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CC BY-NC-ND 4.0 · Indian J Med Paediatr Oncol 2021; 42(05): 395-405
DOI: 10.1055/s-0041-1732861
Review Article

Epigenetic Modifications in Myeloma: Focused Review of Current Data and Potential Therapeutic Applications

Suvir Singh 
1   Department of Clinical Hematology and Stem Cell Transplantation, Dayanand Medical College, Ludhiana, Punjab, India
,
Kunal Jain
2   Department of Medical Oncology, Dayanand Medical College, Ludhiana, Punjab, India
,
Rintu Sharma
1   Department of Clinical Hematology and Stem Cell Transplantation, Dayanand Medical College, Ludhiana, Punjab, India
,
Jagdeep Singh
2   Department of Medical Oncology, Dayanand Medical College, Ludhiana, Punjab, India
,
Davinder Paul
2   Department of Medical Oncology, Dayanand Medical College, Ludhiana, Punjab, India
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Abstract

Multiple myeloma is a common hematologic malignancy with an incidence of 1 per 100,000 population and is characterized by a nearly 100% risk of relapse, necessitating treatment with newer therapeutic agents at each instance of progression. However, use of newer agents is often precluded by cost and accessibility in a resource-constrained setting. Description of newer pathways of disease pathogenesis potentially provides opportunities for identification of therapeutic targets and a better understanding of disease biology. Identification of epigenetic changes in myeloma is an emerging premise, with several pathways contributing to pathogenesis and progression of disease. Greater understanding of epigenetic alterations provides opportunities to detect several targetable enzymes or pathways that can be of clinical use.

Keywords

myeloma - lenalidomide - pomalidomide - transplant - relapse


Publication History

Article published online:
24 December 2021

© 2021. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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  • References

  • 1 Biswas S, Rao CM. Epigenetics in cancer: fundamentals and beyond. Pharmacol Ther 2017; 173: 118-134
    CrossrefPubMedGoogle Scholar
  • 2 Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis 2010; 31 (01) 27-36
    CrossrefPubMedGoogle Scholar
  • 3 Feinberg AP, Ohlsson R, Henikoff S. The epigenetic progenitor origin of human cancer. Nat Rev Genet 2006; 7 (01) 21-33
    CrossrefPubMedGoogle Scholar
  • 4 Ravi P, Kumar SK, Cerhan JR. et al. Defining cure in multiple myeloma: a comparative study of outcomes of young individuals with myeloma and curable hematologic malignancies. Blood Cancer J 2018; 8 (03) 26
    CrossrefPubMedGoogle Scholar
  • 5 Kumar SK, Rajkumar SV, Dispenzieri A. et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008; 111 (05) 2516-2520
    CrossrefPubMedGoogle Scholar
  • 6 Rajkumar SV. Value and cost of myeloma therapy. Am Soc Clin Oncol Educ Book 2018; 38 (38) 662-666
    CrossrefPubMedGoogle Scholar
  • 7 Gupta P, Kochupillai V, Singh S, Berry M, Kumar L, Sundaram K. A twelve year study of multiple myeloma at the All India Institute of Medical Sciences, New Delhi, India. Indian J Med Paediatr Oncol 1995; 16 (02) 108
    Google Scholar
  • 8 Wang Y, Leung FC. An evaluation of new criteria for CpG islands in the human genome as gene markers. Bioinformatics 2004; 20 (07) 1170-1177
    CrossrefPubMedGoogle Scholar
  • 9 Allfrey VG, Faulkner R, Mirsky AE. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc Natl Acad Sci U S A 1964; 51 (05) 786-794
