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  • Spotlight Review
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International Myeloma Working Group molecular classification of multiple myeloma: spotlight review

Leukemia volume 23, pages 2210–2221 (2009)Cite this article

Abstract

Myeloma is a malignant proliferation of monoclonal plasma cells. Although morphologically similar, several subtypes of the disease have been identified at the genetic and molecular level. These genetic subtypes are associated with unique clinicopathological features and dissimilar outcome. At the top hierarchical level, myeloma can be divided into hyperdiploid and non-hyperdiploid subtypes. The latter is mainly composed of cases harboring IgH translocations, generally associated with more aggressive clinical features and shorter survival. The three main IgH translocations in myeloma are the t(11;14)(q13;q32), t(4;14)(p16;q32) and t(14;16)(q32;q23). Trisomies and a more indolent form of the disease characterize hyperdiploid myeloma. A number of genetic progression factors have been identified including deletions of chromosomes 13 and 17 and abnormalities of chromosome 1 (1p deletion and 1q amplification). Other key drivers of cell survival and proliferation have also been identified such as nuclear factor- B-activating mutations and other deregulation factors for the cyclin-dependent pathways regulators. Further understanding of the biological subtypes of the disease has come from the application of novel techniques such as gene expression profiling and array-based comparative genomic hybridization. The combination of data arising from these studies and that previously elucidated through other mechanisms allows for most myeloma cases to be classified under one of several genetic subtypes. This paper proposes a framework for the classification of myeloma subtypes and provides recommendations for genetic testing. This group proposes that genetic testing needs to be incorporated into daily clinical practice and also as an essential component of all ongoing and future clinical trials.

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References

  1. Kyle RA, Rajkumar SV . Multiple myeloma [see comment]. [published erratum appears in N Engl J Med 2005; 352:1163] N Engl J Med 2004; 351: 1860–1873.

    Article  CAS  PubMed  Google Scholar 

  2. Fonseca R . Many and multiple myeloma(s). Leukemia 2003; 17: 1943–1944.

    CAS  PubMed  Google Scholar 

  3. Zhan F, Huang Y, Colla S, Stewart JP, Hanamura I, Gupta S et al. The molecular classification of multiple myeloma. Blood 2006; 108: 2020–2028.

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Ludwig H, Durie BG, Bolejack V, Turesson I, Kyle RA, Blade J et al. Myeloma in patients younger than age 50 years presents with more favorable features and shows better survival: an analysis of 10 549 patients from the International Myeloma Working Group. Blood 2008; 111: 4039–4047.

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Bergsagel PL, Kuehl WM, Zhan F, Sawyer J, Barlogie B, Shaughnessy J et al. Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood 2005; 106: 296–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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: 3489–3495.

    CAS  PubMed  Google Scholar 

  7. 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: 4569–4575.

    CAS  PubMed  Google Scholar 

  8. Debes-Marun C, Dewald G, Bryant S, Picken E, Santana-Dávila S, González-Paz N et al. Chromosome abnormalities clustering and its implications for pathogenesis and prognosis in myeloma. Leukemia 2003; 17: 427–436.

    CAS  PubMed  Google Scholar 

  9. Smadja NV, Fruchart C, Isnard F, Louvet C, Dutel JL, Cheron N et al. Chromosomal analysis in multiple myeloma: cytogenetic evidence of two different diseases. Leukemia 1998; 12: 960–969.

    CAS  PubMed  Google Scholar 

  10. 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: 313–325.

    CAS  PubMed  Google Scholar 

  11. 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: 1520–1529.

    CAS  PubMed  Google Scholar 

  12. Gertz MA, Lacy MQ, Dispenzieri A, Greipp PR, Litzow MR, Henderson KJ et al. Clinical implications of t(11;14)(q13;q32), t(4;14)(p16 3 q32) and -17p13 in myeloma patients treated with high-dose therapy. Blood 2005; 106: 2837–2840.

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Jagannath S, Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA et al. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia 2007; 21: 151–157.

    CAS  PubMed  Google Scholar 

  14. 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: 906–917.

    CAS  PubMed  Google Scholar 

  15. Chng WJ, Kuehl WM, Bergsagel PL, Fonseca R . Translocation t(4;14) retains prognostic significance even in the setting of high-risk molecular signature. [published erratum appears in Leukemia 2008; 22: 462] Leukemia 2008; 22: 459–461, e-pub ahead of print 6 September 2007. No abstract available.

