Stratification of Patients with Multiple Myeloma: State-of-the-Art and Prospects

AUTOIMMUNE THROMBOCYTOPENIA ,

AYu Aksenova1, AS Zhuk2, EI Stepchenkova1,3, SV Gritsaev4

1 Saint Petersburg State University, 7/9 Universitetskaya nab., Saint Petersburg, Russian Federation, 199034

2 ITMO National Research University, 49 lit. A Kronverkskii pr-t, Saint Petersburg, Russian Federation, 197101

3 NI Vavilov Institute of General Genetics, Saint Petersburg branch, 7/9 Universitetskaya nab., Saint Petersburg, Russian Federation, 199034

4 Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya ul., Saint Petersburg, Russian Federation, 191024

For correspondence: Anna Yurevna Aksenova, PhD in Biology, 17 Botanicheskaya ul., Saint Petersburg, Russian Federation, 198504; Tel.: +7(812)428-40-09; e-mail: a.aksenova@spbu.ru; Sergei Vasilevich Gritsaev, MD, PhD, 16 2-ya Sovetskaya ul., Saint Petersburg, Russian Federation, 191024; Tel.: +7(812)717-54-68; e-mail: gritsaevsv@mail.ru

For citation: Aksenova AYu, Zhuk AS, Stepchenkova EI, Gritsaev SV. Stratification of Patients with Multiple Myeloma: State-of-the-Art and Prospects. Clinical oncohematology. 2022;15(3):259–70. (In Russ).

DOI: 10.21320/2500-2139-2022-15-3-259-270

ABSTRACT

In recent years, there has been a substantial progress in improving progression-free survival (PFS) and quality of life of multiple myeloma (MM) patients. This has become possible through implementation of novel drugs into clinical practice which were developed on the basis of multiomic molecular genetic studies in MM. The results of these studies also enabled to assess genetic heterogeneity of tumor cells in MM. That allowed to identify types and prevalence of single-nucleotide variations, structural chromosomal aberrations, and abnormal copy numbers of chromosomes in the genome of malignant plasma cells. It was shown that MM patients can have quite different spectra of detected genetic defects in the tumor. High genetic disease heterogeneity is one of the major causes of differences in drug efficacy and PFS. The present review comprehensively discusses the value of some chromosomal aberrations in risk stratification of MM patients. It describes the most prevalent aberrations, also those associated with high and low risk of early MM progression which have already been included in different international prognostic scores. Besides, the additional aberrations were determined which are potentially applicable in clinical practice. Special attention was paid to risk assessment in case a number of different chromosome rearrangements are identified in a patient. The review outlines challenges and prospects of dealing with the information on chromosome rearrangements in choosing the most optimal treatment strategy and assessing of its efficacy. In this context, emphasis is laid on integrating genetic data and such clinical parameters as age, comorbidity, renal failure, bone lesions, indications for autologous hematopoietic stem cell transplantation, etc.

Keywords: multiple myeloma, international staging systems, chromosome rearrangements, R-ISS, R2-ISS, mSMART, MASS.

