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From: Multi-omics tumor profiling technologies to develop precision medicine in multiple myeloma

Table 1. Agents approved for MM treatment

Drug	Type	Target	Effect	Resistance
Melphalan Melflufen Cyclophosphamide	Alkylating agents	DNA	DNA damage Impairment of DNA replication and transcription	Misregulation/mutation of DDR pathways [25–31] Increased antioxidant defenses [32] Import/export alteration [33] miRNA misregulation [34]
Bortezomib Calfilzomib Ixazomib	PI	PSMB5 (26S proteasome)	Cytotoxicity by accumulation of aberrant proteins	BM microenvironment Upregulation of aggresomal protein degradation pathways Increased autophagy Proteasome subunit mutations Cell cycle misregulation [19, 20, 35, 36]
Thalidomide Lenalidomide Pomalidomide	IMiDs	CRBN	Immune activation Impaired angiogenesis Impaired proliferation of tumor cells Apoptosis induction	Low CRBN expression or mutation of its downstream targets [37–39]
Dexamethasone Prednisolone Methylprednisolone	Corticosteroids	GC receptors	Gene expression regulation Anti-inflammatory Immunosuppressive	Excess of IL-6 Defects on GC receptors FGFR3 overexpression [40–42]
Doxorubicin Pegilated liposomal doxorubicine (PDL)	Anthracyclines	DNA-Topo II	Impairment of DNA replication and transcription DSBs accumulation	DNA-Topo II mutations or misregulation [43–45] Efflux pumps overexpression [46]
Panobinostat	Histone deacetylase inhibitors	Histones	G1/S arrest Apoptosis Activation of tumor suppressor genes	Increased CXCR4, mTOR pathway activation, p21 up-regulation [47]
Daratumumab (DARA) Elotuzumab	Monoclonal Abs	CD38 CD319/ SLAMF7/CS1	ADCC, ADCP, CDC, immunomodulatory effects ADCC, NK-cell activation	Downregulation of the target Deregulation of ADCC, ADCP, CDC Stromal cell production of anti-apoptotic proteins PD1 and PD-L1 [48, 49]
Selinexor	Nuclear export inhibitors	XPO1	Nuclear export blockade Reduction of DDR proteins	(In vitro) alterations in signaling pathways downstream of XPO1 [50]

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ADCC: antibody-dependent cell-mediated cytotoxicity; ADCP: antibody-dependent cellular phagocytosis; CDC: complement-dependent cytotoxicity

Declarations

Author contributions

SO performed data analyses and the writing of the paper. JM supervised the writing of the paper.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was supported by grants from INCa (Institut National du Cancer) PLBIO18-362 PIT-MM and PLBIO19-098 INCA_13832FATidique, ANR (the French National Research Agency) under the “Investissements d’avenir” program with the reference ANR-16-IDEX-0006, ANR (TIE-Skip; 2017-CE15-0024-01), ANR-18-CE15-0010-01 PLASMADIFF-3D, SIRIC Montpellier Cancer (INCa_Inserm_DGOS_12553), Labex EpiGenMed and Institut Universitaire de France. The funders had no role in analysis, decision to publish, or preparation of the manuscript.

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References

Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, et al. SEER Cancer Statistics Review, 1975–2017, National Cancer Institute. Bethesda, MD: , https://seer.cancer.gov/csr/1975_2017/, based on November 2019 SEER data submission, posted to the SEER web site, April 2020.

Robak P, Drozdz I, Szemraj J, Robak T. Drug resistance in multiple myeloma. Cancer Treat Rev. 2018;70:199–208. [DOI] [PubMed]

Yang WC, Lin SF. Mechanisms of drug resistance in relapse and refractory multiple myeloma. Biomed Res Int. 2015;2015:341430. [DOI] [PubMed] [PMC]

Nutt SL, Hodgkin PD, Tarlinton DM, Corcoran LM. The generation of antibody-secreting plasma cells. Nat Rev Immunol. 2015;15:160–71. [DOI] [PubMed]

Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538–48. [DOI] [PubMed]

van Nieuwenhuijzen N, Spaan I, Raymakers R, Peperzak V. From MGUS to multiple myeloma, a paradigm for clonal evolution of premalignant cells. Cancer Res. 2018;78:2449–56. [DOI] [PubMed]

Kyle RA, Therneau TM, Rajkumar SV, Offord JR, Larson DR, Plevak MF, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346:564–9. [DOI] [PubMed]

Kyle RA, Remstein ED, Therneau TM, Dispenzieri A, Kurtin PJ, Hodnefield JM, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med. 2007;356:2582–90. [DOI] [PubMed]

Rajkumar SV, Landgren O, Mateos MV. Smoldering multiple myeloma. Blood. 2015;125:3069–75. [DOI] [PubMed] [PMC]

10.

Keats JJ, Chesi M, Egan JB, Garbitt VM, Palmer SE, Braggio E, et al. Clonal competition with alternating dominance in multiple myeloma. Blood. 2012;120:1067–76. [DOI] [PubMed] [PMC]

11.

Röllig C, Knop S, Bornhäuser M. Multiple myeloma. Lancet. 2015;385:2197–208. [DOI] [PubMed]

12.

Corre J, Cleynen A, Robiou du Pont S, Buisson L, Bolli N, Attal M, et al. Multiple myeloma clonal evolution in homogeneously treated patients. Leukemia. 2018;32:2636–47. [DOI] [PubMed] [PMC]

13.

Manier S, Salem KZ, Park J, Landau DA, Getz G, Ghobrial IM. Genomic complexity of multiple myeloma and its clinical implications. Nat Rev Clin Oncol. 2017;14:100–13. [DOI] [PubMed]

14.

Bergsagel PL, Kuehl WM. Molecular pathogenesis and a consequent classification of multiple myeloma. J Clin Oncol. 2005;23:6333–8. [DOI] [PubMed]

15.

Bergsagel PL, Kuehl WM, Zhan F, Sawyer J, Barlogie B, Shaughnessy JD Jr. Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood. 2005;106:296–303. [DOI] [PubMed] [PMC]

16.

Kaiser MF, Walker BA, Hockley SL, Begum DB, Wardell CP, Gonzalez D, et al. A TC classification-based predictor for multiple myeloma using multiplexed real-time quantitative PCR. Leukemia. 2013;27:1754–7. [DOI] [PubMed]

17.

Zhan F, Huang Y, Colla S, Stewart JP, Hanamura I, Gupta S, et al. The molecular classification of multiple myeloma. Blood. 2006;108:2020–28. [DOI] [PubMed] [PMC]

18.

Bolli N, Biancon G, Moarii M, Gimondi S, Li Y, de Philippis S, et al. Analysis of the genomic landscape of multiple myeloma highlights novel prognostic markers and disease subgroups. Leukemia. 2018;32:2604–16. [DOI] [PubMed] [PMC]

19.

Harding T, Baughn L, Kumar S, Van Ness B. The future of myeloma precision medicine: integrating the compendium of known drug resistance mechanisms with emerging tumor profiling technologies. Leukemia. 2019;33:863–83. [DOI] [PubMed]

20.

Pinto V, Bergantim R, Caires HR, Seca H, Guimarães JE, Vasconcelos MH. Multiple myeloma: available therapies and causes of drug resistance. Cancers. 2020;12:407. [DOI]

21.

Rodríguez-Lobato LG, Ganzetti M, Fernández de Larrea C, Hudecek M, Einsele H, Danhof S, et al. CAR-T-cells in multiple myeloma: state of the art and future directions. Front Oncol. 2020;10:1243. [DOI] [PubMed] [PMC]

22.

Castella M, Fernández de Larrea C, Martín-Antonio B. Immunotherapy: a novel era of promising treatments for multiple myeloma. Int J Mol Sci. 2018;19:3613. [DOI]

23.

Tai YT, Anderson KC. B cell maturation antigen (BCMA)-based immunotherapy for multiple myeloma. Expert Opin Biol Ther. 2019;19:1143–56. [DOI] [PubMed] [PMC]

24.

Caraccio C, Krishna S, Phillips DJ, Schürch CM. Bispecific antibodies for multiple myeloma: a review of targets, drugs, clinical trials, and future directions. Front Immunol. 2020;11:501. [DOI] [PubMed] [PMC]

25.

Yarde DN, Oliveira V, Mathews L, Wang X, Villagra A, Boulware D, et al. Targeting the Fanconi anemia/ BRCA pathway circumvents drug resistance in multiple myeloma. Cancer Res. 2009;69:9367–75. [DOI] [PubMed] [PMC]

26.

Gourzones-Dmitriev C, Kassambara A, Sahota S, Rème T, Moreaux J, Bourquard P, et al. DNA repair pathways in human multiple myeloma: role in oncogenesis and potential targets for treatment. Cell Cycle. 2013;12:2760–73. [DOI] [PubMed] [PMC]

27.

Kassambara A, Gourzones-Dmitriev C, Sahota S, Rème T, Moreaux J, Goldschmidt H, et al. A DNA repair pathway score predicts survival in human multiple myeloma: the potential for therapeutic strategy. Oncotarget. 2014;5:2487–98. [DOI] [PubMed] [PMC]

28.

Alagpulinsa DA, Yaccoby S, Ayyadevara S, Shmookler Reis RJ. A peptide nucleic acid targeting nuclear RAD51 sensitizes multiple myeloma cells to melphalan treatment. Cancer Bio Ther. 2015;16:976–86. [DOI] [PubMed] [PMC]

29.

Viziteu E, Klein B, Basbous J, Lin YL, Hirtz C, Gourzones C, et al. RECQ1 helicase is involved in replication stress survival and drug resistance in multiple myeloma. Leukemia. 2017;31:2104–13. [DOI] [PubMed] [PMC]

30.

Xiong T, Wei H, Chen X, Xiao H. PJ34, a poly (ADP-ribose) polymerase (PARP) inhibitor, reverses melphalan-resistance and inhibits repair of DNA double-strand breaks by targeting the FA/BRCA pathway in multidrug resistant multiple myeloma cell line RPMI8226/R. Int J Oncol. 2015;46:223–32. [DOI] [PubMed]

31.

Patel PR, Senyuk V, Sweiss K, Calip GS, Pan D, Rodriguez N, et al. PARP inhibition synergizes with melphalan but does not reverse resistance completely. Bio Blood Marrow Transplant. 2020;26:1273–9. [DOI] [PubMed]

32.

