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British Journal of Haematology Jun 2023Lenalidomide maintenance in myeloma is well established. Nevertheless, pomalidomide could provide an alternative. Myeloma patients in first relapse, initially treated in...
Lenalidomide maintenance in myeloma is well established. Nevertheless, pomalidomide could provide an alternative. Myeloma patients in first relapse, initially treated in the Intergroupe Francophone du Myélome (IFM) 2009 trial, and subsequently in the IFM 2013-01 phase 2 trial, received four cycles of salvage therapy with pomalidomide plus cyclophosphamide plus dexamethasone (PCD) with transplantation plus 2 PCD consolidation or without transplantation but with 5 PCD and for all patients pomalidomide plus dexamethasone maintenance therapy. This consisted of 28-day cycles of pomalidomide 4 mg daily on days 1-21 and dexamethasone 20 mg weekly until progression. The primary endpoint was an improved response to treatment. A total of 75/100 patients reached therapy. The median follow-up time was 73 months. The median duration of treatment was 23.7 months. One third of patients improved their response from the initiation of treatment: 11%, 19% and 4% to a very good partial response, complete response or stringent complete response respectively. The median progression-free survival time was 33.2 months and the median overall survival time was not reached. Among the 75 patients, the reasons for pomalidomide discontinuation were progressive disease (54%), adverse events (AEs) (30%), investigator discretion (11%) and consent withdrawal (5%). Grade (G) 3/4 haematological AEs included neutropenia (51%) and lymphopenia (35%); G3/4 drug-related non-haematological AEs (>5%) comprised 13% infections. Long-term administration of pomalidomide and dexamethasone is feasible and one third of the patients improved their response.
Topics: Humans; Multiple Myeloma; Salvage Therapy; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone
PubMed: 36974007
DOI: 10.1111/bjh.18772 -
Journal of Cancer Research and Clinical... Aug 2023Outcomes of multiple myeloma (MM) patients who are refractory to daratumumab are dismal and no standard of treatment exists for this patients' population. Here, we...
PURPOSE
Outcomes of multiple myeloma (MM) patients who are refractory to daratumumab are dismal and no standard of treatment exists for this patients' population. Here, we investigate the role of pomalidomide combinations in daratumumab-refractory MM patients.
METHODS
We performed a retrospective analysis of myeloma patients treated at four referral centers (three in Germany and one in Italy). Review chart identified 30 patients with relapsed and refractory myeloma, who progressed during treatment with daratumumab and were treated with pomalidomide-based combinations in the subsequent lines of therapy.
RESULTS
Responses improved from 37% with daratumumab to 53% with pomalidomide. Of seven patients with extramedullary MM (EMM), four achieved a clinical stabilization with pomalidomide, including one patient with a long-lasting complete response. Median progression-free survival and overall survival were 6 and 12 months, respectively. Pomalidomide combinations were well tolerated, no patient discontinued treatment due to adverse events.
CONCLUSION
These data show that pomalidomide-based combinations can be an effective and safe salvage regimen for daratumumab-refractory patients, including those with EMM.
Topics: Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antineoplastic Agents; Drug Therapy, Combination; Multiple Myeloma; Recurrence; Salvage Therapy; Thalidomide; Treatment Failure; Progression-Free Survival
PubMed: 36781500
DOI: 10.1007/s00432-023-04637-x -
Expert Review of Hematology May 2021Despite therapeutic advances, myeloma remains an essentially incurable disease, with a median survival of approximately 8 - 10 years. Most patients will develop... (Review)
Review
INTRODUCTION
Despite therapeutic advances, myeloma remains an essentially incurable disease, with a median survival of approximately 8 - 10 years. Most patients will develop disease that is refractory to immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs), and treatment regimens containing drugs with different mechanisms of action are necessary. Isatuximab is one such novel agent, an anti-CD38 monoclonal antibody (MoAb), and is the second drug in this class after daratumumab. This paper will consider the current role for isatuximab with pomalidomide for the treatment of relapsed/refractory myeloma (RRMM).
AREAS COVERED
This review provides an overview of the pharmacological characteristics of isatuximab, and its clinical development including safety and efficacy data to date.
EXPERT OPINION
Isatuximab in combination with pomalidomide and dexamethasone offers a new treatment option for those patients with RRMM who are refractory to PIs and lenalidomide, a patient group with poor prognosis and unmet clinical need. The challenge of where it is best placed in the treatment algorithm remains, particularly with the increasing application of daratumumab particularly in the front- and second-line settings.
Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Thalidomide
PubMed: 33945375
DOI: 10.1080/17474086.2021.1924052 -
American Journal of Hematology Feb 2010
Review
Topics: Cytokines; Humans; Immunologic Factors; Multiple Myeloma; Neovascularization, Pathologic; Primary Myelofibrosis; Signal Transduction; Thalidomide
PubMed: 20095057
DOI: 10.1002/ajh.21610 -
Cell Transplantation Apr 2019Stroke is a leading cause of death and severe disability worldwide. After cerebral ischemia, inflammation plays a central role in the development of permanent...
Stroke is a leading cause of death and severe disability worldwide. After cerebral ischemia, inflammation plays a central role in the development of permanent neurological damage. Reactive oxygen species (ROS) are involved in the mechanism of post-ischemic inflammation. The activation of several inflammatory enzymes produces ROS, which subsequently suppress mitochondrial activity, leading to further tissue damage. Pomalidomide (POM) is a clinically available immunomodulatory and anti-inflammatory agent. Prior cellular studies demonstrate that POM can mitigate oxidative stress and lower levels of pro-inflammatory cytokines, particularly TNF-α, which plays a prominent role in ischemic stroke-induced brain damage and functional deficits. To evaluate the potential value of POM in cerebral ischemia, POM was initially administered to transgenic mice chronically over-expressing TNF-α surfactant protein (SP)-C promoter (SP-C/TNF-α mice) to assess whether systemically administered drug could lower systemic TNF-α level. POM significantly lowered serum levels of TNF-α and IL-5. Pharmacokinetic studies were then undertaken in mice to evaluate brain POM levels following systemic drug administration. POM possessed a brain/plasma concentration ratio of 0.71. Finally, rats were subjected to transient middle cerebral artery occlusion (MCAo) for 60 min, and subsequently treated with POM 30 min thereafter to evaluate action on cerebral ischemia. POM reduced the cerebral infarct volume in MCAo-challenged rats and improved motor activity, as evaluated by the elevated body swing test. POM's neuroprotective actions on ischemic injury represent a potential therapeutic approach for ischemic brain damage and related disorders, and warrant further evaluation.
Topics: Angiogenesis Inhibitors; Animals; Brain Ischemia; Male; Mice; Rats; Thalidomide
PubMed: 31094216
DOI: 10.1177/0963689719850078 -
Leukemia Apr 2017Myeloproliferative neoplasm (MPN)-associated myelofibrosis is a MPN characterized by bone marrow fibrosis, cytopenias, splenomegaly and constitutional symptoms....
Myeloproliferative neoplasm (MPN)-associated myelofibrosis is a MPN characterized by bone marrow fibrosis, cytopenias, splenomegaly and constitutional symptoms. Pomalidomide, an immune-modifying drug, is reported to improve anaemia and thrombocytopenia in some patients with MPN-associated myelofibrosis. We designed a phase 2 study of pomalidomide in patients with MPN-associated myelofibrosis and anaemia and/or thrombocytopenia and/or neutropenia. Subjects received pomalidomide 2.0 mg/day in cohort 1 (n=38) or 0.5 mg/day in cohort 2 (n=58). Prednisolone was added if there was no response after 3 months in cohort 1 and based on up-front randomization in cohort 2 if there was no response at 3 or 6 months. Response rates were 39% (95% confidence interval (CI), 26-55%) in cohort 1 and 24% (95% CI, 15-37%) in cohort 2. In a multivariable logistic regression model pomalidomide at 2.0 mg/day (odds ratio (OR), 2.62; 95% CI, 1.00-6.87; P=0.05) and mutated TET2 (OR, 5.07; 95% CI, 1.16-22.17; P=0.03) were significantly associated with responses. Median duration of responses was 13.0 months (range 0.9-52.7). There was no significant difference in response rates or duration in subjects receiving or not receiving prednisolone. Clinical trial MPNSG 01-09 is registered at ClinicalTrials.gov (NCT00949364) and clinicaltrialsregister.eu (EudraCT Number: 2009-010738-23).
Topics: Aged; Aged, 80 and over; Alleles; Biomarkers; Chromosome Banding; Female; Humans; Immunologic Factors; Male; Middle Aged; Mutation; Myeloproliferative Disorders; Phenotype; Prednisolone; Primary Myelofibrosis; Thalidomide; Treatment Outcome
PubMed: 27774990
DOI: 10.1038/leu.2016.299 -
BMJ Case Reports Dec 2020Myelomatous pleural effusion (MPE) is an uncommon clinical entity and occurs in less than 1% of all patients with multiple myeloma. MPE indicates a progression of...