Received: March 28, 2022

Accepted: June 5, 2022

Read in PDF

Статистика Plumx английский

REFERENCES

  1. Бессмельцев C.C. Множественная миелома (патогенез, клиника, диагностика, дифференциальный диагноз). Часть I. Онкогематология. 2013;3(6):237–57.
    [Bessmeltsev SS. Multiple myeloma (pathogenesis, clinical features, diagnosis, differential diagnosis). Part I. Onkogematologiya. 2013;3(6):237–57. (In Russ)]
  2. Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95(5):548–67. doi: 10.1002/ajh.25791.
  3. Binder M, Nandakumar B, Rajkumar SV, et al. Mortality trends in multiple myeloma after the introduction of novel therapies in the United States. Leukemia. 2021;36(3):801–8. doi: 10.1038/s41375-021-01453-5.
  4. Chalopin T, Vallet N, Theisen O, et al. No survival improvement in patients with high-risk multiple myeloma harbouring del(17p) and/or t(4;14) over the two past decades. Br J Haematol. 2021;194(3):635–8. doi: 10.1111/bjh.17488.
  5. Aksenova AY, Zhuk AS, Lada AG, et al. Genome Instability in Multiple Myeloma: Facts and Factors. Cancers. 2021;13(23):5949. doi: 10.3390/cancers13235949.
  6. Rasillo A, Tabernero MD, Sanchez ML, et al. Fluorescence in situ hybridization analysis of aneuploidization patterns in monoclonal gammopathy of undetermined significance versus multiple myeloma and plasma cell leukemia. Cancer. 2003;97(3):601–9. doi: 10.1002/cncr.11100.
  7. Rajkumar SV, Kumar S. Multiple myeloma current treatment algorithms. Blood Cancer J. 2020;10(9):94. doi: 10.1038/s41408-020-00359-2.
  8. 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. doi: 10.1038/ncomms7997.
  9. Rustad EH, Yellapantula V, Leongamornlert D, et al. Timing the initiation of multiple myeloma. Nat Commun. 2020;11(1):1–14. doi: 10.1038/s41467-020-15740-9.
  10. Plowright EE, Li Z, Bergsagel PL, et al. Ectopic expression of fibroblast growth factor receptor 3 promotes myeloma cell proliferation and prevents apoptosis. Blood. 2000;95(3):992–8.
  11. Alvarez JV, Frank DA. Genome-wide analysis of STAT target genes: Elucidating the mechanism of STAT-mediated oncogenesis. Cancer Biol Ther. 2004;3(11):1045–50. doi: 10.4161/cbt.3.11.1172.
  12. Ramlee MK, Wang J, Toh WX, Li S. Transcription regulation of the human telomerase reverse transcriptase (hTERT) gene. Genes. 2016;7(8):50. doi: 10.3390/genes7080050.
  13. Marango J, Shimoyama M, Nishio H, et al. The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor. Blood. 2008;111(6):3145–54. doi: 10.1182/blood-2007-06-092122.
  14. Xie Z, Chng WJ. MMSET: Role and therapeutic opportunities in multiple myeloma. Biomed Res Int. 2014;2014:636514. doi: 10.1155/2014/636514.
  15. Dutta AK, Fink JL, Grady JP, et al. Subclonal evolution in disease progression from MGUS/SMM to multiple myeloma is characterised by clonal stability. Leukemia. 2019;33(2):457–68. doi: 10.1038/s41375-018-0206-x.
  16. Maura F, Bolli N, Rustad EH, et al. Moving from Cancer Burden to Cancer Genomics for Smoldering Myeloma: A Review. JAMA Oncol. 2020;6(3):425–32. doi: 10.1001/jamaoncol.2019.4659.
  17. Maura F, Bolli N, Angelopoulos N, et al. Genomic landscape and chronological reconstruction of driver events in multiple myeloma. Nat Commun. 2019;10(1):1–12. doi: 10.1038/s41467-019-11680-1.
  18. Konigsberg R, Ackermann J, Kaufmann H, et al. Deletions of chromosome 13q in monoclonal gammopathy of undetermined significance. Leukemia. 2000;14(11):1975–9. doi: 10.1038/sj.leu.2401909.
  19. Avet-Loiseau H, Li JY, Morineau N, 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(8):2583–9.
  20. Shaughnessy J, Tian E, Sawyer J, et al. High incidence of chromosome 13 deletion in multiple myeloma detected by multiprobe interphase FISH. Blood. 2000;96(4):1505–11. doi: 10.1182/blood.v96.4.1505.