    CAS  PubMed  Google Scholar 

  16. Trudel S, Li ZH, Wei E, Wiesmann M, Chang H, Chen C et al. CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood 2005; 105: 2941–2948.

    CAS  PubMed  Google Scholar 

  17. Shi J, Tricot GJ, Garg TK, Malaviarachchi PA, Szmania SM, Kellum RE et al. Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell-mediated lysis of myeloma. Blood 2008; 111: 1309–1317.

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ et al. Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell 2007; 12: 131–144.

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Kuehl WM, Bergsagel PL . Multiple myeloma: evolving genetic events and host interactions. Nature Rev Cancer 2002; 2: 175–187.

    CAS  Google Scholar 

  20. Fonseca R, Debes-Marun CS, Picken EB, Dewald GW, Bryant SC, Winkler JM et al. The recurrent IgH translocations are highly associated with nonhyperdiploid variant multiple myeloma. Blood 2003; 102: 2562–2567.

    Article  CAS  PubMed  Google Scholar 

  21. Chng WJ, Winkler JM, Greipp PR, Jalal SM, Bergsagel PL, Chesi M et al. Ploidy status rarely changes in myeloma patients at disease progression. Leuk Res 2006; 30: 266–271.

    CAS  PubMed  Google Scholar 

  22. Chng WJ, Van Wier SA, Ahmann GJ, Winkler JM, Jalal SM, Bergsagel PL et al. A validated FISH trisomy index demonstrates the hyperdiploid and nonhyperdiploid dichotomy in MGUS. Blood 2005; 106: 2156–2161.

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Brousseau M, Leleu X, Gerard J, Gastinne T, Godon A, Genevieve F et al. Hyperdiploidy is a common finding in monoclonal gammopathy of undetermined significance and monosomy 13 is restricted to these hyperdiploid patients. Clin Cancer Res 2007; 13: 6026–6031.

    CAS  PubMed  Google Scholar 

  24. Li X, Pennisi A, Zhan F, Sawyer JR, Shaughnessy JD, Yaccoby S . Establishment and exploitation of hyperdiploid and non-hyperdiploid human myeloma cell lines. Br J Haematol 2007; 138: 802–811.

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Avet-Loiseau H, Li C, Magrangeas F, Gouraud W, Charbonnel C, Harousseau J-L et al. J Clin Oncol. Published online 17 August 2009, doi:10.1200/JCO.2008.20.6136.

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Chng WJ, Kumar S, Vanwier S, Ahmann G, Price-Troska T, Henderson K et al. Molecular dissection of hyperdiploid multiple myeloma by gene expression profiling. Cancer Res 2007; 67: 2982–2989.

    CAS  PubMed  Google Scholar 

  27. Hoyer JD, Hanson CA, Fonseca R, Greipp PR, Dewald GW, Kurtin PJ . The (11;14)(q13;q32) translocation in multiple myeloma A morphologic and immunohistochemical study. Am J Clin Pathol 2000; 113: 831–837.

    CAS  PubMed  Google Scholar 

  28. Garand R, Avet-Loiseau H, Accard F, Moreau P, Harousseau J, Bataille R . t(11;14) and t(4;14) translocations correlated with mature lymphoplasmocytoid and immature morphology, respectively, in multiple myeloma. Leukemia 2003; 17: 2032–2035.

    CAS  PubMed  Google Scholar 

  29. Fonseca R, Harrington D, Oken M, Kyle R, Dewald G, Bailey R et al. Myeloma and the t(11;14)(q13;q32) represents a uniquely defined biological subset of patients. Blood 2002; 99: 3735–3741.

    CAS  PubMed  Google Scholar 

  30. Sawyer JR, Lukacs JL, Thomas EL, Swanson CM, Goosen LS, Sammartino G et al. Multicolour spectral karyotyping identifies new translocations and a recurring pathway for chromosome loss in multiple myeloma. Br J Haematol 2001; 112: 167–174.

    CAS  PubMed  Google Scholar 

  31. Chesi M, Nardini E, Brents LA, Schrock E, Ried T, Kuehl WM et al. Frequent translocation t(4;14)(p16 3 q32 3 ) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. Nat Genet 1997; 16: 260–264.

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Chesi M, Nardini E, Lim R, Smith K, Kuehl W, Bergsagel P . The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood 1998; 92: 3025–3034.

    CAS  PubMed  Google Scholar 

  33. Chang H, Sloan S, Li D, Zhuang L, Yi QL, Chen CI et al. The t(4;14) is associated with poor prognosis in myeloma patients undergoing autologous stem cell transplant. Br J Haematol 2004; 125: 64–68.

