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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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Fluorescence in Situ Hybridization Analysis of Immunoglobulin Heavy Chain Translocations in Plasma Cell Myeloma Using Intact Paraffin Sections and Simultaneous CD138 Immunofluorescence
J. Mol. Diagn.,
September 1, 2006;
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[Abstract]
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L. Nadav, B.-Z. Katz, S. Baron, N. Cohen, E. Naparstek, and B. Geiger
The Generation and Regulation of Functional Diversity of Malignant Plasma Cells.
Cancer Res.,
September 1, 2006;
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[Abstract]
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M. Li, S. Cortez, T. Nakamachi, V. Batuman, and A. Arimura
Pituitary Adenylate Cyclase-Activating Polypeptide Is a Potent Inhibitor of the Growth of Light Chain-Secreting Human Multiple Myeloma Cells.
Cancer Res.,
September 1, 2006;
66(17):
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[Abstract]
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A. Vacca, C. Scavelli, G. Serini, G. Di Pietro, T. Cirulli, F. Merchionne, D. Ribatti, F. Bussolino, D. Guidolin, G. Piaggio, et al.
Loss of inhibitory semaphorin 3A (SEMA3A) autocrine loops in bone marrow endothelial cells of patients with multiple myeloma
Blood,
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[Abstract]
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E. Menoret, P. Gomez-Bougie, A. Geffroy-Luseau, S. Daniels, P. Moreau, S. Le Gouill, J.-L. Harousseau, R. Bataille, M. Amiot, and C. Pellat-Deceunynck
Mcl-1L cleavage is involved in TRAIL-R1- and TRAIL-R2-mediated apoptosis induced by HGS-ETR1 and HGS-ETR2 human mAbs in myeloma cells
Blood,
August 15, 2006;
108(4):
1346 - 1352.
[Abstract]
[Full Text]
[PDF]
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W. S. El-Deiry, C. C. Sigman, and G. J. Kelloff
Imaging and Oncologic Drug Development
J. Clin. Oncol.,
July 10, 2006;
24(20):
3261 - 3273.
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Y.-T. Tai, X.-F. Li, I. Breitkreutz, W. Song, P. Neri, L. Catley, K. Podar, T. Hideshima, D. Chauhan, N. Raje, et al.
Role of B-Cell-Activating Factor in Adhesion and Growth of Human Multiple Myeloma Cells in the Bone Marrow Microenvironment.
Cancer Res.,
July 1, 2006;
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[Abstract]
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T. Hideshima, L. Catley, H. Yasui, K. Ishitsuka, N. Raje, C. Mitsiades, K. Podar, N. C. Munshi, D. Chauhan, P. G. Richardson, et al.
Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells
Blood,
May 15, 2006;
107(10):
4053 - 4062.
[Abstract]
[Full Text]
[PDF]
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G. M. Rigolin, C. Fraulini, M. Ciccone, E. Mauro, A. M. Bugli, C. De Angeli, M. Negrini, A. Cuneo, and G. Castoldi
Neoplastic circulating endothelial cells in multiple myeloma with 13q14 deletion
Blood,
March 15, 2006;
107(6):
2531 - 2535.
[Abstract]
[Full Text]
[PDF]
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N. Takebe, X. Cheng, T. E. Fandy, R. K. Srivastava, S. Wu, S. Shankar, K. Bauer, J. Shaughnessy, and G. Tricot
IMP dehydrogenase inhibitor mycophenolate mofetil induces caspase-dependent apoptosis and cell cycle inhibition in multiple myeloma cells.
Mol. Cancer Ther.,
February 1, 2006;
5(2):
457 - 466.
[Abstract]
[Full Text]
[PDF]
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O. Landgren, G. Gridley, I. Turesson, N. E. Caporaso, L. R. Goldin, D. Baris, T. R. Fears, R. N. Hoover, and M. S. Linet
Risk of monoclonal gammopathy of undetermined significance (MGUS) and subsequent multiple myeloma among African American and white veterans in the United States
Blood,
February 1, 2006;
107(3):
904 - 906.
[Abstract]
[Full Text]
[PDF]
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C. S. Mitsiades, N. S. Mitsiades, C. J. McMullan, V. Poulaki, A. L. Kung, F. E. Davies, G. Morgan, M. Akiyama, R. Shringarpure, N. C. Munshi, et al.
Antimyeloma activity of heat shock protein-90 inhibition
Blood,
February 1, 2006;
107(3):
1092 - 1100.