  21. Walker BA, Leone PE, Chiecchio L, et al. A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value. Blood. 2010;116(15). doi: 10.1182/blood-2010-04-279596.
  22. Chavan SS, He J, Tytarenko R, et al. Bi-allelic inactivation is more prevalent at relapse in multiple myeloma, identifying RB1 as an independent prognostic marker. Blood Cancer J. 2017;7(2):e535. doi: 10.1038/bcj.2017.12.
  23. Walker BA, Mavrommatis K, Wardell CP, et al. Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma. Blood. 2018;132(6):587–97. doi: 10.1182/blood-2018-03-840132.
  24. Manier S, Salem KZ, Park J, et al. Genomic complexity of multiple myeloma and its clinical implications. Nat Rev Clin Oncol. 2017;14(2):100–13. doi: 10.1038/nrclinonc.2016.122.
  25. Lode L, Eveillard M, Trichet V, et al. Mutations in TP53 are exclusively associated with del(17p) in multiple myeloma. Haematologica. 2010;95(11):1973–6. doi: 10.3324/haematol.2010.023697.
  26. Oliva S, De Paoli L, Ruggeri M, et al. A longitudinal analysis of chromosomal abnormalities in disease progression from MGUS/SMM to newly diagnosed and relapsed multiple myeloma. Ann Hematol. 2021;100(2):437–43. doi: 10.1007/s00277-020-04384-w.
  27. Lopez-Corral L, Gutierrez NC, Vidriales MB, et al. The progression from MGUS to smoldering myeloma and eventually to multiple myeloma involves a clonal expansion of genetically abnormal plasma cells. Clin Cancer Res. 2011;17(7):1692–700. doi: 10.1158/1078-0432.CCR-10-1066.
  28. Mikulasova A, Smetana J, Wayhelova M, et al. Genomewide profiling of copy-number alteration in monoclonal gammopathy of undetermined significance. Eur J Haematol. 2016;97(6):568–75. doi: 10.1111/EJH.12774.
  29. Bolli N, Avet-Loiseau H, Wedge DC, et al. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat Commun. 2014;5(1):1–13. doi: 10.1038/ncomms3997.
  30. Walker BA, Boyle EM, Wardell CP, et al. Mutational Spectrum, Copy Number Changes, and Outcome: Results of a Sequencing Study of Patients With Newly Diagnosed Myeloma. J Clin Oncol. 2015;33(33):3911–20. doi: 10.1200/JCO.2014.59.1503.
  31. Bolli N, Biancon G, Moarii M, et al. Analysis of the genomic landscape of multiple myeloma highlights novel prognostic markers and disease subgroups. Leukemia. 2018;32(12):2604–16. doi: 10.1038/s41375-018-0037-9.
  32. Avet-Loiseau H, Attal M, Moreau P, et al. Genetic abnormalities and survival in multiple myeloma: The experience of the Intergroupe Francophone du Myelome. Blood. 2007;109(8):3489–95. doi: 10.1182/blood-2006-08-040410.
  33. Jovanovic KK, Escure G, Demonchy J, et al. Deregulation and targeting of TP53 pathway in multiple myeloma. Front Oncol. 2019;8:665. doi: 10.3389/fonc.2018.00665.
  34. Walker BA, Mavrommatis K, Wardell CP, et al. A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis. Leukemia. 2019;33(1):159–70. doi: 10.1038/s41375-018-0196-8.
  35. Chin M, Sive JI, Allen C, et al. Prevalence and timing of TP53 mutations in del(17p) myeloma and effect on survival. Blood Cancer J. 2017;7(9):e610. doi: 10.1038/bcj.2017.76.
  36. Corre J, Perrot A, Caillot D, et al. del(17p) without TP53 mutation confers a poor prognosis in intensively treated newly diagnosed patients with multiple myeloma. Blood. 2021;137(9):1192–5. doi: 10.1182/blood.2020008346.
  37. Martello M, Poletti A, Borsi E, et al. Clonal and subclonal TP53 molecular impairment is associated with prognosis and progression in multiple myeloma. Blood Cancer J. 2022;12(1):15. doi: 10.1038/S41408-022-00610-Y.
  38. Абрамова Т.В., Обухова Т.Н., Грибанова Е.О. и др. Структура и значение цитогенетических перестроек у больных множественной миеломой. Гематология и трансфузиология. 2021;66(1):54–67. doi: 10.35754/0234-5730-2021-66-1-54-67.
