Citations

Abstract Background: MM remains incurable and new tx options are needed, especially in heavily pre-treated R/R pts. REGN5459, a BCMAxCD3 bispecific Ab, binds to BCMA on MM cells and with low affinity to CD3 on T cells, triggering T-cell activation and plasma cell depletion with low cytokine release preclinically. This first-in-human study aimed to assess the safety, tolerability, and preliminary anti-tumor activity of REGN5459 monotherapy in pts with R/R MM. Methods: Eligible pts had received ≥3 prior lines of tx including an anti-CD38 Ab, proteasome inhibitor, and immunomodulatory drug, and had exhausted all available tx options. Pts could receive REGN5459 until progression/intolerable toxicity. Primary objectives were to assess safety, tolerability, dose limiting toxicities (DLTs), and determine the recommended Ph 2 dose (RP2D) of REGN5459 (Ph 1) and assess efficacy of REGN5459 (Ph 2) per ORR. Results: As of June 9, 2022, 43 pts were enrolled (Ph 1, 33; Ph 2, 10): median age 67 yrs (range, 26-85), 51% female, 16% high cytogenetic risk, 14% extramedullary plasmacytoma, 37% R-ISS Stage III disease, 61% triple-class refractory, and median of 5 (range, 2-9) prior lines of tx. In Ph 1, one DLT was reported in a pt receiving the highest dose (900 mg; Gr 3 hypoxia, pt later found to have primary lung cancer). RP2D was identified as 480 mg. All pts enrolled had ≥1 TEAE, 74% had Gr ≥3 TEAEs. TEAEs all-Gr in ≥30% of pts were CRS (54%), fatigue (44%), neutropenia (37%), anemia (35%), cough (30%), and diarrhea (30%). Gr ≥3 TEAEs in ≥15% of pts were neutropenia (37%), anemia (26%), lymphopenia (23%), thrombocytopenia (19%), and hypertension (16%). CRS Gr 1, 2, and 3 were reported in 47%, 2%, and 5%, respectively; there was no Gr 4 or 5 CRS. No Gr 3 CRS with RP2D. Tocilizumab was used in 19% and steroids in 9% of pts. One pt developed ICANS (2%, Gr 2). Incidence of serious TEAEs and TEAEs leading to tx discontinuation was 63% and 16%. Infections occurred in 61% (37% Gr ≥3). After data-cutoff, two deaths due to COVID pneumonia and COVID infection have been reported. ORR was 67% (58% ≥VGPR) for the entire cohort and 100% (85% ≥VGPR; 15% sCR; 39% CR) among pts receiving the RP2D (n=13). Median follow-up was 7 mos (range, 1-26) with longest response ongoing for 22+ mos. Median time to response was 0.8 mos. Median DOR was NR (95% CI, 12-NE); 12-mo DOR for RP2D was 66.7% (95% CI, 5.4-94.5). Of pts in ≥CR with available MRD results (n=8), 50% were MRD negative at the 10−5 threshold. Conclusion: These initial data show that REGN5459 has acceptable safety/tolerability in R/R MM with most CRS of low grade and low incidence of ICANS. Modulation of CD3 affinity on bispecific Abs to maximize tumor killing, and mitigate CRS and T-cell exhaustion, warrants further research. Efficacy in this heavily pre-treated cohort was encouraging, with 100% ORR with the RP2D. Updated data will be presented at the meeting. Citation Format: Attaya Suvannasankha, Prashant Kapoor, Matthew J. Pianko, Joshua Richter, Anita D'Souza, Larry D. Anderson, Andrew Magyar, Oluwaseun Aina, Anita Boyapati, Damien Cronier, Nikhil Singh, Karen Rodriguez-Lorenc, Glenn S. Kroog, Hans C. Lee. Safety and efficacy from the phase 1/2 first-in-human study of REGN5459, a BCMA×CD3 bispecific antibody with low CD3 affinity, in patients with relapsed/refractory multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT013.

