Abstract
Despite improvement in therapeutic efficacy, multiple myeloma (MM) remains incurable with a median survival of approximately 10 years. Gene-expression profiling (GEP) can be used to elucidate the molecular basis for resistance to chemotherapy through global assessment of molecular alterations that exist at diagnosis, after therapeutic treatment and that evolve during tumor progression. Unique GEP signatures associated with recurrent chromosomal translocations and ploidy changes have defined molecular classes with differing clinical features and outcomes. When compared to other stratification systems the GEP70 test remained a significant predictor of outcome, reduced the number of patients classified with a poor prognosis, and identified patients at increased risk of relapse despite their standard clinico-pathologic and genetic findings. GEP studies of serial samples showed that risk increases over time, with relapsed disease showing GEP shifts toward a signature of poor outcomes. GEP signatures of myeloma cells after therapy were prognostic for event-free and overall survival and thus may be used to identify novel strategies for overcoming drug resistance. This brief review will focus on the use of GEP of MM to define high-risk myeloma, and elucidate underlying mechanisms that are beginning to change clinical decision-making and inform drug design.
Similar content being viewed by others
References
Palumbo A, Anderson KC. Multiple myeloma. N Engl J Med. 2011;364:1046–60.
Barlogie B, Zangari M, Bolejack V, Hollmig K, Anaissie E, van RF, et al. Superior 12-year survival after at least 4-year continuous remission with tandem transplantations for multiple myeloma. Clin Lymphoma Myeloma. 2006;6:469–74.
Anderson KC. Oncogenomics to target myeloma in the bone marrow microenvironment. Clin Cancer Res. 2011;17:1225–33.
Palumbo A, Attal M, Roussel M. Shifts in the therapeutic paradigm for patients newly diagnosed with multiple myeloma: maintenance therapy and overall survival. Clin Cancer Res. 2011;17:1253–63.
Lonial S, Mitsiades CS, Richardson PG. Treatment options for relapsed and refractory multiple myeloma. Clin Cancer Res. 2011;17:1264–77.
Hoering A, Crowley J, Shaughnessy JD Jr, Hollmig K, Alsayed Y, Szymonifka J, et al. Complete remission in multiple myeloma examined as time-dependent variable in terms of both onset and duration in Total Therapy protocols. Blood. 2009;114:1299–305.
Barlogie B, Tricot G, Anaissie E, Shaughnessy J, Rasmussen E, van RF, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med. 2006;354:1021–30.
Mitsiades CS, Davies FE, Laubach JP, Joshua D, San MJ, Anderson KC, et al. Future directions of next-generation novel therapies, combination approaches, and the development of personalized medicine in myeloma. J Clin Oncol. 2011;29:1916–23.
Barlogie B, Tricot G, Haessler J, van RF, Cottler-Fox M, Anaissie E, et al. Cytogenetically defined myelodysplasia after melphalan-based autotransplantation for multiple myeloma linked to poor hematopoietic stem-cell mobilization: the Arkansas experience in more than 3,000 patients treated since 1989. Blood. 2008;111:94–100.
Zhan F, Huang Y, Colla S, Stewart JP, Hanamura I, Gupta S, et al. The molecular classification of multiple myeloma. Blood. 2006;108:2020–8.
Nair B, Shaughnessy JD Jr, Zhou Y, Astrid-Cartron M, Qu P, van RF, et al. Gene expression profiling of plasma cells at myeloma relapse from tandem transplantation trial Total Therapy 2 predicts subsequent survival. Blood. 2009;113:6572–5.
Fonseca R, Barlogie B, Bataille R, Bastard C, Bergsagel PL, Chesi M, et al. Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res. 2004;64:1546–58.
Munshi NC, Avet-Loiseau H. Genomics in multiple myeloma. Clin Cancer Res. 2011;17:1234–42.
Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC, et al. Initial genome sequencing and analysis of multiple myeloma. Nature. 2011;471:467–72.
Stewart AK. Union of forces advances myeloma care. Blood. 2010;116:674–5.
Zhan F, Hardin J, Kordsmeier B, Bumm K, Zheng M, Tian E, et al. Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells. Blood. 2002;99:1745–57.
Ribatti D, Nico B, Vacca A. Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma. Oncogene. 2006;25:4257–66.
Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503–11.
Shaughnessy JD Jr, Zhan F, Burington BE, Huang Y, Colla S, Hanamura I, et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood. 2007;109:2276–84.
