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Clinical Lymphoma, Myeloma & Leukemia Sep 2023Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS) but...
INTRODUCTION
Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS) but directionally different overall survival (OS) favoring pomalidomide (hazard ratio [HR], 1.10) in OCEAN.
METHODS
These analyses further investigated prognostic subgroups impacting survival in updated data from the randomized, phase 3 OCEAN study (NCT03151811; date: February 3, 2022) and the phase 2 HORIZON study (NCT02963493; date: February 2, 2022).
RESULTS
In OCEAN, subgroups prognostic for OS were age (P = .011; <65 years favored pomalidomide) and no previous autologous stem cell transplant (ASCT) or progression >36 months after ASCT (P = .001; favored melflufen). Overall, 245 of 495 (49%) patients randomized had received a previous ASCT, of which 202 (82%) had progressed within 36 months following their ASCT. When excluding patients who had progressed <36 months post-ASCT (melflufen group, n = 145; pomalidomide group, n = 148), median OS was 23.6 months with melflufen and 19.8 months with pomalidomide (HR, 0.83 [95% CI, 0.62-1.12]; P = .22). Among patients with triple-class refractory disease in HORIZON, patients who had progressed <36 months post-ASCT (n = 58) had a lower response rate and shorter duration of response and PFS than the remaining patients (n = 52). Safety was consistent with previous reports.
CONCLUSION
These analyses demonstrate a consistent benefit for melflufen and dexamethasone in patients with relapsed/refractory multiple myeloma who have not received an ASCT or progressed >36 months after receiving an ASCT (ClinicalTrials.gov identifier: NCT03151811).
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Follow-Up Studies; Melphalan; Multiple Myeloma; Risk Assessment; Transplantation, Autologous; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Randomized Controlled Trials as Topic
PubMed: 37355418
DOI: 10.1016/j.clml.2023.05.004 -
European Journal of Pharmaceutical... Aug 2023While many novel therapies have been approved in recent years for treating patients with multiple myeloma, there is still no established curative regimen, especially for...
While many novel therapies have been approved in recent years for treating patients with multiple myeloma, there is still no established curative regimen, especially for patients with high-risk disease. In this work, we use a mathematical modeling approach to determine combination therapy regimens that maximize healthy lifespan for patients with multiple myeloma. We start with a mathematical model for the underlying disease and immune dynamics, which was presented and analyzed previously. We add the effects of three therapies to the model: pomalidomide, dexamethasone, and elotuzumab. We consider multiple approaches to optimizing combinations of these therapies. We find that optimal control combined with approximation outperforms other methods, in that it can quickly produce a combination regimen that is clinically-feasible and near-optimal. Implications of this work can be used to optimize doses and advance the scheduling of drugs.
Topics: Humans; Multiple Myeloma; Dexamethasone; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy
PubMed: 37302768
DOI: 10.1016/j.ejps.2023.106492 -
BMJ Case Reports Jun 2023We present the case of an HIV-negative man in his 50s who developed a generalised nodular rash while having first-line bortezomib-cyclophosphamide-dexamethasone...
We present the case of an HIV-negative man in his 50s who developed a generalised nodular rash while having first-line bortezomib-cyclophosphamide-dexamethasone chemotherapy for multiple myeloma. The rash was biopsied and proven to be Kaposi's sarcoma. The patient's treatment was interrupted at the sixth cycle of chemotherapy, by which time the rash had also spread to the oral mucosa and eyelid. The rash regressed spontaneously on stopping treatment. We were reluctant to restart myeloma treatment, but on the other hand, we wished to consolidate the very good partial response achieved. An autologous marrow transplant was done months later without any recurrence of his Kaposi's with the initiation of bortezomib maintenance. Bortezomib has putative activity against Kaposi's. The patient could benefit from imid-based (thalidomide, lenalidomide, pomalidomide) combination chemotherapy once his myeloma progresses or if there is a recurrence of Kaposi's sarcoma.
