Cereblon loss and up-regulation of c-Myc are associated with lenalidomide resistance in multiple myeloma patients
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Multiple myeloma (MM) patients who become refractory to anti-MM drugs have a very poor prognosis. Therefore, it is important to gain insight into the mechanisms of resistance to these drugs. Immunomodulatory drugs (IMiDs) have immune-stimulatory and anti-angiogenic properties as well as direct anti-
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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 Franssen et al. 2018
The Results report reduced Cereblon protein and a small increase in c-Myc at lenalidomide-refractory disease, but no change in IRF4. The Discussion describes Cereblon-pathway mutations as a possible mechanism; the authors did not test for them. Thus the paper supports an association with resistance in these patients, not the claim that resistance often arises from CRL4–CRBN mutations or alterations across the IRF4/c-Myc axis. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn multiple myeloma treated with prolonged IMiD-based therapy, the frequency of CRBN mutations that lead to lenalidomide- and pomalidomide-refractory disease increases.
“in multiple myeloma treated with prolonged iMiD-based therapy, the frequency of CRBN mutations that lead to lenalidomideand pomalidomide-refractory disease increases (Kortüm et al. 2016;Franssen et al. 2018).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Franssen et al. 2018
In the Discussion and conclusion (page not supplied), the paper suggests that acquired Cereblon-pathway mutations may contribute to lenalidomide resistance. It says mutation analysis could not be performed, so it does not establish that CRBN mutation frequency increases with prolonged IMiD therapy or that those mutations cause pomalidomide-refractory disease. (LLM, conf=0.85)
Experimental — accuracy not yet measuredCRBN 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 [153]
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Yeung, A. J.-T., & Ling, S. (2021) · Resistance to targeted anti-cancer therapeutics · doi:10.1007/978-3-030-73440-4_2
SMALL-MOLECULE DEGRADERS OF IKAROS ZINC FINGER (IKZF) TRANSCRIPTION FACTORS
Holmberg‐Douglas, N., Shunatona, H. P., Kumi, G. K., & Purandare, A. V. (2023) · Medicinal chemistry reviews · doi:10.1021/mc-2023-vol58.ch10
Dual CARM1-and IKZF3-targeting: A novel approach to multiple myeloma therapy
Wei Min, N. I., Garg, S., Chowdhury, B., Sattler, M., Sanchez, D., Meng, C., Akatsu, T., Donovan, K. A., Qi, J., Wang, M. Y., et al. (2025) · Molecular Therapy Oncology · doi:10.1016/j.omton.2025.200952
Self-citationDual MYC and GSPT1 Protein Degrader for MYC-Driven CancersPreprint
Nishida, Y., Impedovo, V., Ayoub, E., Baran, N., Scruggs, D. A., Mizuno, H., Khazaei, S., Ostermann, L. B., Singh, S., Bedoy, A. D., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.04.24.650490
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Hirano, M., Imai, Y., Kaito, Y., Murayama, T., Sato, K., Ishida, T., Yamamoto, J., Ito, T., Futami, M., Ri, M., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14303001
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Understanding and addressing resistance to IMiDs immunomodulatory compounds in multiple myeloma
Fuentes-Lacouture, M. C., Nandana, D., Ramasamy, K., & Thakurta, A. (2026) · FEBS Journal · doi:10.1111/febs.70599
Self-citation
- Authors
- Franssen, L. E., Nijhof, I. S., Couto, S., Levin, M.-D., Bos, G. M. J., Broijl, A., Klein, S. K., Ren, Y., Wang, M., Koene, H. R., Bloem, A. C., Beeker, A., Faber, L. M., van der Spek, E., Raymakers, R., Leguit, R. J., Sonneveld, P., Zweegman, S., Lokhorst, H., Mutis, T., Thakurta, A., Qian, X., & van de Donk, N. W. C. J.
- Affiliations
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Celgene (United States) (US)
- Albert Schweitzer Ziekenhuis (NL)
- Maastricht University Medical Centre (NL)
- Erasmus MC (NL)
- Meander Medisch Centrum (NL)
- St. Antonius Ziekenhuis (NL)
- University Medical Center Utrecht (NL)
- Spaarne Ziekenhuis (NL)
- Rode Kruis Ziekenhuis (NL)
- ORCID
- Venue
- Haematologica
- Published
- 2018-03-15
- Volume
- 103
- Issue
- 8
- Pages
- e368-e371
- ISSN
- 0390-6078 (ISSN-L)
- 1592-8721
- PMC
- PMC6068039
- OpenAlex
- W2793984127
- Cited by
- 66
- References
- 17
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 12 · 2023: 4 · 2022: 9 · 2021: 19 · 2020: 9 · 2019: 3 · 2018: 1
- FWCI
- 5.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Haematologica (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, cc-by)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion, cc-by-nc)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Celgene
- Vrije Universiteit Amsterdam
- Universiteit Maastricht
- Erasmus Medisch Centrum
- Maastricht Universitair Medisch Centrum
- St. Antonius Ziekenhuis
- 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
- multiple myeloma, lenalidomide resistance, cereblon, immunomodulators, drug resistance mechanisms, anti-angiogenic therapy
- MeSH terms
- Lenalidomide, Adult, Aged, Aged, 80 and over, Bone Marrow Examination, Drug Resistance, Female, Humans, Male, Middle Aged, Multiple Myeloma, Peptide Hydrolases, Up-Regulation, Proto-Oncogene Proteins c-myc, Ubiquitin-Protein Ligases, Adaptor Proteins, Signal Transducing
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