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DRUG CLASS:

IL-6 inhibitor

1d
Increased CSN5 expression enhances the sensitivity to lenalidomide in multiple myeloma cells. (PubMed, iScience)
Our data suggest that reduced CSN5 expression leads to abnormalities in the ubiquitination cycle of CRL4A, resulting in the inhibition of LEN-mediated degradation of IKZF1 and IKZF3. These findings delineate an additional mechanism of LEN resistance in MM cells and may contribute to the development of alternative therapeutic strategies to overcome LEN resistance.
Journal
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IKZF1 (IKAROS Family Zinc Finger 1) • IKZF3 (IKAROS Family Zinc Finger 3)
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lenalidomide
7d
PRISM: DARA RVD For High Risk SMM (clinicaltrials.gov)
P2, N=61, Active, not recruiting, Omar Nadeem, MD | Recruiting --> Active, not recruiting | Trial completion date: Mar 2029 --> Dec 2030 | Trial primary completion date: Mar 2026 --> Dec 2026
Enrollment closed • Trial completion date • Trial primary completion date
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Chr t(4;14) • Chr t(14;16)
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clonoSEQ
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lenalidomide • bortezomib • Darzalex Faspro (daratumumab and hyaluronidase-fihj)
9d
Siltuximab in Large Granular Lymphocytic Leukemia (LGLL) (clinicaltrials.gov)
P1, N=6, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Recruiting --> Active, not recruiting | N=20 --> 6
Enrollment closed • Enrollment change
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CD8 (cluster of differentiation 8) • B3GAT1 (Beta-1,3-Glucuronyltransferase 1)
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Sylvant (siltuximab)
9d
ADAR1-regulated cytoplasmic dsRNA-sensing pathway is a novel mechanism of lenalidomide resistance in multiple myeloma. (PubMed, Blood)
In summary, we report the involvement of ADAR1-regulated dsRNA-sensing in modulating lenalidomide sensitivity in MM. These findings highlight a novel RNA-related mechanism underlying lenalidomide resistance and underscore the potential of targeting ADAR1 as a novel therapeutic strategy.
Journal
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CRBN (Cereblon) • ADAR (Adenosine Deaminase RNA Specific) • IFIH1 (Interferon Induced With Helicase C Domain 1)
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ADAR overexpression
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lenalidomide
10d
B-Lymphoblastic Leukemia with BCR::ABL1-like Features After Long-term Lenalidomide Therapy. (PubMed, J Assoc Genet Technol)
Lenalidomide, a derivative of thalidomide, is a type of immunomodulatory drug (IMiD) that has been standard therapy for multiple myeloma (MM) and other hematologic malignancies for almost two decades. In addition, treatment with IMiDs is also associated with an increased risk for myelodysplastic neoplasms (MDS), squamous cell carcinoma of the skin, and, less frequently, acute lymphoblastic leukemia (ALL). We present a case of an elderly male with MM and multiple subsequent skin cancers, who presented with pancytopenia and was diagnosed with B-lymphoblastic leukemia (B-ALL) after 10 years of maintenance lenalidomide therapy.
Journal
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ABL1 (ABL proto-oncogene 1)
|
lenalidomide • thalidomide
13d
RECLAIM: Recovering From COVID-19 Lingering Symptoms Adaptive Integrative Medicine (clinicaltrials.gov)
P2/3, N=1000, Recruiting, University Health Network, Toronto | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: May 2025 --> May 2026
Trial completion date • Trial primary completion date
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Eyevinal (ibudilast)
14d
MUKseven: Pomalidomide in Relapsed and Refractory Multiple Myeloma (RRMM) (clinicaltrials.gov)
P2, N=124, Active, not recruiting, University of Leeds | Trial completion date: Jun 2023 --> Jun 2025
Trial completion date
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cyclophosphamide • pomalidomide
15d
A Study of Colesevelam for Lenalidomide-Associated Diarrhea (clinicaltrials.gov)
P2, N=25, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: Jun 2025 --> Nov 2024 | Trial primary completion date: Jun 2025 --> Nov 2024
Trial completion • Trial completion date • Trial primary completion date
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lenalidomide
16d
Synthesis, Biological Evaluation and in Silico Studies of Novel Urea/Thiourea Derivatives of Lenalidomide. (PubMed, J Biochem Mol Toxicol)
These interactions are crucial for the observed inhibitory activity. Molecular dynamics simulation revealed the binding event of the most active compound with class I histone deacetylase and the stability of the complex in a biological environment.