    PubMed  Google Scholar 

  34. Chang H, Qi XY, Samiee S, Yi QL, Chen C, Trudel S et al. Genetic risk identifies multiple myeloma patients who do not benefit from autologous stem cell transplantation. Bone Marrow Transplant 2005; 36: 793–796.

    CAS  PubMed  Google Scholar 

  35. Trudel S, Ely S, Farooqi Y, Affer M, Robbiani DF, Chesi M et al. Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma. Blood 2004; 103: 3521–3528.

    CAS  PubMed  Google Scholar 

  36. Avet-Loiseau H, Facon T, Grosbois B, Magrangeas F, Rapp MJ, Harousseau JL et al. Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation. Blood 2002; 99: 2185–2191.

    CAS  PubMed  Google Scholar 

  37. Fonseca R, Oken MM, Greipp PR . The t(4;14)(p16.3;q32) is strongly associated with chromosome 13 abnormalities in both multiple myeloma and monoclonal gammopathy of undetermined significance. Blood 2001; 98: 1271–1272.

    CAS  PubMed  Google Scholar 

  38. Avet-Loiseau H, Facon T, Daviet A, Godon C, Rapp MJ, Harousseau JL et al. 14q32 translocations and monosomy 13 observed in monoclonal gammopathy of undetermined significance delineate a multistep process for the oncogenesis of multiple myeloma. Intergroupe Francophone du Myelome. Cancer Res 1999; 59: 4546–4550.

    CAS  PubMed  Google Scholar 

  39. Fonseca R, Bailey RJ, Ahmann GJ, Rajkumar SV, Hoyer JD, Lust JA et al. Genomic abnormalities in monoclonal gammopathy of undetermined significance.[see comment]. Blood 2002; 100: 1417–1424.

    CAS  PubMed  Google Scholar 

  40. Tricot G, Barlogie B, Jagannath S, Bracy D, Mattox S, Vesole DH et al. Poor prognosis in multiple myeloma is associated only with partial or complete deletions of chromosome 13 or abnormalities involving 11q and not with other karyotype abnormalities. Blood 1995; 86: 4250–4256.

    CAS  PubMed  Google Scholar 

  41. Tricot G, Sawyer JR, Jagannath S, Desikan KR, Siegel D, Naucke S et al. Unique role of cytogenetics in the prognosis of patients with myeloma receiving high-dose therapy and autotransplants. J Clin Oncol 1997; 15: 2659–2666.

    CAS  PubMed  Google Scholar 

  42. Perez-Simon JA, Garcia-Sanz R, Tabernero MD, Almeida J, Gonzalez M, Fernandez-Calvo J et al. Prognostic value of numerical chromosome aberrations in multiple myeloma: A FISH analysis of 15 different chromosomes. Blood 1998; 91: 3366–3371.

    CAS  PubMed  Google Scholar 

  43. Zojer N, Konigsberg R, Ackermann J, Fritz E, Dallinger S, Kromer E et al. Deletion of 13q14 remains an independent adverse prognostic variable in multiple myeloma despite its frequent detection by interphase fluorescence in situ hybridization. Blood 2000; 95: 1925–1930.

    CAS  PubMed  Google Scholar 

  44. Dewald GW, Therneau T, Larson D, Lee YK, Fink S, Smoley S et al. Relationship of patient survival and chromosome anomalies detected in metaphase and/or interphase cells at diagnosis of myeloma. Blood 2005; 106: 3553–3558.

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Fonseca R, Oken MM, Harrington D, Bailey RJ, Van Wier SA, Henderson KJ et al. Deletions of chromosome 13 in multiple myeloma identified by interphase FISH usually denote large deletions of the q arm or monosomy. Leukemia 2001; 15: 981–986.

    CAS  PubMed  Google Scholar 

  46. Fonseca R, Harrington D, Oken M, Dewald G, Bailey R, Van Wier S et al. Biologic and prognostic significance of interphase FISH detection of chromosome 13 abnormalities (D13) in multiple myeloma: an Eastern Cooperative Oncology Group (ECOG) Study. Cancer Res 2002; 62: 715–720.

    CAS  PubMed  Google Scholar 

  47. Avet-Loiseau H, Li JY, Morineau N, Facon T, Brigaudeau C, Harousseau JL et al. Monosomy 13 is associated with the transition of monoclonal gammopathy of undetermined significance to multiple myeloma. Intergroupe Francophone du Myelome. Blood 1999; 94: 2583–2589.

