title: The flow cytometry-defined light chain cytoplasmic immunoglobulin index and an associated 12-gene expression signature are independent prognostic factors in multiple myeloma.
abstract: As part of Total Therapy (TT) 3b, baseline marrow aspirates were subjected to two-color flow cytometry of nuclear DNA content and cytoplasmic immunoglobulin (DNA/CIG) as well as plasma cell gene expression profiling (GEP). DNA/CIG-derived parameters, GEP and standard clinical variables were examined for their effects on overall survival (OS) and progression-free survival (PFS). Among DNA/CIG parameters, the percentage of the light chain-restricted (LCR) cells and their cytoplasmic immunoglobulin index (CIg) were linked to poor outcome. In the absence of GEP data, low CIg <2.8, albumin <3.5 g/dl and age ⩾65 years were significantly associated with inferior OS and PFS. When GEP information was included, low CIg survived the model along with GEP70-defined high risk and low albumin. Low CIg was linked to beta-2-microglobulin >5.5 mg/l, a percentage of LCR cells exceeding 50%, C-reactive protein ⩾8 mg/l and GEP-derived high centrosome index. Further analysis revealed an association of low CIg with 12 gene probes implicated in cell cycle regulation, differentiation and drug transportation from which a risk score was developed in TT3b that held prognostic significance also in TT3a, TT2 and HOVON trials, thus validating its general applicability. Low CIg is a powerful new prognostic variable and has identified potentially drug-able targets.
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: X
authors.initials: X
authors.lastname: Papanikolaou
authors.affiliation: Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: D
authors.initials: D
authors.lastname: Alapat
authors.affiliation: Cancer Research and Biostatistics, Seattle, WA, USA.
authors.forename: A
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: C
authors.initials: C
authors.lastname: Stein
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: J
authors.initials: J
authors.lastname: Epstein
authors.affiliation: Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: R
authors.initials: R
authors.lastname: Owens
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: S
authors.initials: S
authors.lastname: Yaccoby
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: S
authors.initials: S
authors.lastname: Johnson
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: C
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: C
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: E
authors.initials: E
authors.lastname: Tian
authors.affiliation: Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: A
authors.initials: A
authors.lastname: Joiner
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: F
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: R
authors.initials: R
authors.lastname: Khan
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: M
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: Y
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: S
authors.initials: S
authors.lastname: Waheed
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: F
authors.initials: F
authors.lastname: Davies
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: G
authors.initials: G
authors.lastname: Morgan
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: B
authors.initials: B
authors.lastname: Barlogie
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry / Q000379:methods*; D020869:Gene Expression Profiling; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000378:metabolism*; D008297:Male; D009101:Multiple Myeloma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism* / Q000401:mortality; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D007147:Immunoglobulin Light Chains; D012333:RNA, Messenger