    [Abramova TV, Obukhova TN, Gribanova EO, et al. Structure and significance of cytogenetic abnormalities in patients with multiple myeloma. Russian journal of hematology and transfusiology. 2021;66(1):54–67. doi: 10.35754/0234-5730-2021-66-1-54-67. (In Russ)]
  39. Schmidt TM, Fonseca R, Usmani SZ. Chromosome 1q21 abnormalities in multiple myeloma. Blood Cancer J. 2021;11(4):1–11. doi: 10.1038/s41408-021-00474-8.
  40. 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. doi: 10.18632/ONCOTARGET.105.
  41. Schmidt TM, Barwick BG, Joseph N, et al. Gain of Chromosome 1q is associated with early progression in multiple myeloma patients treated with lenalidomide, bortezomib, and dexamethasone. Blood Cancer J. 2019;9(12):94. doi: 10.1038/s41408-019-0254-0.
  42. Neben K, Lokhorst HM, Jauch A, et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012;119(4):940–8. doi: 10.1182/blood-2011-09-379164.
  43. Minguela A, Vasco-Mogorron MA, Campillo JA, et al. Predictive value of 1q21 gain in multiple myeloma is strongly dependent on concurrent cytogenetic abnormalities and first-line treatment. Am J Cancer Res. 2021;11(9):4438.
  44. Giri S, Huntington SF, Wang R, et al. Chromosome 1 abnormalities and survival of patients with multiple myeloma in the era of novel agents. Blood Adv. 2020;4(10):2245–53. doi: 10.1182/bloodadvances.2019001425.
  45. Weinhold N, Salwender HJ, Cairns DA, et al. Chromosome 1q21 abnormalities refine outcome prediction in patients with multiple myeloma – a meta-analysis of 2,596 trial patients. Haematologica. 2021;106(10):2754–8. doi: 10.3324/HAEMATOL.2021.278888.
  46. Shaughnessy J. Amplification and overexpression of CKS1B at chromosome band 1q21 is associated with reduced levels of p27 Kip1 and an aggressive clinical course in multiple myeloma. Hematology. 2005;10(Suppl 1):117–26. doi: 10.1080/10245330512331390140.
  47. Hanamura I. Gain/amplification of chromosome arm 1q21 in multiple myeloma. Cancers. 2021;13(2):1–16. doi: 10.3390/cancers13020256.
  48. Mikulasova A, Wardell CP, Murison A, et al. The spectrum of somatic mutations in monoclonal gammopathy of undetermined significance indicates a less complex genomic landscape than that in multiple myeloma. Haematologica. 2017;102(9):1617–25. doi: 10.3324/haematol.2017.163766.
  49. Hanamura I, Stewart JP, Huang Y, 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(5):1724–32. doi: 10.1182/blood-2006-03-009910.
  50. Greipp PR, Miguel JS, Dune BGM, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23(15):3412–20. doi: 10.1200/JCO.2005.04.242.
  51. Dimopoulos MA, Barlogie B, Smith TL, Alexanian R. High serum lactate dehydrogenase level as a marker for drug resistance and short survival in multiple myeloma. Ann Intern Med. 1991;115(12):931–5. doi: 10.7326/0003-4819-115-12-931.
  52. Terpos E, Katodritou E, Roussou M, et al. High serum lactate dehydrogenase adds prognostic value to the international myeloma staging system even in the era of novel agents. Eur J Haematol. 2010;85(2):114–9. doi: 10.1111/J.1600-0609.2010.01466.X.
  53. Fonseca R, Bergsagel PL, Drach J, et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia. 2009;23(12):2210–21. doi: 10.1038/LEU.2009.174.
  54. Chng WJ, Dispenzieri A, Chim CS, et al. IMWG consensus on risk stratification in multiple myeloma. Leukemia. 2014;28(2):269–77. doi: 10.1038/LEU.2013.247.
  55. 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):2863–9. doi: 10.1200/JCO.2015.61.2267.
  56. Boyd KD, Ross FM, Chiecchio L, et al. A novel prognostic model in myeloma based on co-segregating adverse FISH lesions and the ISS: analysis of patients treated in the MRC Myeloma IX trial. Leukemia. 2012;26(2):349–55. doi: 10.1038/LEU.2011.204.
