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Vol 52, No 4 (2021)
Review article
Published online: 2021-08-31

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The importance of cytogenetic and molecular aberrations in multiple myeloma

Artur Jurczyszyn1, Grzegorz Charliński2, Anna Suska1, David H. Vesole3
DOI: 10.5603/AHP.2021.0069
Acta Haematol Pol 2021;52(4):361-370.

Abstract

Multiple myeloma (MM) is a heterogeneous clonal malignancy of plasma cells characterized by cytogenetic and molecular abnormalities. Chromosomal abnormalities are present at diagnosis and can evolve during the progression of MM. Metaphase karyotyping and fluorescence in situ hybridization are considered the standard diagnostic procedures performed in clinical practice. These test results are required to determine the Revised International Staging System classification, treatment algorithms, and short- and long-term prognoses.

Given the dynamic development of cytogenetic and molecular research, we should expect further progress in better understanding the biology of MM and changes to patient care in the coming years.

Keywords: cytogenetic abnormalitiesmultiple myelomaprognosisrisk classifications

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References

  1. Palumbo A, Bringhen S, Ludwig H, et al. Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN). Blood. 2011; 118(17): 4519–4529.
    CrossRefPubMed
  2. Usmani SZ, Hoering A, Cavo M, et al. Clinical predictors of long-term survival in newly diagnosed transplant eligible multiple myeloma - an IMWG Research Project. Blood Cancer J. 2018; 8(12): 123.
    CrossRefPubMed
  3. Raport NFZ. Szpiczak plazmocytowy (mnogi). Ocena jakości informacyjnej rejestru kontraktowego. https://zdrowedane.nfz.gov.pl/pluginfile.php/260/mod_resource/content/1/191231_szpiczak_plazmocytowy.pdf (November 25, 2020).
  4. Rajkumar S, Dimopoulos M, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014; 15(12): e538–e548.
    CrossRef
  5. Morgan GJ, Walker BA, Davies FE. The genetic architecture of multiple myeloma. Nat Rev Cancer. 2012; 12(5): 335–348.
    CrossRefPubMed
  6. Hervé AL, Florence M, Philippe M, et al. Molecular heterogeneity of multiple myeloma: pathogenesis, prognosis, and therapeutic implications. J Clin Oncol. 2011; 29(14): 1893–1897.
    CrossRefPubMed
  7. Talley PJ, Chantry AD, Buckle CH. Genetics in myeloma: genetic technologies and their application to screening approaches in myeloma. Br Med Bull. 2015; 113(1): 15–30.
    CrossRefPubMed
  8. Corre J, Munshi N, Avet-Loiseau H. Genetics of multiple myeloma: another heterogeneity level? Blood. 2015; 125(12): 1870–1876.
    CrossRefPubMed
  9. Zandecki M, Laï JL, Facon T. Multiple myeloma: almost all patients are cytogenetically abnormal. Br J Haematol. 1996; 94(2): 217–227.
    CrossRefPubMed
  10. Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for Multiple Myeloma: a report from International Myeloma Working Group. J Clin Oncol. 2015; 33(26): 2863–2869.
    CrossRefPubMed
  11. Scott EC, Hari P, Kumar S, et al. Staging systems for newly diagnosed myeloma patients undergoing autologous hematopoietic cell transplantation: the Revised International Staging System shows the most differentiation between groups. Biol Blood Marrow Transplant. 2018; 24(12): 2443–2449.
    CrossRefPubMed
  12. mSMART 3.0: Classification of Active MM. https://static1.squarespace.com/static/5b44f08ac258b493a25098a3/t/5b802d8270a6adbc6a79a678/1535126914646/Risk+Strat+3.0rev_svr.pdf (July 1, 2021).
