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Background: Hypomethylating agents (HMA) with venetoclax (VEN) have shown encouraging clinical efficacy in single arm clinical trials for patients with myelodysplastic syndrome (MDS) (Garcia JS et al. ASH 2023, Zeidan AM et al. Am J Hematol. 2023). Many centers have started utilizing HMA-VEN in the clinical management of MDS due to unmet need, pending results of the ongoing phase 3 randomized clinical trial (VERONA) using this combination. However, real world studies with large sample size investigating the use of these agents in MDS, practice patterns and clinical outcomes are lacking. Methods: This is a multicenter retrospective study of 13 US academic medical centers. We included contemporary cohorts of adults (age≥18 years) with MDS who were treated with upfront combination of HMA-VEN, upfront HMA monotherapy, or VEN added after inadequate response or progression on HMA (post-HMA failure VEN). Outcomes analyzed includes clinical response, adverse events (AE) of interest, dose administration and survival. Descriptive statistics were used for baseline characteristics. Overall survival 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 454 patients included, 258 patients received VEN in combination with HMA [upfront HMA-VEN (n=175), post-HMA failure VEN (n=83)] and 196 patients received HMA monotherapy. Median age was 69 (59-77) years and majority of patients had MDS with excess blasts (75%), high risk (31.9%) or very-high (41.8%) risk disease by IPSS-R, 23.7% had therapy related disease, 33% had deletion17p or TP53 mutation and 40.9% underwent allogeneic stem cell transplantation. VEN was predominantly started in outpatient setting (78.6%) with tumor lysis syndrome (TLS) prophylaxis and VEN doses ranged from 70-400mg, adjusted for concomitant antifungal drugs. Incidence of TLS was minimal (No TLS- 92.9%, lab-only TLS 6.2%, 1 pt with clinical TLS). Neutropenic fever was the main AE noted [upfront VEN-HMA (34.2%), HMA monotherapy (22.5%), post-HMA VEN (44.5%)]. In the upfront setting, response rate was significantly higher with HMA-VEN than HMA monotherapy (CR: 33% vs 12%; marrow CR: 40% vs 27%, p<.001). VEN given in the post HMA failure setting also resulted in encouraging response rates (CR 10%, marrow CR 32%). After adjusting for covariates in multivariable analysis, patients treated with HMA-VEN in the upfront setting had significantly improved event free survival as compared to HMA monotherapy (HR 0.59, HR 0.44-0.78, p<0.01), but overall survival did not reach statistical significance (overall survival HR 0.77, 95%CI 0.57-1.04, p=0.08). Conclusions: In this large multicenter retrospective analysis from US academic medical centers, we found that VEN in combination with HMA resulted in encouraging clinical outcomes and was effectively administered in the outpatient setting with minimal TLS. Infection risk management and supportive measures would be important to improve the ability to use this treatment widely, pending results of the ongoing phase 3 randomized clinical trial. Updated results with additional variables will be available at the main meeting.

Introduction Multiple Myeloma (MM) precursors Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM) have variable risk of progression to active MM, and identifying which patients may progress remains a clinical challenge. Deep proteome profiling of peripheral blood (PB) plasma may advance non-invasive precursor disease staging, monitoring and characterization. Here, we performed plasma proteomic profiling on patients across the MM disease continuum as well as progressive and stable disease to provide insights into MM disease biology and identify protein-based high-risk disease features that may improve prognostication. Methods We performed high-throughput profiling of >5400 proteins using the Olink® Explore HT library and Proximity Extension Assay (PEA) technology. We profiled 529 PB plasma samples from 485 individuals, including MGUS (n=100), SMM (n=203), MM (n=100), and healthy donors (HDs) (n=82). Sequential samples from SMM-MM progressors (n=32) and stable SMM-SMM non-progressors (n=32) were also profiled, where precursor samples ranged 1.04-6.91 years (median 2.33 years) prior to MM progression. T-tests, ANOVAs, and linear mixed effect (LME) models were used to identify significant proteins across disease stages, progression status, and time. Results were adjusted for multiple testing using Benjamini-Hochberg procedure. A subset of 86 individuals (13 HDs, 14 MGUS, 41 SMM, 18 MM) also had single-cell RNA sequencing (scRNA-seq) performed on tumor and immune