ArticleBlood2022
Loss of COP9 signalosome genes at 2q37 is associated with IMiD resistance in multiple myeloma.
Article in Blood, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 16 citations in OpenAlex.
- Pharmacodynamic changes in tumor and immune cells drive iberdomide's clinical mechanisms of activity in relapsed and refractory multiple myeloma.Cell reports. Medicine · 2024Trial
- IMiD/CELMoD resistance in myeloma is associated with changes in lipid metabolism that may be targetable.Blood neoplasia · 2026Article
- Activating RARβ to overcome immunomodulatory drug resistance in t(4;14) human myeloma.Leukemia · 2026Article
- Understanding and addressing resistance to IMiDs immunomodulatory compounds in multiple myeloma.The FEBS journal · 2026Review
- Targeted KRASG12V Degradation In Vivo Elicits Lung Adenocarcinoma Regression with Subsequent Relapse from Dysregulated Proteolysis.Cancer research · 2026Article
- Promoter hypomethylation drives ABCB1-mediated carfilzomib resistance in multiple myeloma.Clinical epigenetics · 2026Article
- Diagnostic sequencing identifies high-risk markers and mechanisms of resistance to guide immunotherapy selection.Blood advances · 2026Article
- The Role of Genomics in the Development and Treatment of Multiple Myeloma: Understanding the Challenges and Opportunities.OncoTargets and therapy · 2026Review
- Resistance to immunomodulatory drugs in multiple myeloma: the cereblon pathway and beyond.Haematologica · 2025Review
- Article
- The Functional Transcriptomic Landscape Informs Therapeutic Strategies in Multiple Myeloma.Cancer research · 2025Article
- Iberdomide increases innate and adaptive immune cell subsets in the bone marrow of patients with relapsed/refractory multiple myeloma.Cell reports. Medicine · 2024Article
- Large T cell clones expressing immune checkpoints increase during multiple myeloma evolution and predict treatment resistance.Nature communications · 2023Article
- Tumor-Associated Macrophages in Multiple Myeloma: Key Role in Disease Biology and Potential Therapeutic Implications.Current oncology (Toronto, Ont.) · 2023Review
- Article
- Lenalidomide in Multiple Myeloma: Review of Resistance Mechanisms, Current Treatment Strategies and Future Perspectives.Cancers · 2023Review
- Molecular and immunological mechanisms of clonal evolution in multiple myeloma.Frontiers in immunology · 2023Review
- Tumor and microenvironmental mechanisms of resistance to immunomodulatory drugs in multiple myeloma.Frontiers in oncology · 2022Review
Corrections and comments
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Authors and funding
18 authors at 4 institutions in 2 countries.
Funding
Abstract
The acquisition of a multidrug refractory state is a major cause of mortality in myeloma. Myeloma drugs that target the cereblon (CRBN) protein include widely used immunomodulatory drugs (IMiDs), and newer CRBN E3 ligase modulator drugs (CELMoDs), in clinical trials. CRBN genetic disruption causes resistance and poor outcomes with IMiDs. Here, we investigate alternative genomic associations of IMiD resistance, using large whole-genome sequencing patient datasets (n = 522 cases) at newly diagnosed, lenalidomide (LEN)-refractory and lenalidomide-then-pomalidomide (LEN-then-POM)-refractory timepoints. Selecting gene targets reproducibly identified by published CRISPR/shRNA IMiD resistance screens, we found little evidence of genetic disruption by mutation associated with IMiD resistance. However, we identified a chromosome region, 2q37, containing COP9 signalosome members COPS7B and COPS8, copy loss of which significantly enriches between newly diagnosed (incidence 5.5%), LEN-refractory (10.0%), and LEN-then-POM-refractory states (16.4%), and may adversely affect outcomes when clonal fraction is high. In a separate dataset (50 patients) with sequential samples taken throughout treatment, we identified acquisition of 2q37 loss in 16% cases with IMiD exposure, but none in cases without IMiD exposure. The COP9 signalosome is essential for maintenance of the CUL4-DDB1-CRBN E3 ubiquitin ligase. This region may represent a novel marker of IMiD resistance with clinical utility.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.