  13. Rajan AM, Rajkumar SV. Interpretation of cytogenetic results in multiple myeloma for clinical practice. Blood Cancer J. 2015; 5: e365.
    CrossRefPubMed
  14. Goldman-Mazur S, Vesole DH, Jurczyszyn A. Clinical implications of cytogenetic and molecular aberrations in multiple myeloma. Acta Haematol Pol. 2021; 52(3): 18–28.
    CrossRef
  15. Landgren O, Kyle RA, Pfeiffer RM, et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood. 2009; 113(22): 5412–5417.
    CrossRefPubMed
  16. Chesi M, Bergsagel PL. Advances in the pathogenesis and diagnosis of multiple myeloma. Int J Lab Hematol. 2015; 37 Suppl 1: 108–114.
    CrossRefPubMed
  17. Manier S, Salem KZ, Park J, et al. Genomic complexity of multiple myeloma and its clinical implications. Nat Rev Clin Oncol. 2017; 14(2): 100–113.
    CrossRefPubMed
  18. Lu G, Muddasani R, Orlowski RZ, et al. Plasma cell enrichment enhances detection of high-risk cytogenomic abnormalities by fluorescence in situ hybridization and improves risk stratification of patients with plasma cell neoplasms. Arch Pathol Lab Med. 2013; 137(5): 625–631.
    CrossRefPubMed
  19. Sonneveld P, Avet-Loiseau H, Lonial S, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016; 127(24): 2955–2962.
    CrossRefPubMed
  20. Flynt E, Bisht K, Sridharan V, et al. Prognosis, biology, and targeting of dysregulation in multiple myeloma. Cells. 2020; 9(2).
    CrossRefPubMed
  21. Bergsagel PL, Kuehl WM, Zhan F, et al. Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood. 2005; 106(1): 296–303.
    CrossRefPubMed
  22. van Laar R, Flinchum R, Brown N, et al. Translating a gene expression signature for multiple myeloma prognosis into a robust high-throughput assay for clinical use. BMC Med Genomics. 2014; 7: 25.
    CrossRefPubMed
  23. Kuiper R, Broyl A, de Knegt Y, et al. A gene expression signature for high-risk multiple myeloma. Leukemia. 2012; 26(11): 2406–2413.
    CrossRefPubMed
  24. Fonseca R, Bergsagel PL, Drach J, et al. International Myeloma Working Group. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia. 2009; 23(12): 2210–2221.
    CrossRefPubMed
  25. Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020; 95(5): 548–567.
    CrossRefPubMed
  26. Giannopoulos K, Jamroziak K, Usnarska-Zubkiewicz L, et al. Zalecenia Polskiej Grupy Szpiczakowej dotyczące rozpoznawania i leczenia szpiczaka plazmocytowego oraz innych dyskrazji plazmocytowych na rok 2018/2019. Acta Haematol Pol. 2018; 49(4): 157–206.
    CrossRef
  27. Smadja NV, Fruchart C, Isnard F, et al. Chromosomal analysis in multiple myeloma: cytogenetic evidence of two different diseases. Leukemia. 1998; 12(6): 960–969.
    CrossRefPubMed
  28. Chng WJ, Ketterling RP, Fonseca R. Analysis of genetic abnormalities provides insights into genetic evolution of hyperdiploid myeloma. Genes Chromosomes Cancer. 2006; 45(12): 1111–1120.
    CrossRefPubMed
  29. Van Wier S, Braggio E, Baker A, et al. Hypodiploid multiple myeloma is characterized by more aggressive molecular markers than non-hyperdiploid multiple myeloma. Haematologica. 2013; 98(10): 1586–1592.
    CrossRefPubMed
  30. Walker BA, Wardell CP, Murison A, et al. APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma. Nat Commun. 2015; 6: 6997.
    CrossRefPubMed
  31. Lim JH, Seo EJ, Park CJ, et al. Cytogenetic classification in Korean multiple myeloma patients: prognostic significance of hyperdiploidy with 47-50 chromosomes and the number of structural abnormalities. Eur J Haematol. 2014; 92(4): 313–320.
    CrossRefPubMed
