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Abstract Background Prognosis is poor for patients (pts) with relapsed/refractory multiple myeloma (RRMM; median overall survival: <1 year), indicating a clear need to identify agents with novel mechanisms of action. B-cell maturation antigen (BCMA) has recently emerged as a novel treatment target for MM due to its highly selective expression in plasma cells. TNB-383B, a BCMA x CD3 T-cell engaging bispecific antibody, was designed to overcome the toxicity limitations of existing BCMA therapies and has demonstrated promising results in an ongoing first-in-human phase 1 study in pts with RRMM (Rodriguez C, et al. Blood 2020;136[suppl 1]:43-44). Herein, we report the updated efficacy and safety outcomes of this phase 1 study. Methods This multicenter, phase 1, open-label, dose-escalation/expansion study (NCT03933735) enrolled pts with RRMM (≥3 prior lines of therapy that included a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody), estimated glomerular filtration rate ≥30 mL/min as calculated by the Modification of Diet in Renal Disease formula, and ECOG performance status ≤2. Prior BCMA-targeted therapy is prohibited. Primary objectives include safety/tolerability, pharmacokinetics (PK), and determination of recommended phase 2 dose (RP2D); secondary objectives include assessment of clinical activity (per IMWG criteria 2016). TNB-383B is administered intravenously over 1-2 hours every 3 weeks (Q3W) with the first dose administered inpatient. The study uses a 3+3 design with backfilling for dose and permits intrapatient dose escalation to highest safe dose. Dose expansion was initiated on selection of RP2D. Pts are treated until progression, unacceptable toxicity, or other discontinuation criteria are met. The efficacy-evaluable population includes all pts who received at least 1 dose of TNB-383B and have at least 1 postdose assessment. The safety population includes all pts who received at least 1 dose of study drug; adverse events (AEs) are graded according to NCI CTCAE v5.0. Results As of 10 May 2021, 103 pts (dose escalation, n=73; dose expansion, n=30) have been treated with TNB-383B (0.025-120 mg). The RP2D of 60 mg Q3W was selected on the basis of tolerability, safety, PK, and clinical activity. Pt demographics and baseline characteristics are summarized in Table 1. Three dose-limiting toxicities were reported in dose escalation (platelet count decreased: grade [Gr] 4, 60 mg; cytokine release syndrome [CRS]: Gr 3, 90 mg and 120 mg); none were reported as serious. Treatment-related AEs (TRAEs) were reported in 79 (77%) pts, with Gr ≥3 and serious AEs occurring in 33 (32%) and 23 (22%) pts, respectively. The most common TRAEs (Table 2) include CRS (n=54, 52%), neutropenia (n=18, 17%), and fatigue (n=14, 14%). At the RP2D (n=39), the Gr ≥3 CRS rate was 3% (n=1). Onset of CRS typically occurred on the same or next day following the first dose and all pts recovered using tocilizumab or standard supportive care measures. Treatment-emergent AEs (TEAEs) of infusion-related reactions were reported in 8 (8%) pts and infections occurred in 29 (28%) pts; pneumonia (n=5, 5%) and upper respiratory tract infection (n=4, 4%) were the most common. Five deaths from TEAEs were reported; all were unrelated to study drug. Forty-two (40%) pts discontinued treatment due to disease progression. In the dose-escalation cohorts of ≥40 mg Q3W (n=24), the objective response rate (ORR) was 79% (19/24), with a very good partial response or better (≥VGPR) rate of 63% (15/24), and a complete response (CR) rate of 29% (7/24) at the data cutoff date; these pts have the longest follow-up (ie, mature data) with median time on study of 6.1 months (Figure 1). At doses ≥40 mg in the combined dose-escalation and -expansion cohorts (n=44), the observed ORR, ≥VGPR, and CR rates were 64% (28/44), 43% (19/44), and 16% (7/44), respectively; these pts have shorter follow-up (ie, immature data) with median time on study of 3.1 months. Twenty-nine (66%) of the 44 pts administered ≥40 mg were triple-class refractory and reported an ORR of 55% (16/29). Conclusions TNB-383B in pts