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The New England Journal of Medicine Jan 2024Daratumumab, a monoclonal antibody targeting CD38, has been approved for use with standard myeloma regimens. An evaluation of subcutaneous daratumumab combined with... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Daratumumab, a monoclonal antibody targeting CD38, has been approved for use with standard myeloma regimens. An evaluation of subcutaneous daratumumab combined with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma is needed.
METHODS
In this phase 3 trial, we randomly assigned 709 transplantation-eligible patients with newly diagnosed multiple myeloma to receive either subcutaneous daratumumab combined with VRd induction and consolidation therapy and with lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and lenalidomide maintenance therapy alone (VRd group). The primary end point was progression-free survival. Key secondary end points were a complete response or better and minimal residual disease (MRD)-negative status.
RESULTS
At a median follow-up of 47.5 months, the risk of disease progression or death in the D-VRd group was lower than the risk in the VRd group. The estimated percentage of patients with progression-free survival at 48 months was 84.3% in the D-VRd group and 67.7% in the VRd group (hazard ratio for disease progression or death, 0.42; 95% confidence interval, 0.30 to 0.59; P<0.001); the P value crossed the prespecified stopping boundary (P = 0.0126). The percentage of patients with a complete response or better was higher in the D-VRd group than in the VRd group (87.9% vs. 70.1%, P<0.001), as was the percentage of patients with MRD-negative status (75.2% vs. 47.5%, P<0.001). Death occurred in 34 patients in the D-VRd group and 44 patients in the VRd group. Grade 3 or 4 adverse events occurred in most patients in both groups; the most common were neutropenia (62.1% with D-VRd and 51.0% with VRd) and thrombocytopenia (29.1% and 17.3%, respectively). Serious adverse events occurred in 57.0% of the patients in the D-VRd group and 49.3% of those in the VRd group.
CONCLUSIONS
The addition of subcutaneous daratumumab to VRd induction and consolidation therapy and to lenalidomide maintenance therapy conferred a significant benefit with respect to progression-free survival among transplantation-eligible patients with newly diagnosed multiple myeloma. (Funded by the European Myeloma Network in collaboration with Janssen Research and Development; PERSEUS ClinicalTrials.gov number, NCT03710603; EudraCT number, 2018-002992-16.).
Topics: Humans; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Disease Progression; Lenalidomide; Multiple Myeloma
PubMed: 38084760
DOI: 10.1056/NEJMoa2312054 -
Science (New York, N.Y.) Aug 2023A mechanistic understanding of how microbial proteins affect the host could yield deeper insights into gut microbiota-host cross-talk. We developed an enzyme...
A mechanistic understanding of how microbial proteins affect the host could yield deeper insights into gut microbiota-host cross-talk. We developed an enzyme activity-screening platform to investigate how gut microbiota-derived enzymes might influence host physiology. We discovered that dipeptidyl peptidase 4 (DPP4) is expressed by specific bacterial taxa of the microbiota. Microbial DPP4 was able to decrease the active glucagon like peptide-1 (GLP-1) and disrupt glucose metabolism in mice with a leaky gut. Furthermore, the current drugs targeting human DPP4, including sitagliptin, had little effect on microbial DPP4. Using high-throughput screening, we identified daurisoline-d4 (Dau-d4) as a selective microbial DPP4 inhibitor that improves glucose tolerance in diabetic mice.
Topics: Animals; Humans; Mice; Bacteroides; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Feces; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Glucose; Host Microbial Interactions; Isoenzymes; Sitagliptin Phosphate; Hypoglycemic Agents
PubMed: 37535747
DOI: 10.1126/science.add5787 -
Journal of Clinical Oncology : Official... May 2024Azacitidine plus venetoclax is a standard of care for patients with newly diagnosed AML who are unfit for intensive chemotherapy. However, mutations are a common...
PURPOSE
Azacitidine plus venetoclax is a standard of care for patients with newly diagnosed AML who are unfit for intensive chemotherapy. However, mutations are a common mechanism of resistance to this regimen. The addition of gilteritinib, an oral FLT3 inhibitor, to azacitidine and venetoclax may improve outcomes in patients with -mutated AML.
METHODS
This phase I/II study evaluated azacitidine, venetoclax, and gilteritinib in two cohorts: patients with (1) newly diagnosed -mutated AML who were unfit for intensive chemotherapy or (2) relapsed/refractory -mutated AML (ClinicalTrials.gov identifier: NCT04140487). The primary end points were the maximum tolerated dose of gilteritinib (phase I) and the combined complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate (phase II).
