title: Pharmacogenomics of bortezomib test-dosing identifies hyperexpression of proteasome genes, especially PSMD4, as novel high-risk feature in myeloma treated with Total Therapy 3.
abstract: Gene expression profiling (GEP) of purified plasma cells 48 hours after thalidomide and dexamethasone test doses showed these agents' mechanisms of action and provided prognostic information for untreated myeloma patients on Total Therapy 2 (TT2). Bortezomib was added in Total Therapy 3 (TT3), and 48 hours after bortezomib GEP analysis identified 80 highly survival-discriminatory genes in a training set of 142 TT3A patients that were validated in 128 patients receiving TT3B. The 80-gene GEP model (GEP80) also distinguished outcomes when applied at baseline in both TT3 and TT2 protocols. In context of our validated 70-gene model (GEP70), the GEP80 model identified 9% of patients with a grave prognosis among those with GEP70-defined low-risk disease and 41% of patients with favorable prognosis among those with GEP70-defined high-risk disease. PMSD4 was 1 of 3 genes common to both models. Residing on chromosome 1q21, PSMD4 expression is highly sensitive to copy number. Both higher PSMD4 expression levels and higher 1q21 copy numbers affected clinical outcome adversely. GEP80 baseline-defined high risk, high lactate dehydrogenase, and low albumin were the only independent adverse variables surviving multivariate survival model. We are investigating whether second-generation proteasome inhibitors (eg, carfilzomib) can overcome resistance associated with high PSMD4 levels.
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock AR, USA. shaughnessyjohndjr@uams.edu
authors.forename: John D
authors.initials: JD
authors.lastname: Shaughnessy
authors.forename: Pingping
authors.initials: P
authors.lastname: Qu
authors.forename: Saad
authors.initials: S
authors.lastname: Usmani
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Heuck
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhou
authors.forename: Erming
authors.initials: E
authors.lastname: Tian
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hanamura
authors.forename: Frits
authors.initials: F
authors.lastname: van Rhee
authors.forename: Elias
authors.initials: E
authors.lastname: Anaissie
authors.forename: Joshua
authors.initials: J
authors.lastname: Epstein
authors.forename: Bijay
authors.initials: B
authors.lastname: Nair
authors.forename: Owen
authors.initials: O
authors.lastname: Stephens
authors.forename: Ryan
authors.initials: R
authors.lastname: Williams
authors.forename: Sarah
authors.initials: S
authors.lastname: Waheed
authors.forename: Yazan
authors.initials: Y
authors.lastname: Alsayed
authors.forename: John
authors.initials: J
authors.lastname: Crowley
authors.forename: Bart
authors.initials: B
authors.lastname: Barlogie
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological / Q000032:analysis / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000069286:Bortezomib; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm / Q000187:drug effects; D006801:Humans; D008875:Middle Aged; D009101:Multiple Myeloma / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D010597:Pharmacogenetics; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D016601:RNA-Binding Proteins; D012306:Risk; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D001897:Boronic Acids; C498506:PSMD4 protein, human; D011719:Pyrazines; D016601:RNA-Binding Proteins; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex