open access

Vol 52, No 4 (2021)
Review article
Submitted: 2021-07-29
Accepted: 2021-07-29
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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.
Affiliations
  1. Plasma Cell Dyscrasia Center, Department of Hematology, Jagiellonian University Medical College, Krakow, Poland
  2. Department of Hematology, Warmian-Masurian Cancer Center of the Ministry of the Interior and Administration’s Hospital, Olsztyn, Poland
  3. John Theurer Cancer Center at Hackensack Meridian School of Medicine, Hackensack, New Jersey, USA

open access

Vol 52, No 4 (2021)
REVIEW ARTICLE
Submitted: 2021-07-29
Accepted: 2021-07-29

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.

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.

Get Citation

Keywords

cytogenetic abnormalities, multiple myeloma, prognosis, risk classifications

About this article
Title

The importance of cytogenetic and molecular aberrations in multiple myeloma

Journal

Acta Haematologica Polonica

Issue

Vol 52, No 4 (2021)

Article type

Review article

Pages

361-370

DOI

10.5603/AHP.2021.0069

Bibliographic record

Acta Haematol Pol 2021;52(4):361-370.

Keywords

cytogenetic abnormalities
multiple myeloma
prognosis
risk classifications

Authors

Artur Jurczyszyn
Grzegorz Charliński
Anna Suska
David H. Vesole

References (86)
  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.
  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.
  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.
  5. Morgan GJ, Walker BA, Davies FE. The genetic architecture of multiple myeloma. Nat Rev Cancer. 2012; 12(5): 335–348.
  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.
  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.
  8. Corre J, Munshi N, Avet-Loiseau H. Genetics of multiple myeloma: another heterogeneity level? Blood. 2015; 125(12): 1870–1876.
  9. Zandecki M, Laï JL, Facon T. Multiple myeloma: almost all patients are cytogenetically abnormal. Br J Haematol. 1996; 94(2): 217–227.
  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.
  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.
  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.
  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.
  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.
  16. Chesi M, Bergsagel PL. Advances in the pathogenesis and diagnosis of multiple myeloma. Int J Lab Hematol. 2015; 37 Suppl 1: 108–114.
  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.
  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.
  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.
  20. Flynt E, Bisht K, Sridharan V, et al. Prognosis, biology, and targeting of dysregulation in multiple myeloma. Cells. 2020; 9(2).
  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.
  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.
  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.
  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.
  25. Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020; 95(5): 548–567.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  34. Chapman MA, Lawrence MS, Keats JJ, et al. Initial genome sequencing and analysis of multiple myeloma. Nature. 2011; 471(7339): 467–472.
  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.
  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.
  37. Ludwig H, Miguel JS, Dimopoulos MA, et al. International Myeloma Working Group recommendations for global myeloma care. Leukemia. 2014; 28(5): 981–992.
  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.
  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.
  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.
  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.
  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.
  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.
  45. Prideaux SM, Conway O'Brien E, Chevassut TJ. The genetic architecture of multiple myeloma. Adv Hematol. 2014; 2014: 864058.
  46. Yoshida S, Nakazawa N, Iida S, et al. Detection of MUM1/IRF4-IgH fusion in multiple myeloma. Leukemia. 1999; 13(11): 1812–1816.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  61. Tiedemann RE, Gonzalez-Paz N, Kyle RA, et al. Genetic aberrations and survival in plasma cell leukemia. Leukemia. 2008; 22(5): 1044–1052.
  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.
  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).
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.

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