cells from paired PB/BM collected at the same timepoint to enable cellular mapping of signals detected in plasma. Results We successfully captured significantly dysregulated proteins including proteins highly expressed on the surface of plasma cells, such as BCMA, SLAMF7 and CD38, highlighting the utility of PEA technology to monitor soluble levels of clinically relevant targets. Given SMM patients are clinically heterogeneous and can resemble MGUS or MM, we aimed to improve discrimination of disease states using biological features obtained from the plasma proteome. We developed a classifier using an Elastic Net model for each stage, where plasma proteins such as SLAMF7, BCMA, TACI, FCRL5 and others had the highest importance scores for the model. We demonstrated 97% SMM/MM samples could be identified from healthy samples (AUC=0.82), indicating our classifier could reliably screen disease-related cases. Moreover, 84% of SMM cases were correctly classified as clinically defined SMM, while misclassified samples were labelled as MM cases. Interestingly, the misclassified patients had consistently rising M-spike levels during clinical follow-up but without a shift in clinical stage or risk status, suggesting the plasma proteome may provide earlier indication of evolving disease. Since proteomic information may also hold value for improved risk stratification, we evaluated protein levels in precursor stage timepoint samples from SMM-MM progressors and stable SMM non-progressors. We identified a prognostic five-protein signature that was significantly elevated in SMM-MM progressors, of which BCMA and TACI were top proteins, as well as proteins vital for calcium homeostasis and integrin-mediated cell adhesion. BCMA and TACI levels also had a strong positive correlation with BM plasma cell infiltration, which suggests these proteins may be useful surrogates of BM tumor burden during routine blood-based assessment of precursor patients. Lastly, integrative analysis of scRNA-seq of tumor and immune cells was used to elucidate cell origin level information of the prognostic signature proteins. Four proteins were highly expressed in malignant versus non-malignant plasma cells, suggesting our prognostic signature partially provides a readout of plasma cell biology. Meanwhile, one protein was constitutively expressed on most leukocytes, suggesting that the interplay of other cell types in the immune microenvironment involved in progression may also be reflected in the plasma. Conclusion We performed the first comprehensive analysis of the plasma proteome of MM and its precursor conditions. Overall, we developed a classifier that utilizes plasma proteins alone to accurately classify disease stages and identified a prognostic protein signature associated with progressive disease.

Introduction: Acute myeloid leukemia (AML) has been considered by many to be an oncologic emergency often leading to hospital admission for expeditious evaluation and treatment. Previous studies reported that time from diagnosis to treatment (TDT) does not impact outcomes (Sekeres, Blood, 2009), (Bertoli, Blood, 2013), (Rollig, Blood, 2020), however these analyses were restricted to intensively treated and/or non-United States (US) patients (pts). We report on a multi-center, retrospective analysis of TDT in adults with newly diagnosed AML receiving Hypomethylating agent (HMA) + venetoclax (Ven) using real-world data from the COMMAND. Methods: Eight US academic medical centers with AML expertise performed a review of adult pts within their center treated with HMA+Ven for newly diagnosed AML. TDT was defined as days from diagnosis of AML to initiation of treatment with HMA+Ven. Cytoreduction with hydroxyurea or leukapheresis was included to control for the effects of severity of presentation on TDT. The primary outcome was impact of TDT on overall survival (OS) (defined as date of diagnosis to date of death). TDT was treated continuously for time-to-event analyses. Secondary outcomes included measurable residual disease (MRD) by flow cytometric analysis (sensitivity <0.1%), complete response (CR), complete response with incomplete count recovery (CRi), defined by European LeukemiaNet (ELN) 2022 Guidelines (Dohner, Blood,2022), and early mortality (death within 30 and 60 days of initiation of HMA+Ven). Pre-planned subgroup analyses included those based on disease biology (FLT3 ITD, IDH1/2, TP53 mutation, ELN 2022 risk), HMA used (azacitidine vs decitabine) and age (<75 vs ≥75 years). For those analyses where TDT was significant in univariable analysis (P=0.1), multivariable analysis was conducted controlling