  32. Pawlyn C, Melchor L, Murison A, et al. Coexistent hyperdiploidy does not abrogate poor prognosis in myeloma with adverse cytogenetics and may precede IGH translocations. Blood. 2015; 125(5): 831–840.
    CrossRefPubMed
  33. Demchenko Y, Roschke A, Chen WD, et al. Frequent occurrence of large duplications at reciprocal genomic rearrangement breakpoints in multiple myeloma and other tumors. Nucleic Acids Res. 2016; 44(17): 8189–8198.
    CrossRefPubMed
  34. Chapman MA, Lawrence MS, Keats JJ, et al. Initial genome sequencing and analysis of multiple myeloma. Nature. 2011; 471(7339): 467–472.
    CrossRefPubMed
  35. Chesi M, Nardini E, Lim R, et al. The t(4;14) translocation in myeloma dysregulates both FGFR3and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood. 1998; 92(9): 3025–3034.
    CrossRef
  36. Keats JJ, Reiman T, Maxwell CA, et al. In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood. 2003; 101(4): 1520–1529.
    CrossRefPubMed
  37. Ludwig H, Miguel JS, Dimopoulos MA, et al. International Myeloma Working Group recommendations for global myeloma care. Leukemia. 2014; 28(5): 981–992.
    CrossRefPubMed
  38. Fonseca R, Blood E, Rue M, et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood. 2003; 101(11): 4569–4575.
    CrossRefPubMed
  39. Tonon G, Anderson K. Multiple myeloma. 4th ed. Elsevier, Philadelphia 2015.
  40. Lauring J, Abukhdeir AM, Konishi H, et al. The multiple myeloma associated MMSET gene contributes to cellular adhesion, clonogenic growth, and tumorigenicity. Blood. 2008; 111(2): 856–864.
    CrossRefPubMed
  41. Narita T, Inagaki A, Kobayashi T, et al. t(14;16)-positive multiple myeloma shows negativity for CD56 expression and unfavorable outcome even in the era of novel drugs. Blood Cancer J. 2015; 5: e285.
    CrossRefPubMed
  42. Avet-Louseau H, Daviet A, Sauner S, et al. Intergroupe Francophone du Myélome. Chromosome 13 abnormalities in multiple myeloma are mostly monosomy 13. Br J Haematol. 2000; 111(4): 1116–1117.
    CrossRefPubMed
  43. Walker BA, Wardell CP, Johnson DC, et al. Characterization of IGH locus breakpoints in multiple myeloma indicates a subset of translocations appear to occur in pregerminal center B cells. Blood. 2013; 121(17): 3413–3419.
    CrossRefPubMed
  44. Mikhael JR, Dingli D, Roy V, et al. Mayo Clinic. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013. Mayo Clin Proc. 2013; 88(4): 360–376.
    CrossRefPubMed
  45. Prideaux SM, Conway O'Brien E, Chevassut TJ. The genetic architecture of multiple myeloma. Adv Hematol. 2014; 2014: 864058.
    CrossRefPubMed
  46. Yoshida S, Nakazawa N, Iida S, et al. Detection of MUM1/IRF4-IgH fusion in multiple myeloma. Leukemia. 1999; 13(11): 1812–1816.
    CrossRefPubMed
  47. Heintel D, Zojer N, Schreder M, et al. Expression of MUM1/IRF4 mRNA as a prognostic marker in patients with multiple myeloma. Leukemia. 2008; 22(2): 441–445.
    CrossRefPubMed
  48. An G, Xu Y, Shi L, et al. Chromosome 1q21 gains confer inferior outcomes in multiple myeloma treated with bortezomib but copy number variation and percentage of plasma cells involved have no additional prognostic value. Haematologica. 2014; 99(2): 353–359.
    CrossRefPubMed
  49. Jian Y, Chen X, Zhou H, et al. Prognostic impact of cytogenetic abnormalities in multiple myeloma: a retrospective analysis of 229 patients. Medicine (Baltimore). 2016; 95(19): e3521.
    CrossRefPubMed
  50. Fonseca R, Debes-Marun CS, Picken EB, et al. The recurrent IgH translocations are highly associated with nonhyperdiploid variant multiple myeloma. Blood. 2003; 102(7): 2562–2567.
    CrossRefPubMed