    CAS  PubMed  Google Scholar 

  48. Avet-Loiseau H, Daviet A, Saunier S, Bataille R . Chromosome 13 abnormalities in multiple myeloma are mostly monosomy 13. Br J Haematol 2000; 111: 1116–1117.

    Google Scholar 

  49. Gutierrez NC, Castellanos MV, Martin ML, Mateos MV, Hernandez JM, Fernandez M et al. Prognostic and biological implications of genetic abnormalities in multiple myeloma undergoing autologous stem cell transplantation: t(4;14) is the most relevant adverse prognostic factor, whereas RB deletion as a unique abnormality is not associated with adverse prognosis. Leukemia 2007; 21: 143–150.

    CAS  PubMed  Google Scholar 

  50. Chiecchio L, Protheroe RK, Ibrahim AH, Cheung KL, Rudduck C, Dagrada GP et al. Deletion of chromosome 13 detected by conventional cytogenetics is a critical prognostic factor in myeloma. Leukemia 2006; 20: 1610–1617.

    CAS  PubMed  Google Scholar 

  51. Chng WJ, Santana-Davila R, Van Wier SA, Ahmann GJ, Jalal SM, Bergsagel PL et al. Prognostic factors for hyperdiploid-myeloma: effects of chromosome 13 deletions and IgH translocations. Leukemia 2006; 20: 807–813.

    CAS  PubMed  Google Scholar 

  52. Drach J, Ackermann J, Fritz E, Kromer E, Schuster R, Gisslinger H et al. Presence of a p53 gene deletion in patients with multiple myeloma predicts for short survival after conventional-dose chemotherapy. Blood 1998; 92: 802–809.

    CAS  PubMed  Google Scholar 

  53. Chang H, Qi C, Yi QL, Reece D, Stewart AK . p53 gene deletion detected by fluorescence in situ hybridization is an adverse prognostic factor for patients with multiple myeloma following autologous stem cell transplantation. Blood 2005; 105: 358–360.

    CAS  PubMed  Google Scholar 

  54. Chang H, Sloan S, Li D, Keith Stewart A . Multiple myeloma involving central nervous system: high frequency of chromosome 17p13.1 (p53) deletions. Br J Haematol 2004; 127: 280–284.

    CAS  PubMed  Google Scholar 

  55. Tiedemann RE, Gonzalez-Paz N, Kyle RA, Santana-Davila R, Price-Troska T, Van Wier SA et al. Genetic aberrations and survival in plasma cell leukemia. Leukemia 2008; 22: 1044–1052.

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Xiong W, Wu X, Starnes S, Johnson SK, Haessler J, Wang S et al. An analysis of the clinical and biologic significance of TP 53 loss and the identification of potential novel transcriptional targets of TP53 in multiple myeloma. Blood 2008; 112: 4235–4246.

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Schilling G, Hansen T, Shimoni A, Zabelina T, Perez-Simon JA, Gutierrez NC et al. Impact of genetic abnormalities on survival after allogeneic hematopoietic stem cell transplantation in multiple myeloma. Leukemia 2008; 22: 1250–1255.

    CAS  PubMed  Google Scholar 

  58. Shaughnessy Jr JD, Zhan F, Burington BE, Huang Y, Colla S, Hanamura I . A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood 2007; 109: 2276–2284.

    Article  CAS  PubMed  Google Scholar 

  59. Sawyer JR, Tricot G, Mattox S, Jagannath S, Barlogie B . Jumping translocations of chromosome 1q in multiple myeloma: evidence for a mechanism involving decondensation of pericentromeric heterochromatin. Blood 1998; 91: 1732–1741.

    CAS  PubMed  Google Scholar 

  60. 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: 1724–1732.

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Fonseca R, Van Wier SA, Chng WJ, Ketterling R, Lacy MQ, Dispenzieri A et al. Prognostic value of chromosome 1q21 gain by fluorescent in situ hybridization and increase CKS1B expression in myeloma. Leukemia 2006; 20: 2034–2040.

    CAS  PubMed  Google Scholar 

  62. Annunziata CM, Davis RE, Demchenko Y, Bellamy W, Gabrea A, Zhan F et al. Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 2007; 12: 115–130.

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Liu P, Leong T, Quam L, Billadeau D, Kay NE, Greipp P et al. Activating mutations of N- and K-ras in multiple myeloma show different clinical associations: analysis of the Eastern Cooperative Oncology Group Phase III Trial. Blood 1996; 88: 2699–2706.