with RRMM is well tolerated with an ORR of 79% observed at doses ≥40 mg in the dose-escalation cohorts. Despite having a shorter follow-up period, this trend was also observed at doses ≥40 mg in the combined dose-escalation/expansion cohorts (ORR: 64%). Enrollment into the dose-expansion arm is ongoing; updated data will be presented at the meeting. Figure 1 Figure 1. Disclosures Kumar: Novartis: Research Funding; Carsgen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Roche-Genentech: Consultancy, Research Funding; Bluebird Bio: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Antengene: Consultancy, Honoraria; Tenebio: Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. D'Souza: Imbrium, Pfizer, BMS: Membership on an entity's Board of Directors or advisory committees; Sanofi, Takeda, Teneobio, CAELUM, Prothena: Research Funding; Janssen, Prothena: Consultancy. Shah: Oncopeptides: Consultancy; Nektar: Research Funding; Poseida: Research Funding; Janssen: Research Funding; Indapta Therapeutics: Consultancy; GSK: Consultancy; CareDx: Consultancy; BMS/Celgene: Research Funding; Bluebird Bio: Research Funding; CSL Behring: Consultancy; Teneobio: Research Funding; Kite: Consultancy; Sutro Biopharma: Research Funding; Karyopharm: Consultancy; Amgen: Consultancy; Precision Biosciences: Research Funding; Sanofi: Consultancy. Rodriguez: Takeda: Consultancy, Speakers Bureau; Karyopharm: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Speakers Bureau. Voorhees: AbbVie Inc, Bristol-Myers Squibb Company; Consulting Agreement: GlaxoSmithKline, Novartis, Oncopeptides: Other: Advisory Committee; Bristol-Myers Squibb Company.: Other: Data Safety & Monitoring. Bueno: AbbVie: Current Employment, Current equity holder in publicly-traded company. Buelow: Teneobio, Inc.: Current Employment, Current holder of stock options in a privately-held company. Freise: Abbvie, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Yue: Abbvie, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Pothacamury: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Polepally: Abbvie, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Vij: BMS: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; BMS: Honoraria; GSK: Honoraria; Oncopeptides: Honoraria; Karyopharm: Honoraria; CareDx: Honoraria; Legend: Honoraria; Biegene: Honoraria; Adaptive: Honoraria; Harpoon: Honoraria.

Abstract Background and study aims En bloc endoscopic mucosal resection (EMR) is preferred over piecemeal resection for polyps ≤ 20 mm. Data on colorectal EMR training are limited. We aimed to evaluate the en bloc EMR rate of polyps ≤ 20 mm among advanced endoscopy trainees and to identify predictors of failed en bloc EMR. Methods This was a multicenter prospective study evaluating trainee performance in EMR during advanced endoscopy fellowship. A logistic regression model was used to identify the number of procedures and lesion cut-off size associated with an en bloc EMR rate of ≥ 80 %. Multivariate analysis was performed to identify predictors of failed en bloc EMR. Results Six trainees from six centers performed 189 colorectal EMRs, of which 104 (55 %) were for polyps ≤ 20 mm. Of these, 57.7 % (60/104) were resected en bloc. Trainees with ≥ 30 EMRs (OR 6.80; 95 % CI: 2.80–16.50; P = 0.00001) and lesions ≤ 17 mm (OR 4.56;95 CI:1.23–16.88; P = 0.02) were more likely to be associated with an en bloc EMR rate of ≥ 80 %. Independent predictors of failed en bloc EMR on multivariate analysis included: larger polyp size (OR:6.83;95 % CI:2.55–18.4; P = 0.0001), right colon location (OR:7.15; 95 % CI:1.31–38.9; P = 0.02), increased procedural difficulty (OR 2.99; 95 % CI:1.13–7.91; P = 0.03), and having performed < 30 EMRs (OR: 4.87; 95 %CI: 1.05–22.61; P = 0.04). Conclusions In this pilot study, we demonstrated that a relatively low proportion of trainees achieved en bloc EMR for polyps ≤ 20 mm and identified procedure volume and lesion size thresholds for successful en bloc EMR and independent predictors for failed en bloc resection. These preliminary results support the need for future efforts to define EMR procedure competence thresholds during training.

