n = 35, 52%), cladribine-based (n = 25, 37%) or cyclophosphamide alone (n = 7, 10%). The primary reason for use of Flu/Cy LD was institutional guidance or SOC in 378 patients (90%), while the primary reason for use of other LD regimens was due to the fludarabine shortage in 65 patients (97%) with 3% citing physician's choice or institutional guidance. No significant difference was identified among response outcomes, with those receiving Flu/Cy LD achieving an ORR of 84% compared to 81% with other LD regimens (p = 0.59) and no difference observed in rates of ≥ VGPR (66% Flu/Cy LD vs 60% other LD; p = 0.48). Of those evaluable for MRD at 1 and 3 months, the MRD negative rate at 10 -6 for those with Flu/Cy LD was 77% (n= 137) and 77% (n=113) and with other LD regimens was 66% (n=35) and 79% (n=28), respectively. At a median follow-up of 9.7 months, no statistically significant difference was noted in median progression free survival (mPFS) with Flu/Cy vs other LD regimens (9.3 mos vs NR) or overall survival (OS) (19.4 mos vs NR). When stratified by type of CAR-T therapy, treatment with bendamustine-based LD was associated with an inferior mPFS compared to those receiving Flu/Cy LD in patients treated with ide-cel (3.8 vs 8.5 mos; p=0.0056), though not by multivariate analysis. Univariate analysis of patients treated with ide-cel between Flu/Cy and bendamustine LD did not reveal any significant differences in age, gender, ECOG, R-ISS stage, extramedullary disease, high-risk cytogenetics or renal dysfunction (Cr &lt; 45 ml/min). LD regimen was not a predictor for PFS on multivariable analyses amongst patients treated with ide-cel, while ECOG ≥ 3 (hazard ratio [HR]= 4.44, 95% confidence interval [CI]= 1.40, 14.08) and t(4,14) (HR= 2.02, 95% CI=1.14, 3.59) were associated with worse PFS. No difference in mPFS by LD regimen was observed in patients receiving cilta-cel, which was a smaller cohort (mPFS: Flu/Cy 11.7 mos, bendamustine-based NR, cladribine-based NR, cyclophosphamide NR). Rates of all grade CRS (81% vs 70%), Grade ≥ 3 CRS (3% vs 3%), all grade ICANS (19% vs 12%, and Grade ≥ 3 ICANS (4% vs 2%) were similar among those receiving Flu/Cy or other LD regimens, respectively. Patients receiving Flu/Cy LD were less likely to have any grade cytopenia at 1 month (33% vs 55%, p &lt; 0.001) and 3 months (52% vs 69%, p &lt; 0.001), with no observed difference in infection rate. Conclusions: The fludarabine shortage experienced in the US in late 2022 necessitated the use of alternative LD regimens with BCMA-directed CAR-T therapy with most centers relying on bendamustine- or cladribine-based regimens. Use of bendamustine-based LD was associated with inferior PFS in patients receiving ide-cel on univariate analysis, but not on multivariate analysis after adjusting for other prognostic factors. In summary, there is no clear difference in efficacy or safety between Flu/Cy and non-Flu/Cy LD in patients receiving BCMA-directed CAR-T therapy. *Authors contributed equally

Abstract Standard initial therapy of chronic graft vs. host disease (cGVHD) with glucocorticoids results in suboptimal response. Safety and feasibility of therapy with ofatumumab (1000 mg IV on days 0 and 14) and prednisone (1 mg/kg/day) was previously established in our phase I trial (n = 12). We now report the mature results of the phase II expansion of the trial (n = 38). The overall NIH severity of cGVHD was moderate (63%) or severe (37%) with 74% of all patients affected by the overlap subtype of cGVHD and 82% by prior acute cGVHD. The observed 6 month clinician-reported and 2014 NIH-defined overall response rates (ORR = complete + partial response [CR/PR]) of 62.5% (1-sided lower 90% confidence interval=51.5%) were not superior to pre-specified historic benchmark of 60%. Post-hoc comparison of 6 month NIH response suggested benefit compared to more contemporaneous NIH-based benchmark of 48.6% with frontline sirolimus/prednisone (CTN 0801 trial). Baseline cGVHD features (organ involvement, severity, initial immune suppression agents) were not significantly associated with 6-month ORR. The median time to initiation of second-line therapy was 5.4 months (range 0.9-15.1 months). Failure-free survival (FFS) was 64.2% (95% CI 46.5-77.4%) at 6 months and 53.1% (95% CI 35.8-67.7%) at 12 months, whereas FFS with CR/PR at 12 months of 33.5% exceeded a benchmark of 15% in post-hoc analysis, and was associated with greater success in steroid discontinuation by 24 months (odds ratio 8 (95% CI 1.21-52.7). This single-arm phase II trial demonstrated acceptable safety and potential efficacy of the upfront use of ofatumumab in combination with prednisone in cGVHD. This trial was registered at www.clinicaltrials.gov as #NCT01680965.