Gourzones C, Bellanger C, Lamure S, Gadacha QK, De Paco EG, Vincent L, et al. Antioxidant defenses confer resistance to high dose melphalan in multiple myeloma cells. Cancers. 2019;11:439. [DOI]

33.

Kühne A, Tzvetkov MV, Hagos Y, Lage H, Burckhardt G, Brockmöller J. Influx and efflux transport as determinants of melphalan cytotoxicity: resistance to melphalan in MDR1 overexpressing tumor cell lines. Biochem Pharmacol. 2009;78:45–53. [DOI] [PubMed]

34.

Gulla A, Di Martino MT, Gallo Cantafio ME, Morelli E, Amodio N, Botta C, et al. A 13 mer LNA-i-miR-221 iInhibitor restores drug sensitivity in melphalan-refractory multiple myeloma cells. Clin Cancer Res. 2016;22:1222–33. [DOI] [PubMed] [PMC]

35.

Niewerth D, Jansen G, Assaraf YG, Zweegman S, Kaspers GJL, Cloos J. Molecular basis of resistance to proteasome inhibitors in hematological malignancies. Drug Resist Updat. 2015;18:18–35. [DOI] [PubMed]

36.

Nikesitch N, Lee JM, Ling S, Roberts TL. Endoplasmic reticulum stress in the development of multiple myeloma and drug resistance. Clin Transl Immunol. 2018;7:e1007. [DOI]

37.

Kronke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014;343:301–5. [DOI] [PubMed] [PMC]

38.

Zhu YX, Braggio E, Shi CX, Bruins LA, Schmidt JE, Van Wier S, et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood. 2011;118:4771–9. [DOI] [PubMed] [PMC]

39.

Zhu YX, Kortuem KM, Stewart AK. Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma. Leuk Lymphoma. 2013;54:683–7. [DOI] [PubMed] [PMC]

40.

Pollett JB, Trudel S, Stern D, Li AH, Stewart AK. Overexpression of the myeloma-associated oncogene fibroblast growth factor receptor 3 confers dexamethasone resistance. Blood. 2002;100:3819–21. [DOI] [PubMed]

41.

Pandey MK, Amin SG, Zangari M, Talamo G. Drug resistance in multiple myeloma: how to cross the border. Ann Hematol Oncol. 2015;2:1025.

42.

Abraham J, Salama NN, Azab AK. The role of P-glycoprotein in drug resistance in multiple myeloma. Leuk Lymphoma. 2015;56:26–33. [DOI] [PubMed]

43.

Harris AL, Hochhauser D. Mechanisms of multidrug resistance in cancer treatment. Acta Oncologica. 1992;31:205–13. [DOI] [PubMed]

44.

Oloumi A, MacPhail SH, Johnston PJ, Banáth JP, Olive PL. Changes in subcellular distribution of topoisomerase IIα correlate with etoposide resistance in multicell spheroids and xenograft tumors. Cancer Res. 2000;60:5747–53. [PubMed]

45.

Turner JG, Marchion DC, Dawson JL, Emmons MF, Hazlehurst LA, Washausen P, et al. Human multiple myeloma cells are sensitized to topoisomerase II inhibitors by CRM1 inhibition. Cancer Res. 2009;69:6899–905. [DOI] [PubMed] [PMC]

46.

Kruh GD, Zeng H, Rea PA, Liu G, Chen ZS, Lee K, et al. MRP subfamily transporters and resistance to anticancer agents. J Bioenerg Biomembr. 2001;33:493–501. [DOI] [PubMed]

47.

Beider K, Bitner H, Voevoda-Dimenshtein V, Rosenberg E, Sirovsky Y, Magen H, et al. The mTOR inhibitor everolimus overcomes CXCR4-mediated resistance to histone deacetylase inhibitor panobinostat through inhibition of p21 and mitotic regulators. Biochem Pharmacol. 2019;168:412–28. [DOI] [PubMed]

48.

Saltarella I, Desantis V, Melaccio A, Solimando AG, Lamanuzzi A, Ria R, et al. Mechanisms of resistance to anti-CD38 daratumumab in multiple myeloma. Cells. 2020;9:167. [DOI]

49.

Moreaux J. Anticorps anti-CD38 dans le myélome multiple. Med Sci (Paris). 2019;35:1001–4. [DOI] [PubMed]

50.

Crochiere M, Kashyap T, Kalid O, Shechter S, Klebanov B, Senapedis W, et al. Deciphering mechanisms of drug sensitivity and resistance to Selective Inhibitor of Nuclear Export (SINE) compounds. BMC Cancer. 2015;15:910. [DOI] [PubMed] [PMC]

51.

Deans AJ, West SC. DNA interstrand crosslink repair and cancer. Nat Rev Cancer. 2011;11:467–80. [DOI] [PubMed] [PMC]

52.

Hashimoto S, Anai H, Hanada K. Mechanisms of interstrand DNA crosslink repair and human disorders. Genes Environ. 2016;38:9. [DOI] [PubMed] [PMC]

53.

Esma F, Salvini M, Troia R, Boccadoro M, Larocca A, Pautasso C. Melphalan hydrochloride for the treatment of multiple myeloma. Expert Opin Pharmacother. 2017;18:1127–36. [DOI] [PubMed]

54.

Ray A, Ravillah D, Das DS, Song Y, Nordström V, Gullbo J, et al. A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells. Br J Haematol. 2016;174:397–409. [DOI] [PubMed] [PMC]

55.

Wickström M, Nygren P, Larsson R, Harmenberg H, Lindberg J, Sjöberg P, et al. Melflufen - a peptidase-potentiated alkylating agent in clinical trials. Oncotarget. 2017;8:66641–55. [DOI] [PubMed] [PMC]

56.

Abu Eid R, Razavi GSE, Mkrtichyan M, Janik J, Khleif SN. Old-school chemotherapy in immunotherapeutic combination in cancer, a low-cost drug repurposed. Cancer Immunol Res. 2016;4:377–82. [DOI] [PubMed]

57.

Swan D, Gurney M, Krawczyk J, Ryan AE, O’Dwyer M. Beyond DNA damage: exploring the immunomodulatory effects of cyclophosphamide in multiple myeloma. HemaSphere. 2020;4:e350. [DOI] [PubMed] [PMC]

58.

Grigoreva TA, Tribulovich VG, Garabadzhiu AV, Melino G, Barlev NA. The 26S proteasome is a multifaceted target for anti-cancer therapies. Oncotarget. 2015;6:24733–49. [DOI] [PubMed] [PMC]

59.

Gandolfi S, Laubach JP, Hideshima T, Chauhan D, Anderson KC, Richardson PG. The proteasome and proteasome inhibitors in multiple myeloma. Cancer Metastasis Rev. 2017;36:561–84. [DOI] [PubMed]

60.

Ziogas DC, Terpos E, Kastritis E, Dimopoulos MA. An overview of the role of carfilzomib in the treatment of multiple myeloma. Expert Opin Pharmacother. 2017;18:1883–97. [DOI] [PubMed]

61.

Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hájek R, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016;17:27–38. [DOI] [PubMed]

62.

Zanwar S, Abeykoon JP, Kapoor P. Ixazomib: a novel drug for multiple myeloma. Expert Rev Hematol. 2018;11:761–71. [DOI] [PubMed]

63.

Hideshima T, Chauhan D, Shima Y, Raje N, Davies FE, Tai YT, et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood. 2000;96:2943–50. [PubMed]

64.

Anderson KC. Lenalidomide and thalidomide: mechanisms of action — similarities and differences. Semin Hematol. 2005;42:S3–8. [DOI]

65.

Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, et al. Identification of a primary target of thalidomide teratogenicity. Science. 2010;327:1345–50. [DOI] [PubMed]

66.

Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of ikaros proteins. Science. 2014;343:305–9. [DOI] [PubMed] [PMC]

67.

Marriott JB, Muller G, Stirling D, Dalgleish AD. Immunotherapeutic and antitumour potential of thalidomide analogues. Expert Opin Biol Ther. 2001;1:675–82. [DOI] [PubMed]

68.

Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Richardson PG, Hideshima T, et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood. 2002;99:4525–30. [DOI] [PubMed]

69.

Quach H, Ritchie D, Stewart AK, Neeson P, Harrison S, Smyth MJ, et al. Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma. Leukemia. 2010;24:22–32. [DOI] [PubMed] [PMC]

70.

Tageja N. Lenalidomide — current understanding of mechanistic properties. Anticancer Agents Med Chem. 2011;11:315–26. [DOI] [PubMed]

71.

Rychak E, Mendy D, Shi T, Ning Y, Leisten J, Lu L, et al. Pomalidomide in combination with dexamethasone results in synergistic anti-tumour responses in pre-clinical models of lenalidomide-resistant multiple myeloma. Br J Haematol. 2016;172:889–901. [DOI] [PubMed]

72.

Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids — new mechanisms for old drugs. N Engl J Med. 2005;353:1711–23. [DOI] [PubMed]

73.

Stahn C, Buttgereit F. Genomic and nongenomic effects of glucocorticoids. Nat Clin Pract Rheumatol. 2008;4:525–33. [DOI] [PubMed]

74.

Chauhan D, Hideshima T, Pandey P, Treon S, Teoh G, Raje N, et al. RAFTK/PYK2-dependent and -independent apoptosis in multiple myeloma cells. Oncogene. 1999;18:6733–40. [DOI] [PubMed]

75.

Clarisse D, Van Wesemael K, Tavernier J, Offner F, Beck IM, De Bosscher K. Effect of combining glucocorticoids with compound A on glucocorticoid receptor responsiveness in lymphoid malignancies. PLoS ONE. 2018;13:e0197000. [DOI] [PubMed] [PMC]

76.

Burwick N, Sharma S. Glucocorticoids in multiple myeloma: past, present, and future. Ann Hematol. 2019;98:19–28. [DOI] [PubMed]

77.

Facon T, Mary J, Pégourie B, Attal M, Renaud M, Sadoun A, et al. Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood. 2006;107:1292–8. [DOI] [PubMed]

78.

Fornari A, Randolph K, Yalowich C, Ritke MK, Gewirtz DA. Interference by doxorubicin with DNA unwinding in MCF-7 breast tumor cells. Mol Pharmacol. 1994;45:649–56. [PubMed]

79.

Tacar O, Sriamornsak P, Dass CR. Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. J Pharm Pharmacol. 2013;65:157–70. [DOI] [PubMed]

80.

