Clinical and Translational Oncology

, Volume 9, Issue 10, pp 618–624 | Cite as

Molecular biology of myeloma

  • N. C. Gutiérrez
  • R. García-Sanz
  • J. F. San Miguel
Educational Series Blue Series


Multiple myeloma (MM) is a B-cell malignancy characterised by the accumulation of clonal plasma cells (PC) in the bone marrow (BM). The molecular bases for this incurable disease have been widely investigated in the last years, and the development of modern genomic technologies has contributed to the understanding of the pathogenesis of MM. The molecular mechanisms that explain the cellular origin of myeloma cells, the cytogenetic abnormalities and their clinical implications, and the biological information provided by gene expression profiling analysis are reviewed in this paper. In addition, a molecular classification of MM in seven groups based on the relationship between gene expression profiling, chromosomal translocations and prognostic outcome is also presented. And finally, the recent hypothesis of a potential unifying event in the pathogenesis of MM, supported by cyclin D deregulation in virtually all MM tumours, will be summarised.

Key words

Myeloma Plasma cell Cytogenetic abnormalities Gene expression profiling 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kyle RA, Therneau TM, Rajkumar SV et al (2002) A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 346:564–569PubMedCrossRefGoogle Scholar
  2. 2.
    Kyle RA, Rajkumar SV (2005) Monoclonal gammopathy of undetermined significance. Clin Lymphoma Myeloma 6:102–114PubMedCrossRefGoogle Scholar
  3. 3.
    Fugmann SD, Lee AI, Shockett PE et al (2000) The RAG proteins and V(D)J recombination: complexes, ends, and transposition. Annu Rev Immunol 18:495–527PubMedCrossRefGoogle Scholar
  4. 4.
    Honjo T, Kinoshita K, Muramatsu M (2002) Molecular mechanism of class switch recombination: linkage with somatic hypermutation. Annu Rev Immunol 20:165–196PubMedCrossRefGoogle Scholar
  5. 5.
    Papavasiliou FN, Schatz DG (2002) Somatic hypermutation of immunoglobulin genes: merging me chanisms for genetic diversity. Cell 109[Suppl]:S35–S44PubMedCrossRefGoogle Scholar
  6. 6.
    González D, van der BM, García-Sanz R et al (2007) Immunoglobulin gene rearrangements and the pathogenesis of multiple myeloma. Blood (in press)Google Scholar
  7. 7.
    Kuppers R (2005) Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer 5:251–262PubMedCrossRefGoogle Scholar
  8. 8.
    Shaffer AL, Rosenwald A, Staudt LM (2002) Lymphoid malignancies: the dark side of B-cell differentiation. Nat Rev Immunol 2:920–932PubMedCrossRefGoogle Scholar
  9. 9.
    Shapiro-Shelef M, Calame K (2005) Regulation of plasma-cell development. Nat Rev Immunol 5:230–242PubMedCrossRefGoogle Scholar
  10. 10.
    Bakkus MH, Heirman C, Van Riet I et al (1992) Evidence that multiple myeloma Ig heavy chain VDJ genes contain somatic mutations but show no intraclonal variation. Blood 80:2326–2335PubMedGoogle Scholar
  11. 11.
    Sahota SS, Leo R, Hamblin TJ et al (1996) Ig VH gene mutational patterns indicate different tumor cell status in human myeloma and monoclonal gammopathy of undetermined significance. Blood 87:746–755PubMedGoogle Scholar
  12. 12.
    Zandecki M, Lai JL, Facon T (1996) Multiple myeloma: almost all patients are cytogenetically abnormal. Br J Haematol 94:217–227PubMedCrossRefGoogle Scholar
  13. 13.
    Fonseca R, Barlogie B, Bataille R et al (2004) Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res 64:1546–1558PubMedCrossRefGoogle Scholar
  14. 14.
    Gutierrez NC, Hernandez JM, Garcia JL et al (2001) Differences in genetic changes between multiple myeloma and plasma cell leukemia demonstrated by comparative genomic hybridization. Leukemia 15:840–845PubMedCrossRefGoogle Scholar
  15. 15.
    Sawyer JR, Lukacs JL, Munshi N et al (1998) Identification of new nonrandom translocations in multiple myeloma with multicolor spectral karyotyping. Blood 92:4269–4278PubMedGoogle Scholar
  16. 16.
    Tabernero D, San Miguel JF, Garcia-Sanz R et al (1996) Incidence of chromosome numerical changes in multiple myeloma. Am J Pathol 149:153–161PubMedGoogle Scholar
  17. 17.
