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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 Introduction: The CAR-T therapies ide-cel and cilta-cel are approved for patients (pts) with relapsed/refractory multiple myeloma (RRMM). The aim of this study was to determine the incidence, subtypes, and associated risk factors for subsequent primary malignancies (SPMs) in MM pts treated with CAR-T therapy in the real-world setting. Methods: A retrospective, multicenter observational cohort study was conducted of pts who received CAR-T therapy between May 2021 and Dec 2024 at 15 centers within the US Multiple Myeloma Immunotherapy Consortium. Logistic models were used for univariable analyses of invasive SPMs (excluding non-melanoma skin cancers). Variables significant at p < 0.10 were included as candidate variables in the multivariable analysis. Time to event endpoints were analyzed using Kaplan-Meier curves. Results: Of n=1460 CAR-T recipients, median follow-up from the time of CAR-T infusion for the entire cohort, ide-cel, and cilta-cel pts was 13.1, 16.9, and 10 months, respectively. A total of 55 invasive SPMs were noted in 53 pts (SPM incidence 3.6%). The incidence rate of SPMs was 4.55 per 1,000 person-years, based on 53 SPMs occurring over 11,646.14 person-years (calculated from CAR-T to the SPM diagnosis, death, or last follow-up). Baseline characteristics were similar for pts with no SPM versus SPM including: age at CAR-T (median 67 vs 65), female (36% vs 43%), Black (13% vs 16%), prior autologous transplant (87% vs 80%), lenalidomide for ≥2 years (31% vs 27%), high risk cytogenetics (23% vs 29%), and known clonal hematopoiesis (7.5% vs 9.9%). Differences were observed in baseline characteristics among pts with SPM versus no SPM for ≥2 prior alkylator lines of therapy (LOT) (82% vs 60%, p=0.002) and median prior LOT (6 vs 5, p=0.008). There was a trend for more patients with SPMs being age ≥70 (35% vs 37%, p=0.074). Of the 53 SPMs, 26 (49%) were myeloid (MDS or AML), 19 (35.8%) were solid, 7 (13.2%) were of T-cell origin, and 1 was a B-cell lymphoma. Of the T-cell SPMs, three were of T-LGL, though one of the T-LGL pts later developed an invasive CNS T-cell lymphoma (CAR-negative). There were four cases of confirmed CAR-positive T-cell SPMs (all pts treated with cilta-cel), of which two were indolent T-cell lymphoma of the GI tract and two were cutaneous PTCL. There was no difference in total incidence of SPMs among pts who received ide-cel (total=4.4%; myeloid=2.2%, T-cell=0.04%) versus cilta-cel (total=3%; myeloid=1.4%; T-cell=0.5%) (p=0.21). Median OS from the time of CAR-T therapy was 40.8 months for pts without SPM compared to 27.6 months for pts with SPM (p=0.4). Median OS did not differ by myeloid, solid, and T-cell subgroup: 26.4, 37.2, and 24 months, respectively (p=0.21). Median time from CAR-T cell to SPM was 12 months overall, and by subtypes of myeloid, solid, and T-cell was 13.2, 9.6, and 9.6 months, respectively (p=0.74). There was no difference in time to any SPM among pts receiving ide-cel versus cilta-cel (p=0.61). An earlier time to diagnosis of myeloid SPM was observed for cilta-cel versus ide-cel (4.8 vs 20.4 months; p=0.003). Median OS from the time of diagnosis of any SPM, myeloid, solid, or T-cell SPM was 9.6, 7.2, 15.6, and not reached in months, respectively (p=0.006), demonstrating that pts diagnosed with myeloid subtype SPM had inferior OS from the time of their SPM diagnosis compared to other subtypes. The cause of death of 4/11 myeloid SPM pts was the myeloid SPM itself. In univariable analysis for the entire cohort, age ≥70 (p=0.079), ≥5 prior LOT (p=0.012), and ≥2 prior alkylator LOT (p<0.001) were associated with higher risk for SPM. In multivariable analysis, ≥2 LOT containing alkylators was associated with higher risk of SPM (p=0.005). For the univariable analysis of the myeloid subgroup, ≥2 prior alkylator LOT (p=0.016) and ≥2 years of lenalidomide maintenance (p=0.063) were associated with higher risk of SPM. In multivariable analysis, ≥2 years of lenalidomide (p=0.065) was associated with a trend toward increased risk of myeloid SPM. Conclusions: With a median follow up of 13.1 months, the incidence of developing a SPM following CAR-T in pts with RRMM was 3.6%, of which approximately half were myeloid malignancies. There was no difference in SPM incidence when comparing the two CAR-T products. Pts treated with ≥2 alkylator LOT had a higher risk of SPM in multivariable analysis and may warrant additional monitoring for SPM development.