Gabizon AA, Patil Y, La-Beck NM. New insights and evolving role of pegylated liposomal doxorubicin in cancer therapy. Drug Resist Updat. 2016;29:90–106. [DOI] [PubMed]

81.

Hideshima T, Anderson KC. Histone deacetylase inhibitors in the treatment for multiple myeloma. Int J Hematol. 2013;97:324–32. [DOI] [PubMed]

82.

Sborov DW, Benson DM, Williams N, Huang Y, Bowers MA, Humphries K, et al. Lenalidomide and vorinostat maintenance after autologous transplant in multiple myeloma. Br J Haematol. 2015;171:74–83. [DOI] [PubMed] [PMC]

83.

Voorhees PM, Gasparetto C, Moore DT, Winans D, Orlowski RZ, Hurd DD. Final results of a phase 1 study of vorinostat, pegylated liposomal doxorubicin, and bortezomib in relapsed or refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2017;17:424–32. [DOI] [PubMed]

84.

Vogl DT, Raje N, Jagannath S, Richardson P, Hari P, Orlowsk R, 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;23:3307–15. [DOI] [PubMed] [PMC]

85.

Niesvizky R, Ely S, Mark T, Aggarwal S, Gabrilove JL, Wright JJ, et al. Phase 2 trial of the histone deacetylase inhibitor romidepsin for the treatment of refractory multiple myeloma. Cancer. 2011;117:336–42. [DOI] [PubMed] [PMC]

86.

Niesvizky R, Richardson PG, Gabrail NY, Madan S, Yee AJ, Quayle SN, et al. ACY-241, a novel, HDAC6 selective inhibitor: synergy with immunomodulatory (IMiD®) drugs in multiple myeloma (MM) cells and early clinical results (ACE-MM-200 Study). Blood. 2015;126:3040. [DOI]

87.

Afifi S, Michael A, Azimi M, Rodriguez M, Lendvai N, Landgren O. Role of histone deacetylase inhibitors in relapsed refractory multiple myeloma: a focus on vorinostat and panobinostat. Pharmacotherapy. 2015;35:1173–88. [DOI] [PubMed] [PMC]

88.

Cengiz Seval G, Beksac M. A comparative safety review of histone deacetylase inhibitors for the treatment of myeloma. Expert Opin Drug Saf. 2019;18:563–71. [DOI] [PubMed]

89.

Eleutherakis-Papaiakovou E, Kanellias N, Kastritis E, Kastritis E, Gavriatopoulou M, Terpos E, et al. Efficacy of panobinostat for the treatment of multiple myeloma. J Oncol. 2020;2020:1–11. [DOI]

90.

Chari A, Cho HJ, Dhadwal A, Morgan G, La L, Zarychta K, et al. A phase 2 study of panobinostat with lenalidomide and weekly dexamethasone in myeloma. Blood Advances. 2017;1:1575–83. [DOI] [PubMed] [PMC]

91.

Yee AJ, Raje NS. Panobinostat and multiple myeloma in 2018. Oncologist. 2018;23:516–7. [DOI] [PubMed] [PMC]

92.

Kaufman JL, Mina R, Jakubowiak AJ, Zimmerman TL, Wolf JJ, Lewis C, et al. Combining carfilzomib and panobinostat to treat relapsed/refractory multiple myeloma: results of a Multiple Myeloma Research Consortium Phase I Study. Blood Cancer J. 2019;9:3. [DOI] [PubMed] [PMC]

93.

Hsi ED, Steinle R, Balasa B, Szmania S, Draksharapu A, Shum BP, et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res. 2008;14:2775–84. [DOI] [PubMed] [PMC]

94.

Malaer JD, Mathew PA. CS1 (SLAMF7, CD319) is an effective immunotherapeutic target for multiple myeloma. Am J Cancer Res. 2017;7:1637–41. [PubMed] [PMC]

95.

Frerichs KA, Nagy NA, Lindenbergh PL, Bosman P, Soto JM, Broekmans M, et al. CD38-targeting antibodies in multiple myeloma: mechanisms of action and clinical experience. Expert Rev Clin Immunol. 2018;14:197–206. [DOI] [PubMed]

96.

Petrucci MT, Vozella F. The anti-CD38 antibody therapy in multiple myeloma. Cells. 2019;8:1629. [DOI]

97.

Raab MS, Engelhardt M, Blank A, Goldschmidt H, Agis H, Blau IW, et al. MOR202, a novel anti-CD38 monoclonal antibody, in patients with relapsed or refractory multiple myeloma: a first-in-human, multicentre, phase 1–2a trial. Lancet Haematol. 2020;7:e381–94. [DOI] [PubMed]

98.

Krejcik J, Casneuf T, Nijhof IS, Verbist B, Bald J, Plesner T, et al. Daratumumab depletes CD38⁺ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128:384–94. [DOI] [PubMed] [PMC]

99.

Costello C. An update on the role of daratumumab in the treatment of multiple myeloma. Ther Adv Hematol. 2017;8:28–37. [DOI] [PubMed] [PMC]

100.

Bonello F, Mina R, Boccadoro M, Gay F. Therapeutic monoclonal antibodies and antibody products: current practices and development in multiple myeloma. Cancers. 2019;12:15. [DOI]

101.

Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016;387:1551–60. [DOI] [PubMed]

102.

Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:1319–31. [DOI] [PubMed]

103.

Dimopoulos MA, San-Miguel J, Belch A, White D, Benboubker L, Cook G, et al. Daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of POLLUX. Haematologica. 2018;103:2088–96. [DOI] [PubMed] [PMC]

104.

Facon T, Kumar S, Plesner T, Orlowski RZ, Moreau P, Bahlis N, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380:2104–15. [DOI] [PubMed]

105.

Collins SM, Bakan CE, Swartzel GD, Hofmeister CC, Efebera YA, Kwon H, et al. Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC. Cancer Immunol Immunother. 2013;62:1841–9. [DOI] [PubMed] [PMC]

106.

Zonder JA, Mohrbacher AF, Singhal S, van Rhee F, Bensinger WI, Ding H, et al. A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Blood. 2012;120:552–9. [DOI] [PubMed] [PMC]

107.

Dimopoulos MA, Lonial S, Betts KA, Chen C, Zichlin ML, Brun A., et al. Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended 4-year follow-up and analysis of relative progression-free survival from the randomized ELOQUENT-2 trial. Cancer. 2018;124:4032–43. [DOI] [PubMed]

108.

Dimopoulos MA, Dytfeld D, Grosicki S, Moreau P, Takezako N, Hori M, et al. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl J Med. 2018;379:1811–22. [DOI] [PubMed]

109.

Wudhikarn K, Wills B, Lesokhin AM. Monoclonal antibodies in multiple myeloma: current and emerging targets and mechanisms of action. Best Prac Res Clin Haematol. 2020;33:101143. [DOI]

110.

Gong J, Jaiswal R, Mathys JM, Combes V, Grau GER, Bebawy M. Microparticles and their emerging role in cancer multidrug resistance. Cancer Treat Rev. 2012;38:226–34. [DOI] [PubMed]

111.

Nishihori T, Baz R. Selective inhibitors of nuclear export (SINEs) in myeloma: breakthrough or bust? Expert Opin Drug Saf. 2020;19:113–5. [DOI] [PubMed]

112.

Camus V, Miloudi H, Taly A, Sola B, Jardin F. XPO1 in B cell hematological malignancies: from recurrent somatic mutations to targeted therapy. J Hematol Oncol. 2017;10:47. [DOI] [PubMed] [PMC]

113.

Schmidt J, Braggio E, Kortuem KM, Egan JB, Zhu YX, Xin CS, et al. Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276. Leukemia. 2013;27:2357–65. [DOI] [PubMed] [PMC]

114.

Podar K, Shah J, Chari A, Richardson PG, Jagannath S. Selinexor for the treatment of multiple myeloma. Expert Opin Pharmacother. 2020;21:399–408. [DOI] [PubMed]

115.

Barlogie B, Hall R, Zander A, Dicke K, Alexanian R. High-dose melphalan with autologous bone marrow transplantation for multiple myeloma. Blood. 1986;67:1298–301. [PubMed]

116.

Barlogie B, Alexanian R, Dicke KA, Zagars G, Spitzer G, Jagannath S, et al. High-dose chemoradiotherapy and autologous bone marrow transplantation for resistant multiple myeloma. Blood. 1987;70:869–72. [PubMed]

117.

Cook G, Liakopoulou E, Pearce R, Cavet J, Morgan GJ, Kirkland K, et al.; British Society of Blood & Marrow Transplantation Clinical Trials Committee. Factors Influencing the outcome of a second autologous stem cell transplant (ASCT) in relapsed multiple myeloma: a study from the british society of blood and marrow transplantation registry. Biol Blood Marrow Transplant. 2011;17:1638–45. [DOI] [PubMed]

118.

Michel A, Jean-Luc H, Thierry F, Guilhot F, Doyen C, Fuzibet J, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003;349:2495–502. [DOI] [PubMed]

119.

Mai EK, Benner A, Bertsch U, Brossart P, Hänel A, Kunzmann V, et al. Single versus tandem high-dose melphalan followed by autologous blood stem cell transplantation in multiple myeloma: long-term results from the phase III GMMG-HD2 trial. Br J Haematol. 2016;173:731–41. [DOI] [PubMed]

120.

Cavo M, Gay FM, Patriarca F, Zamagni E, Montefusco V, Dozzaet L, et al. Double autologous stem cell transplantation significantly prolongs progression-free survival and overall survival in comparison with single autotransplantation in newly diagnosed multiple myeloma: an analysis of phase 3 EMN02/HO95 study. Blood. 2017;130:401. [DOI]

121.

Al Hamed R, Bazarbachi AH, Malard F, Harousseau J, Mohty M. Current status of autologous stem cell transplantation for multiple myeloma. Blood Cancer J. 2019;9:44. [DOI] [PubMed] [PMC]

122.

Ntanasis-Stathopoulos I, Gavriatopoulou M, Kastritis E, Terpos E, Dimopoulos MA. Multiple myeloma: role of autologous transplantation. Cancer Treat Rev. 2020;82:101929. [DOI] [PubMed]

123.

Barlogie B, Mitchell A, van Rhee F, Epstein J, Morgan JG, Crowley J. Curing myeloma at last: defining criteria and providing the evidence. Blood. 2014;124:3043–51. [DOI] [PubMed] [PMC]

124.

Paiva B, García-Sanz R, San Miguel JF. Multiple myeloma minimal residual disease. Cancer Treat Res. 2016;169:103–122. [DOI] [PubMed]

125.

Bazarbachi AH, Al Hamed R, Malard F, Harousseau J, Mohty M. Relapsed refractory multiple myeloma: a comprehensive overview. Leukemia. 2019;33:2343–57. [DOI] [PubMed]

126.

Rajan AM, Rajkumar SV. Interpretation of cytogenetic results in multiple myeloma for clinical practice. Blood Cancer J. 2015;5:e365. [DOI] [PubMed] [PMC]

127.

Robiou du Pont S, Cleynen A, Fontan C, Attal M, Munshi N, Corre J, et al. Genomics of multiple myeloma. J Clin Oncol. 2017;35:963–7. [DOI] [PubMed]

128.

Yellapantula V, Hultcrantz M, Rustad EH, Wasserman E, Londono D, Cimera R, et al. Comprehensive detection of recurring genomic abnormalities: a targeted sequencing approach for multiple myeloma. Blood Cancer J. 2019;9:101. [DOI] [PubMed] [PMC]

129.

He J, Abdel-Wahab O, Nahas MK, Wang K, Rampal RK, Intlekofer AM, et al. Integrated genomic DNA/RNA profiling of hematologic malignancies in the clinical setting. Blood. 2016;127:3004–14. [DOI] [PubMed] [PMC]

130.

Castaneda O, Baz R. Multiple myeloma genomics — a concise review. Acta Med Acad. 2019;48:57–67. [DOI] [PubMed]

131.

Broderick P, Chubb D, Johnson DC, Weinhold N, Försti A, Lloyd A, et al. Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk. Nat Genet. 2012;44:58–61. [DOI]

132.

Chubb D, Weinhold N, Broderick P, Chen B, Johnson DC, Försti A, et al. Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk. Nat Genet. 2013;45:1221–5. [DOI] [PubMed] [PMC]

133.

Swaminathan B, Thorleifsson G, Jöud M, Ali M, Johnsson E, Ajore R, et al. Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma. Nat Commun. 2015;6:7213. [DOI] [PubMed] [PMC]

134.

Mitchell JS, Li N, Weinhold N, Ali M, van Duin M, Thorleifsson G, et al. Genome-wide association study identifies multiple susceptibility loci for multiple myeloma. Nat Commun. 2016;7:12050. [DOI] [PubMed] [PMC]

135.

Went M, Sud A, Försti A, Halvarsson B, Weinhold N, Kimber S, et al. Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma. Nat Commun. 2018;9:3707. [DOI] [PubMed] [PMC]

136.

Bolli N, Avet-Loiseau H, Wedge DC, Van Loo P, Alexandrov LB, Martincorena I, et al. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat Commun. 2014;5:2997. [DOI] [PubMed] [PMC]

137.

Lohr JG, Stojanov P, Carter SL, Cruz-Gordillo P, Lawrence MS, Auclair D, et al. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell. 2014;25:91–101. [DOI] [PubMed] [PMC]

138.

Walker BA, Boyle EM, Wardell CP, Murison A, Begum DB, Dahir NM, et al. Mutational spectrum, copy number changes, and outcome: results of a sequencing study of patients with newly diagnosed myeloma. J Clin Oncol. 2015;33:3911–20. [DOI] [PubMed] [PMC]

139.

Hoang PH, Dobbins SE, Cornish AJ, Chubb D, Law PJ, Kaiser M, Houlston RS. Whole-genome sequencing of multiple myeloma reveals oncogenic pathways are targeted somatically through multiple mechanisms. Leukemia. 2018;32:2459–70. [DOI] [PubMed] [PMC]

140.

Lopez-Corral L, Gutierrez NC, Vidriales MB, Mateos MV, Rasillo A, García-Sanz R, 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;17:1692–700. [DOI] [PubMed]

141.

Walker BA, Wardell CP, Melchor L, Brioli A, Johnson DC, Kaiser MF, et al. Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms. Leukemia. 2014;28:384–90. [DOI] [PubMed] [PMC]

142.

Dutta AK, Fink JL, Grady JP, Morgan GJ, Mullighan CG, To LB, et al. Subclonal evolution in disease progression from MGUS/SMM to multiple myeloma is characterised by clonal stability. Leukemia. 2019;33:457–68. [DOI] [PubMed] [PMC]

143.

Egan JB, Shi CX, Tembe W, Christoforides A, Kurdoglu A, Sinari S, et al. Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. Blood. 2012;120:1060–66. [DOI] [PubMed] [PMC]

144.

López-Corral L, Sarasquete ME, Beà S, García-Sanz R, Mateos MV, Corchete LA, et al. SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status. Leukemia. 2012;26:2521–9. [DOI] [PubMed]

145.

Chiecchio L, Dagrada GP, Protheroe RKM, Stockley DM, Smith AG, Orchard KH, et al. Loss of 1p and rearrangement of MYC are associated with progression of smouldering myeloma to myeloma: sequential analysis of a single case. Haematologica. 2009;94:1024–8. [DOI] [PubMed] [PMC]

146.

Weinhold N, Ashby C, Rasche L, Chavan SS, Stein C, Stephens OW, et al. Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma. Blood. 2016;128:1735–44. [DOI] [PubMed] [PMC]

147.

Walker BA, Wardell CP, Melchor L, Hulkki S, Potter NE, Johnson DC, et al. Intraclonal heterogeneity and distinct molecular mechanisms characterize the development of t(4;14) and t(11;14) myeloma. Blood. 2012;120:1077–86. [DOI] [PubMed]

148.

Melchor L, Brioli A, Wardell CP, Murison A, Potter NE, Kaiser MF, et al. Single-cell genetic analysis reveals the composition of initiating clones and phylogenetic patterns of branching and parallel evolution in myeloma. Leukemia. 2014;28:1705–15. [DOI] [PubMed]

149.

Lohr JG, Kim S, Gould J, Knoechel B, Drier Y, Cotton MJ, et al. Genetic interrogation of circulating multiple myeloma cells at single-cell resolution. Sci Transl Med. 2016;8:363ra147. [DOI]

150.

Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC, et al. Initial genome sequencing and analysis of multiple myeloma. Nature. 2011;471:467–72. [DOI] [PubMed] [PMC]

151.

Annunziata CM, Davis RE, Demchenko Y, Bellamy W, Gabrea A, Zhan F, et al. Frequent engagement of the classical and alternative NF-κB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell. 2007;12:115–30. [DOI] [PubMed] [PMC]

152.

Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng W, et al. Promiscuous mutations activate the noncanonical NF-κB pathway in multiple myeloma. Cancer Cell. 2007;12:131–44. [DOI] [PubMed] [PMC]

153.

Demchenko YN, Glebov OK, Zingone A, Keats JJ, Bergsagel PL, Kuehl WM, et al. Classical and/or alternative NF-κB pathway activation in multiple myeloma. 2010;115:3541–52. [DOI]

154.

Walker BA, Leone PE, Chiecchio L, Dickens NJ, Jenner MW, Boyd KD, et al. A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value. Blood. 2010;116:e56–65. [DOI] [PubMed]

155.

Samur MK, AktasSamur A, Fulciniti M, Szalat R, Han T, Shammas M, et al. Genome-wide somatic alterations in multiple myeloma reveal a superior outcome group. J Clin Oncol. 2020;38:3107–18. [DOI] [PubMed] [PMC]

156.

Dickens NJ, Walker BA, Leone PE, Johnson DC, Brito JL, Zeisig A, et al. Homozygous deletion mapping in myeloma samples identifies genes and an expression signature relevant to pathogenesis and outcome. Clin Cancer Res. 2010;16:1856–64. [DOI] [PubMed] [PMC]

157.

Shaughnessy JD, Zhan F, Burington BE, Huang Y, Colla S, Hanamura I, et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood. 2007;109:2276–84. [DOI] [PubMed]

158.

Shaughnessy JD, Qu P, Usmani S, Heuck CJ, Zhang Q, Zhou Y, et al. Pharmacogenomics of bortezomib test-dosing identifies hyperexpression of proteasome genes, especially PSMD4, as novel high-risk feature in myeloma treated with total therapy 3. Blood. 2011;118:3512–24. [DOI] [PubMed] [PMC]

159.

Rème T, Hose D, Theillet C, Klein B. Modeling risk stratification in human cancer. Bioinformatics. 2013;29:1149–57. [DOI] [PubMed]

160.

van Duin M, Broyl A, de Knegt Y, Goldschmidt H, Richardson PG, Hop WCJ, et al. Cancer testis antigens in newly diagnosed and relapse multiple myeloma: prognostic markers and potential targets for immunotherapy. Haematologica. 2011;96:1662–9. [DOI] [PubMed] [PMC]

161.

Chng WJ, Braggio E, Mulligan G, Bryant B, Remstein E, Valdez R, et al. The centrosome index is a powerful prognostic marker in myeloma and identifies a cohort of patients that might benefit from aurora kinase inhibition. Blood. 2008;111:1603–9. [DOI] [PubMed]

162.

Chng WJ, Ahmann GJ, Henderson K, Santana-Davila R, Greipp PR, Gertz MA, et al. Clinical implication of centrosome amplification in plasma cell neoplasm. Blood. 2006;107:3669–75. [DOI] [PubMed] [PMC]

163.

Decaux O, Lodé L, Magrangeas F, Charbonnel C, Gouraud W, Jézéquel P, et al. Prediction of survival in multiple myeloma based on gene expression profiles reveals cell cycle and chromosomal instability signatures in high-risk patients and hyperdiploid signatures in low-risk patients: a study of the intergroupe francophone du myélome. J Clin Oncol. 2008;26:4798–805. [DOI] [PubMed]

164.

Hose D, Reme T, Hielscher T, Moreaux J, Messner T, Seckinger A, et al. Proliferation is a central independent prognostic factor and target for personalized and risk-adapted treatment in multiple myeloma. Haematologica. 2011;96:87–95. [DOI] [PubMed] [PMC]

165.

Kuiper R, Broyl A, de Knegt Y, van Vliet MH, van Beers EH, van der Holt B, et al. A gene expression signature for high-risk multiple myeloma. Leukemia. 2012;26:2406–13. [DOI] [PubMed]

166.

