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Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes.
- Source :
-
Blood [Blood] 2016 Sep 01; Vol. 128 (9), pp. 1226-33. Date of Electronic Publication: 2016 Jul 25. - Publication Year :
- 2016
-
Abstract
- In this study, targeted sequencing to screen 50 multidrug refractory multiple myeloma (rMM) patients was performed by using the Multiple Myeloma Mutation Panel. Patients were pretreated with both immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), and 88%, 78%, and 68% were refractory to an IMiD, a PI, or both, respectively. The majority of patients had progressive (82%) or refractory (78%) disease immediately before sampling, with 43% being IMiD refractory and 46% being PI refractory in the most recent line of therapy. Compared with newly diagnosed MM, an increased prevalence of mutations in the Ras pathway genes KRAS, NRAS, and/or BRAF (72%), as well as TP53 (26%), CRBN (12%), and CRBN pathway genes (10%) was observed. Longitudinal analyses performed in 3 patients with CRBN mutations at time of IMiD resistance confirmed that these mutations were undetectable at earlier, IMiD-sensitive time points. Furthermore, the functional introduction of these mutations in MM cells conferred lenalidomide resistance in vitro. These data indicate a differential genetic landscape in rMM associated with drug response.<br /> (© 2016 by The American Society of Hematology.)
- Subjects :
- Adaptor Proteins, Signal Transducing
Adult
Aged
Aged, 80 and over
Drug Resistance, Neoplasm drug effects
Drug Resistance, Neoplasm genetics
Female
High-Throughput Nucleotide Sequencing
Humans
Male
Middle Aged
Multiple Myeloma drug therapy
Signal Transduction drug effects
Tumor Suppressor Protein p53
Ubiquitin-Protein Ligases
GTP Phosphohydrolases genetics
Membrane Proteins genetics
Multiple Myeloma genetics
Mutation
Peptide Hydrolases genetics
Proto-Oncogene Proteins B-raf genetics
Proto-Oncogene Proteins p21(ras) genetics
Signal Transduction genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 128
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 27458004
- Full Text :
- https://doi.org/10.1182/blood-2016-02-698092