REFERENCES
1. Leng Y, Hou J, Jin J, Zhang M, Ke X, Jiang B, Pan L, Yang L, Zhou F, Wang J, Wang Z, Liu L, Li W, Shen Z, Qiu L, Chang N, Li J, Liu J, Pang H, Meng H, Wei P, Jiang H, Liu Y, Zheng X, Yang S, Chen W. Circularly permuted TRAIL plus thalidomide and dexamethasone versus thalidomide and dexamethasone for relapsed/refractory multiple myeloma: a phase 2 study. Cancer Chemother Pharmacol 2017;79:1141-9.
2. Krishnan SR, Jaiswal R, Brown RD, Luk F, Bebawy M. Multiple myeloma and persistence of drug resistance in the age of novel drugs (Review). Int J Oncol 2016;49:33-50.
3. Iida S. Mechanisms of action and resistance for multiple myeloma novel drug treatments. Int J Hematol 2016;104:271-2.
4. Brenner H, Gondos A, Pulte D. Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood 2008;111:2521-6.
6. Krishna R, Mayer LD. Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur J Pharm Sci 2000;11:265-83.
7. Almond JB, Cohen GM. The proteasome: a novel target for cancer chemotherapy. Leukemia 2002;16:433-43.
8. Komander D, Clague MJ, Urbe S. Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol 2009;10:550-63.
9. Reits E, Griekspoor A, Neijssen J, Groothuis T, Jalink K, van Veelen P, Janssen H, Calafat J, Drijfhout JW, Neefjes J. Peptide diffusion, protection, and degradation in nuclear and cytoplasmic compartments before antigen presentation by MHC class I. Immunity 2003;18:97-108.
10. Rock KL, York IA, Saric T, Goldberg AL. Protein degradation and the generation of MHC class I-presented peptides. Adv Immunol 2002;80:1-70.
11. Obeng EA, Carlson LM, Gutman DM, Harrington WJ Jr, Lee KP, Boise LH. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 2006;107:4907-16.
12. Kuhn DJ, Orlowski RZ. The immunoproteasome as a target in hematologic malignancies. Semin Hematol 2012;49:258-62.
13. Ettari R, Zappala M, Grasso S, Musolino C, Innao V, Allegra A. Immunoproteasome-selective and non-selective inhibitors: a promising approach for the treatment of multiple myeloma. Pharmacol Ther 2018;182:176-92.
14. Accardi F, Toscani D, Bolzoni M, Dalla Palma B, Aversa F, Giuliani N. Mechanism of action of bortezomib and the new proteasome inhibitors on myeloma cells and the bone microenvironment: impact on myeloma-induced alterations of bone remodeling. Biomed Res Int 2015;2015:172458.
15. Avet-Loiseau H, Bahlis NJ, Chng WJ, Masszi T, Viterbo L, Pour L, Ganly P, Palumbo A, Cavo M, Langer C, Pluta A, Nagler A, Kumar S, Ben-Yehuda D, Rajkumar SV, San-Miguel J, Berg D, Lin J, van de Velde H, Esseltine DL, di Bacco A, Moreau P, Richardson PG. Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients. Blood 2017;130:2610-8.
16. Eek D, Krohe M, Mazar I, Horsfield A, Pompilus F, Friebe R, Shields AL. Patient-reported preferences for oral versus intravenous administration for the treatment of cancer: a review of the literature. Patient Prefer Adherence 2016;10:1609-21.
17. Infante JR, Mendelson DS, Burris HA 3rd, Bendell JC, Tolcher AW, Gordon MS, Gillenwater HH, Arastu-Kapur S, Wong HL, Papadopoulos KP. A first-in-human dose-escalation study of the oral proteasome inhibitor oprozomib in patients with advanced solid tumors. Invest New Drugs 2016;34:216-24.
18. Spencer A, Harrison S, Zonder J, Badros A, Laubach J, Bergin K, Khot A, Zimmerman T, Chauhan D, Levin N, MacLaren A, Reich SD, Trikha M, Richardson P. A phase 1 clinical trial evaluating marizomib, pomalidomide and low-dose dexamethasone in relapsed and refractory multiple myeloma (NPI-0052-107): final study results. Br J Haematol 2018;180:41-51.
19. Levin N, Spencer A, Harrison SJ, Chauhan D, Burrows FJ, Anderson KC, Reich SD, Richardson PG, Trikha M. Marizomib irreversibly inhibits proteasome to overcome compensatory hyperactivation in multiple myeloma and solid tumour patients. Br J Haematol 2016;174:711-20.
20. Harrison SJ, Mainwaring P, Price T, Millward MJ, Padrik P, Underhill CR, Cannell PK, Reich SD, Trikha M, Spencer A. Phase I clinical trial of marizomib (NPI-0052) in patients with advanced malignancies including multiple myeloma: study NPI-0052-102 final results. Clin Cancer Res 2016;22:4559-66.
21. 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.
22. Shi Y, Gera J, Hu L, Hsu JH, Bookstein R, Li W, Lichtenstein A. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res 2002;62:5027-34.
23. Hideshima T, Chauhan D, Richardson P, Anderson KC. Identification and validation of novel therapeutic targets for multiple myeloma. J Clin Oncol 2005;23:6345-50.
24. Azab F, Vali S, Abraham J, Potter N, Muz B, de la Puente P, Fiala M, Paasch J, Sultana Z, Tyagi A, Abbasi T, Vij R, Azab AK. PI3KCA plays a major role in multiple myeloma and its inhibition with BYL719 decreases proliferation, synergizes with other therapies and overcomes stroma-induced resistance. Br J Haematol 2014;165:89-101.
25. Gera J, Lichtenstein A. The mammalian target of rapamycin pathway as a therapeutic target in multiple myeloma. Leuk Lymphoma 2011;52:1857-66.
26. Balsat M, Cornillon J. m-TOR inhibitors: biology and use in the treatment of haematological diseases. Bull Cancer 2011;98:935-43.