PURPOSE This study sought to determine the prognostic significance of the WHO-defined glioma molecular subgroups along with additional alterations, including MGMT promoter methylation and mutations in ATRX, CIC, FUBP1, TERT, and TP53, in NRG/RTOG 0424 using long-term follow-up data. METHODS Mutations were determined using an Ion Torrent sequencing panel. 1p/19q co-deletion and MGMT promoter methylation were determined by Affymetrix OncoScan and Illumina 450K arrays. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and tested using the log-rank test. Hazard ratios were calculated using the Cox proportional hazard model. Multivariable analyses (MVAs) included patient pretreatment characteristics. RESULTS We obtained complete molecular data to categorize 80/129 eligible patients within the WHO subgroups. Of these, 26 (32.5%) were IDHmutant/co-deleted, 28 (35%) were IDHmutant/non-co-deleted, and 26 (32.5%) were IDHwild-type. Upon single-marker MVA, both IDHmutant subgroups were associated with significantly better OS and PFS ( P values < .001), compared with the IDHwild-type subgroup. MGMT promoter methylation was obtained on 76 patients, where 58 (76%) were methylated and 18 (24%) were unmethylated. Single-marker MVAs demonstrated that MGMT promoter methylation was statistically significant for OS ( P value < .001) and PFS ( P value = .003). In a multimarker MVA, one WHO subgroup comparison ( IDHmutant/co-deleted v IDHwild-type) was significant for OS ( P value = .045), whereas MGMT methylation did not retain significance. CONCLUSION This study reports the long-term prognostic effect of the WHO molecular subgroups, MGMT promoter methylation, and other mutations in NRG/RTOG 0424. These results demonstrate that the WHO molecular classification and MGMT both serve as strong prognostic indicators, but that MGMT does not appear to add statistically significant prognostic value to the WHO subgrouping, above and beyond IDH and 1p/19q status.

BackgroundConsolidative autologous hematopoietic stem cell transplantation (AHCT) is commonly used for patients with multiple myeloma (MM). We studied AHCT use and outcomes in patients with MM ≥75 years old.MethodsPatients with MM ≥75 years old receiving AHCT between 2013 and 2017 in the United States were identified using the Center for International Blood and Marrow Transplant Research database. Relapse and/or progression (REL), progression‐free survival (PFS), and overall survival (OS) were modeled using Cox proportional hazards models. Covariates used were age, sex, Karnofsky performance score (KPS), HCT‐comorbidity index (HCT‐CI), International Staging System and/or Durie‐Salmon stage, high‐risk cytogenetics, melphalan dose, and disease status at and 1 year after transplant. AHCT utilization rate using the Surveillance, Epidemiology, and End Results database was used to estimate specific incidence among ≥75 years old by race and gender.ResultsOf 360 patients, 63% were male, 84% were White, 56% had KPS <90, and 57% had HCT‐CI ≥3. The 100‐day transplant‐related mortality was 1% (0%‐2%) with a 2‐year REL rate of 27% (95% confidence interval [CI], 22%‐33%), PFS of 66% (95% CI, 60%‐72%), and OS of 83% (95% CI, 78%‐87%). On multivariate analysis, only high‐risk cytogenetics was associated with REL risk and decreased PFS. In White males, transplant utilization rate was 5.2%‐5.8% compared to 3.5%‐4.0% in African American males (P = .02). There was 3.37‐3.79% transplant utilization in White females compared to 1.88‐2.12% in African American females (P < .01).ConclusionsThe use of AHCT was associated with excellent 2‐year outcomes in this selected MM population ≥75 years old. Transplant utilization for patients ≥75 years old remains low with significant racial and gender disparities.

BACKGROUND: Intrathecal drug delivery systems (IDDS) have been utilized for over 3 decades for management of chronic pain and spasticity. Patients with IDDS may present for surgical procedures unrelated to the IDDS device, although data are limited regarding perioperative outcomes. METHODS: This is a historical matched cohort study conducted between January 1, 2007 and December 31, 2016 of patients with an opioid-based IDDS versus matched control patients undergoing surgery excluding interventional pain procedures. Patients in the IDDS group were matched with up to 2 patients without an IDDS. Multivariable regression analyses were utilized to assess differences in the primary outcome of cumulative perioperative opioid consumption (ie, intraoperative and postanesthesia care unit [PACU] opioid consumption), and opioid consumption during the first 24 and 72 postoperative hours. Postoperative clinical outcomes were also assessed including escalating oxygen requirements, naloxone administration, pain-sedation mismatch, and perioperative pain service consultation. RESULTS: A total of 321 surgeries were included, 112 with IDDS and 209 controls, with median (interquartile range [IQR]) age of 57 (49–64) years. Compared to matched controls, patients with an IDDS had greater perioperative opioid consumption (median [IQR] oral morphine milligram equivalents [OME] of 110 [60–163] vs 93 [IQR, 53–142]; adjusted multiplicative increase 1.28 [95% confidence interval {CI}, 1.03–1.59]; P = .026). IDDS patients also had greater opioid consumption in the first 24 and 72 postoperative hours (multiplicative increases of 2.23 [95% CI, 1.36–3.63], P = .001, and 2.46 [95% CI, 1.41–4.32], P = .002, respectively). There were no significant differences in postoperative oxygen requirements, naloxone administration, or pain-sedation mismatch. Inpatient pain medicine consultation was more frequent in IDDS patients compared to controls (51.8% vs 6.2%; P < .001). CONCLUSIONS: Patients with opioid-based IDDS received more perioperative opioids and were more likely to receive postoperative pain service consultation compared to matched controls. There were no significant differences in clinical safety outcomes, suggesting tolerance for higher opioid doses. Further research is warranted to optimize perioperative outcomes in those with IDDS.