Kuiper R, van Duin M, van Vliet MH, Broijl A, van der Holt B, El Jarari L, et al. Prediction of high- and low-risk multiple myeloma based on gene expression and the International Staging System. Blood. 2015;126:1996–2004. [DOI] [PubMed] [PMC]

167.

van Beers EH, van Vliet MH, Kuiper R, de Best L, Anderson KC, Char A, et al. Prognostic validation of SKY92 and its combination with ISS in an independent cohort of patients with multiple myeloma. Clin Lymphoma Myeloma Leuk. 2017;17:555–62. [DOI] [PubMed]

168.

Meissner T, Seckinger A, Reme T, Hielscher T, Möhler T, Neben K, et al. Gene expression profiling in multiple myeloma--reporting of entities, risk, and targets in clinical routine. Clin Cancer Res. 2011;17:7240–7. [DOI] [PubMed]

169.

Terragna C, Renzulli M, Remondini D, Tagliafico E, Di Raimondo F, Patriarca F, et al. Correlation between eight-gene expression profiling and response to therapy of newly diagnosed multiple myeloma patients treated with thalidomide–dexamethasone incorporated into double autologous transplantation. Ann Hematol. 2013;92:1271–80. [DOI] [PubMed]

170.

Kassambara A, Hose D, Moreaux J, Walker BA, Protopopov A, Reme T, et al. Genes with a spike expression are clustered in chromosome (sub)bands and spike (sub)bands have a powerful prognostic value in patients with multiple myeloma. Haematologica. 2012;97:622–30. [DOI] [PubMed] [PMC]

171.

Moreaux J, Klein B, Bataille R, Descamps G, Maïga S, Hose D, et al. A high-risk signature for patients with multiple myeloma established from the molecular classification of human myeloma cell lines. Haematologica. 2011;96:574–82. [DOI] [PubMed] [PMC]

172.

Chung TH, Mulligan G, Fonseca R, Chng WJ. A Novel measure of chromosome instability can account for prognostic difference in multiple yeloma. PLoS One. 2013;8:e66361. [DOI] [PubMed] [PMC]

173.

Weston-Bell N, Gibson J, John M, Ennis S, Pfeifer S, Cezard T, et al. Exome sequencing in tracking clonal evolution in multiple myeloma following therapy. Leukemia. 2013;27:1188–91. [DOI] [PubMed]

174.

Magrangeas F, Avet-Loiseau H, Gouraud W, Decaux O, Godmer P, Garderet L, et al. Minor clone provides a reservoir for relapse in multiple myeloma. Leukemia. 2013;27:473–81. [DOI] [PubMed] [PMC]

175.

Vikova V, Jourdan M, Robert N, Requirand G, Boireau S, Bruyer A, et al. Comprehensive characterization of the mutational landscape in multiple myeloma cell lines reveals potential drivers and pathways associated with tumor progression and drug resistance. Theranostics. 2019;9:540–53. [DOI] [PubMed] [PMC]

176.

Elnenaei MO, Knopf P, Cutler SD, Sinclair K, Abou El Hassan M, Greer W, et al. Low-depth sequencing for copy number abnormalities in multiple myeloma supersedes fluorescent in situ hybridization in scope and resolution. Clin Genet. 2019;96:163–8. [DOI] [PubMed]

177.

Kortüm KM, Langer C, Monge J, Bruins L, Egan JB, Zhu YX, et al. Targeted sequencing using a 47 gene multiple myeloma mutation panel (M3P) in -17p high risk disease. Br J Haematol. 2015;168:507–10. [DOI] [PubMed] [PMC]

178.

Kortuem KM, Braggio E, Bruins L, Barrio S, Shi CS, Zhu YX, et al. Panel sequencing for clinically oriented variant screening and copy number detection in 142 untreated multiple myeloma patients. Blood Cancer J. 2016;6:e397. [DOI] [PubMed] [PMC]

179.

Kortüm KM, Mai EK, Hanafiah NH, Shi C, Zhu Y, Bruins L, et al. Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes. Blood. 2016;128:1226–33. [DOI] [PubMed] [PMC]

180.

Perrot A, Lauwers-Cances V, Corre J, Robillard N, Hulin C, Chretien M, et al. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. Blood. 2018;132:2456–64. [DOI] [PubMed] [PMC]

181.

Paiva B, van Dongen JJM, Orfao A. New criteria for response assessment: role of minimal residual disease in multiple myeloma. Blood. 2015;125:3059–68. [DOI] [PubMed] [PMC]

182.

Paiva B, Gutiérrez NC, Rosiñol L, Vídriales M, Montalbán M, Martínez-López J, et al. High-risk cytogenetics and persistent minimal residual disease by multiparameter flow cytometry predict unsustained complete response after autologous stem cell transplantation in multiple myeloma. Blood. 2012;119:687–91. [DOI] [PubMed]

183.

Paiva B, Puig N, Cedena MT, Rosiñol L, Cordón L, Vidriales M, et al. Measurable residual disease by next-generation flow cytometry in multiple myeloma. J Clin Onclo. 2020;38:78–92. [DOI]

184.

Kumar S, Paiva B, Anderson KC, Landgren O, Moreau P, Munshi N, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17:e328–46. [DOI] [PubMed]

185.

Martinez-Lopez J, Sanchez-Vega B, Barrio S, Cuenca I, Ruiz-Heredia Y, Alonso R, et al. Analytical and clinical validation of a novel in-house deep-sequencing method for minimal residual disease monitoring in a phase II trial for multiple myeloma. Leukemia. 2017;31:1446–9. [DOI] [PubMed] [PMC]

186.

Avet-Loiseau H. Minimal residual disease by next-generation sequencing: pros and cons. Am Soc Clin Oncol Educ Book. 2016;35:e425–30. [DOI] [PubMed]

187.

Rashid NU, Sperling AS, Bolli N, Wedge DC, Van Loo P, Tai Y, et al. Differential and limited expression of mutant alleles in multiple myeloma. Blood. 2014;124:3110–7. [DOI] [PubMed] [PMC]

188.

Cleynen A, Szalat R, Kemal Samur M, Robiou du Pont S, Buisson L, Boyle E, et al. Expressed fusion gene landscape and its impact in multiple myeloma. Nat Commun. 2017;8:1893. [DOI] [PubMed] [PMC]

189.

Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T, et al. NF-κB as a therapeutic target in multiple myeloma. J Biol Chem. 2002;277:16639–47. [DOI] [PubMed]

190.

Lin M, Lee PL, Chiu L, Chua C, Ban KHK, Lin AHF, et al. Identification of novel fusion transcripts in multiple myeloma. J Clin Pathol. 2018;71:708–12. [DOI] [PubMed]

191.

Went M, Kinnersley B, Sud A, Johnson DC, Weinhold N, Försti A, et al. Transcriptome-wide association study of multiple myeloma identifies candidate susceptibility genes. Hum Genomics. 2019;13:37. [DOI] [PubMed] [PMC]

192.

Chng WJ, Chung TH, Kumar S, Usmani S, Munshi N, Avet-Loiseau H, et al.; on behalf of the International Myeloma Working Group. Gene signature combinations improve prognostic stratification of multiple myeloma patients. Leukemia. 2016;30:1071–8. [DOI] [PubMed]

193.

Jang JS, Li Y, Mitra AK, Bi L, Abyzov A, van Wijnen AJ, et al. Molecular signatures of multiple myeloma progression through single cell RNA-Seq. Blood Cancer J. 2019;9:2. [DOI] [PubMed] [PMC]

194.

Mitra AK, Mukherjee UK, Harding T, Jang JS, Stessman H, Li Y, et al. Single-cell analysis of targeted transcriptome predicts drug sensitivity of single cells within human myeloma tumors. Leukemia. 2016;30:1094–102. [DOI] [PubMed]

195.

Ledergor G, Weiner A, Zada M, Wang S, Cohen YC, Gatt ME, et al. Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma. Nat Med. 2018;24:1867–76. [DOI] [PubMed]

196.

Vangsted AJ, Helm-Petersen S, Cowland JB, Jensen PB, Gimsing P, Barlogie B, et al. Drug response prediction in high-risk multiple myeloma. Gene. 2018;644:80–6. [DOI] [PubMed]

197.

de Boussac H, Bruyer A, Jourdan M, Maes A, Robert N, Gourzones C, et al. Kinome expression profiling to target new therapeutic avenues in multiple myeloma. Haematologica. 2020;105:784–95. [DOI] [PubMed] [PMC]

198.

Ziccheddu B, Biancon G, Bagnoli F, De Philippis C, Maura F, Rustad EH, et al. Integrative analysis of the genomic and transcriptomic landscape of double-refractory multiple myeloma. Blood Adv. 2020;4:830–44. [DOI] [PubMed] [PMC]

199.

Shi CX, Zhu YX, Bruins LA, Bonolo de Campos C, Stewart W, Braggio E, et al. Proteasome subunits differentially control myeloma cell viability and proteasome inhibitor sensitivity. Mol Cancer Res. 2020;18:1453–64. [DOI] [PubMed] [PMC]

200.

Moreaux J, Rème T, Leonard W, Veyrune JL, Requirand G, Goldschmidt H, et al. Development of gene expression-based score to predict sensitivity of multiple myeloma cells to DNA methylation inhibitors. Mol Cancer Ther. 2012;11:2685–92. [DOI] [PubMed]

201.

Bhutani M, Zhang Q, Friend R, Voorhees PM, Druhan LJ, Barlogie B, et al. Investigation of a gene signature to predict response to immunomodulatory derivatives for patients with multiple myeloma: an exploratory, retrospective study using microarray datasets from prospective clinical trials. Lancet Haematol. 2017;4:e443–51. [DOI] [PubMed]

202.

Moreaux J, Reme T, Leonard W, Veyrune JL, Requirand G, Goldschmidt H, et al. Gene expression-based prediction of myeloma cell sensitivity to histone deacetylase inhibitors. Br J Cancer. 2013;109:676–85. [DOI] [PubMed] [PMC]

203.

Maes K, De Smedt E, Kassambara A, Hose D, Seckinger A, Van Valckenborgh E, et al. In vivo treatment with epigenetic modulating agents induces transcriptional alterations associated with prognosis and immunomodulation in multiple myeloma. Oncotarget. 2015;6:3319–34. [DOI] [PubMed] [PMC]

204.

Terragna C, Remondini D, Martello M, Zamagni E, Pantani L, Patriarca F, et al. The genetic and genomic background of multiple myeloma patients achieving complete response after induction therapy with bortezomib, thalidomide and dexamethasone (VTD). Oncotarget. 2016;7:9666–79. [DOI] [PubMed] [PMC]

205.