    Zhan F, Hardin J, Kordsmeier B et al (2002) Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells. Blood 99:1745–1757PubMedCrossRefGoogle Scholar
  18. 18.
    Kuehl WM, Bergsagel PL (2002) Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer 2:175–187PubMedCrossRefGoogle Scholar
  19. 19.
    Bergsagel PL, Kuehl WM (2005) Molecular pathogenesis and a consequent classification of multiple myeloma. J Clin Oncol 23:6333–6338PubMedCrossRefGoogle Scholar
  20. 20.
    Ronchetti D, Finelli P, Richelda R et al (1999) Molecular analysis of 11q13 breakpoints in multiple myeloma. Blood 93:1330–1337PubMedGoogle Scholar
  21. 21.
    Chesi M, Nardini E, Lim RS et al (1998) The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood 92:3025–3034PubMedGoogle Scholar
  22. 22.
    Keats JJ, Reiman T, Maxwell CA et al (2003) In multiple myeloma, t(4; 14)(p 16; q32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood 101:1520–1529PubMedCrossRefGoogle Scholar
  23. 23.
    Santra M, Zhan F, Tian E et al (2003) A subset of multiple myeloma harboring the t(4; 14) (p16;q32) translocation lacks FGFR3 expression but maintains an IGH/MMSET fusion transcript. Blood 101:2374–2376PubMedCrossRefGoogle Scholar
  24. 24.
    Chesi M, Nardini E, Brents LA et al (1997) 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 16:260–264PubMedCrossRefGoogle Scholar
  25. 25.
    Grand EK, Chase AJ, Heath C et al (2004) Targeting FGFR3 in multiple myeloma: inhibition of t(4; 14)-positive cells by SU5402 and PD173074. Leukemia 18:962–966PubMedCrossRefGoogle Scholar
  26. 26.
    Trudel S, Li ZH, Wei E et al (2005) CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood 105:2941–2948PubMedCrossRefGoogle Scholar
  27. 27.
    Chesi M, Bergsagel PL, Shonukan OO et al (1998) frequent dysregulation of the c-maf proto-oncogene at 16q23 by translocation to an Ig locus in multiple myeloma. Blood 91:4457–4463PubMedGoogle Scholar
  28. 28.
    Bergsagel PL, Kuehl WM (2001) Chromosome translocations in multiple myeloma. Oncogene 20:5611–5622PubMedCrossRefGoogle Scholar
  29. 29.
    Hurt EM, Wiestner A, Rosenwald A et al (2004) Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes proliferation and pathological interactions with bone marrow stroma. Cancer Cell 5:191–199PubMedCrossRefGoogle Scholar
  30. 30.
    Shaughnessy J Jr, Gabrea A, Qi Y et al (2001) Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma. Blood 98:217–223PubMedCrossRefGoogle Scholar
  31. 31.
    Smadja NV, Fruchart C, Isnard F et al (1998) Chromosomal analysis in multiple myeloma: cytogenetic evidence of two different diseases. Leukemia 12:960–969PubMedCrossRefGoogle Scholar
  32. 32.
    Fonseca R, Debes-Marun CS, Picken EB et al (2003) The recurrent IgH translocations are highly associated with nonhyperdiploid variant multiple myeloma. Blood 102:2562–2567PubMedCrossRefGoogle Scholar
  33. 33.
    Smadja NV, Leroux D, Soulier J et al (2003) Further cytogenetic characterization of multiple myeloma confirms that 14q32 translocations are a very rare event in hyperdiploid cases. Genes Chromosomes Cancer 38:234–239PubMedCrossRefGoogle Scholar
  34. 34.
    Mateo G, Castellanos M, Rasillo A et al (2005) Genetic abnormalities and patterns of antigenic expression in multiple myeloma. Clin Cancer Res 11:3661–3667PubMedCrossRefGoogle Scholar
  35. 35.
    Avet-Louseau H, Daviet A, Sauner S et al (2000) Chromosome 13 abnormalities in multiple myeloma are mostly monosomy 13. Br J Haematol 111:1116–1117PubMedCrossRefGoogle Scholar
  36. 36.
    Fonseca R, Oken MM, Harrington D et al (2001) Deletions of chromosome 13 in multiple myeloma identified by interphase FISH usually denote large deletions of the q arm or monosomy. Leukemia 15:981–986PubMedCrossRefGoogle Scholar
  37. 37.
    Fonseca R, Blood E, Rue M et al (2003) Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 101:4569–4575PubMedCrossRefGoogle Scholar
  38. 38.
    Moreau P, Facon T, Leleu X et al (2002) Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy. Blood 100:1579–1583PubMedCrossRefGoogle Scholar
  39. 39.
    Avet-Loiseau H, Attal M, Moreau P et al (2007) Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myelome. Blood 109:3489–3495PubMedCrossRefGoogle Scholar
