title: Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes.
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.
authors.affiliation: Department of Hematology, Mayo Clinic in Arizona, Scottsdale, AZ; Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany;
authors.forename: K Martin
authors.initials: KM
authors.lastname: Kortüm
authors.affiliation: Max-Eder Group "Experimental Therapies for Hematologic Malignancies," Heidelberg University Hospital and German Cancer Research Center, Heidelberg, Germany; Department of Internal Medicine V, and.
authors.forename: Elias K
authors.initials: EK
authors.lastname: Mai
authors.affiliation: Max-Eder Group "Experimental Therapies for Hematologic Malignancies," Heidelberg University Hospital and German Cancer Research Center, Heidelberg, Germany;
authors.forename: Nur H
authors.initials: NH
authors.lastname: Hanafiah
authors.affiliation: Department of Hematology, Mayo Clinic in Arizona, Scottsdale, AZ;
authors.forename: Chang-Xi
authors.initials: CX
authors.lastname: Shi
authors.affiliation: Department of Hematology, Mayo Clinic in Arizona, Scottsdale, AZ;
authors.forename: Yuan-Xiao
authors.initials: YX
authors.lastname: Zhu
authors.affiliation: Department of Hematology, Mayo Clinic in Arizona, Scottsdale, AZ;
authors.forename: Laura
authors.initials: L
authors.lastname: Bruins
authors.affiliation: Department of Hematology, Mayo Clinic in Arizona, Scottsdale, AZ;
authors.forename: Santiago
authors.initials: S
authors.lastname: Barrio
authors.affiliation: Department of Hematology, Mayo Clinic in Arizona, Scottsdale, AZ;
authors.forename: Patrick
authors.initials: P
authors.lastname: Jedlowski
authors.affiliation: Department of Internal Medicine V, and.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Merz
authors.affiliation: Max-Eder Group "Experimental Therapies for Hematologic Malignancies," Heidelberg University Hospital and German Cancer Research Center, Heidelberg, Germany; Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany;
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Hematology, Mayo Clinic in Arizona, Scottsdale, AZ;
authors.forename: Robert A
authors.initials: RA
authors.lastname: Stewart
authors.affiliation: Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany;
authors.forename: Mindaugas
authors.initials: M
authors.lastname: Andrulis
authors.affiliation: Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany;
authors.forename: Anna
authors.initials: A
authors.lastname: Jauch
authors.affiliation: Department of Internal Medicine V, and.
authors.forename: Jens
authors.initials: J
authors.lastname: Hillengass
authors.affiliation: Department of Internal Medicine V, and National Center of Tumor Diseases, Heidelberg, Germany; and.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Goldschmidt
authors.affiliation: Department of Hematology, Mayo Clinic in Arizona, Scottsdale, AZ;
authors.forename: P Leif
authors.initials: PL
authors.lastname: Bergsagel
authors.affiliation: Department of Hematology, Mayo Clinic in Arizona, Scottsdale, AZ;
authors.forename: Esteban
authors.initials: E
authors.lastname: Braggio
authors.affiliation: Department of Hematology, Mayo Clinic in Arizona, Scottsdale, AZ; Center for Individualized Medicine, Mayo Clinic, Rochester, MN.
authors.forename: A Keith
authors.initials: AK
authors.lastname: Stewart
authors.affiliation: Max-Eder Group "Experimental Therapies for Hematologic Malignancies," Heidelberg University Hospital and German Cancer Research Center, Heidelberg, Germany; Department of Internal Medicine V, and.
authors.forename: Marc S
authors.identifier: 0000-0003-4181-6922
authors.initials: MS
authors.lastname: Raab
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics*; D009154:Mutation; D010447:Peptide Hydrolases / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502543:CRBN protein, human; C117307:KRAS protein, human; D008565:Membrane Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D010447:Peptide Hydrolases; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)