Myelomatous pleural effusion (MPE) is an uncommon clinical entity and occurs in less than 1% of all patients with multiple myeloma. MPE indicates a progression of disease, therefore is associated with a poor prognosis and estimated median survival of <3 months. Treatment of MPE is challenging, and the data regarding the role of novel agents lack in the literature. Herein, we report a relapsed IgA myeloma case of a patient presenting with MPE, who was treated with pomalidomide with a very good partial response.
Topics: Dexamethasone; Drainage; Dyspnea; Humans; Male; Middle Aged; Multiple Myeloma; Plasma Cells; Pleural Effusion, Malignant; Radiography, Thoracic; Thalidomide; Thoracentesis; Treatment Outcome
PubMed: 33303498
DOI: 10.1136/bcr-2020-235899 -
Nature Aug 2014In the 1950s, the drug thalidomide, administered as a sedative to pregnant women, led to the birth of thousands of children with multiple defects. Despite the...
In the 1950s, the drug thalidomide, administered as a sedative to pregnant women, led to the birth of thousands of children with multiple defects. Despite the teratogenicity of thalidomide and its derivatives lenalidomide and pomalidomide, these immunomodulatory drugs (IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-deletion-associated dysplasia. IMiDs target the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)) and promote the ubiquitination of the IKAROS family transcription factors IKZF1 and IKZF3 by CRL4(CRBN). Here we present crystal structures of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes that CRBN is a substrate receptor within CRL4(CRBN) and enantioselectively binds IMiDs. Using an unbiased screen, we identified the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4(CRBN). Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4(CRBN) while the ligase complex is recruiting IKZF1 or IKZF3 for degradation. This dual activity implies that small molecules can modulate an E3 ubiquitin ligase and thereby upregulate or downregulate the ubiquitination of proteins.
Topics: Adaptor Proteins, Signal Transducing; Crystallography, X-Ray; DNA-Binding Proteins; Homeodomain Proteins; Humans; Lenalidomide; Models, Molecular; Multiprotein Complexes; Peptide Hydrolases; Protein Binding; Structure-Activity Relationship; Substrate Specificity; Thalidomide; Transcription Factors; Ubiquitin-Protein Ligases
PubMed: 25043012
DOI: 10.1038/nature13527 -
Nature Structural & Molecular Biology Apr 2020Thalidomide-dependent degradation of the embryonic transcription factor SALL4 by the CRL4 E3 ubiquitin ligase is a plausible major driver of thalidomide teratogenicity....
Thalidomide-dependent degradation of the embryonic transcription factor SALL4 by the CRL4 E3 ubiquitin ligase is a plausible major driver of thalidomide teratogenicity. The structure of the second zinc finger of SALL4 in complex with pomalidomide, cereblon and DDB1 reveals the molecular details of recruitment. Sequence differences and a shifted binding position relative to Ikaros offer a path to the rational design of cereblon-binding drugs with reduced teratogenic risk.
Topics: Adaptor Proteins, Signal Transducing; Crystallography, X-Ray; DNA-Binding Proteins; Humans; Multiprotein Complexes; Protein Binding; Protein Conformation; Proteolysis; Substrate Specificity; Thalidomide; Transcription Factors; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 32251415
DOI: 10.1038/s41594-020-0405-9 -
Nature Chemistry Feb 2024Proteolysis-targeting chimeras (PROTACs) are molecules that induce proximity between target proteins and E3 ligases triggering target protein degradation. Pomalidomide,...
Proteolysis-targeting chimeras (PROTACs) are molecules that induce proximity between target proteins and E3 ligases triggering target protein degradation. Pomalidomide, a widely used E3 ligase recruiter in PROTACs, can independently degrade other proteins, including zinc-finger (ZF) proteins, with vital roles in health and disease. This off-target degradation hampers the therapeutic applicability of pomalidomide-based PROTACs, requiring development of PROTAC design rules that minimize off-target degradation. Here we developed a high-throughput platform that interrogates off-target degradation and found that reported pomalidomide-based PROTACs induce degradation of several ZF proteins. We generated a library of pomalidomide analogues to understand how functionalizing different positions of the phthalimide ring, hydrogen bonding, and steric and hydrophobic effects impact ZF protein degradation. Modifications of appropriate size on the C5 position reduced off-target ZF degradation, which we validated through target engagement and proteomics studies. By applying these design principles, we developed anaplastic lymphoma kinase oncoprotein-targeting PROTACs with enhanced potency and minimal off-target degradation.
Topics: Proteolysis; Ubiquitin-Protein Ligases; Proteins; Thalidomide
PubMed: 38110475
DOI: 10.1038/s41557-023-01379-8