Shaughnessy JD Jr, Haessler J, van RF, Anaissie E, Pineda-Roman M, Cottler-Fox M, et al. Testing standard and genetic parameters in 220 patients with multiple myeloma with complete data sets: superiority of molecular genetics. Br J Haematol. 2007;137:530–6.
Waheed S, Shaughnessy JD, van RF, Alsayed Y, Nair B, Anaissie E, et al. International staging system and metaphase cytogenetic abnormalities in the era of gene expression profiling data in multiple myeloma treated with total therapy 2 and 3 protocols. Cancer. 2011;117:1001–9.
Decaux O, Lode L, Magrangeas F, Charbonnel C, Gouraud W, Jezequel P, et al. Prediction of survival in multiple myeloma based on gene expression profiles reveals cell cycle and chromosomal instability signatures in high-risk patients and hyperdiploid signatures in low-risk patients: a study of the Intergroupe Francophone du Myelome. J Clin Oncol. 2008;26:4798–805.
Mulligan G, Mitsiades C, Bryant B, Zhan F, Chng WJ, Roels S, et al. Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib. Blood. 2007;109:3177–88.
Zhan F, Barlogie B, Mulligan G, Shaughnessy JD Jr, Bryant B. High-risk myeloma: a gene expression based risk-stratification model for newly diagnosed multiple myeloma treated with high-dose therapy is predictive of outcome in relapsed disease treated with single-agent bortezomib or high-dose dexamethasone. Blood. 2008;111:968–9.
Chng WJ, Kuehl WM, Bergsagel PL, Fonseca R. Translocation t(4;14) retains prognostic significance even in the setting of high-risk molecular signature. Leukemia. 2008;22:459–61.
Kuehl WM, Bergsagel PL. Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer. 2002;2:175–87.
Keats JJ, Reiman T, Maxwell CA, Taylor BJ, Larratt LM, Mant MJ, et al. In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood. 2003;101:1520–9.
Chesi M, Nardini E, Lim RS, Smith KD, Kuehl WM, Bergsagel PL. The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood. 1998;92:3025–34.
Santra M, Zhan F, Tian E, Barlogie B, Shaughnessy J Jr. A subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lacks FGFR3 expression but maintains an IGH/MMSET fusion transcript. Blood. 2003;101:2374–6.
Dring AM, Davies FE, Fenton JA, Roddam PL, Scott K, Gonzalez D, et al. A global expression-based analysis of the consequences of the t(4;14) translocation in myeloma. Clin Cancer Res. 2004;10:5692–701.
Hurt EM, Wiestner A, Rosenwald A, Shaffer AL, Campo E, Grogan T, et al. Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes proliferation and pathological interactions with bone marrow stroma. Cancer Cell. 2004;5:191–9.
Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med. 2003;349:2483–94.
Lin P, Mahdavy M, Zhan F, Zhang HZ, Katz RL, Shaughnessy JD. Expression of PAX5 in CD20-positive multiple myeloma assessed by immunohistochemistry and oligonucleotide microarray. Mod Pathol. 2004;17:1217–22.
Bergsagel PL, Kuehl WM. Molecular pathogenesis and a consequent classification of multiple myeloma. J Clin Oncol. 2005;23:6333–8.
Bartel TB, Haessler J, Brown TL, Shaughnessy JD Jr, van RF, Anaissie E, et al. F18-fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma. Blood. 2009;114:2068–76.
Yin JJ, Mohammad KS, Kakonen SM, Harris S, Wu-Wong JR, Wessale JL, et al. A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases. Proc Natl Acad Sci USA. 2003;100:10954–9.
Clines GA, Mohammad KS, Bao Y, Stephens OW, Suva LJ, Shaughnessy JD Jr, et al. Dickkopf homolog 1 mediates endothelin-1-stimulated new bone formation. Mol Endocrinol. 2007;21:486–98.
Bergsagel PL, Kuehl WM, Zhan F, Sawyer J, Barlogie B, Shaughnessy J Jr. Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood. 2005;106:296–303.
Chesi M, Bergsagel PL, Brents LA, Smith CM, Gerhard DS, Kuehl WM. Dysregulation of cyclin D1 by translocation into an IgH gamma switch region in two multiple myeloma cell lines. Blood. 1996;88:674–81.