RESULTS
Fifty-two patients were enrolled (frontline [n = 30]; relapsed/refractory [n = 22]). The recommended phase II dose was gilteritinib 80 mg once daily in combination with azacitidine and venetoclax. In the frontline cohort, the median age was 71 years and 73% of patients had an -internal tandem duplication (ITD) mutation. The CR/CRi rate was 96% (CR, 90%; CRi, 6%). Sixty-five percent of evaluable patients achieved -ITD measurable residual disease <5 × 10 within four cycles. With a median follow-up of 19.3 months, the median relapse-free survival (RFS) and overall survival (OS) have not been reached and the 18-month RFS and OS rates are 71% and 72%, respectively. In the relapsed/refractory cohort, the CR/CRi rate was 27%; nine additional patients (41%) achieved a morphologic leukemia-free state. The most common grade 3 or higher nonhematologic adverse events were infection (62%) and febrile neutropenia (38%), which were more frequent in the relapsed/refractory cohort.
CONCLUSION
The combination of azacitidine, venetoclax, and gilteritinib resulted in high rates of CR/CRi, deep molecular responses, and encouraging survival in newly diagnosed -mutated AML. Myelosuppression was manageable with mitigative dosing strategies.
Topics: Humans; Middle Aged; Leukemia, Myeloid, Acute; Male; Aged; Female; fms-Like Tyrosine Kinase 3; Antineoplastic Combined Chemotherapy Protocols; Sulfonamides; Aniline Compounds; Mutation; Bridged Bicyclo Compounds, Heterocyclic; Adult; Pyrazines; Azacitidine; Aged, 80 and over; Drug Resistance, Neoplasm
PubMed: 38277619
DOI: 10.1200/JCO.23.01911 -
Small (Weinheim An Der Bergstrasse,... Oct 2023Extracellular vesicles (EVs) are lipid bilayer nanovesicles released from living or apoptotic cells that can transport DNA, RNA, protein, and lipid cargo. EVs play...
Extracellular vesicles (EVs) are lipid bilayer nanovesicles released from living or apoptotic cells that can transport DNA, RNA, protein, and lipid cargo. EVs play critical roles in cell-cell communication and tissue homeostasis, and have numerous therapeutic uses including serving as carriers for nanodrug delivery. There are multiple ways to load EVs with nanodrugs, such as electroporation, extrusion, and ultrasound. However, these approaches may have limited drug-loading rates, poor EV membrane stability, and high cost for large-scale production. Here, it is shown that apoptotic mesenchymal stem cells (MSCs) can encapsulate exogenously added nanoparticles into apoptotic vesicles (apoVs) with a high loading efficiency. When nano-bortezomib is incorporated into apoVs in culture-expanded apoptotic MSCs, nano-bortezomib-apoVs show a synergistic combination effect of bortezomib and apoVs to ameliorate multiple myeloma (MM) in a mouse model, along with significantly reduced side effects of nano-bortezomib. Moreover, it is shown that Rab7 regulates the nanoparticle encapsulation efficiency in apoptotic MSCs and that activation of Rab7 can increase nanoparticle-apoV production. In this study, a previously unknown mechanism to naturally synthesize nano-bortezomib-apoVs to improve MM therapy is revealed.
Topics: Animals; Mice; Bortezomib; Multiple Myeloma; Extracellular Vesicles; Mesenchymal Stem Cells; Cell Communication
PubMed: 37282762
DOI: 10.1002/smll.202301748 -
The Journal of Clinical Investigation Aug 2023BACKGROUNDIgE-mediated anaphylaxis is a potentially fatal systemic allergic reaction for which there are no currently FDA-approved preventative therapies. Bruton's...
BACKGROUNDIgE-mediated anaphylaxis is a potentially fatal systemic allergic reaction for which there are no currently FDA-approved preventative therapies. Bruton's tyrosine kinase (BTK) is an essential enzyme for IgE-mediated signaling pathways and is an ideal pharmacologic target to prevent allergic reactions. In this open-label trial, we evaluated the safety and efficacy of acalabrutinib, a BTK inhibitor that is FDA approved to treat some B cell malignancies, in preventing clinical reactivity to peanut in adults with peanut allergy.METHODSAfter undergoing graded oral peanut challenge to establish their baseline level of clinical reactivity, 10 patients had a 6-week rest period, then received 4 standard doses of 100 mg acalabrutinib twice daily and underwent repeat food challenge. The primary endpoint was the change in patients' threshold dose of peanut protein to elicit an objective clinical reaction.RESULTSAt baseline, patients tolerated a median of 29 mg of peanut protein before objective clinical reaction. During subsequent food challenge on acalabrutinib, patients' median tolerated dose significantly increased to 4,044 mg (range 444-4,044 mg). 7 patients tolerated the maximum protocol amount (4,044 mg) of peanut protein with no clinical reaction, and the other 3 patients' peanut tolerance increased between 32- and 217-fold. 3 patients experienced a total of 4 adverse events that were considered to be possibly related to acalabrutinib; all events were transient and nonserious.CONCLUSIONAcalabrutinib pretreatment achieved clinically relevant increases in patients' tolerance to their food allergen, thereby supporting the need for larger, placebo-controlled trials.TRIAL REGISTRATIONClinicalTrials.gov NCT05038904FUNDINGAstraZeneca Pharmaceuticals, the Johns Hopkins Institute for Clinical and Translational Research, the Ludwig Family Foundation, and NIH grants AI143965 and AI106043.