for the following: ECOG performance status (PS), age, receipt of cytoreduction, ELN 2022 risk, and presence of individual pathogenic variants detected on broad myeloid gene next generation sequencing panels used at each institution. All analyses were conducted by a central statistician using RStudio statistical package. Results: 488 pts were included in the analysis. Median age was 76 (interquartile range: 70-80) and the majority of pts had an ECOG PS of 0 or 1 (56%). Most pts (67.6%) had adverse risk with 9.4% and 18.6% of pts having favorable and intermediate risk disease by ELN 2022, respectfully. The most common mutations identified were TP53 (27.5%), IDH1/2 (19.3%), NPM1 (16.4%), DNMT3A (16.8%), ASXL1 (15.4%), and FLT3-ITD (13.7%). Twenty-eight percent of pts received cytoreduction prior to initiation of HMA+Ven. Azacitidine+Ven was the most common regimen utilized (53.9%). Median number of cycles of HMA+Ven was 3 (IQR: 1-6). MRD (-) CR, MRD (+) CR, and CRi was achieved in 21.5%, 10.5%, and 16.4% of pts after one cycle of HMA+Ven. Median OS for the cohort was 10.4 months (95% CI: 9.4-12.6). Median TDT for the cohort was 9 days (IQR: 5-17). In univariate Cox model, longer TDT was associated with improved OS (HR: 0.989, 95% CI: 0.981 to 0.998; p = 0.013). In multivariable analysis, longer TDT was still associated with improved OS (HR: 0.987; 95% CI: 0.973-0.999; p=0.049). TDT and presence of bZIP in-frame CEBPA mutations were the only factors associated with improved OS, while ECOG PS of 2 or 3-4, when compared to ECOG PS=0 (p=0.035 and 0.0002, respectively) and therapy-related AML (p=0.002), were associated with worse OS. Notably, ELN 2022 risk and IDH1/2 or NPM1 mutation status did not impact OS. Discussion: In this real-world, multi-center, US-based analysis of pts with newly diagnosed AML treated with HMA+Ven we show that longer TDT is associated with improved OS even when controlling for severity of presentation, ELN 2022 risk score, ECOG PS, and age. This finding is consistent with data in pts treated with 7+3. Similar to results published in an electronic medical record-based analysis out of Germany (Baden, Haemotologica, 2024) in pts treated with lower-intensity Ven regimens, our results show that pts with newly diagnosed AML eventually treated with HMA+Ven are best served with a complete appraisal of disease biology and treatment planning before initiation of induction therapy. Given the consistent negative impact of ECOG PS and the findings of our study, future consideration for potential patient optimization strategies to improve ECOG PS prior to therapy initiation are warranted.

Background: Mavacamten was approved by the US Food and Drug Administration (FDA) in April 2022 for the treatment of adults with New York Heart Association (NYHA) class II-III symptomatic obstructive hypertrophic cardiomyopathy (HCM). Few studies have reported on the long-term real-world effectiveness and safety of mavacamten. We evaluated clinical outcomes in patients on mavacamten in multiple health centers across the United States. Research Questions: This study assessed the real-world effectiveness and safety of mavacamten in patients with symptomatic obstructive HCM. Methods: In this multi-center observational study, we evaluated patient characteristics at baseline, NYHA class, left ventricular outflow tract gradients (LVOTg) at rest and Valsalva, and left ventricular ejection fraction (LVEF) in patients with symptomatic obstructive HCM treated with mavacamten for up to 72 weeks. Results: Mavacamten was initiated in 172 patients across 4 US centers (UCSF, Mayo Arizona, Stanford, and Atlantic Health System/Morristown Medical Center). Baseline characteristics included: 56% female, mean age 64 (standard deviation ±13) years, 47% NYHA class III, mean resting LVOTg of 47 mmHg and mean Valsalva LVOTg of 89 mmHg, and 23% non-White. Comorbidities included hypertension (56%) and atrial fibrillation (25%) at baseline (Table). Patients experienced a notable early response to mavacamten in resting and Valsalva gradients by week 4, which was sustained through week 72 (Figure A). No patients were NYHA class III at week 72, compared to 47% at baseline (Figure B). Mean LVEF did not change substantially between baseline and week 72. No patients experienced an LVEF of <40% and 2% experienced an LVEF of <50%. Conclusions: This is the largest observational study to date demonstrating the effectiveness and safety of mavacamten with substantial sustained reductions in resting and Valsalva LVOTg, and progressive improvements in NYHA class without considerable changes in mean LVEF up to 72 weeks.