Journal
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BCL2 (B-cell CLL/lymphoma 2) • BAX (BCL2-associated X protein) • TGFB1 (Transforming Growth Factor Beta 1)
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lenalidomide
21d
SOCS1 Inhibits IL-6-Induced CD155 Overexpression in Lung Adenocarcinoma. (PubMed, Int J Mol Sci)
Further basic and clinical studies are needed to define the role of these molecules during tumor development and to improve their clinical impact as biomarkers and targets for predicting the efficacy of immunotherapies. This study deepens the understanding of the intricate regulation of the immune checkpoints mediated by soluble factors and allows us to devise new ways to combine conventional treatments with the most innovative anticancer options.
Journal • IO biomarker
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IL6 (Interleukin 6) • PVR (PVR Cell Adhesion Molecule) • SOCS1 (Suppressor Of Cytokine Signaling 1)
22d
Bortezomib, Lenalidomide and Dexamethasone Combination Therapy in Patients With Newly Diagnosed Multiple Myeloma (clinicaltrials.gov)
P1/2, N=68, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Sep 2024 --> Dec 2024
Trial completion date • Combination therapy
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lenalidomide • bortezomib • dexamethasone
26d
Lenalidomide-induced pure red cell aplasia is associated with elevated expression of MHC-I molecules on erythrocytes. (PubMed, Nat Commun)
The RVd therapy, combining lenalidomide, bortezomib, and dexamethasone, is a mainstay treatment for multiple myeloma. Blocking MHC-I or depleting T cells alleviates the defective erythropoiesis of PRCA, suggesting that the interaction between erythroid cells with elevated MHC-I and T cells in the bone marrow might contribute to PRCA. Taken together, our study implicates a mechanism underlying lenalidomide-induced PRCA in treating cancer patients.
Journal
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CD8 (cluster of differentiation 8)
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lenalidomide • bortezomib • dexamethasone
26d
Caffeic acid hinders the proliferation and migration through inhibition of IL-6 mediated JAK-STAT-3 signaling axis in human prostate cancer. (PubMed, Oncol Res)
In addition, CA induces apoptosis by enhancing the expression of Bax and caspase-3; and decreased expression of Bcl-2 in prostate cancer cells. Thus, CA might act as a therapeutical application against prostate cancer by targeting the IL-6/JAK/STAT3 signaling axis.
Journal • IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • CCND1 (Cyclin D1) • IL6 (Interleukin 6) • JAK1 (Janus Kinase 1) • STAT3 (Signal Transducer And Activator Of Transcription 3) • BAX (BCL2-associated X protein) • CASP3 (Caspase 3) • CCND2 (Cyclin D2) • CDK1 (Cyclin-dependent kinase 1) • MAPK8 (Mitogen-activated protein kinase 8)
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BCL2 expression • CCND1 expression • STAT3 expression • BAX expression • IL6 expression
28d
Structural basis of signaling complex inhibition by IL-6 domain-swapped dimers. (PubMed, Structure)
Here, we present the crystal structure of an IL-6 domain-swapped dimer that computational approaches could not predict. The structure explains why the IL-6 dimer is antagonistic to the IL-6 monomer in signaling complex formation and provides insights for IL-6 targeted therapies.