  57. Ravi G, Gonsalves WI. Current diagnosis, risk stratification and treatment paradigms in newly diagnosed multiple myeloma. Cancer Treat Res Commun. 2021;29:100444. doi: 10.1016/J.CTARC.2021.100444.
  58. Wallington-Beddoe CT, Mynott RL. Prognostic and predictive biomarker developments in multiple myeloma. J Hematol Oncol. 2021;14(1):1–15. doi: 10.1186/S13045-021-01162-7.
  59. Mikhael JR, Dingli D, Roy V, et al. 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):360–76. doi: 10.1016/J.MAYOCP.2013.01.019.
  60. Dispenzieri A, Rajkumar SV, Gertz MA, et al. Treatment of newly diagnosed multiple myeloma based on Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART): consensus statement. Mayo Clin Proc. 2007;82(3):323–41. doi: 10.4065/82.3.323.
  61. Cho HJ, Jung SH, Jo JC, et al. Development of a new risk stratification system for patients with newly diagnosed multiple myeloma using R-ISS and 18F-FDG PET/CT. Blood Cancer J. 2021;11(12):190. doi: 10.1038/S41408-021-00577-2.
  62. Galieni P, Travaglini F, Vagnoni D, et al. The detection of circulating plasma cells may improve the Revised International Staging System (R-ISS) risk stratification of patients with newly diagnosed multiple myeloma. Br J Haematol. 2021;193(3):542–50. doi: 10.1111/BJH.17118.
  63. Mellors PW, Binder M, Ketterling RP, et al. Metaphase cytogenetics and plasma cell proliferation index for risk stratification in newly diagnosed multiple myeloma. Blood Adv. 2020;4(10):2236. doi: 10.1182/BLOODADVANCES.2019001275.
  64. Terpos E, Katodritou E, Tsiftsakis E, et al. Cystatin-C is an independent prognostic factor for survival in multiple myeloma and is reduced by bortezomib administration. Haematologica. 2009;94(3):372–9. doi: 10.3324/HAEMATOL.2008.000638.
  65. Zhang J, Jiang Y, Guo D, et al. The role of cystatin C in multiple myeloma. Int J Lab Hematol. 2022;44(1):135–41. doi: 10.1111/IJLH.13695.
  66. Chen X, Liu L, Chen M, et al. A Five-Gene Risk Score Model for Predicting the Prognosis of Multiple Myeloma Patients Based on Gene Expression Profiles. Front Genet. 2021;12:785330. doi: 10.3389/FGENE.2021.785330/BIBTEX.
  67. Rangel-Pozzo A, Yu PLI, Lal S, et al. Telomere Architecture Correlates with Aggressiveness in Multiple Myeloma. Cancers. 2021;13(8):1969. doi: 10.3390/CANCERS13081969.
  68. D’Agostino M, Lahuerta J-J, Wester R, et al. A New Risk Stratification Model (R2-ISS) in Newly Diagnosed Multiple Myeloma: Analysis of Mature Data from 7077 Patients Collected By European Myeloma Network within Harmony Big Data Platform. Blood. 2020;136(Suppl 1):34–7. doi: 10.1182/blood-2020-137021.
  69. Abdallah NH, Binder M, Rajkumar SV, et al. A simple additive staging system for newly diagnosed multiple myeloma. Blood Cancer J. 2022;12(1):21. doi: 10.1038/S41408-022-00611-X.
  70. Dimopoulos MA, Moreau P, Terpos E, et al. Multiple Myeloma: EHA-ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-up. HemaSphere. 2021;5(2):e528. doi: 10.1097/HS9.0000000000000528.
  71. Touzeau C, Maciag P, Amiot M, Moreau P. Targeting Bcl-2 for the treatment of multiple myeloma. Leukemia. 2018;32(9):1899–907. doi: 10.1038/s41375-018-0223-9.
  72. Paner A, Patel P, Dhakal B. The evolving role of translocation t(11;14) in the biology, prognosis, and management of multiple myeloma. Blood Rev. 2020;41:100643. doi: 10.1016/j.blre.2019.100643.
  73. Greenberg AJ, Rajkumar S V, Therneau TM, et al. Relationship between initial clinical presentation and the molecular cytogenetic classification of myeloma. Leukemia. 2014;28(2):398–403. doi: 10.1038/LEU.2013.258.
  74. Abdallah N, Rajkumar SV, Greipp P, et al. Cytogenetic abnormalities in multiple myeloma: association with disease characteristics and treatment response. Blood Cancer J. 2020;10(8):1–9. doi: 10.1038/s41408-020-00348-5.