Shaughnessy J Jr, Gabrea A, Qi Y, Brents L, Zhan F, Tian E, et al. Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma. Blood. 2001;98:217–23.
Hanamura I, Stewart JP, Huang Y, Zhan F, Santra M, Sawyer JR, et al. Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation. Blood. 2006;108:1724–32.
Carrasco DR, Tonon G, Huang Y, Zhang Y, Sinha R, Feng B, et al. High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell. 2006;9:313–25.
Rosinol L, Carrio A, Blade J, Queralt R, Aymerich M, Cibeira MT, et al. Comparative genomic hybridisation identifies two variants of smoldering multiple myeloma. Br J Haematol. 2005;130:729–32.
Fabris S, Ronchetti D, Agnelli L, Baldini L, Morabito F, Bicciato S, et al. Transcriptional features of multiple myeloma patients with chromosome 1q gain. Leukemia. 2007;21:1113–6.
Agnelli L, Mosca L, Fabris S, Lionetti M, Andronache A, Kwee I, et al. A SNP microarray and FISH-based procedure to detect allelic imbalances in multiple myeloma: an integrated genomics approach reveals a wide gene dosage effect. Genes Chromosomes Cancer. 2009;48:603–14.
Carew JS, Nawrocki ST, Krupnik YV, Dunner K Jr, McConkey DJ, Keating MJ, et al. Targeting endoplasmic reticulum protein transport: a novel strategy to kill malignant B cells and overcome fludarabine resistance in CLL. Blood. 2006;107:222–31.
Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C, et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myelome. Blood. 2007;109:3489–95.
Fonseca R, Blood E, Rue M, Harrington D, Oken MM, Kyle RA, et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood. 2003;101:4569–75.
Pineda-Roman M, Zangari M, Haessler J, Anaissie E, Tricot G, van RF, et al. Sustained complete remissions in multiple myeloma linked to bortezomib in total therapy 3: comparison with total therapy 2. Br J Haematol. 2008;140:625–34.
San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906–17.
Avet-Loiseau H, Leleu X, Roussel M, Moreau P, Guerin-Charbonnel C, Caillot D, et al. Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol. 2010;28:4630–4.
Xiong W, Wu X, Starnes S, Johnson SK, Haessler J, Wang S, et al. An analysis of the clinical and biologic significance of TP53 loss and the identification of potential novel transcriptional targets of TP53 in multiple myeloma. Blood. 2008;112:4235–46.
Zhou Y, Chen L, Barlogie B, Stephens O, Wu X, Williams D, et al. High-risk myeloma is associated with global elevation of miRNAs and overexpression of EIF2C2/AGO2. PNAS. 2010;107(17):7904–9.
Chauhan D, Auclair D, Robinson EK, Hideshima T, Li G, Podar K, et al. Identification of genes regulated by dexamethasone in multiple myeloma cells using oligonucleotide arrays. Oncogene. 2002;21:1346–58.
Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X, et al. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci USA. 2002;99:14374–9.
Mitsiades N, Mitsiades CS, Richardson PG, Poulaki V, Tai YT, Chauhan D, et al. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood. 2003;101:2377–80.
Chauhan D, Li G, Auclair D, Hideshima T, Richardson P, Podar K, et al. Identification of genes regulated by 2-methoxyestradiol (2ME2) in multiple myeloma cells using oligonucleotide arrays. Blood. 2003;101:3606–14.
Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Hideshima T, et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci USA. 2004;101:540–5.
Neri P, Tagliaferri P, Di Martino MT, Calimeri T, Amodio N, Bulotta A, et al. In vivo anti-myeloma activity and modulation of gene expression profile induced by valproic acid, a histone deacetylase inhibitor. Br J Haematol. 2008;143:520–31.
Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Akiyama M, et al. Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Cancer Cell. 2004;5:221–30.
Tassone P, Neri P, Burger R, Savino R, Shammas M, Catley L, et al. Combination therapy with interleukin-6 receptor superantagonist Sant7 and dexamethasone induces antitumor effects in a novel SCID-hu In vivo model of human multiple myeloma. Clin Cancer Res. 2005;11:4251–8.
Sukhdeo K, Mani M, Zhang Y, Dutta J, Yasui H, Rooney MD, et al. Targeting the beta-catenin/TCF transcriptional complex in the treatment of multiple myeloma. Proc Natl Acad Sci USA. 2007;104:7516–21.