  51. Fonseca R, Van Wier SA, Chng WJ, et al. Prognostic value of chromosome 1q21 gain by fluorescent in situ hybridization and increase CKS1B expression in myeloma. Leukemia. 2006; 20(11): 2034–2040.
    CrossRefPubMed
  52. Zhan F, Colla S, Wu X, et al. CKS1B, overexpressed in aggressive disease, regulates multiple myeloma growth and survival through SKP2- and p27Kip1-dependent and -independent mechanisms. Blood. 2007; 109(11): 4995–5001.
    CrossRefPubMed
  53. Shi L, Wang S, Zangari M, et al. Over-expression of CKS1B activates both MEK/ERK and JAK/STAT3 signaling pathways and promotes myeloma cell drug-resistance. Oncotarget. 2010; 1(1): 22–33.
    CrossRefPubMed
  54. Hebraud B, Leleu X, Lauwers-Cances V, et al. Deletion of the 1p32 region is a major independent prognostic factor in young patients with myeloma: the IFM experience on 1195 patients. Leukemia. 2014; 28(3): 675–679.
    CrossRefPubMed
  55. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. The Lancet. 2019; 394(10192): 29–38.
    CrossRef
  56. Attal M, Lauwers-Cances V, Hulin C, et al. IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017; 376(14): 1311–1320.
    CrossRefPubMed
  57. Ludwig H, Beksac M, Bladé J, et al. Current multiple myeloma treatment strategies with novel agents: a European perspective. Oncologist. 2010; 15(1): 6–25.
    CrossRefPubMed
  58. Chang H, Qi C, Yi QL, et al. 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(1): 358–360.
    CrossRefPubMed
  59. Hu B, Thall P, Milton DR, et al. High-risk myeloma and minimal residual disease postautologous-HSCT predict worse outcomes. Leuk Lymphoma. 2019; 60(2): 442–452.
    CrossRefPubMed
  60. Avet-Loiseau H, Attal M, Campion L, et al. Long-term analysis of the IFM 99 trials for myeloma: cytogenetic abnormalities [t(4;14), del(17p), 1q gains] play a major role in defining long-term survival. J Clin Oncol. 2012; 30(16): 1949–1952.
    CrossRefPubMed
  61. Tiedemann RE, Gonzalez-Paz N, Kyle RA, et al. Genetic aberrations and survival in plasma cell leukemia. Leukemia. 2008; 22(5): 1044–1052.
    CrossRefPubMed
  62. Merz M, Jauch A, Hielscher T, et al. Longitudinal fluorescence hybridization reveals cytogenetic evolution in myeloma relapsing after autologous transplantation. Haematologica. 2017; 102(8): 1432–1438.
    CrossRefPubMed
  63. Herrero AB, Rojas EA, Misiewicz-Krzeminska I, et al. Molecular mechanisms of p53 deregulation in cancer: an overview in multiple myeloma. Int J Mol Sci. 2016; 17(12).
    CrossRefPubMed
  64. Chang H, Sloan S, Li D, et al. Multiple myeloma involving central nervous system: high frequency of chromosome 17p13.1 (p53) deletions. Br J Haematol. 2004; 127(3): 280–284.
    CrossRefPubMed
  65. Bergsagel PL, Mateos MV, Gutierrez NC, et al. Improving overall survival and overcoming adverse prognosis in the treatment of cytogenetically high-risk multiple myeloma. Blood. 2013; 121(6): 884–892.
    CrossRefPubMed
  66. Gay F, Cerrato C, Petrucci M, et al. Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: Results from the FORTE trial. J Clin Oncol. 2019; 37(15_suppl): 8002–8002.
    CrossRef
  67. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020; 136(8): 936–945.
    CrossRefPubMed
  68. Avet-Loiseau H, Moreau P, Attal M, et al. Efficacy of daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) in transplant-eligible newly diagnosed multiple myeloma (TE NDMM) based on minimal residual disease (MRD) status: Analysis of the CASSIOPEIA trial. J Clin Oncol. 2019; 37(15_suppl): 8017–8017.
    CrossRef
