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Annals of Hematology Jun 2024Improvement in the therapeutics for multiple myeloma (MM) has been continuously developed owing to the application of novel drugs and technologies in the last 20 years.... (Review)
Review
Improvement in the therapeutics for multiple myeloma (MM) has been continuously developed owing to the application of novel drugs and technologies in the last 20 years. The standard first-line therapy for MM consists of a three-drug induction regimen based on immunomodulatory drugs and proteasome inhibitors combined with autologous stem cell transplantation. However, MM remains incurable; therefore, therapies for relapsed/refractory MM (RRMM) are emerging and evolving rapidly. This study aimed to summarize and review the results of RRMM trials over the past 5 years to provide a holistic overview and insights for practitioners in related fields and to provide additional ideas for clinical trialists. This study shows that daratumumab and isatuximab continue to significantly advance as treatment options. Additionally, novel antibody drugs, such as elotuzumab and selinexor, as well as bispecific antibodies, teclistamab and talquetamab, are currently undergoing clinical research with promising outcomes. However, chimeric antigen receptor-T cell therapy targeting B-cell maturation antigen remains the optimal approach for MM treatment.
Topics: Multiple Myeloma; Humans; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Immunotherapy, Adoptive; Recurrence; Antineoplastic Combined Chemotherapy Protocols; Transplantation, Autologous; Clinical Trials as Topic; Antibodies, Bispecific; Hematopoietic Stem Cell Transplantation
PubMed: 38609727
DOI: 10.1007/s00277-024-05730-y -
Trends in Pharmacological Sciences Aug 2023Proteasome inhibitors (PIs) are a fascinating class of small molecules that disrupt protein homeostasis and are highly efficacious in the blood cancer multiple myeloma.... (Review)
Review
Proteasome inhibitors (PIs) are a fascinating class of small molecules that disrupt protein homeostasis and are highly efficacious in the blood cancer multiple myeloma. However, PIs are not curative, and overcoming PI resistance to extend patient survival remains a major unmet need. Recent strategies to overcome PI resistance, including inhibiting alternative protein homeostasis pathways and targeting the mitochondrion as a nexus of metabolic adaptation to PIs, are gaining momentum. However, these focused approaches may be surpassed or even obviated by quickly emerging immunotherapy strategies that do not selectively target PI resistance mechanisms but are highly efficacious in PI-resistant disease, nonetheless. Informed by insights from these promising areas of research moving in parallel, we propose that pharmacological strategies to enforce immunotherapeutic vulnerabilities in resistant disease may provide a unified outlook to overcome PI resistance in a 'new era' of myeloma treatment.
Topics: Humans; Proteasome Inhibitors; Multiple Myeloma; Mitochondria; Immunotherapy; Drug Resistance, Neoplasm
PubMed: 37344251
DOI: 10.1016/j.tips.2023.05.006 -
Blood Reviews Sep 2023Multiple myeloma (MM) is a malignant plasma cell disorder accounting for around 1.8% of all neoplastic diseases. Nowadays, clinicians have a broad arsenal of drugs at... (Review)
Review
Multiple myeloma (MM) is a malignant plasma cell disorder accounting for around 1.8% of all neoplastic diseases. Nowadays, clinicians have a broad arsenal of drugs at their disposal for the treatment of MM, such as proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, bispecific antibodies, CAR T-cell therapies and antibody-drug conjugates. In this paper we briefly highlight essential clinical elements relating to proteasome inhibitors, such as bortezomib, carfilzomib and ixazomib. Studies suggest that the early use of immunotherapy may improve outcomes significantly. Therefore, in our review we specifically focus on the combination therapy of proteasome inhibitors with novel immunotherapies and/or transplant. A high number of patients develop PI resistance. Thus, we also review new generation PIs, such as marizomib, oprozomib (ONX0912) and delanzomib (CEP-18770) and their combinations with immunotherapies.
Topics: Humans; Multiple Myeloma; Proteasome Inhibitors; Proteasome Endopeptidase Complex; Bortezomib; Immunotherapy; Antineoplastic Agents
PubMed: 37291017
DOI: 10.1016/j.blre.2023.101100 -
Cell Chemical Biology Feb 2024Methotrexate (MTX) is a tight-binding dihydrofolate reductase (DHFR) inhibitor, used as both an antineoplastic and immunosuppressant therapeutic. MTX, like folate...
Methotrexate (MTX) is a tight-binding dihydrofolate reductase (DHFR) inhibitor, used as both an antineoplastic and immunosuppressant therapeutic. MTX, like folate undergoes folylpolyglutamate synthetase-mediated γ-glutamylation, which affects cellular retention and target specificity. Mechanisms of MTX resistance in cancers include a decrease in MTX poly-γ-glutamylation and an upregulation of DHFR. Here, we report a series of potent MTX-based proteolysis targeting chimeras (PROTACs) to investigate DHFR degradation pharmacology and one-carbon biochemistry. These on-target, cell-active PROTACs show proteasome- and E3 ligase-dependent activity, and selective degradation of DHFR in multiple cancer cell lines. By comparison, treatment with MTX increases cellular DHFR protein expression. Importantly, these PROTACs produced distinct, less-lethal phenotypes compared to MTX. The chemical probe set described here should complement conventional DHFR inhibitors and serve as useful tools for studying one-carbon biochemistry and dissecting complex polypharmacology of MTX and related drugs. Such compounds may also serve as leads for potential autoimmune and antineoplastic therapeutics.
