Multiple cereblon genetic changes are associated with acquired resistance to lenalidomide or pomalidomide in multiple myeloma
Open accessAbstract
Emergence of drug resistance to all available therapies is the major challenge to improving survival in myeloma. Cereblon (CRBN) is the essential binding protein of the widely used immunomodulatory drugs (IMiDs) and novel CRBN E3 ligase modulator drugs (CELMoDs) in myeloma, as well as certain proteolysis targeting chimeras (PROTACs), in development for a range of diseases. Using whole-genome sequencing (WGS) data from 455 patients and RNA sequencing (RNASeq) data from 655 patients, including newly diagnosed (WGS, n = 198; RNASeq, n = 437), lenalidomide (LEN)-refractory (WGS, n = 203; RNASeq, n = 176), and pomalidomide (POM)-refractory cohorts (WGS, n = 54; RNASeq, n = 42), we found incremental increases in the frequency of 3 CRBN aberrations, namely point mutations, copy losses/structural variations, and a specific variant transcript (exon 10 spliced), with progressive IMiD exposure, until almost one-third of patients had CBRN alterations by the time they were POM refractory. We found all 3 CRBN aberrations were associated with inferior outcomes to POM in those already refractory to LEN, including those with gene copy losses and structural variations, a finding not previously described. This represents the first comprehensive analysis and largest data set of CBRN alterations in myeloma patients as they progress through therapy. It will help inform patient selection for sequential therapies with CRBN-targeting drugs.
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Resistance to iMiDs often arises from mutations in CRL4 CRBN or alterations in the IRF4/c-Myc signaling axis, especially in relapsed/refractory cases.
“while iMiDs are crucial in treating multiple myeloma, resistance often arises from mutations in cRl4 cRBN or alterations in the iRF4/c-Myc signaling axis, especially in relapsed/refractory cases (Franssen et al. 2018;gooding et al. 2021).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as gooding et al. 2021
The discussion (page unavailable) reports that CRBN alterations increase as myeloma becomes lenalidomide- and pomalidomide-refractory and occur in nearly 30% of IMiD-treated relapsed/refractory patients. It does not establish alterations in the IRF4/c-Myc signaling axis as a resistance mechanism; the paper says it excluded CRBN-independent features of resistance from this analysis. (LLM, conf=0.86)
Experimental — accuracy not yet measuredGenetic alterations in CRBN are a major driver of IMiD resistance, occurring in approximately 30% of relapsed or refractory myeloma patients compared to <1% in newly diagnosed patients.
“As such, genetic alterations in CRBN are a major driver of iMiD resistance, occurring in approximately 30% of relapsed or refractory myeloma patients compared to <1% in newly diagnosed patients (gooding et al. 2021).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as gooding et al. 2021
The discussion reports CRBN alterations in nearly 30% of relapsed/refractory patients treated with IMiDs and calls them a major contributor to resistance. But the Introduction’s <1% figure applies specifically to CRBN mutations in newly diagnosed patients, not to all CRBN alterations; the paper also reports an exon 10-spliced alteration at new diagnosis. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThese resistance-associated mutations do not typically occur within the IMiD binding pocket but instead arise along the length of the CRBN protein, suggesting broader structural defects.
“these resistanceassociated mutations do not typically occur within the iMiD binding pocket but instead arise along the length of the cRBN protein suggesting broader structural defects (gooding et al. 2021).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as gooding et al. 2021
Several mutations in relapsed patients, such as CRBNP352S, CRBNF381S and CRBNH57D, overlapped with CRBN hotspots identified by DMS.
“Upon closer inspection, several mutations in relapsed patients, such as CRBNP352S, CRBNF381S and CRBNH57D overlapped with CRBN hotspots identified by DMS (Fig. 2D, 5G and H and Extended Data Fig. 6G and H)42.”
From Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders (2023) · cites this paper as [42]
Up to one-third of patients refractory to pomalidomide treatment present with various types of CRBN alterations.
“Accumulating data has shown that up to one-third of patients refractory to pomalidomide treatment present with various types of CRBN alterations41,42,49.”
From Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders (2023) · cites this paper as [42]
In multiple myeloma, resistance to IMiDs such as pomalidomide and lenalidomide includes genomic alterations in both the target protein (IKZF1/IKZF3) and components of the CRBN ligase machinery.
“Similarly, in the clinical setting in multiple myeloma, resistance to IMiDs such as pomalidomide and lenalidomide has been shown to include genomic alterations in both the target protein (IKZF1/IKZF3) and components of the CRBN ligase machinery102,103.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [102]
CRBN expression levels in patient samples have been positively associated with sensitivity to thalidomide analogues in some studies but not in others.
“CRBN expression levels in patient samples has been positively associated with sensitivity to thalidomide analogues in some studies149–154, but not in others155,156.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [151]
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References 12 · Cited by 172
- Authors
- Gooding, S., Ansari-Pour, N., Towfic, F., Ortiz Estévez, M., Chamberlain, P. P., Tsai, K.-T., Flynt, E., Hirst, M., Rozelle, D., Dhiman, P., Neri, P., Ramasamy, K., Bahlis, N., Vyas, P., & Thakurta, A.
- Affiliations
- University of Oxford (GB)
- NIHR Oxford Biomedical Research Centre,
- Bristol-Myers Squibb (United States) (US)
- Celgene Institute for Translational Research Europe, Sevilla, Spain;
- Rancho BioSciences (United States) (US)
- University of Calgary (CA)
- Corresponding author
- Towfic, Fadi
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2021-01-14
- Volume
- 137
- Issue
- 2
- Pages
- 232-237
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC7893409
- OpenAlex
- W3047048853
- Cited by
- 172
- References
- 12
- Citations by year
- 2026: 29 · 2025: 21 · 2024: 37 · 2023: 28 · 2022: 32 · 2021: 23 · 2020: 2
- FWCI
- 13.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Celgene
- National Institute for Health and Care Research
- Medical Research Council (MC_UU_00016/11, MR/L008963/1)
- NIHR Oxford Biomedical Research Centre
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Keywords
- cereblon, multiple myeloma, lenalidomide resistance, immunomodulators, PROTACs, copy number loss, structural variants, treatment resistance
- MeSH terms
- Lenalidomide, Antineoplastic Agents, Humans, Multiple Myeloma, Thalidomide, Genetic Variation, Drug Resistance, Neoplasm, Ubiquitin-Protein Ligases, Adaptor Proteins, Signal Transducing
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