Abstract Description In the tumor microenvironment of glioblastoma, myeloid cells act as a double-edged sword—they are a major cellular component suppressing the immune response while serving as a promising therapeutic target. Our study sheds light on the voltage-gated proton channel Hv1, predominantly expressed in myeloid cells, as a pivotal regulator of their physiological functions. Elevated Hv1 expression correlates strongly with poor prognosis in glioblastoma patients, underscoring its clinical significance. Using a glioma mouse model, we demonstrated that Hv1 depletion markedly extended survival. To overcome the limitations of existing tools, we engineered novel transgenic mouse lines optimized for Hv1 research. Our findings revealed tumor-induced Hv1 upregulation, with glioma-associated macrophages identified as the principal contributors. Crucially, we identified that Hv1 in infiltrating macrophages as the major driver of survival phenotype differences. Through a multi-faceted approach combining in vivo two-photon imaging, spectral flow cytometry, and spatial transcriptomic sequencing, we discovered that Hv1 depletion limits macrophage infiltration and enhances antigen presentation, ultimately fostering a stronger adaptive immune response. These findings establish the Hv1 channel as a crucial new immune regulator within the brain tumor milieu, offering a promising target for reprogramming macrophage function to combat glioblastoma. Funding Sources Supported by NIH R35NS132326 (LJW); Mayo Clinic Cancer Center and Mayo Clinic Center for Biomedical Discovery. Topic Categories Neuroimmunology (NEUR)

PURPOSE Neoadjuvant immune checkpoint inhibitors (nICIs) have demonstrated high response rates in deficient mismatch repair/microsatellite instability–high (dMMR/MSI-H) gastroesophageal adenocarcinoma (GEA). The NEONIPIGA and INFINITY trials demonstrated high rates of pathologic complete response (pCR) in this patient population. Furthermore, the INFINITY trial explored the feasibility of managing these patients nonoperatively, demonstrating promising results. This study aimed to evaluate clinical outcomes of nICIs in resectable dMMR/MSI-H GEA, with a focus on the feasibility of nonoperative management (NOM). MATERIALS AND METHODS This retrospective cohort study included patients with resectable dMMR/MSI-H GEA and treated with nICIs ± surgery at the Mayo Clinic. Patients were identified from institutional records, and clinical data were retrospectively reviewed. Primary outcomes were clinical complete response (cCR) and pCR. Secondary outcomes included event-free survival (EFS), radiologic complete response (rCR), and immune-related adverse events (irAEs). RESULTS A total of 26 patients treated between April 1, 2017, and July 30, 2025, were identified. Nine patients (34.6%) underwent surgery, of whom six (66.7%) achieved pCR. Seventeen patients (65.4%) pursued NOM, with 10 (71.4%) of 14 evaluable patients achieving cCR and 14 (82.4%) of 17 evaluable achieving rCR. One patient who initially achieved cCR had a local recurrence on surveillance endoscopy and underwent salvage endoscopic resection. At a median follow-up of 19.3 months, 15 (88.2%) of 17 patients in the NOM cohort were alive and metastasis-free, with EFS rates of 87.3% at 12 and 24 months for all patients. irAEs occurred in nine patients (34.6%), with no grade ≥3 toxicities. CONCLUSION In this retrospective cohort study, nICIs led to high cCR and pCR rates in resectable dMMR/MSI-H GEA, supporting the use of immune checkpoint inhibitors in this setting and the feasibility of NOM in select patients.

Abstract Uterine leiomyosarcoma (ULMS) is an orphan disease that frequently recurs and metastasizes, with patients undergoing multiple lines of chemotherapy due to lack of effective therapeutic targets. To address this gap, we used single-cell RNA sequencing and spatial transcriptomic analysis to comprehensively profile ULMS. We uncovered multiple states of tumor cells, including tumor cells with mesenchyme-like features, ischemic tumor cells defined by a MYC program, inflammatory tumor cells with active interferon signaling, and stem cell-like hormone receptor-positive cells. The inferred spatial correlates of these tumor cell states demonstrated unique localization patterns. By correlating these signatures to bulk RNA sequencing data, we demonstrate the relevance of these findings to clinical outcomes. Finally, using the single-cell integration and drug response prediction algorithm (scIDUC), we propose drug predictions that may target specific tumor states. Our findings suggest new avenues for further exploration of individualized and multifaceted therapeutic strategies to treat ULMS.

Malignant glioma is considered invariably recalcitrant, thus necessitating development of new therapeutic approaches. Spontaneously arising canine glioma exhibits important molecular and pathological similarities to malignant pediatric glioma, making it an invaluable model for testing novel therapies. We evaluated safety and activity of RNA lipid particle aggregates (LPAs) designed to provoke cancer immunogenicity in 10 dogs with histologically confirmed glioma. Vaccine manufacturing was feasible in all subjects and generally well tolerated. Median survival time was 123 and 155 days in dogs receiving three (Group A) or four (Group B) vaccines, respectively; this was increased from historical reporting of subjects receiving palliative care. Responding animals had a robust cytokine response following infusions. In animals receiving non-specific RNA-LPAs, there was localization of messenger RNA (mRNA) payloads to the brain tumor microenvironment and a rapid shift in immunologic gene signatures consistent with a viral response. These data demonstrate the ability to induce rapid viremic response in the tumor microenvironment following a single peripherally administered mRNA vaccine. Since RNA-LPAs are amenable to repeat boosts, these formulations may overcome challenges of tumor immunosuppression and therapeutic access and are currently under evaluation in first-in-human trials ( NCT04573140 , NCT06389591 ).