  75. Sato S, Kamata W, Okada S, Tamai Y. Clinical and prognostic significance of t(4;14) translocation in multiple myeloma in the era of novel agents. Int J Hematol. 2021;113(2):207–13. doi: 10.1007/S12185-020-03005-6.
  76. Shah MY, Martinez-Garcia E, Phillip JM, et al. MMSET/WHSC1 enhances DNA damage repair leading to an increase in resistance to chemotherapeutic agents. Oncogene. 2016;35(45):5905–15. doi: 10.1038/onc.2016.116.
  77. Jaksic W, Trudel S, Chang H, et al. Clinical outcomes in t(4;14) multiple myeloma: a chemotherapy-sensitive disease characterized by rapid relapse and alkylating agent resistance. J Clin Oncol. 2005;23(28):7069–73. doi: 10.1200/JCO.2005.17.129.
  78. Avet-Loiseau H, Leleu X, Roussel M, 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(30):4630–4. doi: 10.1200/JCO.2010.28.3945.
  79. 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):353–9. doi: 10.3324/haematol.2013.088211.
  80. Caro J, Al Hadidi S, Usmani S, et al. How to Treat High-Risk Myeloma at Diagnosis and Relapse. Am Soc Clin Oncol Educ Book. 2021;41(41):291–309. doi: 10.1200/edbk_320105.
  81. Marneni N, Chakraborty R. Current Approach to Managing Patients with Newly Diagnosed High-Risk Multiple Myeloma. Curr Hematol Malig Rep. 2021;16(2):148–61. doi: 10.1007/S11899-021-00631-7.
  82. Rajkumar SV. Sequencing of myeloma therapy: Finding the right path among many standards. Hematol Oncol. 2021;39(Suppl 1):68–72. doi: 10.1002/HON.2848.
  83. Bal S, Giri S, Godby KN, Costa LJ. New regimens and directions in the management of newly diagnosed multiple myeloma. Am J Hematol. 2021;96(3):367–78. doi: 10.1002/AJH.26080.
  84. Ntanasis-Stathopoulos I, Gavriatopoulou M, Kastritis E, et al. Multiple myeloma: Role of autologous transplantation. Cancer Treat Rev. 2020;82:101929. doi: 10.1016/j.ctrv.2019.101929.
  85. Cavo M, Gay F, Beksac M, et al. Autologous haematopoietic stem-cell transplantation versus bortezomib–melphalan–prednisone, with or without bortezomib–lenalidomide–dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): multicentre, randomised, open-label, phase 3 study. Lancet Haematol. 2020;7(6):e456–e468. doi: 10.1016/S2352-3026(20)30099-5.
  86. Vaxman I, Visram A, Kapoor P, et al. Outcomes of multiple myeloma patients with del 17p undergoing autologous stem cell transplantation. Am J Hematol. 2021;96(1):E35–E38. doi: 10.1002/AJH.26023.
  87. Gagelmann N, Eikema DJ, de Wreede LC, et al. Upfront stem cell transplantation for newly diagnosed multiple myeloma with del(17p) and t(4;14): a study from the CMWP-EBMT. Bone Marrow Transplant. 2021;56(1):210–7. doi: 10.1038/S41409-020-01007-W.
  88. Srour SA, Saliba RM, Bashir Q, et al. Influence of Overlapping Genetic Abnormalities on Treatment Outcomes of Multiple Myeloma. Transplant Cell Ther. 2021;27(3):243.e1–243.e6. doi: 10.1016/j.jtct.2020.10.021.
  89. Croft J, Ellis S, Sherborne AL, et al. Copy number evolution and its relationship with patient outcome—an analysis of 178 matched presentation-relapse tumor pairs from the Myeloma XI trial. Leukemia. 2021;35(7):2043–53. doi: 10.1038/s41375-020-01096-y.
  90. Perrot A, Lauwers-Cances V, Tournay E, et al. Development and validation of a cytogenetic prognostic index predicting survival in multiple myeloma. J Clin Oncol. 2019;37(19):1657–65. doi: 10.1200/JCO.18.00776.
  91. Shah V, Sherborne AL, Walker BA, et al. Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1905 trial patients. Leukemia. 2018;32(1):102–10. doi: 10.1038/LEU.2017.179.
  92. Kumar S, Fonseca R, Ketterling RP, et al. Trisomies in multiple myeloma: impact on survival in patients with high-risk cytogenetics. Blood. 2012;119(9):2100–5. doi: 10.1182/BLOOD-2011-11-390658.
