Citations

Introduction MM is characterized by the proliferation of abnormal clonal plasma cells, causing destructive bone lesions, kidney injury, anemia, and hypercalcemia. Treatment of MM involves immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies to achieve disease remission. AL amyloidosis comprises disorders of abnormal extracellular deposition of misfolded proteins in various organs with resultant damage, and the key strategy of treatment is to prolong the time to or reverse organ dysfunction. However, many patients will relapse from the standard triplet or quadruplet therapies, necessitating additional treatments with novel mechanisms of action. Lisaftoclax is a novel investigational BCL-2 inhibitor with strong antitumor activity in hematologic malignancies. Here, we report clinical trial data on lisaftoclax combined with novel therapeutic regimens in pts with R/R MM or R/R AL amyloidosis. Methods Eligible patients had an ECOG performance status ≤ 2, ≥ 1 prior line of therapy, and adequate organ function. Patients with R/R AL amyloidosis had confirmed symptomatic organ involvement, purpura, and/or carpal tunnel syndrome. Lisaftoclax was administered orally daily at doses assigned in repeated 28-day cycles. Pomalidomide, daratumumab, and lenalidomide were administered per label use. Dexamethasone 40 mg (20 mg, pts > 75 years old) was administered on days 1, 8, 15, and 22 of 28-day cycles. This study evaluated the safety and efficacy of lisaftoclax combined with pomalidomide and dexamethasone (Pd; Arm A) or daratumumab, lenalidomide, and dexamethasone (DRd; Arm B) in R/R MM and lisaftoclax combined with Pd in R/R AL amyloidosis (Arm C). Intensive blood samples were collected for pharmacokinetic (PK) analyses. Results As of May 29, 2024, 52 pts were enrolled, including 42 with R/R MM and 10 with AL amyloidosis. In Arm A (n = 35), lisaftoclax was administered orally at dose assigned: 400 mg (n = 3), 600 mg (n = 4), 800 mg (n = 15), 1,000 mg (n = 7), and 1,200 mg (n = 6). In Arm B (n = 7), all pts were treated with lisaftoclax 600 mg. In Arm C (n = 10), lisaftoclax was administered at 400 mg (n = 1), 600 mg (n = 4), 800 mg (n = 3), and 1,000 mg (n = 2). The median (range) age of all patients was 69.5 (24-88) years, of whom 63.5% were male and 63.5% were ≥ 65 years of age. The enrolled patients were heavily treated, with a median (range) number of treatment cycles of 4 (1-26), and a median (range) number of prior therapy lines of 3 (1-19). In Arm A, out of 31 evaluable patients, 3 (9.7%) achieved complete remission (CR), 7 (22.6%) reached very good partial remission (VGPR), and 9 (29.0%) achieved partial response (PR). The overall response rate (ORR) was 19 (61.3%), and the ≥ VGPR rate was 10 (32.3%). In Arm B, of 4 evaluable patients, 2 (50%) achieved CR and 2 (50%) ≥ VGPR. In Arm C, of 7 assessed patients, 1 (14.3%) achieved CR, 4 (57.1%) VGPR, 1 (14.3%) PR, and 5 (71.4%) ≥ VGPR, for an ORR of 6 (85.7%); 2 pts had cardiac response. Among 49 pts in the safety population, 34 (69.4%) reported any-grade lisaftoclax treatment-related AEs (TRAEs; ≥ 5% incidence), including neutropenia (20.4%), thrombocytopenia (6.1%), leukopenia (10.2%), nausea (16.3%), abdominal distension (10.2%), diarrhea (12.2%), and constipation (8.2%). A total of 11 pts experienced grade ≥ 3 TRAEs, including neutropenia (14.3%) and febrile neutropenia (2%), and 3 pts experienced lisaftoclax-related serious AEs (1 each): febrile neutropenia, acute kidney injury, and diarrhea with electrolyte imbalance. In Arm B, 1 pt experienced a dose-limiting toxicity (prolonged QT interval). Pharmacokinetic analyses showed no drug-drug interaction (DDI) in all pts treated with lisaftoclax at all doses in combination with other therapeutic agents used in 3 arms. Conclusions Our findings suggest that lisaftoclax improves the depth of response in pts with R/R MM or AL amyloidosis when combined with Pd or DRd. These combination therapies demonstrated a favorable safety profile with no drug-drug interactions, particularly in hematologic side effects. ClinicalTrials.gov registration: NCT04942067; internal study identifier: APG2575MU101.

Abstract Regulatory T (Treg) cell activation and expansion during neonatal life and in response to inflammation are critical for immunosuppression, yet the mechanisms governing these events are incompletely understood. We report that the oncogene and transcriptional regulator c-Myc (Myc) controls immune homeostasis through regulation of Treg cell accumulation and functional activation. Myc activity is enriched in Treg cells generated during neonatal life and responding to inflammation. Myc-deficient Treg cells show cell-intrinsic defects in overall accumulation and ability to transition to an activated state during early life or acute inflammation. Consequently, loss of Myc in Treg cells results in a rapid, early-onset autoimmune disorder accompanied by uncontrolled effector CD4+ and CD8+ T cell responses. We also provide evidence that Myc regulates mitochondrial oxidative metabolism but is dispensable for fatty acid oxidation (FAO). Indeed, Treg cell-specific deletion of Cox10, which is required for oxidative phosphorylation, but not Cpt1a, the rate-limiting enzyme for FAO, results in impaired Treg cell function and maturation. Thus, Myc coordinates Treg cell accumulation, transitional activation and metabolic programming to orchestrate immune homeostasis.

Extremes of sleep duration and obstructive sleep apnea (OSA) are both associated with hypertension. We aimed to explore whether sleep duration modifies the relationship between OSA and prevalent hypertension, using both objective and subjective measures of total sleep duration. A total of 7107 OSA patients and 1118 primary snorers were included in the study. Hypertension was defined based either on direct blood pressure measures or on diagnosis by a physician. Objective sleep duration was derived by polysomnography and subjective sleep duration was self-reported. Logistic regression models were used to estimate the associations between objective/subjective sleep duration and hypertension prevalence in OSA and primary snorers. Compared with primary snorers, OSA combined with objective sleep duration of 5 to 6 hours increased the odds of hypertension by 45% (odds ratio, 1.45; 95% confidence interval, 1.14–1.84), whereas OSA combined with objective sleep duration <5 hours further increased the odds of hypertension by 80% (odds ratio, 1.80; 95% confidence interval, 1.33–2.42). These results were independent of major confounding factors frequently associated with OSA or hypertension. In stratified analysis by sleep duration, risk of hypertension in those with extremely short sleep (<5 hours) was not significantly different between OSA and primary snorers, whereas odds were significant for OSA in the other 4 sleep duration strata (5–6, 6–7, 7–8, and >8 hours). No significance was evident using subjective sleep duration. We conclude that objective short sleep duration is associated with hypertension in OSA patients. Extremely short sleep duration in itself may actually be even more detrimental than OSA in terms of hypertension risk.