    CAS  PubMed  Google Scholar 

  64. Bezieau S, Devilder MC, Avet-Loiseau H, Mellerin MP, Puthier D, Pennarun E et al. High incidence of N and K-Ras activating mutations in multiple myeloma and primary plasma cell leukemia at diagnosis. Human Mutat 2001; 18: 212–224.

    CAS  Google Scholar 

  65. Rasmussen T, Kuehl M, Lodahl M, Johnsen HE, Dahl IM . Possible roles for activating RAS mutations in the MGUS to MM transition and in the intramedullary to extramedullary transition some plasma cell tumors. Blood 2005; 105: 317–323.

    CAS  PubMed  Google Scholar 

  66. Chng WJ, Gonzalez-Paz N, Price-Troska T, Jacobus S, Rajkumar SV, Oken MM et al. Clinical and biological significance of RAS mutations in multiple myeloma. Leukemia 2008; 22: 2280–2284.

    CAS  PubMed  Google Scholar 

  67. Urashima M, Teoh G, Ogata A, Chauhan D, Treon SP, Sugimoto Y et al. Characterization of p16(INK4A) expression in multiple myeloma and plasma cell leukemia. Clin Cancer Res 1997; 3: 2173–2179.

    CAS  PubMed  Google Scholar 

  68. Tasaka T, Asou H, Munker R, Said JW, Berenson J, Vescio RA et al. Methylation of the p16INK4A gene in multiple myeloma. Br J Haematol 1998; 101: 558–564.

    CAS  PubMed  Google Scholar 

  69. Mateos MV, Garcia-Sanz R, Lopez-Perez R, Moro MJ, Ocio E, Hernandez J et al. Methylation is an inactivating mechanism of the p16 gene in multiple myeloma associated with high plasma cell proliferation and short survival. Br J Haematol 2002; 118: 1034–1040.

    CAS  PubMed  Google Scholar 

  70. Chen W, Wu Y, Zhu J, Liu J, Tan S, Xia C . Methylation of p16 and p15 genes in multiple myeloma. Chi Med Sci J 2002; 17: 101–105.

    CAS  Google Scholar 

  71. Guillerm G, Depil S, Wolowiec D, Quesnel B . Different prognostic values of p15(INK4b) and p16(INK4a) gene methylations in multiple myeloma. Haematologica 2003; 88: 476–478.

    PubMed  Google Scholar 

  72. Uchida T, Kinoshita T, Ohno T, Ohashi H, Nagai H, Saito H . Hypermethylation of p16 INK4A gene promoter during the progression of plasma cell dyscrasia. Leukemia 2001; 15: 157–165.

    CAS  PubMed  Google Scholar 

  73. Gonzalez-Paz N, Chng WJ, McClure RF, Blood E, Oken MM, Van Ness B et al. Tumor suppressor p16 methylation in multiple myeloma: biological and clinical implications. Blood 2007; 109: 1228–1232.

    CAS  PubMed  Google Scholar 

  74. Sarasquete ME, Garcia-Sanz R, Armellini A, Fuertes M, Martin-Jimenez P, Sierra M et al. The association of increased p14ARF/p16INK4a and p15INK4a gene expression with proliferative activity and the clinical course of multiple myeloma. Haematologica 2006; 91: 1551–1554.

    CAS  PubMed  Google Scholar 

  75. Pichiorri F, Suh SS, Ladetto M, Kuehl M, Palumbo T, Drandi D et al. MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis. Proc Natl Acad Sci USA 2008; 105: 12885–12890.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Loffler D, Brocke-Heidrich K, Pfeifer G, Stocsits C, Hackermuller J, Kretzschmar AK et al. Interleukin-6 dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer. Blood 2007; 110: 1330–1333.

    PubMed  Google Scholar 

  77. Walker BA, Leone PE, Jenner MW, Li C, Gonzalez D, Johnson DC et al. Integration of global SNP-based mapping and expression arrays reveals key regions, mechanisms, and genes important in the pathogenesis of multiple myeloma. Blood 2006; 108: 1733–1743.

    CAS  PubMed  Google Scholar 

  78. Jenner MW, Leone PE, Walker BA, Ross FM, Johnson DC, Gonzalez D et al. Gene mapping and expression analysis of 16q loss of heterozygosity identifies WWOX and CYLD as being important in determining clinical outcome in multiple myeloma. Blood 2007; 110: 3291–3300.