27. Hofmeister CC, Yang X, Pichiorri F, Chen P, Rozewski DM, Johnson AJ, Lee S, Liu Z, Garr CL, Hade EM, Ji J, Schaaf LJ, Benson DM Jr, Kraut EH, Hicks WJ, Chan KK, Chen CS, Farag SS, Grever MR, Byrd JC, Phelps MA. Phase I trial of lenalidomide and CCI-779 in patients with relapsed multiple myeloma: evidence for lenalidomide-CCI-779 interaction via P-glycoprotein. J Clin Oncol 2011;29:3427-34.
28. Yee AJ, Hari P, Marcheselli R, Mahindra AK, Cirstea DD, Scullen TA, Burke JN, Rodig SJ, Hideshima T, Laubach JP, Ghobrial IM, Schlossman RL, Munshi NC, Anderson KC, Weller EA, Richardson PG, Raje NS. Outcomes in patients with relapsed or refractory multiple myeloma in a phase I study of everolimus in combination with lenalidomide. Br J Haematol 2014;166:401-9.
29. Spencer A, Yoon SS, Harrison SJ, Morris SR, Smith DA, Brigandi RA, Gauvin J, Kumar R, Opalinska JB, Chen C. The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma. Blood 2014;124:2190-5.
30. Tolcher AW, Patnaik A, Papadopoulos KP, Rasco DW, Becerra CR, Allred AJ, Orford K, Aktan G, Ferron-Brady G, Ibrahim N, Gauvin J, Motwani M, Cornfeld M. Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma. Cancer Chemother Pharmacol 2015;75:183-9.
31. Trametinib and Akt Inhibitor GSK2141795 in Treating Patients With Relapsed or Refractory Multiple Myeloma. In: U.S. National Library of Medicine; 2018. ClinicalTrials.gov Identifier: NCT01989598.
32. Clinical Trials Using Akt inhibitor AZD5363. Available from: https://www.cancer.gov/about-cancer/treatment/clinical-trials/intervention/akt-inhibitor-azd5363 [Last accessed on 14 May 2018].
33. Oral ONC201 in Relapsed/Refractory Multiple Myeloma. In: U.S. National Library of Medicine; 2018. ClinicalTrials.gov Identifier: NCT02863991.
34. Richardson PG, Wolf J, Jakubowiak A, Zonder J, Lonial S, Irwin D, Densmore J, Krishnan A, Raje N, Bar M, Martin T, Schlossman R, Ghobrial IM, Munshi N, Laubach J, Allerton J, Hideshima T, Colson K, Poradosu E, Gardner L, Sportelli P, Anderson KC. Perifosine plus bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma previously treated with bortezomib: results of a multicenter phase I/II trial. J Clin Oncol 2011;29:4243-9.
35. Earwaker P, Anderson C, Willenbrock F, Harris AL, Protheroe AS, Macaulay VM. RAPTOR up-regulation contributes to resistance of renal cancer cells to PI3K-mTOR inhibition. PLoS One 2018;13:e0191890.
36. Xu J, Pfarr N, Endris V, Mai EK, Md Hanafiah NH, Lehners N, Penzel R, Weichert W, Ho AD, Schirmacher P, Goldschmidt H, Andrulis M, Raab MS. Molecular signaling in multiple myeloma: association of RAS/RAF mutations and MEK/ERK pathway activation. Oncogenesis 2017;6:e337.
37. Chng WJ, Gonzalez-Paz N, Price-Troska T, Jacobus S, Rajkumar SV, Oken MM, Kyle RA, Henderson KJ, Van Wier S, Greipp P, Van Ness B, Fonseca R. Clinical and biological significance of RAS mutations in multiple myeloma. Leukemia 2008;22:2280-4.
38. Bisping G, Wenning D, Kropff M, Gustavus D, Muller-Tidow C, Stelljes M, Munzert G, Hilberg F, Roth GJ, Stefanic M, Volpert S, Mesters RM, Berdel WE, Kienast J. Bortezomib, dexamethasone, and fibroblast growth factor receptor 3-specific tyrosine kinase inhibitor in t(4;14) myeloma. Clin Cancer Res 2009;15:520-31.
39. Ramakrishnan V, Timm M, Haug JL, Kimlinger TK, Wellik LE, Witzig TE, Rajkumar SV, Adjei AA, Kumar S. Sorafenib, a dual Raf kinase/vascular endothelial growth factor receptor inhibitor has significant anti-myeloma activity and synergizes with common anti-myeloma drugs. Oncogene 2010;29:1190-202.
40. Ramakrishnan V, Timm M, Haug JL, Kimlinger TK, Halling T, Wellik LE, Witzig TE, Rajkumar SV, Adjei AA, Kumar S. Sorafenib, a multikinase inhibitor, is effective in vitro against non-Hodgkin lymphoma and synergizes with the mTOR inhibitor rapamycin. Am J Hematol 2012;87:277-83.
41. Srkalovic G, Hussein MA, Hoering A, Zonder JA, Popplewell LL, Trivedi H, Mazzoni S, Sexton R, Orlowski RZ, Barlogie B. A phase II trial of BAY 43-9006 (sorafenib) (NSC-724772) in patients with relapsing and resistant multiple myeloma: SWOG S0434. Cancer Med 2014;3:1275-83.
42. Kumar SK, Jett J, Marks R, Richardson R, Quevedo F, Moynihan T, Croghan G, Markovic SN, Bible KC, Qin R, Tan A, Molina J, Kaufmann SH, Erlichman C, Adjei AA. Phase 1 study of sorafenib in combination with bortezomib in patients with advanced malignancies. Invest New Drugs 2013;31:1201-6.
43. Tai YT, Fulciniti M, Hideshima T, Song W, Leiba M, Li XF, Rumizen M, Burger P, Morrison A, Podar K, Chauhan D, Tassone P, Richardson P, Munshi NC, Ghobrial IM, Anderson KC. Targeting MEK induces myeloma-cell cytotoxicity and inhibits osteoclastogenesis. Blood 2007;110:1656-63.
44. Ocio EM, Fernandez-Lazaro D, San-Segundo L, Lopez-Corral L, Corchete LA, Gutierrez NC, Garayoa M, Paino T, Garcia-Gomez A, Delgado M, Montero JC, Diaz-Rodriguez E, Mateos MV, Pandiella A, Couto S, Wang M, Bjorklund CC, San-Miguel JF. In vivo murine model of acquired resistance in myeloma reveals differential mechanisms for lenalidomide and pomalidomide in combination with dexamethasone. Leukemia 2015;29:705-14.
45. Holkova B, Zingone A, Kmieciak M, Bose P, Badros AZ, Voorhees PM, Baz R, Korde N, Lin HY, Chen JQ, Herrmann M, Xi L, Raffeld M, Zhao X, Wan W, Tombes MB, Shrader E, Weir-Wiggins C, Sankala H, Hogan KT, Doyle A, Annunziata CM, Wellons M, Roberts JD, Sullivan D, Landgren O, Grant S. A phase II trial of AZD6244 (Selumetinib, ARRY-142886), an oral MEK1/2 inhibitor, in relapsed/refractory multiple myeloma. Clin Cancer Res 2016;22:1067-75.
46. Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci 2004;117:1281-3.
47. Beldi-Ferchiou A, Skouri N, Ben Ali C, Safra I, Abdelkefi A, Ladeb S, Mrad K, Ben Othman T, Ben Ahmed M. Abnormal repression of SHP-1, SHP-2 and SOCS-1 transcription sustains the activation of the JAK/STAT3 pathway and the progression of the disease in multiple myeloma. PLoS One 2017;12:e0174835.
48. Ramakrishnan V, Kimlinger T, Haug J, Timm M, Wellik L, Halling T, Pardanani A, Tefferi A, Rajkumar SV, Kumar S. TG101209, a novel JAK2 inhibitor, has significant in vitro activity in multiple myeloma and displays preferential cytotoxicity for CD45+ myeloma cells. Am J Hematol 2010;85:675-86.
49. de Oliveira MB, Fook-Alves VL, Eugenio AIP, Fernando RC, Sanson LFG, de Carvalho MF, Braga WMT, Davies FE, Colleoni GWB. Anti-myeloma effects of ruxolitinib combined with bortezomib and lenalidomide: a rationale for JAK/STAT pathway inhibition in myeloma patients. Cancer Lett 2017;403:206-15.
50. Sagawa M, Tabayashi T, Kimura Y, Tomikawa T, Nemoto-Anan T, Watanabe R, Tokuhira M, Ri M, Hashimoto Y, Iida S, Kizaki M. TM-233, a novel analog of 1'-acetoxychavicol acetate, induces cell death in myeloma cells by inhibiting both JAK/STAT and proteasome activities. Cancer Sci 2015;106:438-46.
51. Sagawa M, Nakazato T, Uchida H, Ikeda Y, Kizaki M. Cantharidin induces apoptosis of human multiple myeloma cells via inhibition of the JAK/STAT pathway. Cancer Sci 2008;99:1820-6.
52. Nakaya A, Sagawa M, Muto A, Uchida H, Ikeda Y, Kizaki M. The gold compound auranofin induces apoptosis of human multiple myeloma cells through both down-regulation of STAT3 and inhibition of NF-kappaB activity. Leuk Res 2011;35:243-9.
53. Le Gouill S, Pellat-Deceunynck C, Harousseau JL, Rapp MJ, Robillard N, Bataille R, Amiot M. Farnesyl transferase inhibitor R115777 induces apoptosis of human myeloma cells. Leukemia 2002;16:1664-7.
54. Li J, Favata M, Kelley JA, Caulder E, Thomas B, Wen X, Sparks RB, Arvanitis A, Rogers JD, Combs AP, Vaddi K, Solomon KA, Scherle PA, Newton R, Fridman JS. INCB16562, a JAK1/2 selective inhibitor, is efficacious against multiple myeloma cells and reverses the protective effects of cytokine and stromal cell support. Neoplasia 2010;12:28-38.
55. Jin Z, Zhou S, Zhang Y, Ye H, Jiang S, Yu K, Ma Y. Lycorine induces cell death in MM by suppressing Janus kinase/signal transducer and activator of transcription via inducing the expression of SOCS1. Biomed Pharmacother 2016;84:1645-53.
56. Pedranzini L, Dechow T, Berishaj M, Comenzo R, Zhou P, Azare J, Bornmann W, Bromberg J. Pyridone 6, a pan-Janus-activated kinase inhibitor, induces growth inhibition of multiple myeloma cells. Cancer Res 2006;66:9714-21.
57. Amit-Vazina M, Shishodia S, Harris D, Van Q, Wang M, Weber D, Alexanian R, Talpaz M, Aggarwal BB, Estrov Z. Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells. Br J Cancer 2005;93:70-80.
58. Safety and Efficacy of Atiprimod for Patients With Refractory Multiple Myeloma. In: U.S. National Library of Medicine; 2018. ClinicalTrials.gov Identifier: NCT00086216. .
59. Kampan NC, Xiang SD, McNally OM, Stephens AN, Quinn MA, Plebanski M. Immunotherapeutic Interleukin-6 or Interleukin-6 receptor blockade in cancer: challenges and opportunities. Curr Med Chem 2017; doi: 10.2174/0929867324666170712160621. doi: 10.2174/0929867324666170712160621
60. Orlowski RZ, Gercheva L, Williams C, Sutherland H, Robak T, Masszi T, Goranova-Marinova V, Dimopoulos MA, Cavenagh JD, Spicka I, Maiolino A, Suvorov A, Blade J, Samoylova O, Puchalski TA, Reddy M, Bandekar R, van de Velde H, Xie H, Rossi JF. A phase 2, randomized, double-blind, placebo-controlled study of siltuximab (anti-IL-6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma. Am J Hematol 2015;90:42-9.
61. San-Miguel J, Blade J, Shpilberg O, Grosicki S, Maloisel F, Min CK, Polo Zarzuela M, Robak T, Prasad SV, Tee Goh Y, Laubach J, Spencer A, Mateos MV, Palumbo A, Puchalski T, Reddy M, Uhlar C, Qin X, van de Velde H, Xie H, Orlowski RZ. Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti-IL-6) in multiple myeloma. Blood 2014;123:4136-42.
62. Follin-Arbelet V, Torgersen ML, Naderi EH, Misund K, Sundan A, Blomhoff HK. Death of multiple myeloma cells induced by cAMP-signaling involves downregulation of Mcl-1 via the JAK/STAT pathway. Cancer Lett 2013;335:323-31.
63. Ko JH, Ho Baek S, Nam D, Chung WS, Lee SG, Lee J, Mo Yang W, Um JY, Seok Ahn K. 3-Formylchromone inhibits proliferation and induces apoptosis of multiple myeloma cells by abrogating STAT3 signaling through the induction of PIAS3. Immunopharmacol Immunotoxicol 2016;38:334-43.
64. Monaghan KA, Khong T, Burns CJ, Spencer A. The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells. Leukemia 2011;25:1891-9.
65. Che Y, Hou S, Kang Z, Lin Q. Serenoa repens induces growth arrest and apoptosis of human multiple myeloma cells via inactivation of STAT 3 signaling. Oncol Rep 2009;22:377-83.
66. Pandey MK, Sung B, Ahn KS, Aggarwal BB. Butein suppresses constitutive and inducible signal transducer and activator of transcription (STAT) 3 activation and STAT3-regulated gene products through the induction of a protein tyrosine phosphatase SHP-1. Mol Pharmacol 2009;75:525-33.
67. Nelson EA, Walker SR, Kepich A, Gashin LB, Hideshima T, Ikeda H, Chauhan D, Anderson KC, Frank DA. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3. Blood 2008;112:5095-102.
68. De Vos J, Jourdan M, Tarte K, Jasmin C, Klein B. JAK2 tyrosine kinase inhibitor tyrphostin AG490 downregulates the mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) pathways and induces apoptosis in myeloma cells. Br J Haematol 2000;109:823-8.
70. Grainger S, Traver D, Willert K. Wnt signaling in hematological malignancies. Prog Mol Biol Transl Sci 2018;153:321-41.
71. Cheng Q, Liu L, Fu Y, Zhang Y, Yang Y, Liu J. RhPDCD5 combined with dexamethasone increases antitumor activity in multiple myeloma partially via inhibiting the Wnt signalling pathway. Clin Exp Pharmacol Physiol 2018;45:140-5.
72. Wang JH, Zhang Y, Li HY, Liu YY, Sun T. Dickkopf-1 negatively regulates the expression of osteoprotegerin, a key osteoclastogenesis inhibitor, by sequestering Lrp6 in primary and metastatic lytic bone lesions. Medicine (Baltimore) 2016;95:e3767.
73. Zhou F, Meng S, Song H, Claret FX. Dickkopf-1 is a key regulator of myeloma bone disease: opportunities and challenges for therapeutic intervention. Blood Rev 2013;27:261-7.
74. Study of BHQ880 in Patients With High Risk Smoldering Multiple Myeloma. In: U.S. National Library of Medicine; 2018. ClinicalTrials.gov Identifier: NCT01302886.
75. Terpos E, Christoulas D, Gavriatopoulou M, Dimopoulos MA. Mechanisms of bone destruction in multiple myeloma. Eur J Cancer Care (Engl) 2017;26:12761.
76. McDonald MM, Reagan MR, Youlten SE, Mohanty ST, Seckinger A, Terry RL, Pettitt JA, Simic MK, Cheng TL, Morse A, Le LMT, Abi-Hanna D, Kramer I, Falank C, Fairfield H, Ghobrial IM, Baldock PA, Little DG, Kneissel M, Vanderkerken K, Bassett JHD, Williams GR, Oyajobi BO, Hose D, Phan TG, Croucher PI. Inhibiting the osteocyte-specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma. Blood 2017;129:3452-64.
77. Bjorklund CC, Ma W, Wang ZQ, Davis RE, Kuhn DJ, Kornblau SM, Wang M, Shah JJ, Orlowski RZ. Evidence of a role for activation of Wnt/beta-catenin signaling in the resistance of plasma cells to lenalidomide. J Biol Chem 2011;286:11009-20.
78. Butrym A, Rybka J, Lacina P, Gebura K, Frontkiewicz D, Bogunia-Kubik K, Mazur G. Polymorphisms within beta-catenin encoding gene affect multiple myeloma development and treatment. Leuk Res 2015;39:1462-6.
79. Demchenko YN, Kuehl WM. A critical role for the NFkB pathway in multiple myeloma. Oncotarget 2010;1:59-68.
80. Chim CS. Updated survivals and prognostic factor analysis in myeloma treated by a staged approach use of bortezomib/thalidomide/dexamethasone in transplant eligible patients. J Transl Med 2010;8:124.
81. Chng WJ, Kumar S, Vanwier S, Ahmann G, Price-Troska T, Henderson K, Chung TH, Kim S, Mulligan G, Bryant B, Carpten J, Gertz M, Rajkumar SV, Lacy M, Dispenzieri A, Kyle R, Greipp P, Bergsagel PL, Fonseca R. Molecular dissection of hyperdiploid multiple myeloma by gene expression profiling. Cancer Res 2007;67:2982-9.
82. Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ, Van Wier S, Tiedemann R, Shi CX, Sebag M, Braggio E, Henry T, Zhu YX, Fogle H, Price-Troska T, Ahmann G, Mancini C, Brents LA, Kumar S, Greipp P, Dispenzieri A, Bryant B, Mulligan G, Bruhn L, Barrett M, Valdez R, Trent J, Stewart AK, Carpten J, Bergsagel PL. Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell 2007;12:131-44.
83. Bolzoni M, Toscani D, Storti P, Marchica V, Costa F, Giuliani N. Possible targets to treat myeloma-related osteoclastogenesis. Expert Rev Hematol 2018;11:325-36.
84. Terpos E, Efstathiou E, Christoulas D, Roussou M, Katodritou E, Dimopoulos MA. RANKL inhibition: clinical implications for the management of patients with multiple myeloma and solid tumors with bone metastases. Expert Opin Biol Ther 2009;9:465-79.
85. Raje N, Vadhan-Raj S, Willenbacher W, Terpos E, Hungria V, Spencer A, Alexeeva Y, Facon T, Stewart AK, Feng A, Braun A, Balakumaran A, Roodman GD. Evaluating results from the multiple myeloma patient subset treated with denosumab or zoledronic acid in a randomized phase 3 trial. Blood Cancer J 2016;6:e378.
86. Body JJ, Greipp P, Coleman RE, Facon T, Geurs F, Fermand JP, Harousseau JL, Lipton A, Mariette X, Williams CD, Nakanishi A, Holloway D, Martin SW, Dunstan CR, Bekker PJ. A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer 2003;97:887-92.
87. Terpos E, Mihou D, Szydlo R, Tsimirika K, Karkantaris C, Politou M, Voskaridou E, Rahemtulla A, Dimopoulos MA, Zervas K. The combination of intermediate doses of thalidomide with dexamethasone is an effective treatment for patients with refractory/relapsed multiple myeloma and normalizes abnormal bone remodeling, through the reduction of sRANKL/osteoprotegerin ratio. Leukemia 2005;19:1969-76.
88. Tsubaki M, Takeda T, Yoshizumi M, Ueda E, Itoh T, Imano M, Satou T, Nishida S. RANK-RANKL interactions are involved in cell adhesion-mediated drug resistance in multiple myeloma cell lines. Tumour Biol 2016;37:9099-110.
89. Santo L, Siu KT, Raje N. Targeting cyclin-dependent kinases and cell cycle progression in human cancers. Semin Oncol 2015;42:788-800.
90. Casimiro MC, Velasco-Velazquez M, Aguirre-Alvarado C, Pestell RG. Overview of cyclins D1 function in cancer and the CDK inhibitor landscape: past and present. Expert Opin Investig Drugs 2014;23:295-304.
91. Ramakrishnan VG, Kumar SK. Inhibitors of the cyclin-dependent kinase and PIM kinase pathways in the treatment of myeloma. Cancer J 2016;22:7-11.
92. MacCallum DE, Melville J, Frame S, Watt K, Anderson S, Gianella-Borradori A, Lane DP, Green SR. Seliciclib (CYC202, R-Roscovitine) induces cell death in multiple myeloma cells by inhibition of RNA polymerase II-dependent transcription and down-regulation of Mcl-1. Cancer Res 2005;65:5399-407.
93. Hofmeister CC, Poi M, Bowers MA, Zhao W, Phelps MA, Benson DM, Kraut EH, Farag S, Efebera YA, Sexton J, Lin TS, Grever M, Byrd JC. A phase I trial of flavopiridol in relapsed multiple myeloma. Cancer Chemother Pharmacol 2014;73:249-57.
94. Holkova B, Perkins EB, Ramakrishnan V, Tombes MB, Shrader E, Talreja N, Wellons MD, Hogan KT, Roodman GD, Coppola D, Kang L, Dawson J, Stuart RK, Peer C, Figg WD Sr, Kolla S, Doyle A, Wright J, Sullivan DM, Roberts JD, Grant S. Phase I trial of bortezomib (PS-341; NSC 681239) and alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory B-cell neoplasms. Clin Cancer Res 2011;17:3388-97.
95. Fandy TE, Ross DD, Gore SD, Srivastava RK. Flavopiridol synergizes TRAIL cytotoxicity by downregulation of FLIPL. Cancer Chemother Pharmacol 2007;60:313-9.
96. Pei XY, Dai Y, Grant S. The small-molecule Bcl-2 inhibitor HA14-1 interacts synergistically with flavopiridol to induce mitochondrial injury and apoptosis in human myeloma cells through a free radical-dependent and Jun NH2-terminal kinase-dependent mechanism. Mol Cancer Ther 2004;3:1513-24.
97. Niesvizky R, Badros AZ, Costa LJ, Ely SA, Singhal SB, Stadtmauer EA, Haideri NA, Yacoub A, Hess G, Lentzsch S, Spicka I, Chanan-Khan AA, Raab MS, Tarantolo S, Vij R, Zonder JA, Huang X, Jayabalan D, Di Liberto M, Huang X, Jiang Y, Kim ST, Randolph S, Chen-Kiang S. Phase 1/2 study of cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib (PD-0332991) with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. Leuk Lymphoma 2015;56:3320-8.
98. Kumar SK, LaPlant B, Chng WJ, Zonder J, Callander N, Fonseca R, Fruth B, Roy V, Erlichman C, Stewart AK, Mayo Phase 2 Consortium. Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma. Blood 2015;125:443-8.
99. Feng R, Li S, Lu C, Andreas C, Stolz DB, Mapara MY, Lentzsch S. Targeting the microtubular network as a new antimyeloma strategy. Mol Cancer Ther 2011;10:1886-96.
100. Maes A, Menu E, Veirman K, Maes K, Vand Erkerken K, De Bruyne E. The therapeutic potential of cell cycle targeting in multiple myeloma. Oncotarget 2017;8:90501-20.
101. Kyle RA, Jacobus S, Friedenberg WR, Slabber CF, Rajkumar SV, Greipp PR. The treatment of multiple myeloma using vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (VBMCP) alternating with high-dose cyclophosphamide and alpha(2)beta interferon versus VBMCP: results of a phase III Eastern Cooperative Oncology Group Study E5A93. Cancer 2009;115:2155-64.
102. Dimopoulos MA, Arbuck S, Huber M, Weber D, Luckett R, Delasalle K, Alexanian R. Primary therapy of multiple myeloma with paclitaxel (taxol). Ann Oncol 1994;5:757-9.
103. Miller HJ, Leong T, Khandekar JD, Greipp PR, Gertz MA, Kyle RA. Paclitaxel as the initial treatment of multiple myeloma: an Eastern Cooperative Oncology Group Study (E1A93). Am J Clin Oncol 1998;21:553-6.
104. Kawano T, Agata N, Kharbanda S, Avigan D, Kufe D. A novel isocoumarin derivative induces mitotic phase arrest and apoptosis of human multiple myeloma cells. Cancer Chemother Pharmacol 2007;59:329-35.