Introduction Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) used to treat type 2 diabetes mellitus (T2D), has potential associations with higher rates of diabetic retinopathy (DR) complications including proliferative DR (PDR) and diabetic macular edema (DME). The purpose of this study was to determine whether an association exists between semaglutide and PDR and treatment-requiring DR/DME. Research design and methods This was a retrospective cohort study of 14 databases (six administrative claims and eight electronic health records) in the Observational Health Data Sciences and Informatics Evidence Network. Adults with T2D on semaglutide, other GLP-1RA (dulaglutide, exenatide), or non-GLP-1RA medications (empagliflozin, sitagliptin, glipizide) from 1 December 2017 to 31 December 2023 were included. The association between semaglutide and PDR or treatment-requiring DR/DME was assessed using an active-comparator cohort design comparing new users of semaglutide as second-line T2D treatment to those on other GLP-1RAs and non-GLP-1RAs. Propensity score-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs). Network-wide HR estimates were generated using a random-effects meta-analysis. Results The study included 810 390 new semaglutide users for T2D. PDR risk for semaglutide was similar to dulaglutide (HR 0.81, 95% CI 0.42 to 1.54, p=0.51), empagliflozin (HR 0.83, 95% CI 0.53 to 1.30, p=0.41) and sitagliptin (HR 0.83, 95% CI 0.45 to 1.55, p=0.57) but was lower than glipizide (HR 0.59, 95% CI 0.39 to 0.88, p=0.01). The risk for treatment-requiring DR/DME for semaglutide was similar to empagliflozin (HR 0.66, 95% CI 0.43 to 1.02, p=0.06) but lower than dulaglutide (HR 0.53, 95% CI 0.31 to 0.91, p=0.02), sitagliptin (HR 0.46, 95% CI 0.26 to 0.81, p=0.008) and glipizide (HR 0.55, 95% CI 0.33 to 0.91, p=0.02). Conclusions and relevance We did not identify increased risk for either PDR or treatment-requiring DR/DME comparing semaglutide with other GLP-1RAs or non-GLP-1RAs. Patients with T2D should still undergo close eye care follow-up, particularly when initiating new antihyperglycemic medications.

Background: Propofol is a first-line sedative for critically ill adults receiving invasive mechanical ventilation (IMV). However, it can contribute to hemodynamic instability, especially in the setting of intubation. The magnitude, timing, risk factors, and variability of sedation-associated mean arterial pressure (MAP) changes remain poorly characterized in ICU settings. Objectives: To quantify MAP changes following propofol sedation, identify risk factors for hemodynamic instability, and characterize associated interventions. Methods: We included adults (≥18 years old) across 11 ICUs in the Mayo Clinic Enterprise who required IMV and received ≥6 consecutive hours of propofol infusion between 05/05/2018 and 07/31/2024. The primary outcome was MAP change within 2-hours following sedation. Secondary outcomes included vasopressor use and hypotension (MAP ≤60 mmHg). Mixed-effects modeling was utilized to account for individual patient differences. The main model used a “neutral” adjustment, estimating a 5 mmHg MAP increase per 0.05 mcg/kg/min of norepinephrine equivalents, reduced to 3 mmHg per 0.05 mcg/kg/min after reaching a dose of 0.20 mcg/kg/min. Those on any vasopressors prior to propofol sedation initiation were analyzed separately. Results: Across 16,418 patients, 25.2% were on vasopressors before sedation initiation. Among the remaining 12,281 patients, 40.3% required vasopressors and 7.7% experienced hypotension within 2 hours of sedation ( Image 1 ). Post-intubation sedation was associated with a MAP reduction within the first 30 minutes (-6.58 mmHg; 95% CI: -6.85 to -6.32; P<0.001; Images 2 and 3 ). There was substantial inter-patient variability in both baseline MAP (9.5% variation attributable to between-patient differences) and MAP decline after sedation (40.9% between-patient differences). Higher SOFA scores (-0.31 mmHg per point), older age (-0.04 mmHg per year), and male sex (-0.47 mmHg) were associated with lower MAP. Patients with higher illness severity experienced progressively greater MAP changes over time (-0.20 mmHg per hour per increasing SOFA point; P<0.001). Conclusions: Propofol sedation is associated with clinically significant hemodynamic effects requiring intervention in the early post-intubation period. The marked inter-patient variability in hemodynamic responses highlights the importance of personalized management approaches. Risk stratification may help identify patients who could benefit from preemptive hemodynamic optimization.