    CAS  PubMed  Google Scholar 

  79. Mateos MV, Hernandez JM, Hernandez MT, Gutierrez NC, Palomera L, Fuertes M et al. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase I/II study. Blood 2006; 108: 2165–2172.

    CAS  PubMed  Google Scholar 

  80. Chng WJ, Ahmann GJ, Henderson K, Santana-Davila R, Greipp PR, Gertz MA et al. Clinical implication of centrosome amplification in plasma cell neoplasm. Blood 2006; 107: 3669–3675.

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Ahmann GJ, Jalal SM, Juneau AL, Christensen ER, Hanson CA, Dewald GW et al. A novel three-color, clone-specific fluorescence in situ hybridization procedure for monoclonal gammopathies. Cancer Genet Cytogenet 1998; 101: 7–11.

    CAS  PubMed  Google Scholar 

  82. Harrison CJ, Mazzullo H, Ross FM, Cheung KL, Gerrard G, Harewood L et al. Translocations of 14q32 and deletions of 13q14 are common chromosomal abnormalities in systemic amyloidosis. Br J Haematol 2002; 117: 427–435.

    CAS  PubMed  Google Scholar 

  83. Hayman SR, Bailey RJ, Jalal SM, Ahmann GJ, Dispenzieri A, Gertz MA et al. Translocations involving heavy-chain locus are possible early genetic events in patients with primary systemic amyloidosis. Blood 2001; 98: 2266–2268.

    CAS  PubMed  Google Scholar 

  84. Avet-Loiseau H, Garand R, Lode L, Harousseau J-L, Bataille R . Translocation t(11;14)(q13;q32) is the hallmark of IgM, IgE, and nonsecretory multiple myeloma variants. Blood 2003; 101: 1570–1571.

    CAS  PubMed  Google Scholar 

  85. Schop RF, Van Wier SA, Xu R, Ghobrial I, Ahmann GJ, Greipp PR et al. 6q deletion discriminates Waldenstrom macroglobulinemia from IgM monoclonal gammopathy of undetermined significance. Cancer Genet Cytogenet 2006; 169: 150–153.

    CAS  PubMed  Google Scholar 

  86. Chng WJ, Glebov O, Bergsagel PL, Kuehl WL . Genetic events in the pathogenesis of multiple myeloma. Best Prac Res Clin Haematol 2007; 20: 571–596.

    CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Hematology–Oncology, Mayo Clinic, Scottsdale, AZ, USA

    R Fonseca, P L Bergsagel, A K Stewart & M Chesi

  2. Clinical Division of Oncology, Department of Medicine, University Hospital Vienna, Vienna, Austria

    J Drach

  3. Department of MIRT, University of Arkansas for Medical Sciences, MIRT, Little Rock, AR, USA

    J Shaughnessy & B Barlogie

  4. Department of Hematology, Hospital Un,

    N Gutierrez

  5. i,

    N Gutierrez

  6. versitario de Salamanca, CIC, Salamanca, Spain

    N Gutierrez

  7. Institute of Cancer Research, Royal Marsden Hospital, Sutton, UK

    G Morgan & F Davies

  8. Department of Genetics, Institute of Human Genetics, University of Minnesota, Minneapolis, MN, USA

    B Van Ness

  9. Université de Nantes,

    S Minvielle & H Avet-Loiseau

  10. Institut de Biologie, Laboratoire d’Hematologie, Nantes, France

    S Minvielle & H Avet-Loiseau

  11. Servizio di Ematol,

    A Neri

  12. o,

    A Neri

  13. gia, Istituto di Scienze Mediche, Universita di Milano, Ospedale Maggiore, IRCCS, Milan, Italy

    A Neri

  14. The Genetics Branch, National Cancer Institute, Bethesda, MD, USA

    W M Kuehl

  15. Department of Internal Medicine III, University of Ulm, Ulm, Germany

    P Liebisch

  16. Department of Patho,

    S Chen-Kiang

  17. l,

    S Chen-Kiang

  18. ogy, Columbia University, Weill-Cornell Medical College, New York, NY, USA

    S Chen-Kiang

  19. Cedars-Sinai Outpatient Cancer Center at the Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA

    B G M Durie

  20. Department of Medical O,

    R Carrasco

  21. n,

    R Carrasco

  22. cology/ Hematologic Neoplasia, Dana-Farber Cancer Institute, Harvard University, Boston, MA, USA

    R Carrasco

  23. Department of Hem/Onc, Universitatsklinikum Charite, Berlin, Germany

    Orhan Sezer

  24. Dalhousie University Department of Oncology, Saint John Regional Hospital, Halifax, Nova Scotia, Canada,

    Tony Reiman

  25. Cross Cancer Institute, University of Alberta, Alberta, Edmontoin, Canada,

    Linda Pilarski

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Corresponding author

Correspondence to R Fonseca.