  69. Cavo M, Petrucci M, Raimondo FDi, et al. Upfront single versus double autologous stem cell transplantation for newly diagnosed multiple myeloma: an intergroup, multicenter, phase III study of the European Myeloma Network (EMN02/HO95 MM trial). Blood. 2016; 128(22): 991–991.
    CrossRef
  70. Hari P, Pasquini M, Stadtmauer E, et al. Long-term follow-up of BMT CTN 0702 (STaMINA) of postautologous hematopoietic cell transplantation (autoHCT) strategies in the upfront treatment of multiple myeloma (MM). J Clin Oncol. 2020; 38(15_suppl): 8506–8506.
    CrossRef
  71. Jackson GH, Davies FE, Pawlyn C, et al. UK NCRI Haematological Oncology Clinical Studies Group. Response-adapted intensification with cyclophosphamide, bortezomib, and dexamethasone versus no intensification in patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Haematol. 2019; 6(12): e616–e629.
    CrossRefPubMed
  72. Chng WJ, Goldschmidt H, Dimopoulos MA, et al. Carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study ENDEAVOR. Leukemia. 2017; 31(6): 1368–1374.
    CrossRefPubMed
  73. Avet-Loiseau H, Fonseca R, Siegel D, et al. Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma. Blood. 2016; 128(9): 1174–1180.
    CrossRefPubMed
  74. Moreau P, Masszi T, Grzasko N, et al. TOURMALINE-MM1 Study Group. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016; 374(17): 1621–1634.
    CrossRefPubMed
  75. Dimopoulos M, Gay F, Schjesvold F, et al. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial. The Lancet. 2019; 393(10168): 253–264.
    CrossRef
  76. Leleu X, Karlin L, Macro M, et al. Intergroupe Francophone du Myélome (IFM). Pomalidomide plus low-dose dexamethasone in multiple myeloma with deletion 17p and/or translocation (4;14): IFM 2010-02 trial results. Blood. 2015; 125(9): 1411–1417.
    CrossRefPubMed
  77. Durie BGM, Hoering A, Abidi M, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017; 389(10068): 519–527.
    CrossRef
  78. Mateos MV, Dimopoulos MA, Cavo M, et al. ALCYONE Trial Investigators. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018; 378(6): 518–528.
    CrossRefPubMed
  79. Facon T, Kumar S, Plesner T, et al. MAIA Trial Investigators. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019; 380(22): 2104–2115.
    CrossRefPubMed
  80. Costa L, Chhabra S, Godby K, et al. Daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRD) induction, autologous transplantation and MRD response-adapted consolidation in newly diagnosed multiple myeloma. EHA Libr. 2020; 294845: EP928.
  81. Kaufman JL, Usmani S, San-Miguel J, et al. Four-year follow-up of the phase 3 Pollux study of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) alone in relapsed or refractory multiple myeloma (RRMM). Blood. 2019; 134(Suppl_1): 1866–1866.
    CrossRef
  82. Richardson PG, Oriol A, Beksac M, et al. OPTIMISMM trial investigators. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Lancet Oncol. 2019; 20(6): 781–794.
    CrossRefPubMed
  83. Attal M, Richardson P, Rajkumar S, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019; 394(10214): 2096–2107.
    CrossRef
  84. Rosiñol L, Oriol A, Rios R, et al. Bortezomib, lenalidomide, and dexamethasone as induction therapy prior to autologous transplant in multiple myeloma. Blood. 2019; 134(16): 1337–1345.
    CrossRefPubMed
  85. Dhodapkar MV, Sexton R, Waheed S, et al. Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120). Blood. 2014; 123(1): 78–85.
    CrossRefPubMed
  86. Palumbo A, Chanan-Khan A, Weisel K, et al. CASTOR Investigators. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016; 375(8): 754–766.
    CrossRefPubMed

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