    CrossrefPubMedGoogle Scholar
  • 10 Kouzarides T. Chromatin modifications and their function. Cell 2007; 128 (04) 693-705
    CrossrefPubMedGoogle Scholar
  • 11 Mattick JS, Makunin IV. Non-coding RNA. Hum Mol Genet 2006; 15 (Suppl. 01) R17-R29
    CrossrefPubMedGoogle Scholar
  • 12 Rajkumar SV, Gupta V, Fonseca R. et al. Impact of primary molecular cytogenetic abnormalities and risk of progression in smoldering multiple myeloma. Leukemia 2013; 27 (08) 1738-1744
    CrossrefPubMedGoogle Scholar
  • 13 Kumar S, Fonseca R, Ketterling RP. et al. Trisomies in multiple myeloma: impact on survival in patients with high-risk cytogenetics. Blood 2012; 119 (09) 2100-2105
    CrossrefPubMedGoogle Scholar
  • 14 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 (08) 82
    CrossrefPubMedGoogle Scholar
  • 15 Kumar SK, Rajkumar SV. The multiple myelomas - current concepts in cytogenetic classification and therapy. Nat Rev Clin Oncol 2018; 15 (07) 409-421
    CrossrefPubMedGoogle Scholar
  • 16 San-Miguel JF, Paiva B, Gutiérrez NC. New tools for diagnosis and monitoring of multiple myeloma. Am Soc Clin Oncol Educ Book 2013
    PubMedGoogle Scholar
  • 17 Galm O, Wilop S, Reichelt J. et al. DNA methylation changes in multiple myeloma. Leukemia 2004; 18 (10) 1687-1692
    CrossrefPubMedGoogle Scholar
  • 18 Agirre X, Castellano G, Pascual M. et al. Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers. Genome Res 2015; 25 (04) 478-487
    CrossrefPubMedGoogle Scholar
  • 19 Liang G, Weisenberger DJJE. DNA methylation aberrancies as a guide for surveillance and treatment of human cancers. Epigenetics 2017; 12 (06) 416-432
    CrossrefPubMedGoogle Scholar
  • 20 Schulz WA, Elo JP, Florl AR. et al. Genome-wide DNA hypomethylation is associated with alterations on chromosome 8 in prostate carcinoma. Genes Chromosomes Cancer 2002; 35 (01) 58-65
    CrossrefPubMedGoogle Scholar
  • 21 Bollati V, Fabris S, Pegoraro V. et al. Differential repetitive DNA methylation in multiple myeloma molecular subgroups. Carcinogenesis 2009; 30 (08) 1330-1335
    CrossrefPubMedGoogle Scholar
  • 22 Heuck CJ, Mehta J, Bhagat T. et al. Myeloma is characterized by stage-specific alterations in DNA methylation that occur early during myelomagenesis. J Immunol 2013; 190 (06) 2966-2975
    CrossrefPubMedGoogle Scholar
  • 23 Latalova P, Minarik J, Smesny Trtkova K. De novo methyltransferases, DNMT3a and DNMT3b are underexpressed in multiple myeloma. Blood 2015; 126 (23) 4818
    CrossrefGoogle Scholar
  • 24 Auclair G, Weber M. Mechanisms of DNA methylation and demethylation in mammals. Biochimie 2012; 94 (11) 2202-2211
    CrossrefPubMedGoogle Scholar
  • 25 Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993; 75 (05) 843-854
    CrossrefPubMedGoogle Scholar
  • 26 Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 2010; 11 (09) 597-610
    CrossrefPubMedGoogle Scholar
  • 27 Zhou Y, Chen L, Barlogie B. et al. High-risk myeloma is associated with global elevation of miRNAs and overexpression of EIF2C2/AGO2. Proc Natl Acad Sci U S A 2010; 107 (17) 7904-7909
    CrossrefPubMedGoogle Scholar
  • 28 Lionetti M, Biasiolo M, Agnelli L. et al. Identification of microRNA expression patterns and definition of a microRNA/mRNA regulatory network in distinct molecular groups of multiple myeloma. Blood 2009; 114 (25) e20-e26
    CrossrefPubMedGoogle Scholar
  • 29 Rossetto D, Avvakumov N, Côté J. Histone phosphorylation: a chromatin modification involved in diverse nuclear events. Epigenetics 2012; 7 (10) 1098-1108