Additional information

Members of the IMWG are listed in the appendix.

Appendix

Appendix

Rafat Abonour, Indiana University School of Medicine, Indianapolis, IN, USA

Ray Alexanian, MD Anderson, Houston, TX, USA

Kenneth Anderson, DFCI, Boston, MA, USA

Michael Attal, Purpan Hospital, Toulouse, France

Herve Avet-Loiseau, Institute de Biologie, Nantes, France

Ashraf Badros, University of Maryland, Baltimore, MD, USA

Leif Bergsagel, Mayo Clinic Scottsdale, Scottsdale, AZ, USA

Joan Bladé, Hospital Clinica, Barcelona, Spain

Bart Barlogie, MIRT UAMS Little Rock, AR, USA

Regis Batille, Institute de Biologie, Nantes, France

Meral Beksac, Ankara University, Ankara, Turkey

Andrew Belch, Cross Cancer Institute, Alberta, Canada

Bill Bensinger, Fred Hutchinson Cancer Center, Seattle, WA, USA

Mario Boccadoro, University of Torino, Torino, Italy

Michele Cavo, Universita di Bologna, Bologna, Italy

Wen Ming Chen, MM Research Center of Beijing, Beijing, China

Tony Child, Leeds General Hospital, Leeds, UK

James Chim, Department of Medicine, Queen Mary Hospital, Hong Kong

Ray Comenzo, Tufts Medical Center, Boston, MA, USA

John Crowley, Cancer Research and Biostatistics, Seattle, WA, USA

William Dalton, H Lee Moffitt, Tampa, FL, USA

Faith Davies, Royal Marsden Hospital, London, England

Cármino de Souza, Univeridade de Campinas, Caminas, Brazil

Michel Delforge, University Hospital Gasthuisberg, Leuven, Belgium

Meletios Dimopoulos, Alexandra Hospital, Athens, Greece

Angela Dispenzieri, Mayo Clinic, Rochester, MN, USA

Brian GM Durie, Cedars-Sinai Outpatient Cancer Center, Los Angeles, CA, USA

Hermann Einsele, Universitätsklinik Würzburg, Würzburg, Germany

Theirry Facon, Centre Hospitalier Regional Universitaire de Lille, Lille, France

Dorotea Fantl, Socieded Argentinade Hematolgia, Buenos Aires, Argentina

Jean-Paul Fermand, Hopitaux de Paris, Paris, France

Rafael Fonseca, Mayo Clinic Arizona, Scottsdale, AZ, USA

Gosta Gahrton, Karolinska Institute for Medicine, Huddinge, Sweden

Morie Gertz, Mayo Clinic, Rochester, MN, USA

John Gibson, Royal Prince Alfred Hospital, Sydney, Australia

Sergio Giralt, MD Anderson Cancer Center, Houston, TX, USA

Hartmut Goldschmidt, University Hospital Heidelberg, Heidelberg, Germany

Philip Greipp, Mayo Clinic, Rochester, MN, USA

Roman Hajek, Brno University, Brno, Czech Republic

Izhar Hardan, Tel Aviv University, Tel Aviv, Israel

Jean-Luc Harousseau, Institute de Biologie, Nantes, France

Hiroyuki Hata, Kumamoto University Hospital, Kumamoto, Japan

Yutaka Hattori, Keio University School of Medicine, Tokyo, Japan

Joy Ho, Royal Prince Alfred Hospital, Sydney, Australia

Vania Hungria, Clinica San Germano, Sao Paolo, Brazil

Shinsuke Ida, Nagoya City University Medical School, Nagoya, Japan

Peter Jacobs, Constantiaberg Medi-Clinic, Plumstead, South Africa

Sundar Jagannath, St Vincent's Comprehensive Cancer Center, New York, NY, USA

Hou Jian, Shanghai Chang Zheng Hospital, Shanghai, China

Douglas Joshua, Royal Prince Alfred Hospital, Sydney, Australia

Michio Kawano, Yamaguchi University, Ube, Japan

Nicolaus Kröger, University Hospital Hamburg, Hamburg, Germany

Shaji Kumar, Department of Hematology, Mayo Clinic, MN, USA

Robert Kyle, Department of Laboratory Med. and Pathology, Mayo Clinic, MN, USA

Juan Lahuerta, Grupo Espanol di Mieloma, Hospital Universitario, Madrid, Spain

Jae Hoon Lee, Gachon University Gil Hospital, Incheon, Korea