Herviou L, Kassambara A, Boireau S, Rober N, Requirand G, Müller-Tidow C, et al. PRC2 targeting is a therapeutic strategy for EZ score defined high-risk multiple myeloma patients and overcome resistance to IMiDs. Clin Epigenet. 2018;10:121. [DOI]

206.

Croucher PI, McDonald MM, Martin TJ. Bone metastasis: the importance of the neighbourhood. Nat Rev Cancer. 2016;16:373–86. [DOI] [PubMed]

207.

Khoo WH, Ledergor G, Weiner A, Roden DL, Terry RL, McDonald MM, et al. A niche-dependent myeloid transcriptome signature defines dormant myeloma cells. Blood. 2019;134:30–43. [DOI] [PubMed]

208.

Sarïman M, Abacï N, SïrmaEkmekçi S, Çakiris A, Paçal FP, Üstek D, et al. Investigation of gene expressions of myeloma cells in the bone marrow of multiple myeloma patients by transcriptome analysis. Balkan Med J. 2019;23–31. [DOI] [PubMed] [PMC]

209.

Schinke C, Qu P, Mehdi SJ, Hoering A, Epstein J, Johnson SK, et al. The pattern of mesenchymal stem cell expression is an independent marker of outcome in multiple myeloma. Clin Cancer Res. 2018;24:2913–19. [DOI] [PubMed]

210.

Ryu D, Kim SJ, Hong Y, Jo A, Kim N, Kim H, et al. Alterations in the transcriptional programs of myeloma cells and the microenvironment during extramedullary progression affect proliferation and immune evasion. Clin Cancer Res. 2020;26:935–44. [DOI] [PubMed]

211.

Gooding S, Olechnowicz SWZ, Morris EV, Armitage AE, Arezes J, Frost J, et al. Transcriptomic profiling of the myeloma bone-lining niche reveals BMP signalling inhibition to improve bone disease. Nat Commun. 2019;10:4533. [DOI] [PubMed] [PMC]

212.

Rodríguez-Paredes M, Esteller M. Cancer epigenetics reaches mainstream oncology. Nat Med. 2011;17:330–9. [DOI] [PubMed]

213.

Miranda Furtado CL, Dos Santos Luciano MC, Silva Santos RD, Furtado GP, Moraes MO, Pessoa C, et al. Epidrugs: targeting epigenetic marks in cancer treatment. Epigenetics. 2019;14:1164–76. [DOI] [PubMed] [PMC]

214.

Pawlyn C, Kaiser MF, Heuck C, Melchor L, Wardell CP, Murison A, et al. The spectrum and clinical impact of epigenetic modifier mutations in myeloma. Clin Cancer Res. 2016;22:5783–94. [DOI] [PubMed] [PMC]

215.

Yan H, Zheng G, Qu J, Liu Y, Huang X, Zhang E, et al. Identification of key candidate genes and pathways in multiple myeloma by integrated bioinformatics analysis. J Cell Physiol. 2019;234:23785–97. [DOI] [PubMed] [PMC]

216.

Nebbioso A, Tambaro FP, Dell’Aversana C, Altucci L. Cancer epigenetics: moving forward. PLoS Genet. 2018;14:e1007362. [DOI] [PubMed] [PMC]

217.

Agirre X, Castellano G, Pascual M, Heath S, Kulis M, Segura V, et al. Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers. Genome Res. 2015;25:478–87. [DOI] [PubMed] [PMC]

218.

Jones PA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet. 2012;13:484–92. [DOI] [PubMed]

219.

De Smedt E, Lui H, Maes K, De Veirman K, Menu E, Vanderkerken K, et al. The epigenome in multiple myeloma: impact on tumor cell plasticity and drug response. Front Oncol. 2018;8:566. [DOI] [PubMed] [PMC]

220.

Walker BA, Wardell CP, Chiecchio L, Smith EM, Boyd KD, Neri A, et al. Aberrant global methylation patterns affect the molecular pathogenesis and prognosis of multiple myeloma. Blood. 2011;117:553–62. [DOI] [PubMed]

221.

Heuck CJ, Mehta J, Bhagat T, Gundabolu K, Yu Y, Khan S, et al. Myeloma is characterized by stage-specific alterations in DNA methylation that occur early during myelomagenesis. J Immunol. 2013;190:2966–75. [DOI] [PubMed] [PMC]

222.

Kaiser MF, Johnson DC, Wu P, Walker BA, Brioli A, Mirabella F, et al. Global methylation analysis identifies prognostically important epigenetically inactivated tumor suppressor genes in multiple myeloma. Blood. 2013;122:219–26. [DOI] [PubMed] [PMC]

223.

Cao Y, Qiu GQ, Wu HQ, Wang ZL, Lin Y, Wu W, et al. Decitabine enhances bortezomib treatment in RPMI 8226 multiple myeloma cells. Mol Med Reps. 2016;14:3469–75. [DOI]

224.

Jin Y, Xu L, Wu X, Feng J, Shu M, Gu H, et al. Synergistic efficacy of the demethylation agent decitabine in combination with the protease inhibitor bortezomib for treating multiple myeloma through the wnt/β-catenin pathway. Oncol Res. 2019;27:729–37. [DOI] [PubMed] [PMC]

225.

De Beck L, Melhaoui S, De Veirman K, Menu E, De Bruyne E, Vanderkerken K, et al. Epigenetic treatment of multiple myeloma mediates tumor intrinsic and extrinsic immunomodulatory effects. OncoImmunology. 2018;7:e1484981. [DOI] [PubMed] [PMC]

226.

Chatonnet F, Pignarre A, Sérandour AA, Caron G, Avner S, Robert N, et al. The hydroxymethylome of multiple myeloma identifies FAM72D as a 1q21 marker linked to proliferation. Haematologica. 2020;105:774–83. [DOI] [PubMed] [PMC]

227.

Alberge JB, Magrangeas F, Wagner M, Denié S, Guérin-Charbonnel C, Campion L, et al. DNA hydroxymethylation is associated with disease severity and persists at enhancers of oncogenic regions in multiple myeloma. Clin Epigenetics. 2020;12:163. [DOI] [PubMed] [PMC]

228.

Martinez-Garcia E, Popovic R, Min DJ, Sweet SMM, Thomas PM, Zamdborg L, et al. The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells. Blood. 2011;117:211–20. [DOI] [PubMed] [PMC]

229.

Wei X, Calvo-Vidal MN, Chen S, Wu G, Revuelta MV, Sun J, et al. Germline lysine-specific demethylase 1 (LSD1/KDM1A) mutations confer susceptibility to multiple myeloma. Cancer Res. 2018;78:2747–59. [DOI] [PubMed] [PMC]

230.

Ikeda S, Kitadate A, Abe F, Takahashi N, Tagawa H. Hypoxia-inducible KDM3A addiction in multiple myeloma. Blood Advances. 2018;2:323–34. [DOI] [PubMed] [PMC]

231.

Ohguchi H, Hideshima T, Bhasin MK, Gorgun GT, Santo L, Cea M, et al. The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival. Nat Commun. 2016;7:10258. [DOI] [PubMed] [PMC]

232.

Pawlyn C, Kaiser MF, Walker BA, Wardell CP, Murison A, Johnson DC, et al. The spectrum of epigenetic mutations in myeloma and their clinical impact. Blood. 2014;124:2194. [DOI]

233.

Schuettengruber B, Bourbon HM, Di Croce L, Cavalli G. Genome regulation by polycomb and trithorax: 70 years and counting. Cell. 2017;171:34–57. [DOI] [PubMed]

234.

Bruyer A, Maes K, Herviou L, Kassambara A, Seckinger A, Cartron G, et al. DNMTi/HDACi combined epigenetic targeted treatment induces reprogramming of myeloma cells in the direction of normal plasma cells. Br J Cancer. 2018;118:1062–73. [DOI] [PubMed] [PMC]

235.

Agarwal P, Alzrigat M, Párraga AA, Enroth S, Singh Ü, Üngerstedt J, et al. Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of polycomb gene targeting and highlights EZH2 as a potential therapeutic target. Oncotarget. 2016;7:6809–23. [DOI] [PubMed] [PMC]

236.

Jin Y, Chen K, De Paepe A, Krstic AD, Metang L, Gustafsson C, et al. Active enhancer and chromatin accessibility landscapes chart the regulatory network of primary multiple myeloma. Blood. 2018;131:2138–50. [DOI] [PubMed] [PMC]

237.

Ordoñez R, Kulis M, Russiñol N, Chapaprieta V, Carrasco-Leon A, García-Torre B, et al. Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma. Genome Res. 2020;30:1217–27. [DOI] [PubMed] [PMC]

238.

Dupéré-Richer D, Licht JD. Epigenetic regulatory mutations and epigenetic therapy for multiple myeloma. Curr Opin Hematol. 2017;24:336–44. [DOI] [PubMed] [PMC]

239.

Kyle RA, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Dispenzieri A, et al. Review of 1,027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78:21–33. [DOI] [PubMed]

240.

Durie BGM, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467–73. [DOI] [PubMed]

241.

Morrison T, Booth RA, Hauff K, Berardi P, Visram A. Laboratory assessment of multiple myeloma. Adv Clin Chem. 2019;89:1–58. [DOI] [PubMed]

242.

McTaggart MP, Lindsay J, Kearney EM. Replacing urine protein electrophoresis with serum free light chain analysis as a first-line test for detecting plasma cell disorders offers increased diagnostic accuracy and potential health benefit to patients. Am J Clin Pathol. 2013;140:890–7. [DOI] [PubMed]

243.

Martellosio JP, Leleu X, Roblot P, Martin M, Puyade M. Dosage des chaînes légères libres : indications et méthodes. Rev Méd Interne. 2019;40:297–305. [DOI] [PubMed]

244.

Ayliffe MJ, Davies FE, de Castro D, Morgan GJ. Demonstration of changes in plasma cellsubsets in multiple myeloma. Haematologica. 2007;92:1135–8. [DOI] [PubMed]

245.

Kühnemund A, Liebisch P, Bauchmüller K, zur Hausen A, Veelken H, Wäsch R, et al. ‘Light-chain escape-multiple myeloma’-an escape phenomenon from plateau phase: report of the largest patient series using LC-monitoring. J Cancer Res Clin Oncol. 2009;135:477–84. [DOI] [PubMed]

246.