    CrossrefPubMedGoogle Scholar
  • 30 Li B, Carey M, Workman JL. The role of chromatin during transcription. Cell 2007; 128 (04) 707-719
    CrossrefPubMedGoogle Scholar
  • 31 Young NL, Dimaggio PA, Garcia BA. The significance, development and progress of high-throughput combinatorial histone code analysis. Cell Mol Life Sci 2010; 67 (23) 3983-4000
    CrossrefPubMedGoogle Scholar
  • 32 Martinez-Garcia E, Popovic R, Min D-J. et al. The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells. Blood 2011; 117 (01) 211-220
    CrossrefPubMedGoogle Scholar
  • 33 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 (04) 1520-1529
    CrossrefPubMedGoogle Scholar
  • 34 Xie Z, Bi C, Chooi JY, Chan ZL, Mustafa N, Chng WJ. MMSET regulates expression of IRF4 in t(4;14) myeloma and its silencing potentiates the effect of bortezomib. Leukemia 2015; 29 (12) 2347-2354
    CrossrefPubMedGoogle Scholar
  • 35 Pawlyn C, Bright MD, Buros AF. et al. Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control. Blood Cancer J 2017; 7 (03) e549
    CrossrefPubMedGoogle Scholar
  • 36 Alzrigat M, Párraga AA, Agarwal P. et al. EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions. Oncotarget 2017; 8 (06) 10213-10224
    CrossrefPubMedGoogle Scholar
  • 37 Ohguchi H, Hideshima T, Bhasin MK. et al. The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival. Nat Commun 2016; 7: 10258
    CrossrefPubMedGoogle Scholar
  • 38 Haberland M, Montgomery RL, Olson EN. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 2009; 10 (01) 32-42
    CrossrefPubMedGoogle Scholar
  • 39 Mithraprabhu S, Kalff A, Chow A, Khong T, Spencer A. Dysregulated Class I histone deacetylases are indicators of poor prognosis in multiple myeloma. Epigenetics 2014; 9 (11) 1511-1520
    CrossrefPubMedGoogle Scholar
  • 40 Chen BJ, Epstein J. Circulating clonal lymphocytes in myeloma constitute a minor subpopulation of B cells. Blood 1996; 87 (05) 1972-1976
    CrossrefPubMedGoogle Scholar
  • 41 Sharma SV, Lee DY, Li B. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 2010; 141 (01) 69-80
    CrossrefPubMedGoogle Scholar
  • 42 Rastgoo N, Abdi J, Hou J, Chang H. Role of epigenetics-microRNA axis in drug resistance of multiple myeloma. J Hematol Oncol 2017; 10 (01) 121
    CrossrefPubMedGoogle Scholar
  • 43 Furukawa Y, Kikuchi J. Epigenetic mechanisms of cell adhesion-mediated drug resistance in multiple myeloma. Int J Hematol 2016; 104 (03) 281-292
    CrossrefPubMedGoogle Scholar
  • 44 Fenaux P, Mufti GJ, Hellstrom-Lindberg E. et al. International Vidaza High-Risk MDS Survival Study Group. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009; 10 (03) 223-232
    CrossrefPubMedGoogle Scholar
  • 45 Khong T, Sharkey J, Spencer A. The effect of azacitidine on interleukin-6 signaling and nuclear factor-kappaB activation and its in vitro and in vivo activity against multiple myeloma. Haematologica 2008; 93 (06) 860-869
    CrossrefPubMedGoogle Scholar
  • 46 Kiziltepe T, Hideshima T, Catley L. et al. 5-Azacytidine, a DNA methyltransferase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myeloma cells. Mol Cancer Ther 2007; 6 (06) 1718-1727
    CrossrefPubMedGoogle Scholar
  • 47 Amodio N, Leotta M, Bellizzi D. et al. DNA-demethylating and anti-tumor activity of synthetic miR-29b mimics in multiple myeloma. Oncotarget 2012; 3 (10) 1246-1258
    CrossrefPubMedGoogle Scholar