We present clinical and imaging predictors of ocular injuries that required medical management versus surgical intervention in cases of orbital fractures. From 2014 to 2020, a retrospective review of patients with orbital fractures who received ophthalmologic consultation and computed scan (CT) analysis at a level I trauma center was performed. Inclusion criteria were patients with confirmed orbital fracture on CT and ophthalmology consultation. Patient demographics, associated injuries, comorbidities, management, and outcomes were collected. Two hundred and one patients and 224 eyes (11.4% bilateral orbital fractures) were included. Overall, 21.9% of orbital fractures presented with a significant concomitant ocular injury. Associated facial fractures were present in 68.8% of eyes. Management included surgical treatment in 33.5% of eyes and ophthalmology-directed medical treatment in 17.4%. On multivariate analysis, clinical predictors of surgical intervention were retinal hemorrhage (OR=4.7 (1.0–21.0), P=0.0437), motor vehicle accident injury (OR=2.7 (1.4–5.1), P=0.0030) and diplopia (OR=2.8 (1.5–5.3), P=0.0011). Imaging predictors of surgical intervention were herniation of orbital contents (OR=2.1 (1.1–4.0), P=0.0281) and multiple wall fractures (OR=1.9 (1.01–3.6), P=0.0450). Predictors of medical management were corneal abrasion (OR=7.7 (1.9–31.4), P=0.0041), periorbital laceration (OR=5.7 (2.1–15.6), P=0.0006), and traumatic iritis (OR=4.7 (1.1–20.3), P=0.0444). We demonstrated a 22% incidence of concomitant ocular trauma in orbital fracture patients at our level I trauma center. Predictors of the surgical intervention included multiple wall fractures, herniation of orbital contents, retinal hemorrhage, diplopia, and motor vehicle accident injury. These findings emphasize the importance of a multidisciplinary team in managing ocular and facial trauma.

Abstract Pathogenic protein-truncating variants of RAD51C, which plays an integral role in promoting DNA damage repair, increase the risk of breast and ovarian cancer. A large number of RAD51C missense variants of uncertain significance (VUS) have been identified, but the effects of the majority of these variants on RAD51C function and cancer predisposition have not been established. Here, analysis of 173 missense variants by a homology-directed repair (HDR) assay in reconstituted RAD51C−/− cells identified 30 nonfunctional (deleterious) variants, including 18 in a hotspot within the ATP-binding region. The deleterious variants conferred sensitivity to cisplatin and olaparib and disrupted formation of RAD51C/XRCC3 and RAD51B/RAD51C/RAD51D/XRCC2 complexes. Computational analysis indicated the deleterious variant effects were consistent with structural effects on ATP-binding to RAD51C. A subset of the variants displayed similar effects on RAD51C activity in reconstituted human RAD51C-depleted cancer cells. Case–control association studies of deleterious variants in women with breast and ovarian cancer and noncancer controls showed associations with moderate breast cancer risk [OR, 3.92; 95% confidence interval (95% CI), 2.18–7.59] and high ovarian cancer risk (OR, 14.8; 95% CI, 7.71–30.36), similar to protein-truncating variants. This functional data supports the clinical classification of inactivating RAD51C missense variants as pathogenic or likely pathogenic, which may improve the clinical management of variant carriers. Significance: Functional analysis of the impact of a large number of missense variants on RAD51C function provides insight into RAD51C activity and information for classification of the cancer relevance of RAD51C variants.

BACKGROUND: Pulmonary function test (PFT) impairments are common after allogeneic hematopoietic stem cell transplantation. The prognostic significance of these declines on outcomes is not well understood. The objectives were to determine the frequency of declines in pulmonary function (FVC, FEV 1 , and diffusing capacity for carbon monoxide [D LCO ]) in the early post-transplantation period; and to determine the prognostic significance of these declines on mortality or development of bronchiolitis obliterans syndrome. METHODS: This was a retrospective cohort study conducted at Mayo Clinic, Rochester, Minnesota. PFTs were obtained at baseline and at day +100. Competing risk survival models were developed, which accounted for pre-transplantation pulmonary function and relapse status. RESULTS: Between January 1, 2005, and December 31, 2020, 1,145 subjects underwent allogeneic hematopoietic stem cell transplantation and had a pre-transplantation PFT performed. Of these, 900 (78.6%) survived to day 100 and had post-transplantation PFTs performed (median [interquartile range] 97 [94–103] d). A decline of ≥10% in FEV 1, FVC, or D LCO was seen in 401 of 900 subjects (44.5%). Declines of ≥20% in FEV 1 (hazard ratio 1.65, 95% CI 1.07–2.56; P = .02), FVC (hazard ratio 1.72, 95% CI [1.11–2.67]; P = .02), and D LCO (hazard ratio 1.46, 95% CI 1.04–2.07; P = .028) were all associated with reduced survival when compared with those with < 10% decline in PFT measures. These findings were independent of pre-transplantation pulmonary function or relapse status. Bronchiolitis obliterans syndrome was diagnosed in 118 subjects (10.3%), and there was no relationship between early PFT decline and a subsequent diagnosis of bronchiolitis obliterans syndrome. The subjects who received myeloablative conditioning with cyclophosphamide plus total body irradiation or cyclophosphamide plus fludarabine plus total body irradiation were more likely to have lower spirometry values after hematopoietic stem cell transplantation. The subjects who received reduced intensity conditioning or nonmyeloablative conditioning with fludarabine plus total body irradiation were more likely to have higher post–hematopoietic stem cell transplantation FEV 1 , FVC, and D LCO . CONCLUSIONS: An absolute decline of ≥20% in FEV 1 , FVC, or D LCO were associated with reduced survival independent of pre-transplantation pulmonary function or relapse status. In contrast to previous work, early declines in PFT measures were not associated with future development of bronchiolitis obliterans syndrome.