Brioli A, Giles H, Pawlyn C, Campbell JP, Kaiser MF, Melchor L, et al. Serum free immunoglobulin light chain evaluation as a marker of impact from intraclonal heterogeneity on myeloma outcome. Blood. 2014;123:3414–9. [DOI] [PubMed]

247.

Barnidge DR, Tschumper RC, Theis JD, Snyder MR, Jelinek DF, Katzmann JA, et al. Monitoring M-proteins in patients with multiple myeloma using heavy-chain variable region clonotypic peptides and LC–MS/ MS. J Proteome Res. 2014;13:1905–10. [DOI] [PubMed]

248.

Remily-Wood ER, Benson K, Baz RC, Chen YA, Hussein M, Hartley-Brown MA, et al. Quantification of peptides from immunoglobulin constant and variable regions by LC-MRM MS for assessment of multiple myeloma patients. Prot Clin Appl. 2014;8:783–95. [DOI]

249.

Martins CO, Huet S, Yi SS, Landgren O, Dogan A, Chapman JR, et al. Mass spectrometry-based method targeting Ig variable regions for assessment of minimal residual disease in multiple myeloma. J Mol Diagn. 2020;22:901–11. [DOI] [PubMed] [PMC]

250.

Ogata A, Chauhan D, Teoh G, Treon SP, Urashima M, Schlossman RL, et al. IL-6 triggers cell growth via the Ras-dependent mitogen-activated protein kinase cascade. J Immunol. 1997;159:2212–21. [PubMed]

251.

Chauhan D, Kharbanda S, Ogata A, Urashima M, Teoh G, Robertson M, et al. Interleukin-6 inhibits fas-induced apoptosis and stress-activated protein kinase activation in multiple myeloma cells. Blood. 1997;89:227–34. [PubMed]

252.

Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, et al. Constitutive activation of stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity. 1999;10:105–15. [DOI] [PubMed]

253.

Tu Y, Gardner A, Lichtenstein A. The phosphatidylinositol 3-kinase/AKT kinase pathway in multiple myeloma plasma cells: roles in cytokine-dependent survival and proliferative responses. Cancer Res. 2000;60:6763–70. [PubMed]

254.

Lin YHT, Way GP, Barwick BG, Mariano MC, Marcoulis M, Fergusonet ID, et al. Integrated phosphoproteomics and transcriptional classifiers reveal hidden RAS signaling dynamics in multiple myeloma. Blood Adv. 2019;3:3214–27. [DOI] [PubMed] [PMC]

255.

Ge F, Xiao CL, Bi LJ, Tao S, Xiong S, Yin XF, et al. Quantitative phosphoproteomics of proteasome inhibition in multiple myeloma cells. PLoS ONE. 2010;5:e13095. [DOI] [PubMed] [PMC]

256.

Rees-Unwin KS, Craven RA, Davenport E, Hanrahan S, Totty NF, Dring AM, et al. Proteomic evaluation of pathways associated with dexamethasone-mediated apoptosis and resistance in multiple myeloma. Br J Haematol. 2007;139:559–67. [DOI] [PubMed]

257.

Litichevskiy L, Peckner R, Abelin JG, Asiedu JK, Creech AL, Davis JF, et al. A library of phosphoproteomic and chromatin signatures for characterizing cellular responses to drug perturbations. Cell Syst. 2018;6:424–43.e7. [DOI] [PubMed] [PMC]

258.

Xiang Y, Remily-Wood ER, Oliveira V, Yarde D, He L, Cheng JQ, et al. Monitoring a nuclear factor-κB signature of drug resistance in multiple myeloma. Mol Cell Proteomics. 2011;10:M110.005520. [DOI]

259.

Zub KA, Sousa MML de, Sarno A, Sharma A, Demirovic A, Rao S, et al. Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells. PLoS ONE. 2015;10:e0119857. [DOI] [PubMed] [PMC]

260.

Koomen DC, Guingab-Cagmat JD, Oliveira PS, Fang B, Liu M, Welsh EA, et al. Proteometabolomics of melphalan resistance in multiple myeloma. Methods Mol Biol. 2019;1996:273–96. [DOI] [PubMed] [PMC]

261.

Dytfeld D, Luczak M, Wrobel T, Usnarska-Zubkiewicz L, Brzezniakiewicz K, Jamroziak K, et al. Comparative proteomic profiling of refractory/relapsed multiple myeloma reveals biomarkers involved in resistance to bortezomib-based therapy. Oncotarget. 2016;7:56726–36. [DOI] [PubMed] [PMC]

262.

Zaal EA, Wu W, Jansen G, Cloos J, Berkers CR. Bortezomib resistance in multiple myeloma is associated with increased serine synthesis. Cancer Metab. 2017;5:7. [DOI] [PubMed] [PMC]

263.

Soriano GP, Besse L, Li N, Kraus M, Besse A, Meeuwenoord N, et al. Proteasome inhibitor-adapted myeloma cells are largely independent from proteasome activity and show complex proteomic changes, in particular in redox and energy metabolism. Leukemia. 2016;30:2198–207. [DOI] [PubMed] [PMC]

264.

Dytfeld D, Rosebeck S, Kandarpa M, Mayampurath A, Mellacheruvu D, Alonge MM, et al. Proteomic profiling of naïve multiple myeloma patient plasma cells identifies pathways associated with favourable response to bortezomib-based treatment regimens. Br J Haematol. 2015;170:66–79. [DOI] [PubMed]

265.

Xiao CL, Zhang ZP, Xiong S, Lu CH, Wei HP, Zeng HL, et al. Comparative proteomic analysis to discover potential therapeutic targets in human multiple myeloma. Prot Clin Appl. 2009;3:1348–60. [DOI]

266.

Rajpal R, Dowling P, Meiller J, Clarke C, Murphy WG, O’Connor R, et al. A novel panel of protein biomarkers for predicting response to thalidomide-based therapy in newly diagnosed multiple myeloma patients. Proteomics. 2011;11:1391–402. [DOI] [PubMed]

267.

Danailova A, Todinova S, Dimitrova K, Petkova V, Guenova M, Mihaylov G, et al. Effect of autologous stem-cells transplantation of patients with multiple myeloma on the calorimetric markers of the serum proteome. Correlation with the immunological markers. Thermochim Acta. 2017;655:351–7. [DOI]

268.

Łuczak M, Kubicki T, Rzetelska Z, Szczepaniak T, Przybyłowicz-Chalecka A, Ratajczak B, et al. Comparative proteomic profiling of sera from patients with refractory multiple myeloma reveals potential biomarkers predicting response to bortezomib-based therapy. Pol Arch Intern Med. 2017;127:392–400. [DOI] [PubMed]

269.

Shenoy A, Geiger T. Super-SILAC: current trends and future perspectives. Expert Rev Proteomics. 2015;12:13–9. [DOI] [PubMed]

270.

Jelinek T, Kryukov F, Rihova L, Hajek R. Plasma cell leukemia: from biology to treatment. Eur J Haematol. 2015;95:16–26. [DOI] [PubMed]

271.

Zatula A, Dikic A, Mulder C, Sharma A, Vågbo CB, Sousa MML, et al. Proteome alterations associated with transformation of multiple myeloma to secondary plasma cell leukemia. Oncotarget. 2017;8:19427–42. [DOI] [PubMed] [PMC]

272.

Vander Heiden MG, Cantley LC, Thompson CB. Understanding the warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33. [DOI] [PubMed] [PMC]

273.

Liberti MV, Locasale JW. The warburg effect: how does it benefit cancer cells? Trends Biochem Sci. 2016;41:211–8. [DOI] [PubMed] [PMC]

274.

Dang CV, Le A, Gao P. MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res. 2009;15:6479–83. [DOI] [PubMed] [PMC]

275.

Sanchez WY, McGee SL, Connor T, Mottram B, Wilkinson A, Whitehead JP, et al. Dichloroacetate inhibits aerobic glycolysis in multiple myeloma cells and increases sensitivity to bortezomib. Br J Cancer. 2013;108:1624–33. [DOI] [PubMed] [PMC]

276.

Fujiwara S, Kawano Y, Yuki H, Nosaka K, Mitsuya H, Hata H, et al. PDK1 inhibition is a novel therapeutic target in multiple myeloma. Br J Cancer. 2013;108:170–8. [DOI] [PubMed] [PMC]

277.

Maiso P, Huynh D, Moschetta M, Sacco A, Aljawai Y, Mishima Y, et al. Metabolic signature identifies novel targets for drug resistance in multiple myeloma. Cancer Res. 2015;75:2071–82. [DOI] [PubMed] [PMC]

278.

Panchabhai S, Schlam I, Sebastian S, Fonseca R. PKM2 and other key regulators of Warburg effect positively correlate with CD147 (EMMPRIN) gene expression and predict survival in multiple myeloma. Leukemia. 2017;31:991–4. [DOI] [PubMed]

279.

He A, Bai J, Huang C, Yang J, Zhang W, Wang J, et al. Detection of serum tumor markers in multiple myeloma using the CLINPROT system. Int J Hematol. 2012;95:668–74. [DOI] [PubMed]

280.

Bai J, Yang Y, Wang J, Wang F, He A. Variability of serum novel serum peptide biomarkers correlates with the disease states of multiple myeloma. Clin Proteom. 2019;16:17. [DOI]

281.

Wang J, Hendrix A, Hernot S, Lemaire M, De Bruyne E, Van Valckenborgh E, et al. Bone marrow stromal cell–derived exosomes as communicators in drug resistance in multiple myeloma cells. Blood. 2014;124:555–66. [DOI] [PubMed]

282.

Glavey SV, Naba A, Manier S, Clauser K, Tahri S, Park J, et al. Proteomic characterization of human multiple myeloma bone marrow extracellular matrix. Leukemia. 2017;31:2426–34. [DOI] [PubMed]

283.

Harshman SW, Canella A, Ciarlariello PD, Agarwal K, Branson OE, Rocci A, et al. Proteomic characterization of circulating extracellular vesicles identifies novel serum myeloma associated markers. J Proteomics. 2016;136:89–98. [DOI] [PubMed] [PMC]

284.

Suvannasankha A, Crean CD, Leyes HM, Wongsaengsak S, Qi G, Kim JW, et al. Proteomic characterization of plasma cells from patients with multiple myeloma. J Proteomics Bioinfor. 2018;11:8–16.

285.