  • 48 Amodio N, Di Martino MT, Foresta U. et al. miR-29b sensitizes multiple myeloma cells to bortezomib-induced apoptosis through the activation of a feedback loop with the transcription factor Sp1. Cell Death Dis 2012; 3 (11) e436
    CrossrefPubMedGoogle Scholar
  • 49 Pichiorri F, Suh S-S, Rocci A. et al. Downregulation of p53-inducible microRNAs 192, 194, and 215 impairs the p53/MDM2 autoregulatory loop in multiple myeloma development. Cancer Cell 2010; 18 (04) 367-381
    CrossrefPubMedGoogle Scholar
  • 50 Zarone MR, Misso G, Grimaldi A. et al. Evidence of novel miR-34a-based therapeutic approaches for multiple myeloma treatment. Sci Rep 2017; 7 (01) 17949
    CrossrefPubMedGoogle Scholar
  • 51 Li Y, Zhang B, Li W. et al. MiR-15a/16 regulates the growth of myeloma cells, angiogenesis and antitumor immunity by inhibiting Bcl-2, VEGF-A and IL-17 expression in multiple myeloma. Leuk Res 2016; 49: 73-79
    CrossrefPubMedGoogle Scholar
  • 52 Richardson PG, Hungria VT, Yoon SS. et al. Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment. Blood 2016; 127 (06) 713-721
    CrossrefPubMedGoogle Scholar
  • 53 San-Miguel JF, Hungria VT, Yoon SS. et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 2014; 15 (11) 1195-1206
    CrossrefPubMedGoogle Scholar
  • 54 Vesole DH, Bilotti E, Richter JR. et al. Phase I study of carfilzomib, lenalidomide, vorinostat, and dexamethasone in patients with relapsed and/or refractory multiple myeloma. Br J Haematol 2015; 171 (01) 52-59
    CrossrefPubMedGoogle Scholar
  • 55 Moreaux J, Rème T, Leonard W. et al. Gene expression-based prediction of myeloma cell sensitivity to histone deacetylase inhibitors. Br J Cancer 2013; 109 (03) 676-685
    CrossrefPubMedGoogle Scholar
  • 56 Zagni C, Floresta G, Monciino G, Rescifina A. The search for potent, small-molecule HDACIs in cancer treatment: a decade after vorinostat. Med Res Rev 2017; 37 (06) 1373-1428
    CrossrefPubMedGoogle Scholar
  • 57 Dimopoulos K, Gimsing P, Grønbæk K. The role of epigenetics in the biology of multiple myeloma. Blood Cancer J 2014; 4 (05) e207
    CrossrefPubMedGoogle Scholar
  • 58 Greer EL, Shi Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet 2012; 13 (05) 343-357
    CrossrefPubMedGoogle Scholar
  • 59 Sprangers R, Groves MR, Sinning I, Sattler M. High-resolution X-ray and NMR structures of the SMN Tudor domain: conformational variation in the binding site for symmetrically dimethylated arginine residues. J Mol Biol 2003; 327 (02) 507-520
    CrossrefPubMedGoogle Scholar
  • 60 Bedford MT, Clarke SG. Protein arginine methylation in mammals: who, what, and why. Mol Cell 2009; 33 (01) 1-13
    CrossrefPubMedGoogle Scholar
  • 61 Yang Y, Bedford MT. Protein arginine methyltransferases and cancer. Nat Rev Cancer 2013; 13 (01) 37-50
    CrossrefPubMedGoogle Scholar
  • 62 Völkel P, Angrand P-O. The control of histone lysine methylation in epigenetic regulation. Biochimie 2007; 89 (01) 1-20
    CrossrefPubMedGoogle Scholar
  • 63 Ruthenburg AJ, Li H, Patel DJ, Allis CD. Multivalent engagement of chromatin modifications by linked binding modules. Nat Rev Mol Cell Biol 2007; 8 (12) 983-994
    CrossrefPubMedGoogle Scholar
  • 64 Mirabella F, Wu P, Wardell CP. et al. MMSET is the key molecular target in t(4;14) myeloma. Blood Cancer J 2013; 3 (05) e114
    CrossrefPubMedGoogle Scholar
  • 65 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 (02) 856-864
    CrossrefPubMedGoogle Scholar
  • 66 Park JW, Chae YC, Kim JY, Oh H, Seo SB. Methylation of Aurora kinase A by MMSET reduces p53 stability and regulates cell proliferation and apoptosis. Oncogene 2018; 37 (48) 6212-6224