Abstract Background: Prostate cancer is the most common cancer among men. Monitoring of patient-reported outcomes (PROs) can enhance provider-patient communication, promote better decision-making, and improve survival. Geospatial factors, namely rurality and neighborhood socioeconomic deprivation, could influence the experience across cancer treatment, thus impacting PROs and survival. This study examined associations of rurality, neighborhood socioeconomic deprivation (Area Deprivation Index [ADI]) with cancer treatment-related PROs and survival in men with prostate cancer. Methods: Data from men with prostate cancer in the trial NRG Oncology/RTOG 0415 were analyzed. In this trial, 1092 men were randomized to receive conventional radiotherapy (RT) or hypofractionated RT. Patients had Gleason scores of 2-6 and prostate-specific antigen of &lt;10 ng/mL. Rurality was categorized as urban vs rural using Rural-Urban Continuum Codes via patient zip codes. Neighborhood socioeconomic deprivation was assessed by the ADI calculated via the American Community Survey by patient zip codes. The Expanded Prostate Cancer Index Composite (EPIC) measures cancer-specific quality of life (QOL); Hopkins Symptom Checklist measures anxiety and depression; EuroQoL-5 Dimension (EQ-5D) VAS and Index scores assess general health. All PROs were measured at baseline before and 6, 12, 24 and 60 months after RT. Overall survival (OS) and disease-free survival (DFS) were assessed using Cox proportional hazards models. Mixed effects models and generalized estimating equations were used to analyze PROs. Results: We analyzed 751 patients with complete data. Patients from the ADI 25% most deprived neighborhoods (vs. the other 75% of neighborhoods) were more likely to be non-white, unmarried and from rural areas. At baseline, patients from the most deprived areas had worse EPIC bowel score (P=0.011), worse sexual score (P=0.042) and worse hormonal score (P=0.015); patients from the most deprived areas had worse self-care (P=0.04) and more pain (P=0.047). Patients from rural areas had worse EPIC urinary score (P=0.03) and sexual score (P=0.003). Longitudinal analyses showed that ADI 25% most deprived areas (β=4.05, P=0.001) and rural areas (β=-5.70, P=0.003) were associated with worse EQ-5D VAS score. Compared to the 75% less deprived neighborhoods and urban, the ADI 25% most deprived neighborhoods and rural areas respectively had 47% (HR=1.466, P=0.033) and 93% (HR=1.925, P=0.026) relative increase in risk of recurrence or death (DFS). No differences were seen in OS. Conclusions: Patients with prostate cancer from the most deprived neighborhoods and rural areas had low QOL at baseline, poor general health and DFS. Interventions should target populations from socioeconomic deprived neighborhoods and rural areas to improve patient access to supportive care services and DFS. Citation Format: Jinbing Bai, Stephanie L. Pugh, Ronald Eldridge, Katherine Yeager, Qi Zhang, W Robert Lee, Amit B. Shah, Ian S. Dayes, David P. D'Souza, Jeff M. Michalski, Jason A. Efstathiou, John M. Longo, Thomas M. Pisansky, Jordan M. Maier, Sergio L. Faria, Anand B. Desai, Samantha A. Seaward, Howard M. Sandler, Mary E. Cooley, Deborah W. Bruner. Rurality and neighborhood socioeconomic deprivation associated with patient-reported outcomes andsurvivalin men with prostate cancer in NRG RTOG 0415 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2528.

