A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1.
To molecularly define high-risk disease, we performed microarray analysis on tumor cells from 532 newly diagnosed patients with multiple myeloma (MM) treated on 2 separate protocols. Using log-rank tests of expression quartiles, 70 genes, 30% mapping to chromosome 1 (P < .001), were linked to early disease-related death. Importantly, most up-regulated genes mapped to chromosome 1q, and down-regulated genes mapped to chromosome 1p. The ratio of mean expression levels of up-regulated to down-regulated genes defined a high-risk score present in 13% of patients with shorter durations of complete remission, event-free survival, and overall survival (training set: hazard ratio [HR], 5.16; P < .001; test cohort: HR, 4.75; P < .001). The high-risk score also was an independent predictor of outcome endpoints in multivariate analysis (P < .001) that included the International Staging System and high-risk translocations. In a comparison of paired baseline and relapse samples, the high-risk score frequency rose to 76% at relapse and predicted short postrelapse survival (P < .05). Multivariate discriminant analysis revealed that a 17-gene subset could predict outcome as well as the 70-gene model. Our data suggest that altered transcriptional regulation of genes mapping to chromosome 1 may contribute to disease progression, and that expression profiling can be used to identify high-risk disease and guide therapeutic interventions.
Shaughnessy
John D
JD
Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics at the Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. shaughnessyjohn@uams.edu
Zhan
Fenghuang
F
Burington
Bart E
BE
Huang
Yongsheng
Y
Colla
Simona
S
Hanamura
Ichiro
I
Stewart
James P
JP
Kordsmeier
Bob
B
Randolph
Christopher
C
Williams
David R
DR
Xiao
Yan
Y
Xu
Hongwei
H
Epstein
Joshua
J
Anaissie
Elias
E
Krishna
Somashekar G
SG
Cottler-Fox
Michele
M
Hollmig
Klaus
K
Mohiuddin
Abid
A
Pineda-Roman
Mauricio
M
Tricot
Guido
G
van Rhee
Frits
F
Sawyer
Jeffrey
J
Alsayed
Yazan
Y
Walker
Ronald
R
Zangari
Maurizio
M
Crowley
John
J
Barlogie
Bart
B
D000368:Aged; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D015331:Cohort Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008957:Models, Genetic; D005810:Multigene Family; D009101:Multiple Myeloma / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D012008:Recurrence; D012307:Risk Factors; D015996:Survival Rate