[Abstract]
[Full Text]
[PDF]
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E. Menu, H. Jernberg-Wiklund, T. Stromberg, H. De Raeve, L. Girnita, O. Larsson, M. Axelson, K. Asosingh, K. Nilsson, B. Van Camp, et al.
Inhibiting the IGF-1 receptor tyrosine kinase with the cyclolignan PPP: an in vitro and in vivo study in the 5T33MM mouse model
Blood,
January 15, 2006;
107(2):
655 - 660.
[Abstract]
[Full Text]
[PDF]
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T. Stromberg, S. Ekman, L. Girnita, L. Y. Dimberg, O. Larsson, M. Axelson, J. Lennartsson, U. Hellman, K. Carlson, A. Osterborg, et al.
IGF-1 receptor tyrosine kinase inhibition by the cyclolignan PPP induces G2/M-phase accumulation and apoptosis in multiple myeloma cells
Blood,
January 15, 2006;
107(2):
669 - 678.
[Abstract]
[Full Text]
[PDF]
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R. H. Prabhala, P. Neri, J. E. Bae, P. Tassone, M. A. Shammas, C. K. Allam, J. F. Daley, D. Chauhan, E. Blanchard, H. S. Thatte, et al.
Dysfunctional T regulatory cells in multiple myeloma
Blood,
January 1, 2006;
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301 - 304.
[Abstract]
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E. David, S.-Y. Sun, E. K. Waller, J. Chen, F. R. Khuri, and S. Lonial
The combination of the farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT
Blood,
December 15, 2005;
106(13):
4322 - 4329.
[Abstract]
[Full Text]
[PDF]
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A. Kardosh, N. Soriano, Y.-T. Liu, J. Uddin, N. A. Petasis, F. M. Hofman, T. C. Chen, and A. H. Schonthal
Multitarget inhibition of drug-resistant multiple myeloma cell lines by dimethyl-celecoxib (DMC), a non-COX-2 inhibitory analog of celecoxib
Blood,
December 15, 2005;
106(13):
4330 - 4338.
[Abstract]
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[PDF]
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L. Agnelli, S. Bicciato, M. Mattioli, S. Fabris, D. Intini, D. Verdelli, L. Baldini, F. Morabito, V. Callea, A. Zanella, et al.
Molecular Classification of Multiple Myeloma: A Distinct Transcriptional Profile Characterizes Patients Expressing CCND1 and Negative for 14q32 Translocations.
Blood (ASH Annual Meeting Abstracts),
November 16, 2005;
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1548 - 1548.
[Abstract]
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R. K. Thomas, M. L. Sos, T. Zander, O. Mani, A. Popov, D. Berenbrinker, S. Smola-Hess, J. L. Schultze, and J. Wolf
Inhibition of Nuclear Translocation of Nuclear Factor-{kappa}B Despite Lack of Functional I{kappa}B{alpha} Protein Overcomes Multiple Defects in Apoptosis Signaling in Human B-Cell Malignancies
Clin. Cancer Res.,
November 15, 2005;
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[Abstract]
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T. Stuhmer, M. Chatterjee, M. Hildebrandt, P. Herrmann, H. Gollasch, C. Gerecke, S. Theurich, L. Cigliano, R. A. Manz, P. T. Daniel, et al.
Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma
Blood,
November 15, 2005;
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[Abstract]
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L. Agnelli, S. Bicciato, M. Mattioli, S. Fabris, D. Intini, D. Verdelli, L. Baldini, F. Morabito, V. Callea, L. Lombardi, et al.
Molecular Classification of Multiple Myeloma: A Distinct Transcriptional Profile Characterizes Patients Expressing CCND1 and Negative for 14q32 Translocations
J. Clin. Oncol.,
October 10, 2005;
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[Abstract]
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K. C. Anderson, R. Pazdur, and A. T. Farrell
Development of Effective New Treatments for Multiple Myeloma
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October 1, 2005;
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N. Giuliani, S. Colla, F. Morandi, M. Lazzaretti, R. Sala, S. Bonomini, M. Grano, S. Colucci, M. Svaldi, and V. Rizzoli
Myeloma cells block RUNX2/CBFA1 activity in human bone marrow osteoblast progenitors and inhibit osteoblast formation and differentiation
Blood,
October 1, 2005;
106(7):
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[Abstract]
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A. K. Stewart and R. Fonseca
Prognostic and Therapeutic Significance of Myeloma Genetics and Gene Expression Profiling
J. Clin. Oncol.,
September 10, 2005;
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[Abstract]
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H. Yasui, T. Hideshima, N. Raje, A. M. Roccaro, N. Shiraishi, S. Kumar, M. Hamasaki, K. Ishitsuka, Y.-T. Tai, K. Podar, et al.
