title: A novel panel of protein biomarkers for predicting response to thalidomide-based therapy in newly diagnosed multiple myeloma patients.
abstract: Multiple myeloma (MM) is a heterogeneous group of disorders both genotypically and phenotypically. Response to thalidomide-based induction therapy in newly diagnosed patients varies significantly in published clinical trials. Proteomic analysis was performed on 39 newly diagnosed MM patients treated with a thalidomide-based regimen (22 responders; 17 non-responders) using immunodepletion, 2-D DIGE analysis and mass spectrometry. Zinc-α-2-glycoprotein (ZAG), vitamin D-binding protein (VDB), serum amyloid-A protein (SAA) and β-2-microglobulin (B2M) had statistically significant higher concentrations in non-responders compared to responders, while haptoglobin (Hp) had a lower concentration. ELISAs were used to validate the candidate protein biomarkers using unfractionated serum from 51 newly diagnosed MM patients (29 responders; 22 non-responders). Using logistic regression, the best possible area under the curve (AUC) was 0.96 using ZAG, VDB and SAA in combination. Leave-one-out-cross-validation (LOOCV) indicated an overall predictive accuracy of 84% with associated sensitivity and specificity values of 81.8 and 86.2%, respectively. Subsequently, 16 of 22 thalidomide-refractory patients successfully achieved complete response or very good partial response using second-line treatment suggesting that the biomarker profile is specific to thalidomide response rather than identifying patients with MM refractory to all therapies. Using a novel panel of predictive biomarkers, the feasibility of predicting response to thalidomide-based therapy in previously untreated MM has been demonstrated.
authors.affiliation: National Institute for Cellular Biotechnology (NICB), Dublin City University, Dublin, Ireland.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Rajpal
authors.forename: Paul
authors.initials: P
authors.lastname: Dowling
authors.forename: Justine
authors.initials: J
authors.lastname: Meiller
authors.forename: Colin
authors.initials: C
authors.lastname: Clarke
authors.forename: William G
authors.initials: WG
authors.lastname: Murphy
authors.forename: Robert
authors.initials: R
authors.lastname: O'Connor
authors.forename: Malcolm
authors.initials: M
authors.lastname: Kell
authors.forename: Constantine
authors.initials: C
authors.lastname: Mitsiades
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Martin
authors.initials: M
authors.lastname: Clynes
authors.forename: Peter
authors.initials: P
authors.lastname: O'Gorman
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood / Q000188:drug therapy*; D011379:Prognosis; D012680:Sensitivity and Specificity; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D013792:Thalidomide