Raje N, Kumar S, Hideshima T, Ishitsuka K, Yasui H, Chhetri S, et al. Didox, a ribonucleotide reductase inhibitor, induces apoptosis and inhibits DNA repair in multiple myeloma cells. Br J Haematol. 2006;135:52–61.
Neri P, Tassone P, Shammas M, Yasui H, Schipani E, Batchu RB, et al. Biological pathways and in vivo antitumor activity induced by Atiprimod in myeloma. Leukemia. 2007;21:2519–26.
Heller G, Schmidt WM, Ziegler B, Holzer S, Mullauer L, Bilban M, et al. Genome-wide transcriptional response to 5-aza-2′-deoxycytidine and trichostatin a in multiple myeloma cells. Cancer Res. 2008;68:44–54.
Duus J, Bahar HI, Venkataraman G, Ozpuyan F, Izban KF, Al-Masri H, et al. Analysis of expression of heat shock protein-90 (HSP90) and the effects of HSP90 inhibitor (17-AAG) in multiple myeloma. Leuk Lymphoma. 2006;47:1369–78.
Ocio EM, Maiso P, Chen X, Garayoa M, Alvarez-Fernandez S, San-Segundo L, et al. Zalypsis: a novel marine-derived compound with potent antimyeloma activity that reveals high sensitivity of malignant plasma cells to DNA double-strand breaks. Blood. 2009;113:3781–91.
Burington B, Barlogie B, Zhan F, Crowley J, Shaughnessy JD Jr. Tumor cell gene expression changes following short-term in vivo exposure to single agent chemotherapeutics are related to survival in multiple myeloma. Clin Cancer Res. 2008;14:4821–9.
Shaughnessy JD, Jr., Qu P, Usmani S, Heuck CJ, Zhang Q, Zhou Y, et al. Pharmacogenomics of bortezomib test-dosing identifies hyperexpression of proteasome genes, especially PSMD4, as novel high-risk feature in myeloma treated with total therapy 3. Blood 2011 (Epub 2011 May 31).
Kumar SK, Jacobus SJ, Van Wier SA, Ahmann GJ, Henderson KJ, Callander NS, et al. Impact of gene expression profiling-based risk stratification in patients with myeloma receiving initial therapy with lenalidomide and dexamethasone. Blood. 2011 (Epub 2011 Aug 22).
Hose D, Rème T, Hielscher T, Moreaux J, Messner T, Seckinger A, et al. Proliferation is a central independent prognostic factor and target for personalized and risk-adapted treatment in multiple myeloma. Haematologica. 2011;96(1):87–95.
Dickens N, Walker B, Leone P, Johnson D, Brito J, Zeisig A, et al. Homozygous deletion mapping in myeloma samples identifies genes and an expression signature relevant to pathogenesis and outcome. Clin Cancer Res. 2010;16:1856–64.
Fabris S, Agnelli L, Mattioli M, Baldini L, Ronchetti D, Morabito F, et al. Characterization of oncogene dysregulation in multiple myeloma by combined FISH and DNA microarray analyses. Genes Chromosomes Cancer. 2005;42:117–27.
Broyl A, Hose D, Lokhorst H, de Knegt Y, Peeters J, Jauch A, et al. Gene expression profiling for molecular classification of multiple myeloma in newly diagnosed patients. Blood. 2010;116:2543–53.
Shaughnessy J, Jacobson J, Sawyer J, McCoy J, Fassas A, Zhan F, et al. Continuous absence of metaphase-defined cytogenetic abnormalities, especially of chromosome 13 and hypodiploidy, ensures long-term survival in multiple myeloma treated with Total Therapy I: interpretation in the context of global gene expression. Blood. 2003;101:3849–56.
Shaughnessy J. Amplification and overexpression of CKS1B at chromosome band 1q21 is associated with reduced levels of p27Kip1 and an aggressive clinical course in multiple myeloma. Hematology. 2005;10(Suppl 1):117–26.
Acknowledgments
This work was supported by the Lebow Fund to Cure Myeloma.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Johnson, S.K., Heuck, C.J., Albino, A.P. et al. The use of molecular-based risk stratification and pharmacogenomics for outcome prediction and personalized therapeutic management of multiple myeloma. Int J Hematol 94, 321–333 (2011). https://doi.org/10.1007/s12185-011-0948-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12185-011-0948-y