FTY720 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Drug Resistance
Cancer Res.,
August 15, 2005;
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J. Moreaux, F. W. Cremer, T. Reme, M. Raab, K. Mahtouk, P. Kaukel, V. Pantesco, J. De Vos, E. Jourdan, A. Jauch, et al.
The level of TACI gene expression in myeloma cells is associated with a signature of microenvironment dependence versus a plasmablastic signature
Blood,
August 1, 2005;
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1021 - 1030.
[Abstract]
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[PDF]
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N. Raje, S. Kumar, T. Hideshima, A. Roccaro, K. Ishitsuka, H. Yasui, N. Shiraishi, D. Chauhan, N. C. Munshi, S. R. Green, et al.
Seliciclib (CYC202 or R-roscovitine), a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of Mcl-1 in multiple myeloma
Blood,
August 1, 2005;
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1042 - 1047.
[Abstract]
[Full Text]
[PDF]
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H. Yasui, T. Hideshima, M. Hamasaki, A. M. Roccaro, N. Shiraishi, S. Kumar, P. Tassone, K. Ishitsuka, N. Raje, Y.-T. Tai, et al.
SDX-101, the R-enantiomer of etodolac, induces cytotoxicity, overcomes drug resistance, and enhances the activity of dexamethasone in multiple myeloma
Blood,
July 15, 2005;
106(2):
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[Abstract]
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[PDF]
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O. Goker-Alpan and E. Sidransky
Risky business: Gaucher disease and multiple myeloma
Blood,
June 15, 2005;
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M. Ladetto, S. Vallet, A. Trojan, M. Dell'Aquila, L. Monitillo, R. Rosato, L. Santo, D. Drandi, A. Bertola, P. Falco, et al.
Cyclooxygenase-2 (COX-2) is frequently expressed in multiple myeloma and is an independent predictor of poor outcome
Blood,
June 15, 2005;
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4784 - 4791.
[Abstract]
[Full Text]
[PDF]
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M. Hamasaki, T. Hideshima, P. Tassone, P. Neri, K. Ishitsuka, H. Yasui, N. Shiraishi, N. Raje, S. Kumar, D. H. Picker, et al.
Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine) inhibits human multiple myeloma cell growth in the bone marrow milieu in vitro and in vivo
Blood,
June 1, 2005;
105(11):
4470 - 4476.
[Abstract]
[Full Text]
[PDF]
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X. Carvajal-Vergara, S. Tabera, J. C. Montero, A. Esparis-Ogando, R. Lopez-Perez, G. Mateo, N. Gutierrez, M. Parmo-Cabanas, J. Teixido, J. F. San Miguel, et al.
Multifunctional role of Erk5 in multiple myeloma
Blood,
June 1, 2005;
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[Abstract]
[Full Text]
[PDF]
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K. Ito, T. Nakazato, M. J. Xian, T. Yamada, N. Hozumi, A. Murakami, H. Ohigashi, Y. Ikeda, and M. Kizaki
1'-Acetoxychavicol Acetate Is a Novel Nuclear Factor {kappa}B Inhibitor with Significant Activity against Multiple Myeloma In vitro and In vivo
Cancer Res.,
May 15, 2005;
65(10):
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[Abstract]
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F.-J. Li, N. Tsuyama, H. Ishikawa, M. Obata, S. Abroun, S. Liu, K.-i. Otsuyama, X. Zheng, Z. Ma, Y. Maki, et al.
A rapid translocation of CD45RO but not CD45RA to lipid rafts in IL-6-induced proliferation in myeloma
Blood,
April 15, 2005;
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3295 - 3302.
[Abstract]
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L. Guedez, A. Martinez, S. Zhao, A. Vivero, S. Pittaluga, M. Stetler-Stevenson, M. Raffeld, and W. G. Stetler-Stevenson
Tissue inhibitor of metalloproteinase 1 (TIMP-1) promotes plasmablastic differentiation of a Burkitt lymphoma cell line: implications in the pathogenesis of plasmacytic/plasmablastic tumors
Blood,
February 15, 2005;
105(4):
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[Abstract]
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H. Jernberg-Wiklund and K. Nilsson
Toward a rational combinaTORial therapy for multiple myeloma
Blood,
December 15, 2004;
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