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Blood, 1 August 2004, Vol. 104, No. 3, pp. 607-618.
Prepublished online as a Blood First Edition Paper on April 15, 2004; DOI 10.1182/blood-2004-01-0037.
 Previous Article | Next Article 
Submitted January 9, 2004
Accepted March 26, 2004
Advances in Biology of Multiple Myeloma: Clinical Applications
Teru Hideshima, P L Bergsagel, W M Kuehl, and Kenneth C Anderson*
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Weill Medical College of Cornell University, New York, NY, USA
Genetics Branch, National Cancer Institute, Bethesda, MD, USA
* Corresponding author; email: kenneth_anderson{at}dfci.harvard.edu.
There appear to be two pathways involved in the early pathogenesis of premalignant monoclonal gammopathy of undetermined significance (MGUS) and malignant multiple myeloma (MM) tumors. Nearly half of these tumors are non-hyperdiploid and mostly have IgH translocations that involve five recurrent chromosomal loci, including 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (FGFR3 & MMSET), 16q23 (c-maf), and 20q11 (mafB). The remaining tumors are hyperdiploid and contain multiple trisomies involving chromosomes 3,5,7,9,11,15,19, and 21, but infrequently have IgH translocations involving the five recurrent loci. Dysregulated expression of cyclin D1, D2, or D3 appears to occur as an early event in virtually all of these tumors. This may render the cells more susceptible to proliferative stimuli, resulting in selective expansion as a result of interaction with bone marrow stromal cells that produce IL-6 and other cytokines. Five proposed tumor groups, defined by IgH translocations and/or cyclin D expression, appear to have differences in biological properties, including interaction with stromal cells, prognosis and response to specific therapies. Delineation of the mechanisms mediating MM cell proliferation, survival, and migration in the bone marrow (BM) microenvironment may both enhance understanding of pathogenesis and provide the framework for identification and validation of novel molecular targets.
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