Abstract Introduction: Immune checkpoint inhibitors (ICI) are an essential systemic therapy for advanced melanoma. However, most melanomas develop resistance to ICI. Tumor-derived soluble PD-L1 (sPD-L1) and other soluble immunosuppressive factors drive checkpoint inhibitor resistance and correlate with inferior survival. We previously showed that therapeutic plasma exchange (TPE) removes sPD-L1 from circulation. Thus, we hypothesized that TPE-mediated removal of sPD-L1 and other immunosuppressive factors could overcome immunotherapy resistance in refractory melanoma. Methods: In this clinical trial (NCT04581382), we prospectively enrolled eighteen (18) patients with widely metastatic melanoma with progression despite anti-PD-1 ICI and elevated sPD-L1 by ELISA (≥1.7ng/mL). Each patient received radiotherapy to between one and three metastatic lesions (at least two unirradiated lesions) followed by three TPE sessions on consecutive days and re-challenge with checkpoint inhibitor. The primary safety and efficacy endpoints of the study were adverse events (AEs) and sPD-L1 reduction by TPE, respectively. Secondary endpoints included RECIST-based response in unirradiated lesions and overall survival. Correlative studies included kinetics of sPD-L1 and soluble immonsuppressive factors and dynamics of peripheral immune cell phenotypes. Results: Mean age was 62 (SD 13) and seven of eighteen (39%) were female. Mean baseline sPD-L1 was 26.31 ng/mL (40.01). The treatment was well-tolerated with one (6%) patient with grade 3 and 4 adverse events from a central line infection after TPE. Levels of sPD-L1 were significantly reduced by TPE (mean 80.2% reduction, p<0.0001). Two patients (11.1%) experienced complete response (CR), one (5.6%) partial response, three (16.7%) stable disease, and 12 (66.7%) progressive disease. In one case, immunotherapy was discontinued after two years due to no detectable lesions. Changes in tumor-reactive (TTR) GZMB+/CX3CR1+/CD11ahigh and other peripheral immune cell populations predicted overall survival in this cohort. In addition to sPD-L1, other soluble mediators of ICI resistance were also reduced by TPE and predicted overall survival in this cohort. Summary/Conclusion: sPD-L1 and other soluble immunoregulatory signaling molecules are important mediators of ICI resistance. SBRT and TPE can resensitize ICI-refractory melanoma by removing these factors. Patients with persistently elevated or rapid rebound of sPD-L1 following TPE experienced poor response and overall survival. Serial monitoring of sPD-L1 may predict response to ICI and multiple courses of TPE may be necessary. Our findings may apply in other ICI-resistant cancers with elevated sPD-L1. ClinicalTrials.gov registration: NCT04581382, ReCIPE-M1 (Rescuing Cancer Immunotherapy with Plasma Exchange in Melanoma 1).

Reduced skeletal muscle mass and oxidative capacity coexist in patients with pulmonary emphysema and are independently associated with higher mortality. If reduced cellular respiration contributes to muscle atrophy in that setting remains unknown. Using a mouse with genetically induced pulmonary emphysema that recapitulates muscle dysfunction, we found that reduced activity of succinate dehydrogenase (SDH) is a hallmark of its myopathic changes. We generated an inducible, muscle-specific SDH knockout mouse that demonstrates lower mitochondrial oxygen consumption, myofiber contractility, and exercise endurance. Respirometry analyses show that in vitro complex I respiration is unaffected by loss of SDH subunit C in muscle mitochondria, which is consistent with the pulmonary emphysema animal data. SDH knockout initially causes succinate accumulation associated with a down-regulated transcriptome but modest proteome effects. Muscle mass, myofiber type composition, and overall body mass constituents remain unaltered in the transgenic mice. Thus, while SDH regulates myofiber respiration in experimental pulmonary emphysema, it does not control muscle mass or other body constituents.

AbstractBackground and PurposeTo compare the performance of the photon‐counting detector (PCD)‐CT against a cutting‐edge energy‐integrated detector (EID)‐CT to visualize different segments of the chorda tympani nerve.Materials and MethodsAn IRB‐approved protocol prospectively enrolled patients for temporal bone CT on both EID‐CT and PCD‐CT scanners. Fellowship‐trained neuroradiologists compared visualization of chorda tympani segments on each scanner using a 5‐point Likert scale (1 indicating EID is far superior to PCD, 3 indicating they are equivalent, and 5 indicating PCD is far superior to EID). Scores were averaged across segments and tested using a one‐sample Wilcoxon signed‐rank test with a one‐sided alternative hypothesis.ResultsForty temporal bones were evaluated. Average Likert scores for visualization of chorda tympani segments‐chorda tympani canal/proximal segment, middle ear/posterior tympanic segment, and petrotympanic fissure/distal segment‐ on the PCD compared to EID scanner were 4.2 (SD = 0.4), 4.4 (0.5), and 4 (0.0), respectively. The anterior tympanic segment of the chorda tympani was not well visualized on either platform or therefore not scored. PCD compared to the EID scanner had better overall performance (Median = 4.2, 95% CI: [4.1, 5.0], p‐value < .001).ConclusionPCD‐CT improves visualization of the petrous and intratympanic chorda tympani nerve segments, chorda tympani canaliculus, and petrotympanic fissure compared to comparable EID‐CT examinations. The improved visualization of the chorda tympani is important for the characterization of middle ear pathology involving this structure and presurgical planning to determine the size of the facial recess for cochlear implantation and to estimate the risk of nerve injury.