Topics: Adult; Humans; Anaphylaxis; Agammaglobulinaemia Tyrosine Kinase; Benzamides; Pyrazines; Peanut Hypersensitivity; Allergens; Arachis
PubMed: 37384412
DOI: 10.1172/JCI172335 -
Molecular Cell Nov 2023While 19S proteasome regulatory particle (RP) inhibition is a promising new avenue for treating bortezomib-resistant myeloma, the anti-tumor impact of inhibiting 19S RP...
While 19S proteasome regulatory particle (RP) inhibition is a promising new avenue for treating bortezomib-resistant myeloma, the anti-tumor impact of inhibiting 19S RP component PSMD14 could not be explained by a selective inhibition of proteasomal activity. Here, we report that PSMD14 interacts with NSD2 on chromatin, independent of 19S RP. Functionally, PSMD14 acts as a histone H2AK119 deubiquitinase, facilitating NSD2-directed H3K36 dimethylation. Integrative genomic and epigenomic analyses revealed the functional coordination of PSMD14 and NSD2 in transcriptional activation of target genes (e.g., RELA) linked to myelomagenesis. Reciprocally, RELA transactivates PSMD14, forming a PSMD14/NSD2-RELA positive feedback loop. Remarkably, PSMD14 inhibitors enhance bortezomib sensitivity and fosters anti-myeloma synergy. PSMD14 expression is elevated in myeloma and inversely correlated with overall survival. Our study uncovers an unappreciated function of PSMD14 as an epigenetic regulator and a myeloma driver, supporting the pursuit of PSMD14 as a therapeutic target to overcome the treatment limitation of myeloma.
Topics: Humans; Histones; Proteasome Endopeptidase Complex; Bortezomib; Multiple Myeloma; Cell Line, Tumor; Deubiquitinating Enzymes; Proteasome Inhibitors; Trans-Activators
PubMed: 37935198
DOI: 10.1016/j.molcel.2023.10.019 -
American Journal of Hematology Dec 2023
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Antineoplastic Agents; Pyrazines; Protein Kinase Inhibitors
PubMed: 37811799
DOI: 10.1002/ajh.27110 -
Diabetes Jan 2024Metabolic effects of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and not fully recapitulated by increasing endogenous GLP-1. We... (Randomized Controlled Trial)
Randomized Controlled Trial
UNLABELLED
Metabolic effects of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and not fully recapitulated by increasing endogenous GLP-1. We tested the hypothesis that GLP-1 receptor (GLP-1R) agonists exert weight loss-independent, GLP-1R-dependent effects that differ from effects of increasing endogenous GLP-1. Individuals with obesity and prediabetes were randomized to receive for 14 weeks the GLP-1R agonist liraglutide, a hypocaloric diet, or the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin. The GLP-1R antagonist exendin(9-39) and placebo were administered in a two-by-two crossover study during mixed-meal tests. Liraglutide and diet, but not sitagliptin, caused weight loss. Liraglutide improved insulin sensitivity measured by HOMA for insulin resistance (HOMA-IR), the updated HOMA model (HOMA2), and the Matsuda index after 2 weeks, prior to weight loss. Liraglutide decreased fasting and postprandial glucose levels, and decreased insulin, C-peptide, and fasting glucagon levels. In contrast, diet-induced weight loss improved insulin sensitivity by HOMA-IR and HOMA2, but not the Matsuda index, and did not decrease glucose levels. Sitagliptin increased endogenous GLP-1 and GIP values without altering insulin sensitivity or fasting glucose levels, but decreased postprandial glucose and glucagon levels. Notably, sitagliptin increased GIP without altering weight. Acute GLP-1R antagonism increased glucose levels in all groups, increased the Matsuda index and fasting glucagon level during liraglutide treatment, and increased endogenous GLP-1 values during liraglutide and sitagliptin treatments. Thus, liraglutide exerts rapid, weight loss-independent, GLP-1R-dependent effects on insulin sensitivity that are not achieved by increasing endogenous GLP-1.