  93. Chretien ML, Corre J, Lauwers-Cances V, et al. Understanding the role of hyperdiploidy in myeloma prognosis: Which trisomies really matter? Blood. 2015;126(25):2713–9. doi: 10.1182/blood-2015-06-650242.
  94. Hebraud B, Magrangeas F, Cleynen A, et al. Role of additional chromosomal changes in the prognostic value of t(4;14) and del(17p) in multiple myeloma: the IFM experience. Blood. 2015;125(13):2095–100. doi: 10.1182/BLOOD-2014-07-587964.
  95. Takamatsu H, Yamashita T, Kurahashi S, et al. Clinical Implications of t(11;14) in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation. Biol Blood Marrow Transplant. 2019;25(3):474–9. doi: 10.1016/J.BBMT.2018.11.003.
  96. John L, Krauth MT, Podar K, Raab MS. Pathway-directed therapy in multiple myeloma. Cancers. 2021;13(7):1668. doi: 10.3390/cancers13071668.
  97. Leow CCY, Low MSY. Targeted therapies for multiple myeloma. J Pers Med. 2021;11(5):334. doi: 10.3390/jpm11050334.
  98. Goldman-Mazur S, Vesole DH, Jurczyszyn A. Clinical implications of cytogenetic and molecular aberrations in multiple myeloma. Acta Haematol Pol. 2021;52(1):18–28. doi: 10.5603/AHP.2021.0004.
  99. Cardona-Benavides IJ, de Ramon C, Gutierrez NC. Genetic Abnormalities in Multiple Myeloma: Prognostic and Therapeutic Implications. Cells. 2021;10(2):336. doi: 10.3390/cells10020336.
  100. Mao XH, Zhuang JL, Zhao DD, et al. IgH translocation with undefined partners is associated with superior outcome in multiple myeloma patients. Eur J Haematol. 2020;105(3):326–34. doi: 10.1111/ejh.13440.
  101. Hassan H, Szalat R. Genetic predictors of mortality in patients with multiple myeloma. Appl Clin Genet. 2021;14:241–54. doi: 10.2147/TACG.S262866.
  102. Sessa M, Cavazzini F, Cavallari M, et al. Tangle of genomic aberrations drives multiple myeloma and correlates with clinical aggressiveness of the disease: a comprehensive review from a biological perspective to clinical trial results. Genes. 2020;11(12):1–24. doi: 10.3390/GENES11121453.
  103. Jackson GH, Pawlyn C, Cairns DA, et al. Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial. PLOS Med. 2021;18(1):e1003454. doi: 10.1371/JOURNAL.PMED.1003454.
  104. Qiang YW, Ye S, Chen Y, et al. MAF protein mediates innate resistance to proteasome inhibition therapy in multiple myeloma. Blood. 2016;128(25):2919–30. doi: 10.1182/BLOOD-2016-03-706077.
  105. Rajkumar VS. Multiple myeloma: selection of initial chemotherapy for symptomatic disease. Available from: https://www.uptodate.com/contents/multiple-myeloma-selection-of-initial-chemotherapy-for-symptomatic-disease (accessed 23.03.2022).
  106. Qiang YW, Ye S, Huang Y, et al. MAFb protein confers intrinsic resistance to proteasome inhibitors in multiple myeloma. BMC Cancer. 2018;18(1):1–13. doi: 10.1186/S12885-018-4602-4/FIGURES/6.
  107. Mateos MV, Martinez BP, Gonzalez-Calle V. High-risk multiple myeloma: how to treat at diagnosis and relapse? Hematology. 2021;2021(1):30–6. doi: 10.1182/HEMATOLOGY.2021000229.
  108. 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):2955–62. doi: 10.1182/blood-2016-01-631200.
  109. Costa LJ, Usmani SZ. Defining and Managing High-Risk Multiple Myeloma: Current Concepts. J Natl Compr Canc Netw. 2020;18(12):1730–7. doi: 10.6004/JNCCN.2020.7673.
  110. Jurczyszyn A, Charlinski G, Suska A, Vesole DH. The importance of cytogenetic and molecular aberrations in multiple myeloma. Acta Haematol Pol. 2021;52(4):361–70. doi: 10.5603/AHP.2021.0069.
  111. Garifullin A, Voloshin S, Shuvaev V, et al. Significance of Modified Risk Stratification Msmart 3.0 and Autologous Stem Cell Transplantation for Patients with Newly Diagnosed Multiple Myeloma. Blood. 2019;134(Suppl_1):5593. doi: 10.1182/BLOOD-2019-130092.