Introduction Visceral obesity is associated with GERD and, traditionally, it has been assumed that visceral fat predisposes to GERD primarily by increasing intra‐abdominal pressure. However, transmission electron microscopy (TEM) of esophageal biopsies from obese individuals without GERD exhibit dilated intercellular spaces (DIS) and, in earlier studies, we found that substances secreted by mature adipocytes in visceral fat from obese patients impair esophageal epithelial barrier function, induce DIS and reduce transepithelial resistance (TER). There is a fat pad at the gastroesophageal junction (GEJ) that is in intimate contact with the distal esophagus. We now explore whether whole GEJ fat tissue of obese individuals secretes substances that impair esophageal barrier function. Methods We obtained GEJ fat from 3 obese (BMI 46, 60, 74) and 3 non‐obese (BMI 24, 26, 27) patients having foregut surgery. Human esophageal squamous cells were seeded into transwells and grown to confluence for 3 days. On day 4, cells were raised to an air‐liquid interface (ALI) to allow for differentiation, stratification, and esophageal barrier formation. ALI cultures were exposed to conditioned media (CM) from GEJ fat or to control medium beginning at day 4. TER was measured on days 4, 6, and 8 using the EVOM2 Epithelial Volt/Ohm Meter. On day 8, ALI cultures were stained with H&E and Ki‐67 and imaged; barrier permeability was assessed by a biotinylation reagent applied to the ALI surface. TEM of ALIs and of esophageal biopsies from 2 non‐obese and 2 obese patients without GERD were assessed. Results CM from all 3 obese patients significantly reduced TER on days 6 and 8; CM from 2 non‐obese patients did not reduce TER whereas CM from 1 non‐obese patient induced a slight reduction in TER at day 8 (Table 1). Marked DIS were found only in ALI cultures grown with CM from obese patients. In ALIs grown with CM from non‐obese patients, the biotinylation reagent stopped at the superficial layers of esophageal cells. In contrast, the biotinylation reagent diffused through all cell layers in ALIs grown with obese patient CM. Increases in basaloid cells and in Ki‐67 were found in ALIs grown with obese patient CM. TEMs of ALIs grown with non‐obese patient CM demonstrated well‐oriented cell‐cell junctions similar to TEMs of non‐obese patient esophageal biopsies. In contrast, ALIs grown with obese patient CM demonstrated cell‐cell junctional structures that were disorganized, aggregated, and floating within the DIS, similar in appearance to TEMs of the obese patients’ esophageal biopsies. Conclusion Substances produced by GEJ fat of obese patients impair esophageal epithelial barrier integrity, cause basal cell hyperplasia and DIS, and disrupt intercellular connections. These findings in ALI cultures recapitulate abnormalities seen by TEM in esophageal biopsies of obese patients.

Currently, the effect of aging on sympathetic baroreflex control is equivocal, with some studies finding that integrated sympathetic baroreflex threshold gain is not affected by age, and others finding that it is blunted in older compared to young adults. While these studies evaluated the effect of aging on baroreflex control of integrated sympathetic burst frequency, it remains unclear how aging modulates the baroreflex control of postganglionic action potentials (AP). In young adults, the arterial baroreflex exerts non‐uniform control over varying‐sized APs spontaneously firing within bursts of muscle sympathetic nerve activity (MSNA), with the strongest control over medium sized AP clusters, and less control over the smallest and largest APs. Therefore, we tested the hypothesis that resting baroreflex control of AP subpopulations and integrated sympathetic bursts would be blunted in older compared to young adults. Baroreflex threshold relationships for integrated MSNA bursts and the underlying subpopulations of AP clusters (obtained using microneurography and a continuous wavelet transform) were assessed during 5 minutes of supine rest in eleven older (45‐75 years, 5 females) and eleven young (21‐30 years, 5 females) adults. Baroreflex threshold was quantified as the slope of the linear regression between AP probability (%) and MSNA burst probability (%) versus diastolic blood pressure (DBP, mmHg; Finger plethysmography). AP discharge was greater in older compared to young adults (Older: 614 ± 327 spikes/100 beats vs. Young: 211 ± 107 spikes/100 beats, P < 0.001), and the baroreflex control of AP subpopulations was reset towards greater firing probabilities in older adults (group‐by‐cluster effect: P < 0.001). Specifically, the arterial baroreflex threshold gain of medium AP clusters was greater in older compared to young adults (e.g. Cluster 4, Older: ‐7.8 ± 3.1 %/mmHg vs. Young: ‐4.1 ± 2.9 %/mmHg, P = 0.010), whereas the baroreflex threshold gains for the smallest (e.g. Cluster 1, Older: ‐1.2 ± 1.1 %/mmHg vs. Young: ‐0.7 ± 0.4 %/mmHg, P = 0.197) and largest (e.g. Cluster 10, Older: ‐0.5 ± 0.4 %/mmHg vs. Young: ‐0.6 ± 0.6 %/mmHg, P = 0.673) AP clusters were not modified by aging. Additionally, integrated sympathetic burst threshold gain was greater in older compared to young adults (Older: ‐7.9 ± 3.8 %/mmHg vs. Young: ‐3.9 ± 1.8 %/mmHg, P = 0.005), and the operating point was shifted rightward towards a higher DBP (Older: 76 ± 8 mmHg vs. Young: 68 ± 7 mmHg, P = 0.021). Contrary to our hypothesis, the strength of baroreflex control over medium sized AP clusters as well as integrated sympathetic baroreflex threshold gain was greater in this group of older adults compared to young adults.