Xavier LeLeu, Hospital Huriez, CHRU Lille, France

Suzanne Lentzsch, University of Pittsburgh, Pittsburgh, PA, USA

Henk Lokhorst, University Medical CenterUtrecht, Utrecht, The Netherlands

Sagar Lonial, Emory University Medical School, Atlanta, GA, USA

Heinz Ludwig, Wilhelminenspital Der Stat Wien, Vienna, Austria

Angelo Maiolino, Rua fonte da Saudade, Rio de Janeiro, Brazil

Maria Mateos, University of Salamanca, Salamanca, Spain

Jayesh Mehta, Northwestern University, Chicago, IL, USA

GianPaolo Merlini, University of Pavia, Pavia, Italy

Joseph Mikhael, Mayo Clinic Arizona, Scottsdale, AZ, USA

Philippe Moreau, University Hospital, Nantes, France

Gareth Morgan, Royal Marsden Hospital, London, England

Nikhil Munshi, Diane Farber Cancer Institute, Boston, MA, USA

Ruben Niesvizky, Weill Medical College of Cornell University, New York, NY, USA

Yana Novis, Hospital SírioLibanês, Bela Vista, Brazil

Amara Nouel, Hospital Rutz y Paez, Bolivar, Venezuela

Robert Orlowski, MD Anderson Cancer Center, Houston, TX, USA

Antonio Palumbo, Cathedra Ematologia, Torino, Italy

Santiago Pavlovsky, Fundaleu, Buenos Aires, Argentina

Linda Pilarski, University of Alberta, Alberta, Canada

Raymond Powles, Leukaemia & Myeloma, Wimbledon, England

S. Vincent Rajkumar, Mayo Clinic, Rochester, MN, USA

Donna Reece, Princess Margaret Hospital, Toronto, Canada

Tony Reiman, Cross Cancer Institute, Alberta, Canada

Paul Richardson, Dana Farber Cancer Institute, Boston, MA, USA

Angelina Rodriquez Morales, Bonco Metro Politano de Sangre, Caracas, Venezuela

Orhan Sezer, Department of Hem/Onc, Universitatsklinikum Charite, Berlin, Germany

John Shaughnessy, MIRT UAMS, Little Rock, AR, USA

Kazuyuki Shimizu, Nagoya City Midori General Hospital, Nagoya, Japan

David Siegel, Hackensack, Cancer Center, Hackensack, NJ, USA

Jesus San Miguel, University of Salamanca, Salamanca, Spain

Chaim Shustik, McGill University, Montreal, Canada

Seema Singhal, Northwestern University, Chicago, IL, USA

Pieter Sonneveld, Erasmus MC, Rotterdam, The Netherlands

Andrew Spencer, The Alfred Hospital, Melbourne, Australia

Edward Stadtmauer, University of Pennsylvania, Philadelphia, PA, USA

A Keith Stewart, Mayo Clinic Arizona, Scottsdale, AZ, USA

Patrizia Tosi, Italian Cooperative Group, Istituto di Ematologia Seragnoli, Bologna, Italy

Guido Tricot, Huntsman Cancer Institute, Salt Lake City, UT, USA

Ingemar Turesson, Department of Hematology, Malmo University, Malmo, Sweden

Brian Van Ness, University of Minnesota, Minneapolis, MN, USA

Ivan Van Riet, Brussels Vrija University, Brussels, Belgium

Robert Vescio, Cedars-Sinai Cancer Center, Los Angeles, CA, USA

David Vesole, Loyola University Chicago, IL, USA

Anders Waage, University Hospital, Trondheim, Norway NSMG

Michael Wang, MD Anderson, Houston, TX, USA

Donna Weber, MD Anderson, Houston, TX, USA

Jan Westin, Sahlgrenska University Hospital, Gothenburg, Sweden

Keith Wheatley, University of Birmingham, Birmingham, UK

Dina B Yehuda, Department of Hematology, Hadassah University Hospital, Hadassah, Israel

Jeffrey Zonder, SWOG, Department of Hem/Onc., Karmanos Cancer Institute, MI, USA

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Fonseca, R., Bergsagel, P., Drach, J. et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia 23, 2210–2221 (2009). https://doi.org/10.1038/leu.2009.174

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