Journal
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IL6 (Interleukin 6)
30d
Efficacy and Safety of Olokizumab in Patients With Progressive Fibrosing Interstitial Lung Diseases (clinicaltrials.gov)
P2/3, N=138, Recruiting, R-Pharm International, LLC | Trial completion date: Dec 2026 --> Dec 2028 | Trial primary completion date: Jun 2026 --> Apr 2027
Trial completion date • Trial primary completion date
30d
Carfilzomib, Pomalidomide, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov)
P1/2, N=101, Active, not recruiting, University of Chicago | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025
Trial completion date • Trial primary completion date
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Darzalex (daratumumab) • carfilzomib • pomalidomide
30d
Trial completion
|
lenalidomide • carfilzomib • pomalidomide
1m
Enrollment open
1m
Trial completion
|
lenalidomide • dexamethasone • aspirin
1m
New P2 trial
|
melphalan • Sylvant (siltuximab)
1m
Cell-Free DNA Whole Genome Sequencing for Non-Invasive MRD Detection in Multiple Myeloma (ASH 2024)
MRD testing was performed at 100 days post-autologous stem cell transplant (ASCT) (n=39) and/or after one year of lenalidomide (len) maintenance (n=33)...However, these findings are based on preliminary data from a small cohort, requiring further validation in larger studies. Future research will focus on enhancing sensitivity and validating these findings in a broader patient population.
Whole genome sequencing • Cell-free DNA
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SDC1 (Syndecan 1)
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clonoSEQ
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lenalidomide
1m
Implications of MRD Progression in Newly Diagnosed Multiple Myeloma (NDMM) Treated with Quadruplet Therapy and Autologous Stem Cell Transplantation (ASH 2024)
Understanding the implication of increasing MRD burden is particularly relevant in patients with NDMM treated with quadruplet therapy (QUAD, consisting of a PI, an IMiD, an anti-CD38 mAb and dexamethasone) and autologous stem cell transplantation (ASCT), since most will reach MRD negativity...Among the 19 patients with MRD-P, 12 (63%) were on observation at time of MRD-P, 2 were receiving single agent lenalidomide, 5 were receiving a QUAD, 17 (89%) had previously obtained MRD negativity at <10-5 including 10 (53%) who had also achieved MRD negativity at 10-6...Outcomes of patients with MRD-P are similar to those of patients with IMWG-defined PD. These findings challenge the paradigm of IMWG-defined PD and paraprotein measurability as minimal parameters for change in therapy and Introduction of agents with new mechanisms of action.
IO biomarker
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Chr del(17p)
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clonoSEQ
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lenalidomide • dexamethasone
1m
Cyclophosphamide, Lenalidomide and Dexamethasone (CRD) Versus Melphalan (200 mg/m2) Followed By Autologous Stem Cell Transplant (ASCT) In Newly Diagnosed Multiple Myeloma Subjects (clinicaltrials.gov)
P3, N=389, Completed, Fondazione EMN Italy Onlus | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Jul 2024
Trial completion • Trial completion date
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lenalidomide • cyclophosphamide • melphalan
1m
YTHDF2 upregulation and subcellular localization dictate CD8 T cell polyfunctionality in anti-tumor immunity. (PubMed, Nat Commun)
Accordingly, immunotherapy-induced efficacy could be largely restored in YTHDF2-deficient T cells through combinational use of IKZF1/3 inhibitor lenalidomide in a mouse model. Thus, YTHDF2 coordinates epi-transcriptional and transcriptional networks to potentiate T cell immunity, which could inform therapeutic intervention.