    CrossrefPubMedGoogle Scholar
  • 67 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) 7069-7073
    CrossrefPubMedGoogle Scholar
  • 68 Margueron R, Reinberg D. The polycomb complex PRC2 and its mark in life. Nature 2011; 469 (7330) 343-349
    CrossrefPubMedGoogle Scholar
  • 69 Chase A, Cross NC. Aberrations of EZH2 in cancer. Clin Cancer Res 2011; 17 (09) 2613-2618
    CrossrefPubMedGoogle Scholar
  • 70 Tremblay-LeMay R, Rastgoo N, Pourabdollah M, Chang H. EZH2 as a therapeutic target for multiple myeloma and other haematological malignancies. Biomark Res 2018; 6 (01) 34
    CrossrefPubMedGoogle Scholar
  • 71 Gullà A, Hideshima T, Bianchi G. et al. Protein arginine methyltransferase 5 has prognostic relevance and is a druggable target in multiple myeloma. Leukemia 2018; 32 (04) 996-1002
    CrossrefPubMedGoogle Scholar
  • 72 Nicholson TB, Chen T. LSD1 demethylates histone and non-histone proteins. Epigenetics 2009; 4 (03) 129-132
    CrossrefPubMedGoogle Scholar
  • 73 Wei X, Calvo-Vidal MN, Chen S. et al. Germline lysine-specific demethylase 1 (LSD1/KDM1A) mutations confer susceptibility to multiple myeloma. Cancer Res 2018; 78 (10) 2747-2759
    CrossrefPubMedGoogle Scholar
  • 74 Ikeda S, Kitadate A, Abe F, Takahashi N, Tagawa H. Hypoxia-inducible KDM3A addiction in multiple myeloma. Blood Adv 2018; 2 (04) 323-334
    CrossrefPubMedGoogle Scholar
  • 75 van Haaften G, Dalgliesh GL, Davies H. et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat Genet 2009; 41 (05) 521-523
    CrossrefPubMedGoogle Scholar
  • 76 Ezponda T, Dupéré-Richer D, Will CM. et al. UTX/KDM6A loss enhances the malignant phenotype of multiple myeloma and sensitizes cells to EZH2 inhibition. Cell Rep 2017; 21 (03) 628-640
    CrossrefPubMedGoogle Scholar
  • 77 Ohguchi H, Harada T, Sagawa M. et al. KDM6B modulates MAPK pathway mediating multiple myeloma cell growth and survival. Leukemia 2017; 31 (12) 2661-2669
    CrossrefPubMedGoogle Scholar
  • 78 Gitan RS, Shi H, Chen CM, Yan PS, Huang TH. Methylation-specific oligonucleotide microarray: a new potential for high-throughput methylation analysis. Genome Res 2002; 12 (01) 158-164
    CrossrefPubMedGoogle Scholar
  • 79 Zang C, Schones DE, Zeng C, Cui K, Zhao K, Peng W. A clustering approach for identification of enriched domains from histone modification ChIP-Seq data. Bioinformatics 2009; 25 (15) 1952-1958
    CrossrefPubMedGoogle Scholar
  • 80 Cornett EM, Dickson BM, Rothbart SB. Analysis of histone antibody specificity with peptide microarrays. J Vis Exp 2017; (126) 55912
    PubMedGoogle Scholar
  • 81 Krepelkova I, Mrackova T, Izakova J. et al. Evaluation of miRNA detection methods for the analytical characteristic necessary for clinical utilization. Biotechniques 2019; 66 (06) 277-284
    CrossrefPubMedGoogle Scholar
  • 82 Chim C-S, Liang R, Leung M-H, Kwong YL. Aberrant gene methylation implicated in the progression of monoclonal gammopathy of undetermined significance to multiple myeloma. J Clin Pathol 2007; 60 (01) 104-106
    CrossrefPubMedGoogle Scholar
  • 83 Chim C-S, Fung T-K, Cheung W-C, Liang R, Kwong Y-LJB. SOCS1 and SHP1 hypermethylation in multiple myeloma: implications for epigenetic activation of the Jak/STAT pathway. Blood 2004; 103 (12) 4630-4635
    CrossrefPubMedGoogle Scholar
  • 84 Sharma A, Heuck CJ, Fazzari MJ. et al. DNA methylation alterations in multiple myeloma as a model for epigenetic changes in cancer. Wiley Interdiscip Rev Syst Biol Med 2010; 2 (06) 654-669
