Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes
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Key Points: The incidence of mutations within the MAPK pathway, the CRBN pathway, and TP53 is significantly increased in drug-refractory MM. Mutations in CRBN might contribute to IMiD resistance in drug-refractory MM.
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In 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 Kortüm et al. 2016
The CRBN-associated mutations section reports longer IMiD exposure among CRBN-mutant patients, and the Discussion says mutations were absent from earlier, IMiD-sensitive samples in three patients. These findings support an association with prolonged treatment and acquired resistance, but the Discussion describes treatment-driven selection and its contribution to resistance as probable. The cell experiment demonstrated lenalidomide resistance; pomalidomide-refractory disease was observed clinically, not shown to be caused by the mutations. (LLM, conf=0.84)
Experimental — accuracy not yet measuredUp 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 [49]
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 [149]
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“…treated with prolonged iMiD-based therapy, the frequency of CRBN mutations that lead to lenalidomide-and pomalidomide-refractory disease increases (Kortüm et al. 2016; Franssen et al. 2018). these resistance-associated mutations do not typically occur within the iMiD binding pocket but instead…”
- Authors
- Kortüm, K. M., Mai, E. K., Hanafiah, N. H., Shi, C.-X., Zhu, Y.-X., Bruins, L., Barrio, S., Jedlowski, P., Merz, M., Xu, J., Stewart, R. A., Andrulis, M., Jauch, A., Hillengass, J., Goldschmidt, H., Bergsagel, P. L., Braggio, E., Stewart, A. K., & Raab, M. S.
- Affiliations
- Mayo Clinic in Arizona (US)
- German Cancer Research Center (DE)
- Department of Internal Medicine V, and
- University Hospital Heidelberg (DE)
- Heidelberg University (DE)
- National Center for Tumor Diseases (DE)
- Mayo Clinic (US)
- Corresponding author
- Kortüm, K. Martin
- Mai, Elias K.
- Hanafiah, Nur H.
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2016-09-01
- Volume
- 128
- Issue
- 9
- Pages
- 1226-1233
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC5524534
- OpenAlex
- W2494443970
- Cited by
- 255
- References
- 60
- Citations by year
- 2026: 20 · 2025: 25 · 2024: 26 · 2023: 17 · 2022: 40 · 2021: 32 · 2020: 34 · 2019: 26 · 2018: 21 · 2017: 14
- FWCI
- 19.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Deutsche Krebshilfe
- National Cancer Institute (P50CA186781)
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- multiple myeloma, refractory multiple myeloma, RAS pathway mutations, KRAS, NRAS, BRAF, TP53, lenalidomide resistance, immunomodulators, proteasome inhibitors, drug resistance, genetic landscape
- MeSH terms
- Adult, Aged, Aged, 80 and over, Female, Humans, Male, Membrane Proteins, Middle Aged, Multiple Myeloma, Mutation, Peptide Hydrolases, Signal Transduction, Tumor Suppressor Protein p53, Proto-Oncogene Proteins p21(ras), Drug Resistance, Neoplasm, GTP Phosphohydrolases, Ubiquitin-Protein Ligases, Proto-Oncogene Proteins B-raf, Adaptor Proteins, Signal Transducing, High-Throughput Nucleotide Sequencing
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