ABSTRACT Background Virtual interviews may limit an applicant’s ability to ascertain the culture of a training program. No-stakes campus visits (NSCVs) have been offered but their value is unknown. Objective The purpose of our study was to determine factors that influence applicants’ rank lists and determine barriers to and perceptions of NSCVs and their impact on applicants’ final rank lists. Methods All interviewed applicants of graduate medical education (GME) programs who agreed to participate in the study were emailed a survey after the 2023 National Resident Matching Program Match. The survey contained sections on demographics, perspectives on factors affecting ranking decisions, and perceptions of NSCVs. Results Of 796 applicants, 183 (22.9%) who interviewed at 16 different Mayo Clinic GME programs responded to the survey. Of 131 respondents who answered whether they accepted an NSCV offer, 39 (29.8%) accepted. Of 35 respondents who answered whether they thought attending NSCVs impacted their rank, 19 (54.3%) were either uncertain or said yes. Of 34 respondents who answered whether the NSCV influenced their ranking of the program, 16 (47.1%) said their rank did not change, 12 (35.3%) said they ranked the program higher, and 5 (14.7%) said they ranked the program lower. For respondents who did not attend NSCVs, financial burden and lack of time were primary reasons. Conclusions NSCVs are perceived positively by most respondents. Many either believed they influenced their position on the program’s rank list or were unsure. Most respondents said NSCVs either improved or did not change their ranking of the program.

Abstract Background: Several immune effector cell (IEC) therapies have been approved for multiple myeloma (MM), including chimeric antigen receptor T-cell (CAR-T) therapies such as idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). We report 14 cases of IEC-associated enterocolitis, in five cases fatal, following CAR-T therapy in MM. Methods: We performed a retrospective analysis of cases of diarrhea, enterocolitis, or colitis following commercial ide-cel or cilta-cel (including out-of-specification products) at 10 centers within the United States Myeloma Immunotherapy Consortium. Patients were treated according to the local standard of care at each participating center. Results: We identified 14 cases of IEC-associated enterocolitis out of 1159 CAR-T infusions, corresponding to a 1.2% incidence (0.2% for ide-cel and 2.3% for cilta-cel). This proportion excludes 3 cases of potential or confirmed T-cell lymphoproliferative disorders of the bowel. Patients developed acute-onset symptoms (typically non-bloody Grade 3+ diarrhea) with negative infectious workup beginning a median of 79 days (range: 22-210 days) after CAR-T therapy and a median of 74 days after cytokine release syndrome resolution (range: 2-202 days). Biopsies uniformly demonstrated inflammation, with specific findings including intra-epithelial lymphocytosis, crypt dropout on colon biopsies, and villous blunting on duodenal biopsies. Systemic corticosteroids were initiated in 10 patients (71%) a median of 26 days (range: 1-80 days) following symptom onset. Only 40% of steroid-treated patients had symptomatic improvement; subsequent infliximab or vedolizumab led to improvement in 50% and 33% of corticosteroid-refractory patients, respectively. With a median follow-up of 224 days, n = 4 have had diarrhea resolution, n = 5 have had improved or stable symptoms, and n = 5 (36%) have died from IEC-associated enterocolitis or treatment-emergent infections. Conclusions: IEC-associated enterocolitis is a distinct but rare complication of CAR-T therapy characterized by non-bloody diarrhea typically beginning 1-3 months after infusion. Thorough diagnostic workup (including evaluation for potential T-cell malignancies) and appropriate management with an expert gastroenterologist are essential. Further research is critical to understand the pathogenesis of this novel toxicity. In the interim, the early use of infliximab or vedolizumab may potentially hasten symptom resolution and lower reliance on high-dose corticosteroids during the post-CAR-T period.