Topics: Humans; Antineoplastic Agents; Carbon; Folic Acid Antagonists; Methotrexate; Neoplasms; Proteolysis Targeting Chimera; Tetrahydrofolate Dehydrogenase
PubMed: 37875111
DOI: 10.1016/j.chembiol.2023.09.014 -
Journal of Thrombosis and Haemostasis :... Jul 2024Carfilzomib (CFZ) is a second-generation proteasome inhibitor used to treat multiple myeloma. Potent inhibition of the proteasome results in chronic proteotoxic...
BACKGROUND
Carfilzomib (CFZ) is a second-generation proteasome inhibitor used to treat multiple myeloma. Potent inhibition of the proteasome results in chronic proteotoxic endoplasmic reticulum (ER) stress, leading to apoptosis. While CFZ has improved survival rates in multiple myeloma, it is associated with an increased risk of cardiovascular adverse effects. While this has been putatively linked to cardiotoxicity, CFZ could potentially also exhibit adverse effects on the endothelium.
OBJECTIVES
To investigate the effects of CFZ on the endothelium.
METHODS
Human umbilical vein endothelial cells (HUVECs) were treated with CFZ, and expression of relevant markers of ER stress, inflammation, and thrombosis was measured and functionally assessed.
RESULTS
CFZ failed to induce ER stress in HUVECs but induced the expression of Kruppel-like factor 4, endothelial nitric oxide synthase, tissue plasminogen activator, and thrombomodulin and reduced tumor necrosis factor alpha (TNFα)-mediated intercellular adhesion molecule 1 and tissue factor expression, suggesting a potential protective effect on the endothelium. Consistent with these observations, CFZ reduced leukocyte adhesion under shear stress and reduced factor Xa generation and fibrin clot formation on the endothelium following TNFα treatment and inhibited von Willebrand factor (VWF) and angiopoietin-2 exocytosis from Weibel-Palade bodies. Subsequently, CFZ inhibited the formation of VWF-platelet strings, and moreover, media derived from myeloma cell lines induced VWF release, a process also inhibited by CFZ.
CONCLUSION
These data demonstrate that CFZ is unable to induce ER stress in confluent resting endothelial cells and can conversely attenuate the prothrombotic effects of TNFα on the endothelium. This study suggests that CFZ does not negatively alter HUVECs, and proteasome inhibition of the endothelium may offer a potential way to prevent thrombosis.
Topics: Humans; Human Umbilical Vein Endothelial Cells; Oligopeptides; Proteasome Inhibitors; Endoplasmic Reticulum Stress; Fibrinolytic Agents; Anti-Inflammatory Agents; Cell Adhesion; Tumor Necrosis Factor-alpha; Nitric Oxide Synthase Type III; Intercellular Adhesion Molecule-1; Thromboplastin; Leukocytes; Thrombosis; Cells, Cultured; Inflammation; Thrombomodulin
PubMed: 38608731
DOI: 10.1016/j.jtha.2024.03.024 -
Cell Reports. Medicine Nov 2023Internal tandem duplication mutations of the FMS-like tyrosine kinase-3 (FLT3-ITDs) occur in 25%-30% of patients with acute myeloid leukemia (AML) and are associated...
Internal tandem duplication mutations of the FMS-like tyrosine kinase-3 (FLT3-ITDs) occur in 25%-30% of patients with acute myeloid leukemia (AML) and are associated with dismal prognosis. Although FLT3 inhibitors have demonstrated initial clinical efficacy, the overall outcome of patients with FLT3-ITD AML remains poor, highlighting the urgency to develop more effective treatment strategies. In this study, we reveal that FLT3 inhibitors reduced protein stability of the anti-cancer protein p53, resulting in drug resistance. Blocking p53 degradation with proteasome inhibitors restores intracellular p53 protein levels and, in combination with FLT3-ITD inhibitors, shows superior therapeutic effects against FLT3-ITD AML in cells, mouse models, and patients. These data suggest that this combinatorial therapeutic approach may represent a promising strategy to target FLT3-ITD AML.
Topics: Animals; Mice; Humans; Tumor Suppressor Protein p53; Leukemia, Myeloid, Acute; Mutation; Prognosis; Treatment Outcome; Protein Kinase Inhibitors; fms-Like Tyrosine Kinase 3
PubMed: 37951217
DOI: 10.1016/j.xcrm.2023.101286 -
Journal of Medicinal Chemistry Sep 2023The phosphoinositide kinase PIKfyve has emerged as a new potential therapeutic target in various cancers. However, limited clinical progress has been achieved with...