105. Maginn EN, Browne PV, Hayden P, Vandenberghe E, MacDonagh B, Evans P, Goodyer M, Tewari P, Campiani G, Butini S, Williams DC, Zisterer DM, Lawler MP, McElligott AM. PBOX-15, a novel microtubule targeting agent, induces apoptosis, upregulates death receptors, and potentiates TRAIL-mediated apoptosis in multiple myeloma cells. Br J Cancer 2011;104:281-9.
106. Spagnuolo PA, Hu J, Hurren R, Wang X, Gronda M, Sukhai MA, Di Meo A, Boss J, Ashali I, Beheshti Zavareh R, Fine N, Simpson CD, Sharmeen S, Rottapel R, Schimmer AD. The antihelmintic flubendazole inhibits microtubule function through a mechanism distinct from Vinca alkaloids and displays preclinical activity in leukemia and myeloma. Blood 2010;115:4824-33.
107. Pandey MK, Gowda K, Sung SS, Abraham T, Budak-Alpdogan T, Talamo G, Dovat S, Amin S. A novel dual inhibitor of microtubule and Bruton's tyrosine kinase inhibits survival of multiple myeloma and osteoclastogenesis. Exp Hematol 2017;53:31-42.
108. Rozic G, Paukov L, Jakubikova J, Ben-Shushan D, Duek A, Leiba A, Avigdor A, Nagler A, Leiba M. The novel compound STK405759 is a microtubule-targeting agent with potent and selective cytotoxicity against multiple myeloma in vitro and in vivo. Oncotarget 2016;7:62572-84.
109. Liu M, Aneja R, Liu C, Sun L, Gao J, Wang H, Dong JT, Sarli V, Giannis A, Joshi HC, Zhou J. Inhibition of the mitotic kinesin Eg5 up-regulates Hsp70 through the phosphatidylinositol 3-kinase/Akt pathway in multiple myeloma cells. J Biol Chem 2006;281:18090-7.
110. Hernandez-Garcia S, San-Segundo L, Gonzalez-Mendez L, Corchete LA, Misiewicz-Krzeminska I, Martin-Sanchez M, Lopez-Iglesias AA, Algarin EM, Mogollon P, Diaz-Tejedor A, Paino T, Tunquist B, Mateos MV, Gutierrez NC, Diaz-Rodriguez E, Garayoa M, Ocio EM. The kinesin spindle protein inhibitor filanesib enhances the activity of pomalidomide and dexamethasone in multiple myeloma. Haematologica 2017;102:2113-24.
111. Shah JJ, Kaufman JL, Zonder JA, Cohen AD, Bensinger WI, Hilder BW, Rush SA, Walker DH, Tunquist BJ, Litwiler KS, Ptaszynski M, Orlowski RZ, Lonial S. A phase 1 and 2 study of Filanesib alone and in combination with low-dose dexamethasone in relapsed/refractory multiple myeloma. Cancer 2017;123:4617-30.
112. Chari A, Htut M, Zonder JA, Fay JW, Jakubowiak AJ, Levy JB, Lau K, Burt SM, Tunquist BJ, Hilder BW, Rush SA, Walker DH, Ptaszynski M, Kaufman JL. A phase 1 dose-escalation study of filanesib plus bortezomib and dexamethasone in patients with recurrent/refractory multiple myeloma. Cancer 2016;122:3327-35.
113. Song IS, Jeong YJ, Nyamaa B, Jeong SH, Kim HK, Kim N, Ko KS, Rhee BD, Han J. KSP inhibitor SB743921 induces death of multiple myeloma cells via inhibition of the NF-kappaB signaling pathway. BMB Rep 2015;48:571-6.
114. Tang A, Gao K, Chu L, Zhang R, Yang J, Zheng J. Aurora kinases: novel therapy targets in cancers. Oncotarget 2017;8:23937-54.
115. Shi Y, Reiman T, Li W, Maxwell CA, Sen S, Pilarski L, Daniels TR, Penichet ML, Feldman R, Lichtenstein A. Targeting aurora kinases as therapy in multiple myeloma. Blood 2007;109:3915-21.
116. Aurora A Kinase Inhibitor MLN8237 and Bortezomib in Treating Patients With Relapsed or Refractory Multiple Myeloma. In: U.S. National Institutes of Health; 2018. ClinicalTrials.gov Identifier: NCT01034553.
117. Hay AE, Murugesan A, DiPasquale AM, Kouroukis T, Sandhu I, Kukreti V, Bahlis NJ, Lategan J, Reece DE, Lyons JF, Sederias J, Xu H, Powers J, Seymour LK, Reiman T. A phase II study of AT9283, an aurora kinase inhibitor, in patients with relapsed or refractory multiple myeloma: NCIC clinical trials group IND.191. Leuk Lymphoma 2016;57:1463-6.
118. Abdi J, Rastgoo N, Li L, Chen W, Chang H. Role of tumor suppressor p53 and micro-RNA interplay in multiple myeloma pathogenesis. J Hematol Oncol 2017;10:169.
119. Hientz K, Mohr A, Bhakta-Guha D, Efferth T. The role of p53 in cancer drug resistance and targeted chemotherapy. Oncotarget 2017;8:8921-46.
120. Gillardin PS, Descamps G, Maiga S, Tessoulin B, Djamai H, Lucani B, Chiron D, Moreau P, Le Gouill S, Amiot M, Pellat-Deceunynck C, Moreau-Aubry A. Decitabine and melphalan fail to reactivate p73 in p53 deficient myeloma cells. Int J Mol Sci 2017;19:E40.
121. Hideshima T, Cottini F, Nozawa Y, Seo HS, Ohguchi H, Samur MK, Cirstea D, Mimura N, Iwasawa Y, Richardson PG, Munshi NC, Chauhan D, Massefski W, Utsugi T, Dhe-Paganon S, Anderson KC. p53-related protein kinase confers poor prognosis and represents a novel therapeutic target in multiple myeloma. Blood 2017;129:1308-19.
122. Liu N, Li S, Wu N, Cho KS. Acetylation and deacetylation in cancer stem-like cells. Oncotarget 2017;8:89315-25.
123. Mihaila RG. From a better understanding of the mechanisms of action of histone deacetylases inhibitors to the progress of the treatment of malignant lymphomas and plasma cell myeloma. Recent Pat Anticancer Drug Discov 2017;12:283-95.