Summary: Aging of the face is the result of the interrelation of three-dimensional changes occurring over time among the 5 different layers of the face and its associated structures. Knowledge regarding the causes of these changes and identification of new key anatomic structures have helped elucidate one of the most complex areas of the human body. This has resulted in the introduction of pharmacologic agents to help stop, mitigate, or counteract signs of aging and restore the youthful appearance of the face. The authors performed a systematic search of the literature to review the current highest-level evidence of facial antiaging pharmacologic agents. Pharmacologic and minimally invasive antiaging treatments can target different components of facial aging and continue to evolve. With continuous research efforts, traditional treatments, such as botulinum toxin type A, injectable fillers, and chemical peels, are emerging in newer, more effective formulations, with longer lasting clinical results. However, for soft-tissue descent and facial volume loss, surgery remains the standard treatment. An adequate understanding of the three-dimensional process of facial aging over time (the fourth dimension), facial anatomy, and the pharmacologic properties of antiaging/rejuvenation agents are the sine qua non of facial antiaging treatment. The specific modality should be tailored to patient characteristics, preferences, and goals.

Total abdominal proctocolectomy with ileal pouch–anal anastomosis (IPAA) for ulcerative colitis (UC) is associated with substantial complications despite the benefits of managing refractory and/or neoplasia-associated disease. For the purpose of this review, we focused on the diagnosis of some of the most common inflammatory and structural pouch disorders and their respective management. Pouchitis is the most common complication, and it is typically responsive to antibiotics. However, chronic antibiotic refractory pouchitis (CARP) has been increasingly recognized, and biologic therapies have emerged as the mainstay of therapy. Crohn's-like disease of the pouch (CLDP) can affect up to 10% of patients with UC after IPAA. Medical options are similar to CARP therapies, including biologics with immunomodulators. Studies have shown higher efficacy rates of biologics for CLDP when compared with those for CARP. In addition, managing stricturing and fistulizing CLDP is challenging and often requires interventional endoscopy (balloon dilation and/or stricturotomy) and/or surgery. The implementation of standardized diagnostic criteria for inflammatory pouch disorders will help in advancing future therapeutic options. Structural pouch disorders are commonly related to surgical complications after IPAA. We focused on the diagnosis and management of anastomotic leaks, strictures, and floppy pouch complex. Anastomotic leaks and anastomotic strictures occur in approximately 15% and 11% of patients with UC after IPAA, respectively. Further complications from pouch leaks include the development of sinuses, fistulas, and pouch sepsis requiring excision. Novel endoscopic interventions and less invasive surgical procedures have emerged as options for the management of these disorders.

Background: Microbiota restoration is highly effective to treat recurrent Clostridioides difficile infection (CDI) in observational studies (cure rates >90%) but efficacy in controlled clinical trials appears to be lower. Objectives: To perform an updated meta-analysis to assess the efficacy of microbiota restoration for recurrent CDI in open-label registered prospective clinical trials compared to randomized controlled trials (RCTs). Design: A systematic review and meta-analysis was conducted. Data Sources and Methods: A systematic search of various databases was performed up to July 2022 to identify studies of interest. Clinical trials of microbiota restoration for recurrent CDI with clinical resolution with one dose were included. We calculated weighted pooled rates (WPRs) with 95% confidence intervals (CIs). Results: In all, 19 clinical trials with 1176 recurrent CDI patients were included. Of the patients treated with microbiota restoration, 897 experienced a clinical cure with a single microbiota restoration therapy (WPR, 78%; 95% CI, 71–85%). There was significant heterogeneity among studies with an I2 of 88%. Analysis of trials with a control arm (non-microbiota restoration) revealed CDI resolution in 373 of 523 patients (WPR, 72%; 95% CI, 60–82%) with microbiota restoration. Among the nine open-label clinical trials, CDI resolution was seen in 524 of 653 patients after initial microbiota restoration (WPR, 84%; 95% CI, 74–92%). Comparison of resolution rates between RCTs and open-label trials revealed a lower cure rate in RCTs compared to open-label trials (WPR, 73 versus 84%, p < 0.0001). Conclusions: Microbiota restoration in a randomized controlled setting leads to lower resolution rates compared to open label and observational settings, likely due to stricter definitions and inclusion criteria. Resolution rates in open-label studies were similar to observational studies.