  40. 40.
    Gutierrez NC, Castellanos MV, Martin ML et al (2007) 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 21:143–150PubMedCrossRefGoogle Scholar
  41. 41.
    Gutiérrez NC, García JL, Hernández JM et al (2004) Prognostic and biologic significance of chromosomal imbalances assessed by comparative genomic hybridization in multiple myeloma. Blood 104:2661–2666.PubMedCrossRefGoogle Scholar
  42. 42.
    Pérez-Simón JA, García-Sanz R, Tabernero MD et al (1998) Prognostic value of numerical chromosome aberrations in multiple myeloma: A FISH analysis of 15 different chromosomes. Blood 91:3366–3371PubMedGoogle Scholar
  43. 43.
    Shaughnessy J Jr, Tian E, Sawyer J et al (2003) Prognostic impact of cytogenetic and interphase fluorescence in situ hybridization-defined chromosome 13 deletion in multiple myeloma: early results of total therapy II. Br J Haematol 120:44–52PubMedCrossRefGoogle Scholar
  44. 44.
    Tricot G, Barlogie B, Jagannath S et al (1995) 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 86:4250–4256PubMedGoogle Scholar
  45. 45.
    Drach J, Ackermann J, Fritz E et al (1998) Presence of a p53 gene deletion in patients with multiple myeloma predicts for short survival after conventional-dose chemotherapy. Blood 92:802–809PubMedGoogle Scholar
  46. 46.
    Shaughnessy J (2005) Amplification and overexpression of CKS1B at chromosome band 1q21 is associated with reduced levels of p27Kipl and an aggressive clinical course in multiple myeloma. Hematology 10[Suppl 1]:117–126PubMedCrossRefGoogle Scholar
  47. 47.
    Avet-Loiseau H, Facon T, Daviet A et al (1999) 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 59:4546–4550PubMedGoogle Scholar
  48. 48.
    Fonseca R, Bailey RJ, Ahmann GJ et al (2002) Genomic abnormalities in monoclonal gammopathy of undetermined significance. Blood 100:1417–1424PubMedGoogle Scholar
  49. 49.
    Avet-Loiseau H, Li JY, Morineau N et al (1999) Monosomy 13 is associated with the transition of monoclonal gammopathy of undetermined significance to multiple myeloma. Intergroupe Francophone du Myelome. Blood 94:2583–2589PubMedGoogle Scholar
  50. 50.
    Chng WJ, Van Wier SA, Ahmann GJ et al (2005) A validated FISH trisomy index demonstrates the hyperdiploid and nonhyperdiploid dichotomy in MGUS. Blood 106:2156–2161PubMedCrossRefGoogle Scholar
  51. 51.
    Shou Y, Martelli ML, Gabrea A et al (2000) Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma. Proc Natl Acad Sci U S A 97:228–233PubMedCrossRefGoogle Scholar
  52. 52.
    Liu P, Leong T, Quam L et al (1996) 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 88:2699–2706PubMedGoogle Scholar
  53. 53.
    Neri A, Baldini L, Trecca D et al (1993) p53 gene mutations in multiple myeloma are associated with advance of malignancy. Blood 81:128–135PubMedGoogle Scholar
  54. 54.
    Guillerm G, Gyan E, Wolowiec D et al (2001) p16(INK4a) andp15(INK4b) gene methylations in plasma cells from monoclonal gammopathy of undetermined significance. Blood 98:244–246PubMedCrossRefGoogle Scholar
  55. 55.
    Mateos MV, García-Sanz R, López-Pérez R et al (2001) p16/INK4a gene inactivation by hypermethylation is associated with aggressive variants of monoclonal gammopathies. Hematol J 2:146–149PubMedCrossRefGoogle Scholar
  56. 56.
    Davies FE, Dring AM, Li C et al (2003) Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis. Blood 102:4504–4511PubMedCrossRefGoogle Scholar
  57. 57.
    Zhan F, Huang Y, Colla S et al (2006) The molecular classification of multiple myeloma. Blood 108:2020–2028PubMedCrossRefGoogle Scholar
  58. 58.
    Bergsagel PL, Kuehl WM, Zhan F et al (2005) Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood 106:296–303PubMedCrossRefGoogle Scholar

Copyright information

© Feseo 2007

Authors and Affiliations

  • N. C. Gutiérrez
    • 1
    • 2
  • R. García-Sanz
    • 1
    • 2
  • J. F. San Miguel
    • 1
    • 2
  1. 1.Servicio de HematologíaHospital Universitario de SalamancaSalamancaSpain
  2. 2.Centro de Investigación del Cáncer (CIC)Universidad de Salamanca-CSICSalamancaSpain

Personalised recommendations