Ho M, Bianchi G, Anderson KC. Proteomics-inspired precision medicine for treating and understanding multiple myeloma. Expert Rev Precis Med Drug Dev. 2020;5:67–85. [DOI]

286.

Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab. 2016;23:27–47. [DOI] [PubMed] [PMC]

287.

Goveia J, Pircher A, Conradi L, Kalucka J, Lagani V, Dewerchin M, et al. Meta-analysis of clinical metabolic profiling studies in cancer: challenges and opportunities. EMBO Mol Med. 2016;8:1134–42. [DOI] [PubMed] [PMC]

288.

Currie E, Schulze A, Zechner R, Walther TC, Farese RV Jr. Cellular fatty acid metabolism and cancer. Cell Metab. 2013;18:153–61. [DOI] [PubMed] [PMC]

289.

Röhrig F, Schulze A. The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer. 2016;16:732–49. [DOI] [PubMed]

290.

Mancini R, Noto A, Pisanu ME, De Vitis C, Maugeri-Saccà M, Ciliberto G. Metabolic features of cancer stem cells: the emerging role of lipid metabolism. Oncogene. 2018;37:2367–78. [DOI] [PubMed]

291.

Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. 2008;371:569–78. [DOI]

292.

Teras LR, Kitahara CM, Birmann BM, Hartge PA, Wang SS, Robien K, et al. Body size and multiple myeloma mortality: a pooled analysis of 20 prospective studies. Br J Haematol. 2014;166:667–76. [DOI] [PubMed] [PMC]

293.

Lauby-Secretan B, Scoccianti C, Loomis D, Grosse Y, Bianchini F, Straif K, et al. Body fatness and cancer — viewpoint of the IARC working group. N Engl J Med. 2016;375:794–8. [DOI] [PubMed] [PMC]

294.

Morris EV, Edwards CM. Adipokines, adiposity, and bone marrow adipocytes: dangerous accomplices in multiple myeloma. J Cell Physiol. 2018;233:9159–66. [DOI] [PubMed]

295.

Tirado-Vélez JM, Joumady I, Sáez-Benito A, Cózar-Castellano I, Perdomo G. Inhibition of fatty acid metabolism reduces human myeloma cells proliferation. PLoS ONE. 2012;7:e46484. [DOI] [PubMed] [PMC]

296.

Medina EA, Oberheu K, Polusani SR, Ortega V, Velagaleti GVN, Oyajobi BO. PKA/AMPK signaling in relation to adiponectin’s antiproliferative effect on multiple myeloma cells. Leukemia. 2014;28:2080–9. [DOI] [PubMed]

297.

Nagata Y, Ishizaki I, Waki M, Ide Y, Hossen MA, Ohnishi K, et al. Palmitic acid, verified by lipid profiling using secondary ion mass spectrometry, demonstrates anti-multiple myeloma activity. Leuk Res. 2015;39:638–45. [DOI] [PubMed]

298.

Jurczyszyn A, Czepiel J, Gdula-Argasińska J, Czapkiewicz A, Biesiada G, Dróżdż M, et al. Erythrocyte membrane fatty acids in multiple myeloma patients. Leuk Res. 2014;38:1260–5. [DOI] [PubMed]

299.

Jurczyszyn A, Czepiel J, Gdula-Argasińska J, Paśko P, Czapkiewicz A, Librowski T, et al. Plasma fatty acid profile in multiple myeloma patients. Leuk Res. 2015;39:400–5. [DOI] [PubMed]

300.

Gonsalves WI, Broniowska K, Jessen E, Petterson XM, Bush AG, Gransee J, et al. Metabolomic and lipidomic profiling of bone marrow plasma differentiates patients with monoclonal gammopathy of undetermined significance from multiple myeloma. Sci Rep. 2020;10:10250. [DOI] [PubMed] [PMC]

301.

Mohamed A, Collins J, Jiang H, Molendijk J, Stoll T, Torta F, et al. Concurrent lipidomics and proteomics on malignant plasma cells from multiple myeloma patients: probing the lipid metabolome. PLoS ONE. 2020;15:e0227455. [DOI] [PubMed] [PMC]

302.

Breitkopf SB, Yuan M, Helenius KP, Lyssiotis CA, Asara JM. Triomics analysis of imatinib-treated myeloma cells connects kinase inhibition to RNA processing and decreased lipid biosynthesis. Anal Chem. 2015;87:10995–1006. [DOI] [PubMed] [PMC]

303.

Maekawa K, Ri M, Nakajima M, Sekine A, Ueda R, Tohkin M, et al. Serum lipidomics for exploring biomarkers of bortezomib therapy in patients with multiple myeloma. Cancer Sci. 2019;110:3267–74. [DOI] [PubMed] [PMC]

304.

Perrotta C, Cervia D, De Palma C, Assi E, Pellegrino P, Bassi MT, et al. The emerging role of acid sphingomyelinase in autophagy. Apoptosis. 2015;20:635–44. [DOI] [PubMed]

305.

Faict S, Oudaert I, D’Auria L, Dehairs J, Maes K, Vlummens P, et al. The transfer of sphingomyelinase contributes to drug resistance in multiple myeloma. Cancers. 2019;11:1823. [DOI]

306.

Hannun YA, Obeid LM. Sphingolipids and their metabolism in physiology and disease. Nat Rev Mol Cell Biol. 2018;19:175–91. [DOI] [PubMed] [PMC]

307.

Ludwig C, Williams DS, Bartlett DB, Essex SJ, McNee G, Allwood JW, et al. Alterations in bone marrow metabolism are an early and consistent feature during the development of MGUS and multiple myeloma. Blood Cancer J. 2015;5:e359. [DOI] [PubMed] [PMC]

308.

Sharma A, Tripathi M, Satyam A, Kumar L. Study of antioxidant levels in patients with multiple myeloma. Leuk Lymphoma. 2009;50:809–15. [DOI] [PubMed]

309.

Steiner N, Müller U, Hajek R, Sevcikova S, Borjan B, Jöhrer K, et al. The metabolomic plasma profile of myeloma patients is considerably different from healthy subjects and reveals potential new therapeutic targets. PLoS ONE. 2018;13:e0202045. [DOI] [PubMed] [PMC]

310.

Jones DR, Wu Z, Chauhan D, Anderson KC, Peng J. A Nano ultra-performance liquid chromatography-high resolution mass spectrometry approach for global metabolomic profiling and case study on drug-resistant multiple myeloma. Anal Chem. 2014;86:3667–75. [DOI] [PubMed] [PMC]

311.

Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004;4:891–9. [DOI] [PubMed]

312.

McBrayer SK, Cheng JC, Singhal S, Krett NL, Rosen ST, Shanmugam M, et al. Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11: implications for glucose transporter-directed therapy. Blood. 2012;119:4686–97. [DOI] [PubMed] [PMC]

313.

Dalva-Aydemir S, Bajpai R, Martinez M, Adekola KUA, Kandela I, Wei C, et al. Targeting the metabolic plasticity of multiple myeloma with FDA-approved ritonavir and metformin. Clin Cancer Res. 2015;21:1161–71. [DOI] [PubMed] [PMC]

314.

Chaima El Arfani, Kim De Veirman, Ken Maes, De Bruyne E, Menu E. Metabolic features of multiple myeloma. IJMS. 2018;19:1200. [DOI]

315.

Podar K, Gouill SL, Zhang J, Zorn E, Tai YT, Hideshima T, et al. A pivotal role for Mcl-1 in Bortezomib-induced apoptosis. Oncogene. 2008;27:721–31. [DOI] [PubMed]

316.

Graham NA, Tahmasian M, Kohli B, Komisopoulou E, Zhu M, Vivanco I, et al. Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death. Mol Syst Biol. 2012;8:589. [DOI] [PubMed] [PMC]

317.

Bajpai R, Matulis SM, Wei C, Nooka AK, Von Hollen HE, Lonial S, et al. Targeting glutamine metabolism in multiple myeloma enhances BIM binding to BCL-2 eliciting synthetic lethality to venetoclax. Oncogene. 2016;35:3955–64. [DOI] [PubMed] [PMC]

318.

Lodi A, Tiziani S, Khanim FL, Günther UL, Viant MR, Morgan GJ, et al. Proton NMR-based metabolite analyses of archived serial paired serum and urine samples from myeloma patients at different stages of disease activity identifies acetylcarnitine as a novel marker of active disease. PLoS ONE. 2013;8:e56422. [DOI] [PubMed] [PMC]

319.

Du H, Wang L, Liu B, Wang J, Su H, Zhang T, et al. Analysis of the metabolic characteristics of serum samples in patients with multiple myeloma. Front Pharmacol. 2018;9:884. [DOI] [PubMed] [PMC]

320.

Puchades-Carrasco L, Lecumberri R, Martinez-Lopez J, Lahuerta JJ, Mateos MV, Prósper F, et al. Multiple myeloma patients have a specific serum metabolomic profile that changes after achieving complete remission. Clin Cancer Res. 2013;19:4770–9. [DOI] [PubMed]

321.

Medriano CAD, Eng M, Na J, Lim KM, Chung JH, Park YH. Liquid chromatography mass spectrometry-based metabolite pathway analyses of myeloma and non-hodgkin’s lymphoma patients. Cell J. 2017;19:44–54. [DOI] [PubMed] [PMC]

322.

Tavel L, Fontana F, Garcia Manteiga J, Mari S, Mariani E, Caneva E, et al. Assessing heterogeneity of osteolytic lesions in multiple myeloma by ¹H HR-MAS NMR metabolomics. IJMS. 2016;17:1814. [DOI]

323.

Allegra A, Innao V, Gerace D, Bianco O, Musolino C. The metabolomic signature of hematologic malignancies. Leuk Res. 2016;49:2–35. [DOI]

324.

Donk NWCJ van de, Pawlyn C, Yong KL. Multiple myeloma. The Lancet. 2021;397:410–27.

325.

Roodman GD. Role of the bone marrow microenvironment in multiple myeloma. J Bone Miner Res. 2002;17:1921–5. [DOI] [PubMed]

326.

Ria R, Vacca A. Bone marrow stromal cells-induced drug resistance in multiple myeloma. IJMS. 2020;21:613. [DOI]

327.

Allegra A, Innao V, Gerace D, Allegra AG, Vaddinelli D, Bianco O, et al. The adipose organ and multiple myeloma: impact of adipokines on tumor growth and potential sites for therapeutic intervention. Eur J Int Med. 2018;53:12–20. [DOI]