Journal
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CD8 (cluster of differentiation 8) • IKZF1 (IKAROS Family Zinc Finger 1) • YTHDF2 (YTH N6-Methyladenosine RNA Binding Protein 2)
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lenalidomide
1m
Trial completion • Combination therapy
|
Lucentis (ranibizumab)
1m
Siltuximab to Decrease Symptom Burden After Autologous Stem Cell Transplantation for Patients With Multiple Myeloma and AL Amyloidosis (clinicaltrials.gov)
P2, N=30, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Oct 2024 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Oct 2025
Trial completion date • Trial primary completion date
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CD34 (CD34 molecule)
|
Sylvant (siltuximab)
2ms
New P1/2 trial
|
pomalidomide • aspirin
2ms
Ziltivekimab for anemia and atherosclerosis in chronic kidney disease: a new hope? (PubMed, J Nephrol)
These trials have shown that ziltivekimab does not increase the risk for cytopenia or infectious complications as has been described for other interleukin-6-targeting monoclonal antibodies, like tocilizumab. In addition, ziltivekimab has shown efficacy in improving anemia parameters, including hemoglobin levels and iron studies. Ziltivekimab deserves full scale clinical development, and to this aim, large-scale clinical trials are under way.
Review • Journal
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IL6 (Interleukin 6)
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Actemra IV (tocilizumab)
2ms
Siltuximab for Chimeric Antigen Receptor T-Cell Therapy Related CRS and ICANS - A Multicenter Retrospective Analysis. (PubMed, Blood Adv)
Sixteen patients had CRS previously treated with tocilizumab and 17 patients had ICANS previously treated with steroids. Siltuximab appeared to be effective for both CRS and ICANS, including previously treated toxicities. These data support the use of siltuximab in CRS and ICANS as well as provide rationale for future prospective studies.
Retrospective data • Journal • CAR T-Cell Therapy
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IL6 (Interleukin 6)
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Actemra IV (tocilizumab) • Sylvant (siltuximab)
2ms
Structure-Activity Relationship of Potent, Selective, and Orally Bioavailable Molecular Glue Degraders of CK1α. (PubMed, ACS Med Chem Lett)
The original molecular glue degraders (thalidomide, lenalidomide, and pomalidomide) are known to bind to cereblon (CRBN) and alter its surface to induce recruitment, ubiquitination, and degradation of therapeutically valuable neosubstrates (IKZF1, IKZF3, and CK1α). Herein, we describe the medicinal chemistry efforts that resulted in the discovery of SJ3149 as well as other potent and selective CK1α degraders. We report kinetic profiling and parameters of CK1α degradation, ternary complex, antiproliferative effects, in vitro ADME data, and in vivo pharmacokinetic studies with demonstrated oral bioavailability.
Journal
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IKZF1 (IKAROS Family Zinc Finger 1) • CRBN (Cereblon) • IKZF3 (IKAROS Family Zinc Finger 3)
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lenalidomide • pomalidomide • thalidomide
2ms
Tranilast vs. Steroids to Prevent Esophageal Stricture (TAPES) After Endoscopic Resection for Superficial Neoplasms (clinicaltrials.gov)
P2, N=394, Not yet recruiting, Second Affiliated Hospital, School of Medicine, Zhejiang University
New P2 trial
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dexamethasone
2ms
High Dose Carfilzomib for Newly Diagnosed Myeloma (clinicaltrials.gov)
P1/2, N=37, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed
Trial completion
|
lenalidomide • carfilzomib • dexamethasone
2ms
Deep hematologic response to RD treatment in patients with multiple myeloma is associated with overexpression of IL-17R in CD138+ plasma cells. (PubMed, Sci Rep)
Lenalidomide (LEN) is widely used immunomodulatory drug (IMiD)...The study included newly diagnosed MM patients (NDMM) and MM patients treated with first-line LEN and dexamethasone (RD) who achieved and least very good partial remission (VGPR)...This should be emphasized because IL-17-related signaling can potentially be targeted, providing the rationale for future research. Establishing the molecular background associated with long-lasting and profound response to LEN may improve LEN-based chemotherapy regimens and facilitate the development of adjuvant therapies to enhance its anti-MM activity.