124. Raedler LA. Farydak (Panobinostat): first HDAC inhibitor approved for patients with relapsed multiple myeloma. Am Health Drug Benefits 2016;9:84-7.
125. Badros A, Burger AM, Philip S, Niesvizky R, Kolla SS, Goloubeva O, Harris C, Zwiebel J, Wright JJ, Espinoza-Delgado I, Baer MR, Holleran JL, Egorin MJ, Grant S. Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Clin Cancer Res 2009;15:5250-7.
126. Deming DA, Ninan J, Bailey HH, Kolesar JM, Eickhoff J, Reid JM, Ames MM, McGovern RM, Alberti D, Marnocha R, Espinoza-Delgado I, Wright J, Wilding G, Schelman WR. A phase I study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors. Invest New Drugs 2014;32:323-9.
127. Cho H, Yoon DH, Kim KP, Bae KS, Kim WS, Eom HS, Kim JS, Hong JY, Kim SJ, Lee H, Kim SJ, Suh C. Phase I study of CKD-581, a pan-histone deacetylase inhibitor, in patients with lymphoma or multiple myeloma refractory to standard therapy. Invest New Drugs 2018; doi: 10.1007/s10637-018-0582-0. doi: 10.1007/s10637-018-0582-0.
128. Klappe K, Hinrichs JW, Kroesen BJ, Sietsma H, Kok JW. MRP1 and glucosylceramide are coordinately over expressed and enriched in rafts during multidrug resistance acquisition in colon cancer cells. Int J Cancer 2004;110:511-22.
129. Furukawa Y, Kikuchi J. Epigenetic mechanisms of cell adhesion-mediated drug resistance in multiple myeloma. Int J Hematol 2016;104:281-92.
130. Raaijmakers MH. ATP-binding-cassette transporters in hematopoietic stem cells and their utility as therapeutical targets in acute and chronic myeloid leukemia. Leukemia 2007;21:2094-102.
131. Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, Harrell PM, Trinh YT, Zhang Q, Urbatsch IL, Chang G. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 2009;323:1718-22.
132. Ward A, Reyes CL, Yu J, Roth CB, Chang G. Flexibility in the ABC transporter MsbA: alternating access with a twist. Proc Natl Acad Sci U S A 2007;104:19005-10.
133. Ferreira RJ, Ferreira MJ, Dos Santos DJ. Insights on P-glycoprotein's efflux mechanism obtained by molecular dynamics simulations. J Chem Theory Comput 2012;8:1853-64.
134. Abraham J, Salama NN, Azab AK. The role of P-glycoprotein in drug resistance in multiple myeloma. Leuk Lymphoma 2015;56:26-33.
135. Verbrugge SE, Assaraf YG, Dijkmans BA, Scheffer GL, Al M, den Uyl D, Oerlemans R, Chan ET, Kirk CJ, Peters GJ, van der Heijden JW, de Gruijl TD, Scheper RJ, Jansen G. Inactivating PSMB5 mutations and P-glycoprotein (multidrug resistance-associated protein/ATP-binding cassette B1) mediate resistance to proteasome inhibitors: ex vivo efficacy of (immuno)proteasome inhibitors in mononuclear blood cells from patients with rheumatoid arthritis. J Pharmacol Exp Ther 2012;341:174-82.
136. O'Connor R, Ooi MG, Meiller J, Jakubikova J, Klippel S, Delmore J, Richardson P, Anderson K, Clynes M, Mitsiades CS, O'Gorman P. The interaction of bortezomib with multidrug transporters: implications for therapeutic applications in advanced multiple myeloma and other neoplasias. Cancer Chemother Pharmacol 2013;71:1357-68.
137. Dalton WS, Grogan TM, Meltzer PS, Scheper RJ, Durie BG, Taylor CW, Miller TP, Salmon SE. Drug-resistance in multiple myeloma and non-Hodgkin's lymphoma: detection of P-glycoprotein and potential circumvention by addition of verapamil to chemotherapy. J Clin Oncol 1989;7:415-24.
138. Grogan T, Dalton W, Rybski J, Spier C, Meltzer P, Richter L, Gleason M, Pindur J, Cline A, Scheper R. Optimization of immunocytochemical P-glycoprotein assessment in multidrug-resistant plasma cell myeloma using three antibodies. Lab Invest 1990;63:815-24.
139. Fonti R, Del Vecchio S, Zannetti A, De Renzo A, Catalano L, Pace L, Rotoli B, Salvatore M. Functional imaging of multidrug resistant phenotype by 99mTc-MIBI scan in patients with multiple myeloma. Cancer Biother Radiopharm 2004;19:165-70.
140. Fallahi B, Beiki D, Mousavi SA, Gholamrezanezhad A, Eftekhari M, Fard-Esfahani A, Alimoghaddam K, Mirpour S, Eskandarian A, Saghari M. 99mTc-MIBI whole body scintigraphy and P-glycoprotein for the prediction of multiple drug resistance in multiple myeloma patients. Hell J Nucl Med 2009;12:255-9.
141. Marie JP. P-glycoprotein in adult hematologic malignancies. Hematol Oncol Clin North Am 1995;9:239-49.
142. Turner JG, Gump JL, Zhang C, Cook JM, Marchion D, Hazlehurst L, Munster P, Schell MJ, Dalton WS, Sullivan DM. ABCG2 expression, function, and promoter methylation in human multiple myeloma. Blood 2006;108:3881-9.
143. Advani AS, Shadman M, Ali-Osman F, Barker A, Rybicki L, Kalaycio M, Sekeres MA, de Castro CM, Diehl LF, Moore JO, Beaven A, Copelan E, Sobecks R, Talea P, Rizzieri DA. A phase II trial of gemcitabine and mitoxantrone for patients with acute myeloid leukemia in first relapse. Clin Lymphoma Myeloma Leuk 2010;10:473-6.
