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Blood, 15 September 2006, Vol. 108, No. 6, pp. 2020-2028.
Prepublished online as a Blood First Edition Paper on May 25, 2006; DOI 10.1182/blood-2005-11-013458.
 Previous Article | Table of Contents | Next Article 
NEOPLASIA
The molecular classification of multiple myeloma
Fenghuang Zhan,
Yongsheng Huang,
Simona Colla,
James P. Stewart,
Ichiro Hanamura,
Sushil Gupta,
Joshua Epstein,
Shmuel Yaccoby,
Jeffrey Sawyer,
Bart Burington,
Elias Anaissie,
Klaus Hollmig,
Mauricio Pineda-Roman,
Guido Tricot,
Frits van Rhee,
Ronald Walker,
Maurizio Zangari,
John Crowley,
Bart Barlogie, and
John D. Shaughnessy, Jr
From the Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics, the Myeloma Institute for Research and Therapy, the Department of Pathology, and the Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, AR; and Cancer Research and Biostatistics, Seattle, WA.
To better define the molecular basis of multiple myeloma (MM), we performed unsupervised hierarchic clustering of mRNA expression profiles in CD138-enriched plasma cells from 414 newly diagnosed patients who went on to receive high-dose therapy and tandem stem cell transplants. Seven disease subtypes were validated that were strongly influenced by known genetic lesions, such as c-MAF– and MAFB-, CCND1- and CCND3-, and MMSET-activating translocations and hyperdiploidy. Indicative of the deregulation of common pathways by gene orthologs, common gene signatures were observed in cases with c-MAF and MAFB activation and CCND1 and CCND3 activation, the latter consisting of 2 subgroups, one characterized by expression of the early B-cell markers CD20 and PAX5. A low incidence of focal bone disease distinguished one and increased expression of proliferation-associated genes of another novel subgroup. Comprising varying fractions of each of the other 6 subgroups, the proliferation subgroup dominated at relapse, suggesting that this signature is linked to disease progression. Proliferation and MMSET-spike groups were characterized by significant overexpression of genes mapping to chromosome 1q, and both exhibited a poor prognosis relative to the other groups. A subset of cases with a predominating myeloid gene expression signature, excluded from the profiling analyses, had more favorable baseline characteristics and superior prognosis to those lacking this signature.
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