ARTICLE HIGHLIGHTS
Metabolic benefits of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and are not fully achieved by increasing endogenous GLP-1 through dipeptidyl peptidase 4 (DPP-4) inhibition. We investigated weight loss-independent, GLP-1 receptor (GLP-1R)-dependent metabolic effects of liraglutide versus a hypocaloric diet or the DPP-4 inhibitor sitagliptin. GLP-1R antagonism with exendin(9-39) was used to assess GLP-1R-dependent effects during mixed meals. Liraglutide improved insulin sensitivity and decreased fasting and postprandial glucose prior to weight loss, and these benefits were reversed by exendin(9-39). GLP-1R agonists exert rapid, weight loss-independent, GLP-1R-dependent effects on insulin sensitivity not achieved by increasing endogenous GLP-1.
Topics: Humans; Liraglutide; Insulin Resistance; Glucagon-Like Peptide-1 Receptor; Dipeptidyl Peptidase 4; Glucagon; Prediabetic State; Diet, Reducing; Cross-Over Studies; Obesity; Blood Glucose; Hypoglycemic Agents; Sitagliptin Phosphate; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Weight Loss
PubMed: 37874653
DOI: 10.2337/db23-0356 -
The Journal of Clinical Investigation Jan 2024Mineralocorticoid excess commonly leads to hypertension (HTN) and kidney disease. In our study, we used single-cell expression and chromatin accessibility tools to...
Mineralocorticoid excess commonly leads to hypertension (HTN) and kidney disease. In our study, we used single-cell expression and chromatin accessibility tools to characterize the mineralocorticoid target genes and cell types. We demonstrated that mineralocorticoid effects were established through open chromatin and target gene expression, primarily in principal and connecting tubule cells and, to a lesser extent, in segments of the distal convoluted tubule cells. We examined the kidney-protective effects of steroidal and nonsteroidal mineralocorticoid antagonists (MRAs), as well as of amiloride, an epithelial sodium channel inhibitor, in a rat model of deoxycorticosterone acetate, unilateral nephrectomy, and high-salt consumption-induced HTN and cardiorenal damage. All antihypertensive therapies protected against cardiorenal damage. However, finerenone was particularly effective in reducing albuminuria and improving gene expression changes in podocytes and proximal tubule cells, even with an equivalent reduction in blood pressure. We noted a strong correlation between the accumulation of injured/profibrotic tubule cells expressing secreted posphoprotein 1 (Spp1), Il34, and platelet-derived growth factor subunit b (Pdgfb) and the degree of fibrosis in rat kidneys. This gene signature also showed a potential for classifying human kidney samples. Our multiomics approach provides fresh insights into the possible mechanisms underlying HTN-associated kidney disease, the target cell types, the protective effects of steroidal and nonsteroidal MRAs, and amiloride.
Topics: Rats; Humans; Animals; Mineralocorticoid Receptor Antagonists; Chromatin; Amiloride; Mineralocorticoids; Kidney; Hypertension; Kidney Diseases; Gene Expression Profiling
PubMed: 37906287
DOI: 10.1172/JCI157165 -
European Journal of Medicinal Chemistry Oct 2023Heterocycles are common in the structure of drugs used clinically to deal with diseases. Such drugs usually contain nitrogen, oxygen and sulfur, which possess... (Review)
Review
Heterocycles are common in the structure of drugs used clinically to deal with diseases. Such drugs usually contain nitrogen, oxygen and sulfur, which possess electron-accepting capacity and can form hydrogen bonds. These properties often bring enhanced target binding ability to these compounds when compared to alkanes. Pyrazine is a nitrogen-containing six-membered heterocyclic ring and many of its derivatives are identified as bioactive molecules. We review here the most active pyrazine compounds in terms of their structure, activity in vitro and in vivo (mainly antitumor activity) and the reported mechanisms of action. References have been downloaded through Web of Science, PubMed, Science Direct, Google Scholar and SciFinder Scholar. Publications reporting only the chemistry of pyrazine derivatives are beyond the scope of this review and have not been included. We found that compounds in which a pyrazine ring was fused into other heterocycles especially pyrrole or imidazole were the highly studied pyrazine derivatives, whose antineoplastic activity had been widely investigated. To the best of our knowledge, this is the first review of pyrazine derivatives and their bioactivity, especially their antitumor activity. This review should be useful for those engaged in development of medications based on heterocyclic compounds especially those based on pyrazine.
Topics: Pyrazines; Heterocyclic Compounds; Antineoplastic Agents; Nitrogen
PubMed: 37300915
DOI: 10.1016/j.ejmech.2023.115544