    CrossrefPubMedGoogle Scholar
  • 85 Ohguchi H, Hideshima T, Anderson KC. The biological significance of histone modifiers in multiple myeloma: clinical applications. Blood Cancer J 2018; 8 (09) 83
    CrossrefPubMedGoogle Scholar
  • 86 Kalff A, Khong T, Mithraprabhu S. et al. Oral azacitidine (CC-486) in combination with lenalidomide and dexamethasone in advanced, lenalidomide-refractory multiple myeloma (ROAR study. Leuk Lymphoma 2019; 60 (09) 2143-2151
    CrossrefPubMedGoogle Scholar
  • 87 Khouri J, Faiman BM, Grabowski D. et al. DNA methylation inhibition in myeloma: experience from a phase 1b study of low-dose continuous azacitidine in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. Semin Hematol 2021; 58 (01) 45-55
    CrossrefPubMedGoogle Scholar
  • 88 Ossenkoppele GJ, Lowenberg B, Zachee P. et al. A phase I first-in-human study with tefinostat - a monocyte/macrophage targeted histone deacetylase inhibitor - in patients with advanced haematological malignancies. Br J Haematol 2013; 162 (02) 191-201
    CrossrefPubMedGoogle Scholar
  • 89 Niesvizky R, Ely S, Mark T. et al. Phase 2 trial of the histone deacetylase inhibitor romidepsin for the treatment of refractory multiple myeloma. Cancer 2011; 117 (02) 336-342
    CrossrefPubMedGoogle Scholar
  • 90 Dimopoulos M, Siegel DS, Lonial S. et al. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. Lancet Oncol 2013; 14 (11) 1129-1140
    CrossrefPubMedGoogle Scholar
  • 91 Vogl DT, Raje N, Jagannath S. et al. Ricolinostat, the first selective histone deacetylase 6 inhibitor, in combination with bortezomib and dexamethasone for relapsed or refractory multiple myeloma. Clin Cancer Res 2017; 23 (13) 3307-3315
    CrossrefPubMedGoogle Scholar
  • 92 Díaz T, Rodríguez V, Lozano E. et al. The BET bromodomain inhibitor CPI203 improves lenalidomide and dexamethasone activity in in vitro and in vivo models of multiple myeloma by blockade of Ikaros and MYC signaling. Haematologica 2017; 102 (10) 1776-1784
    CrossrefPubMedGoogle Scholar
  • 93 Piha-Paul SA, Hann CL, French CA. et al. Phase 1 study of Molibresib (GSK525762), a bromodomain and extra-terminal domain protein inhibitor, in NUT carcinoma and other solid tumors. JNCI Cancer Spectr 2019; 4 (02) pkz093
    CrossrefPubMedGoogle Scholar
  • 94 Ramasamy K, Nooka A, Quach H. et al. Open label, multicenter, dose-escalation/ expansion phase Ib study to evaluate safety and activity of BET inhibitor RO6870810 (RO), given as monotherapy to patients (pts) with advanced multiple myeloma. Blood 2020; 136 (Suppl. 01) 12-14
    CrossrefGoogle Scholar
  • 95 Herviou L, Kassambara A, Boireau S. et al. PRC2 targeting is a therapeutic strategy for EZ score defined high-risk multiple myeloma patients and overcome resistance to IMiDs. Clin Epigenetics 2018; 10 (01) 121
    CrossrefPubMedGoogle Scholar
  • 96 Kaiser MF, Johnson DC, Wu P. et al. Global methylation analysis identifies prognostically important epigenetically inactivated tumor suppressor genes in multiple myeloma. Blood 2013; 122 (02) 219-226
    CrossrefPubMedGoogle Scholar
  • 97 Barwick BG, Skerget S, Keats JJ. et al. Multiple myeloma epigenetic programming prognostic of outcome converges with loci reprogrammed in relapsed/refractory disease. Blood 2019; 134 (Suppl. 01) 858
    CrossrefGoogle Scholar
  • 98 Pawlyn C, Kaiser MF, Heuck C. et al. The spectrum and clinical impact of epigenetic modifier mutations in myeloma. Clin Cancer Res 2016; 22 (23) 5783-5794
    CrossrefPubMedGoogle Scholar