The phosphoinositide kinase PIKfyve has emerged as a new potential therapeutic target in various cancers. However, limited clinical progress has been achieved with PIKfyve inhibitors. Here, we report the discovery of a first-in-class PIKfyve degrader by employing the proteolysis-targeting chimera approach. potently degraded PIKfyve protein with a DC value of 1.48 nM and a value of 97.7% in prostate cancer VCaP cells. Mechanistic studies revealed that it selectively induced PIKfyve degradation in a VHL- and proteasome-dependent manner. PIKfyve degradation by caused massive cytoplasmic vacuolization and blocked autophagic flux in multiple prostate cancer cell lines. Importantly, was more effective in suppressing the growth of prostate cancer cells than the parent inhibitor and exerted prolonged inhibition of downstream signaling. Further, intraperitoneal administration of exhibited potent PIKfyve degradation and suppressed tumor proliferation in vivo. Overall, is a valuable chemical tool for exploring PIKfyve-based targeted therapy.
Topics: Humans; Male; Autophagy; Cell Line; Cytoplasm; Lipids; Prostatic Neoplasms
PubMed: 37605297
DOI: 10.1021/acs.jmedchem.3c00912 -
Journal of the National Comprehensive... Dec 2023Patients with relapsed or refractory multiple myeloma (RRMM) that is refractory to a proteasome inhibitor, an immunomodulatory drug (IMiD), and an anti-CD38 antibody... (Review)
Review
Patients with relapsed or refractory multiple myeloma (RRMM) that is refractory to a proteasome inhibitor, an immunomodulatory drug (IMiD), and an anti-CD38 antibody (triple-class refractory MM) have poor outcomes. Recently, 2 classes of T-cell engaging therapies-CAR T-cell therapy and bispecific T-cell engaging antibodies (BsAbs)-have resulted in unprecedented response rates and survival outcomes in these heavily pretreated patients. The most common targets are BCMA and GPRC5D, with other targets in development. The main classes of adverse effects include cytokine release syndrome, neurotoxicity, infections, and cytopenias, as well as adverse effects unique to specific products. As of September 2023, 2 BCMA-targeting CAR-T cell products, 2 BCMA-targeting BsAbs, and 1 GPRC5D-targeting BsAb, are FDA-approved for standard-of-care use in patients with RRMM who received at least 4 prior lines of therapy, including prior treatment with a proteasome inhibitor, an IMiD, and an anti-CD38 antibody. Earlier-line use is under investigation and has shown promising results. Several other investigational CAR-T constructs and bispecific antibodies are in clinical development. As these therapies become more widely used, including in earlier-line setting, efforts to understand optimal sequencing and mitigate toxicities remain critical.
Topics: Humans; Multiple Myeloma; B-Cell Maturation Antigen; Proteasome Inhibitors; Drug-Related Side Effects and Adverse Reactions; Antibodies, Bispecific; Antiviral Agents; Immunotherapy, Adoptive
PubMed: 38081142
DOI: 10.6004/jnccn.2023.7100 -
European Journal of Medicinal Chemistry Sep 2023Multiple myeloma (MM) is a hematologic neoplasm of plasma cells that is currently deemed incurable. Despite the introduction of novel immunomodulators and proteasome... (Review)
Review
Multiple myeloma (MM) is a hematologic neoplasm of plasma cells that is currently deemed incurable. Despite the introduction of novel immunomodulators and proteasome inhibitors, MM remains a challenging disease with high rates of relapse and refractoriness. The management of refractory and relapsed MM patients remains a formidable task, primarily due to the emergence of multiple drug resistance. Consequently, there is an urgent need for novel therapeutic agents to address this clinical challenge. In recent years, a significant amount of research has been dedicated to the discovery of novel therapeutic agents for the treatment of MM. The clinical utilization of proteasome inhibitor carfilzomib and immunomodulator pomalidomide has been successively introduced. As basic research continues to advance, novel therapeutic agents, including panobinostat, a histone deacetylase inhibitor, and selinexor, a nuclear export inhibitor, have progressed to the clinical trial and application phase. This review aims to furnish a comprehensive survey of the clinical applications and synthetic pathways of select drugs, with the intention of imparting valuable insights for future drug research and development geared towards MM.
Topics: Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Panobinostat; Histone Deacetylase Inhibitors; Proteasome Inhibitors; Immunologic Factors; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37210838
DOI: 10.1016/j.ejmech.2023.115492 -
Blood and Lymphatic Cancer : Targets... 2023Multiple myeloma (MM) is a hematologic malignancy characterized by the abnormal clonal proliferation of plasma cells that may result in focal bone lesions, renal... (Review)
Review
Multiple myeloma (MM) is a hematologic malignancy characterized by the abnormal clonal proliferation of plasma cells that may result in focal bone lesions, renal failure, anemia, and/or hypercalcemia. Recently, the diagnosis and treatment of MM have evolved due to a better understanding of disease pathophysiology, improved risk stratification, and new treatments. The incorporation of new drugs, including proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies and high-dose chemotherapy followed by hematopoietic stem cell transplantation, has resulted in a significant improvement in patient outcomes and QoL. In this review, we summarize differential diagnoses and therapeutic advances in MM.
PubMed: 37731771
DOI: 10.2147/BLCTT.S272703