title: Four genes predict high risk of progression from smoldering to symptomatic multiple myeloma (SWOG S0120).
abstract: Multiple myeloma is preceded by an asymptomatic phase, comprising monoclonal gammopathy of uncertain significance and smoldering myeloma. Compared to the former, smoldering myeloma has a higher and non-uniform rate of progression to clinical myeloma, reflecting a subset of patients with higher risk. We evaluated the gene expression profile of smoldering myeloma plasma cells among 105 patients enrolled in a prospective observational trial at our institution, with a view to identifying a high-risk signature. Baseline clinical, bone marrow, cytogenetic and radiologic data were evaluated for their potential to predict time to therapy for symptomatic myeloma. A gene signature derived from four genes, at an optimal binary cut-point of 9.28, identified 14 patients (13%) with a 2-year therapy risk of 85.7%. Conversely, a low four-gene score (< 9.28) combined with baseline monoclonal protein < 3 g/dL and albumin ≥ 3.5 g/dL identified 61 patients with low-risk smoldering myeloma with a 5.0% chance of progression at 2 years. The top 40 probe sets showed concordance with indices of chromosome instability. These data demonstrate high discriminatory power of a gene-based assay and suggest a role for dysregulation of mitotic checkpoints in the context of genomic instability as a hallmark of high-risk smoldering myeloma.
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Rashid
authors.initials: R
authors.lastname: Khan
authors.affiliation: Yale School of Medicine, New Haven, CT, USA.
authors.forename: Madhav
authors.initials: M
authors.lastname: Dhodapkar
authors.affiliation: Cancer Research And Biostatistics, Seattle, WA, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Rosenthal
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Heuck
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Xenofon
authors.initials: X
authors.lastname: Papanikolaou
authors.affiliation: Cancer Research And Biostatistics, Seattle, WA, USA.
authors.forename: Pingping
authors.initials: P
authors.lastname: Qu
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Frits
authors.initials: F
authors.lastname: van Rhee
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Zangari
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Jethava
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Epstein
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Shmuel
authors.initials: S
authors.lastname: Yaccoby
authors.affiliation: Cancer Research And Biostatistics, Seattle, WA, USA.
authors.forename: Antje
authors.initials: A
authors.lastname: Hoering
authors.affiliation: Cancer Research And Biostatistics, Seattle, WA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Crowley
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Petty
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Clyde
authors.initials: C
authors.lastname: Bailey
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Gareth
authors.initials: G
authors.lastname: Morgan
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA bart.barlogie@mssm.edu.
authors.forename: Bart
authors.initials: B
authors.lastname: Barlogie
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001853:Bone Marrow / Q000473:pathology; D005260:Female; D052138:Genes, Neoplasm; D042822:Genomic Instability; D006801:Humans; D008297:Male; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics*; D011446:Prospective Studies
chemical_list: D009363:Neoplasm Proteins