Topics: Male; Humans; Multiple Myeloma; Sarcoma, Kaposi; Bortezomib; Induction Chemotherapy; Dexamethasone; Iatrogenic Disease; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37263679
DOI: 10.1136/bcr-2022-251044 -
Blood Cancer Journal May 2023
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Multiple Myeloma; POEMS Syndrome; Thalidomide
PubMed: 37253713
DOI: 10.1038/s41408-023-00859-x -
Biomolecules Apr 2023The immunomodulatory imide drug (IMiD) class, which includes the founding drug member thalidomide and later generation drugs, lenalidomide and pomalidomide, has... (Review)
Review
The immunomodulatory imide drug (IMiD) class, which includes the founding drug member thalidomide and later generation drugs, lenalidomide and pomalidomide, has dramatically improved the clinical treatment of specific cancers, such as multiple myeloma, and it combines potent anticancer and anti-inflammatory actions. These actions, in large part, are mediated by IMiD binding to the human protein cereblon that forms a critical component of the E3 ubiquitin ligase complex. This complex ubiquitinates and thereby regulates the levels of multiple endogenous proteins. However, IMiD-cereblon binding modifies cereblon's normal targeted protein degradation towards a new set of neosubstrates that underlies the favorable pharmacological action of classical IMiDs, but also their adverse actions-in particular, their teratogenicity. The ability of classical IMiDs to reduce the synthesis of key proinflammatory cytokines, especially TNF-α levels, makes them potentially valuable to reposition as drugs to mitigate inflammatory-associated conditions and, particularly, neurological disorders driven by an excessive neuroinflammatory element, as occurs in traumatic brain injury, Alzheimer's and Parkinson's diseases, and ischemic stroke. The teratogenic and anticancer actions of classical IMiDs are substantial liabilities for effective drugs in these disorders and can theoretically be dialed out of the drug class. We review a select series of novel IMiDs designed to avoid binding with human cereblon and/or evade degradation of downstream neosubstrates considered to underpin the adverse actions of thalidomide-like drugs. These novel non-classical IMiDs hold potential as new medications for erythema nodosum leprosum (ENL), a painful inflammatory skin condition associated with Hansen's disease for which thalidomide remains widely used, and, in particular, as a new treatment strategy for neurodegenerative disorders in which neuroinflammation is a key component.
Topics: Humans; Thalidomide; Immunomodulating Agents; Neuroinflammatory Diseases; Multiple Myeloma; Ubiquitin-Protein Ligases; Neurodegenerative Diseases
PubMed: 37238617
DOI: 10.3390/biom13050747 -
ACS Chemical Neuroscience Jun 2023Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine kinase and an attractive therapeutic target for Alzheimer's disease. Based on proteolysis-targeting chimera...
Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine kinase and an attractive therapeutic target for Alzheimer's disease. Based on proteolysis-targeting chimera (PROTAC) technology, a small set of novel GSK-3β degraders was designed and synthesized by linking two different GSK-3β inhibitors, SB-216763 and tideglusib, to pomalidomide, as E3 recruiting element, through linkers of different lengths. Compound emerged as the most effective PROTAC being nontoxic up to 20 μM to neuronal cells and already able to degrade GSK-3β starting from 0.5 μM in a dose-dependent manner. PROTAC significantly reduced the neurotoxicity induced by Aβ peptide and CuSO in SH-SY5Y cells in a dose-dependent manner. Based on its encouraging features, PROTAC may serve as a starting point to develop new GSK-3β degraders as potential therapeutic agents.
Topics: Humans; Alzheimer Disease; Glycogen Synthase Kinase 3 beta; Neuroblastoma; Protein Serine-Threonine Kinases; Phosphorylation
PubMed: 37218653
DOI: 10.1021/acschemneuro.3c00096 -
Bioorganic Chemistry Sep 2023Here, we rationally designed a human neutrophil elastase (HNE) inhibitors 4a-4f derived from thalidomide. The HNE inhibition assay showed that synthesized compounds 4a,...
Here, we rationally designed a human neutrophil elastase (HNE) inhibitors 4a-4f derived from thalidomide. The HNE inhibition assay showed that synthesized compounds 4a, 4b, 4e and 4f demonstrated strong HNE inhibiton properties with IC values of 21.78-42.30 nM. Compounds 4a, 4c, 4d and 4f showed a competitive mode of action. The most potent compound 4f shows almost the same HNE inhibition as sivelestat. The molecular docking analysis revealed that the strongest interactions occur between the azetidine-2,4-dione group and the following three aminoacids: Ser195, Arg217 and His57. A high correlation between the binding energies and the experimentally determined IC values was also demonstrated. The study of antiproliferative activity against human T47D (breast carcinoma), RPMI 8226 (multiple myeloma), and A549 (non-small-cell lung carcinoma) revealed that designed compounds were more active compared to thalidomide, pomalidomide and lenalidomide used as the standard drugs. Additionally, the most active compound 4f derived from lenalidomide induces cell cycle arrest at the G2/M phase and apoptosis in T47D cells.
Topics: Humans; Molecular Structure; Structure-Activity Relationship; Thalidomide; Molecular Docking Simulation; Lenalidomide; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Proteinase Inhibitory Proteins, Secretory; Antineoplastic Agents; Drug Screening Assays, Antitumor; Cell Proliferation; Cell Line, Tumor
PubMed: 37207596
DOI: 10.1016/j.bioorg.2023.106608 -
Discovery of Novel Bruton's Tyrosine Kinase PROTACs with Enhanced Selectivity and Cellular Efficacy.Journal of Medicinal Chemistry Jun 2023Bruton's tyrosine kinase (BTK) is a target for treating B-cell malignancies and autoimmune diseases, and several BTK inhibitors are already approved for use in humans....
Bruton's tyrosine kinase (BTK) is a target for treating B-cell malignancies and autoimmune diseases, and several BTK inhibitors are already approved for use in humans. Heterobivalent BTK protein degraders are also in development, based on the premise that proteolysis targeting chimeras (PROTACs) may provide additional therapeutic benefits. However, most BTK PROTACs are based on the BTK inhibitor ibrutinib raising concerns about their selectivity profiles, given the known off-target effects of ibrutinib. Here, we disclose the discovery and characterization of BTK PROTACs based on the selective BTK inhibitor and the cereblon recruitment ligand pomalidomide. is a highly potent BTK degrader (DC 0.5 nM) that inhibited cell growth and induced apoptosis at lower concentrations than the two parent molecules, as well as three previously reported BTK PROTACs, and had improved selectivity compared to ibrutinib-based BTK PROTACs.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; B-Lymphocytes; Cell Proliferation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proteolysis Targeting Chimera
PubMed: 37195170
DOI: 10.1021/acs.jmedchem.3c00176 -
Biomedicine & Pharmacotherapy =... Jul 2023CD4 + regulatory T cells (Tregs) play a central role in regulating and suppressing anti-tumor immune responses. FoxP3 is a transcription factor and master regulator of...
CD4 + regulatory T cells (Tregs) play a central role in regulating and suppressing anti-tumor immune responses. FoxP3 is a transcription factor and master regulator of the Treg lineage. We developed and characterized a proteolysis targeting chimeric (PROTAC) drug that targets FoxP3 (PF). PF was created by linking the FoxP3 binding peptide P60 to pomalidomide, a ligand for E3 ligase. Ternary complex formation between PF, FoxP3, and cereblon (component of an E3 ligase) was confirmed using surface plasmon resonance assay (cooperativity factor of 2.27). PF decreased mouse and human FoxP3 expression in vitro in a proteasome-dependent manner. In mice, PF decreased FoxP3 in both the spleen and peripheral lymphocytes. PF-treated lymphocytes (human or mice) were better at stimulating CD8 + lymphocyte proliferation and activation. PF treatment decreased RENCA tumor growth in mice. PF enhanced antitumor immunity associated with αPD1 or mTOR inhibitor (mTORi). Lymphocytes from mice treated with PF and mTORi showed reduced metastatic tumor growth in untreated mice, providing further evidence for an adaptive immune response as the mechanism of action. We showed that PF binds FoxP3 and decreases FoxP3 expression in Tregs, reducing Treg function and generating antitumor immunity.
Topics: Animals; Humans; Mice; Forkhead Transcription Factors; Lymphocyte Activation; Neoplasms; Proteolysis; T-Lymphocytes, Regulatory; Transcription Factors; Proteolysis Targeting Chimera
PubMed: 37182514
DOI: 10.1016/j.biopha.2023.114871 -
Frontiers in Oncology 2023Infections are a leading cause of morbidity and mortality in patients with multiple myeloma (MM).
INTRODUCTION
Infections are a leading cause of morbidity and mortality in patients with multiple myeloma (MM).
METHODS
To examine the effects of modern second-generation novel agent therapy on immune cell subsets, in particular CD4+-T-cells, and infectious complications in patients with relapsed/refractory MM (RRMM), we conducted a prospective cohort study in 112 RRMM patients.
RESULTS
Substantially decreased CD4+-T-cells <200/µl before initiation of relapse therapy were detected in 27.7% of patients and were associated with a higher number of previous lines of therapy. Relapse therapy with carfilzomib or pomalidomide showed a significant further decrease of CD4+-T-cells. All novel agents led to a significant decrease of B-cell counts. Overall, infections were frequent with 21.3% of patients requiring antibacterial therapy within the first 3 months of relapse therapy, 5.6% requiring hospitalization. However, in the setting of standard antimicrobial prophylaxis in RRMM patients with very low CD4+-T-cells, no significant association of CD4+T-cell count and an increased risk of infection could be detected.
DISCUSSION
Our findings imply that reduced CD4+-T-cell numbers and infections are common in patients with RRMM. We also demonstrate an association with the number of previous therapies and certain substances suggesting an increased need for personalized prophylaxis strategies for opportunistic infections in this patient cohort.
PubMed: 37152008
DOI: 10.3389/fonc.2023.1078725