Journal
|
SDC1 (Syndecan 1) • IL17A (Interleukin 17A)
|
lenalidomide • dexamethasone
2ms
Cytokine Release Syndrome Associated With Immune-Modulating Chemotherapy: Potential Mitigating Role of Intravenous Omega-3 Fatty Acid Triglycerides. (PubMed, Cancer Rep (Hoboken))
Optimizing the formulation, for example, enriched fish oil that meets drug concentration standards for EPA and DHA, a continuous infusion rate, reductions in long-chain saturated fatty acids concentrations, and addition of medium-chain triglycerides to improve EPA + DHA utilization and physical stability are key pharmaceutical factors. This may result in a safer and more effective option than targeted abrogation of cytokines and consequent risks of adverse drug reactions, but will require formal study in randomized control trials in humans.
Review • Journal
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IL6 (Interleukin 6)
|
Actemra IV (tocilizumab) • Sylvant (siltuximab) • Kineret (anakinra)
3ms
Trial completion • Enrollment change
|
lenalidomide • dexamethasone • Darzalex Faspro (daratumumab and hyaluronidase-fihj)
3ms
Lenalidomide in Anti-MAG Neuropathy: Phase 1b Study (clinicaltrials.gov)
P1, N=11, Terminated, Ohio State University | Phase classification: P1b --> P1
Phase classification
|
lenalidomide • dexamethasone
3ms
Cell-free DNA Whole Genome Sequencing for Non-Invasive MRD Detection in Multiple Myeloma (IMW 2024)
MRD testing was performed at 100 days post-autologous stem cell transplant (ASCT) (n=39) and/or after one year of lenalidomide (len) maintenance (n=33)... cfWGS is a promising MRD alternative which is less invasive than MFC and clonoSEQ. It benefits non-secretory and some light chain only patients where EasyM is not currently feasible and uniquely informs of clonal dynamics at progression. Future work will aim to improve sensitivity and validate findings in a larger cohort.
Whole genome sequencing • Cell-free DNA
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SDC1 (Syndecan 1)
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clonoSEQ
|
lenalidomide
3ms
Pomalidomide in patients with multiple myeloma: potential impact on the reconstitution of a functional T-cell immunity. (PubMed, Immunol Res)
These observations imply that Pomalidomide treatment influences the T-cell repertoire, particularly in the CD4 + subpopulation during the later stages of treatment, raising speculation about the potential involvement of these lymphocyte expansions in mechanisms related to antitumor immunity.
Journal
|
CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule)
|
lenalidomide • bortezomib • pomalidomide
3ms
Femoral bone mineral density as a tool of personalized medicine for rheumatoid arthritis: Interleukin-6 inhibitors for patients with low density whereas tumor necrosis factor inhibitor for patients with preserved density? (PubMed, SAGE Open Med)
In the whole group H, significantly more patients obtained Clinical Disease Activity Index remission by tumor necrosis factor inhibitors (7/9, 77.8%) than by interleukin-6 inhibitors (1/6 (16.7%); p = 0.04). In patients with rheumatoid arthritis, interleukin-6 inhibitors may be more beneficial for patients with low femoral bone mineral density, whereas tumor necrosis factor inhibitors may be advantageous for those with preserved bone mineral density.
Journal
|
IL6 (Interleukin 6) • CRP (C-reactive protein)
3ms
New P2 trial
|
IL6 (Interleukin 6) • CRP (C-reactive protein)
3ms
Does immunohistochemical staining predict mobilization success in multiple myeloma patients? (PubMed, Transfus Apher Sci)
Even though we could not find any predictive value of CD56, c-myc, and cyclin D1 expression on mobilization, c-myc was found to be associated with low OS. Further studies with large and homogenous study population would be more informative.
Journal
|
MYC (V-myc avian myelocytomatosis viral oncogene homolog) • CCND1 (Cyclin D1) • NCAM1 (Neural cell adhesion molecule 1)
|
MYC expression • CCND1 expression
|
lenalidomide