144. Yin G, Xiao Z, Ni Y, Qu X, Wu H, Lu H, Qian S, Chen L, Li J, Qiu H, Miao K. Association of MDR1 single-nucleotide polymorphisms and haplotype variants with multiple myeloma in Chinese Jiangsu Han population. Tumour Biol 2016;37:9549-54.
145. Martino A, Campa D, Buda G, Sainz J, Garcia-Sanz R, Jamroziak K, Reis RM, Weinhold N, Jurado M, Rios R, Szemraj-Rogucka Z, Marques H, Szemraj J, Stein A, Kumar R, Orciuolo E, Gemignani F, Landi S, Goldschmidt H, Petrini M, Dumontet C, Canzian F, Rossi AM. Polymorphisms in xenobiotic transporters ABCB1, ABCG2, ABCC2, ABCC1, ABCC3 and multiple myeloma risk: a case-control study in the context of the International Multiple Myeloma rESEarch (IMMEnSE) consortium. Leukemia 2012;26:1419-22.
146. Drain S, Catherwood MA, Bjourson AJ, Drake MB, Kettle PJ, Alexander HD. Neither P-gp SNP variants, P-gp expression nor functional P-gp activity predicts MDR in a preliminary study of plasma cell myeloma. Cytometry B Clin Cytom 2012;82:229-37.
147. Schaich M, Soucek S, Thiede C, Ehninger G, Illmer T; SHG AML96 Study Group. MDR1 and MRP1 gene expression are independent predictors for treatment outcome in adult acute myeloid leukaemia. Br J Haematol 2005;128:324-32.
148. Ao L, Wu Y, Kim D, Jang ER, Kim K, Lee DM, Kim KB, Lee W. Development of peptide-based reversing agents for p-glycoprotein-mediated resistance to carfilzomib. Mol Pharm 2012;9:2197-205.
149. Lilienbaum A. Relationship between the proteasomal system and autophagy. Int J Biochem Mol Biol 2013;4:1-26.
150. White E, DiPaola RS. The double-edged sword of autophagy modulation in cancer. Clin Cancer Res 2009;15:5308-16.
151. Milani M, Rzymski T, Mellor HR, Pike L, Bottini A, Generali D, Harris AL. The role of ATF4 stabilization and autophagy in resistance of breast cancer cells treated with bortezomib. Cancer Res 2009;69:4415-23.
152. Ding WX, Ni HM, Gao W, Chen X, Kang JH, Stolz DB, Liu J, Yin XM. Oncogenic transformation confers a selective susceptibility to the combined suppression of the proteasome and autophagy. Mol Cancer Ther 2009;8:2036-45.
153. Yoshida GJ. Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment. J Hematol Oncol 2017;10:67.
154. Podar K, Raab MS, Zhang J, McMillin D, Breitkreutz I, Tai YT, Lin BK, Munshi N, Hideshima T, Chauhan D, Anderson KC. Targeting PKC in multiple myeloma: in vitro and in vivo effects of the novel, orally available small-molecule inhibitor enzastaurin (LY317615.HCl). Blood 2007;109:1669-77.
155. Raab MS, Breitkreutz I, Tonon G, Zhang J, Hayden PJ, Nguyen T, Fruehauf JH, Lin BK, Chauhan D, Hideshima T, Munshi NC, Anderson KC, Podar K. Targeting PKC: a novel role for beta-catenin in ER stress and apoptotic signaling. Blood 2009;113:1513-21.
156. Yang Y, Chen Y, Saha MN, Chen J, Evans K, Qiu L, Reece D, Chen GA, Chang H. Targeting phospho-MARCKS overcomes drug-resistance and induces antitumor activity in preclinical models of multiple myeloma. Leukemia 2015;29:715-26.
157. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997;3:730-7.
158. Franqui-Machin R, Wendlandt EB, Janz S, Zhan F, Tricot G. Cancer stem cells are the cause of drug resistance in multiple myeloma: fact or fiction? Oncotarget 2015;6:40496-506.
159. Hu JS, Huang X, Huang YD, Lu YY, Lu QY. Effect of Hedgehog signaling pathway abnormality on chemothe-rapeutic resistance of multiple myeloma. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2017;25:465-70. (in Chinese)
160. Zhao JJ, Lin J, Zhu D, Wang X, Brooks D, Chen M, Chu ZB, Takada K, Ciccarelli B, Admin S, Tao J, Tai YT, Treon S, Pinkus G, Kuo WP, Hideshima T, Bouxsein M, Munshi N, Anderson K, Carrasco R. miR-30-5p functions as a tumor suppressor and novel therapeutic tool by targeting the oncogenic Wnt/beta-catenin/BCL9 pathway. Cancer Res 2014;74:1801-13.
161. Tang B, Xu A, Xu J, Huang H, Chen L, Su Y, Zhang L, Li J, Fan F, Deng J, Tang L, Sun C, Hu Y. MicroRNA-324-5p regulates stemness, pathogenesis and sensitivity to bortezomib in multiple myeloma cells by targeting hedgehog signaling. Int J Cancer 2018;142:109-20.
162. Xu Z, Huang C, Hao D. MicroRNA-1271 inhibits proliferation and promotes apoptosis of multiple myeloma cells through inhibiting smoothened-mediated Hedgehog signaling pathway. Oncol Rep 2017;37:1261-9.
163. Yang Y, Shi J, Tolomelli G, Xu H, Xia J, Wang H, Zhou W, Zhou Y, Das S, Gu Z, Levasseur D, Zhan F, Tricot G. RARalpha2 expression confers myeloma stem cell features. Blood 2013;122:1437-47.
164. Cheng T, Rodrigues N, Shen H, Yang Y, Dombkowski D, Sykes M, Scadden DT. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 2000;287:1804-8.
165. Januchowski R, Wojtowicz K, Zabel M. The role of aldehyde dehydrogenase (ALDH) in cancer drug resistance. Biomed Pharmacother 2013;67:669-80.
166. Saltarella I, Lamanuzzi A, Reale A, Vacca A, Ria R. Identify multiple myeloma stem cells: Utopia? World J Stem Cells 2015;7:84-95.
167. Mirandola L, Apicella L, Colombo M, Yu Y, Berta DG, Platonova N, Lazzari E, Lancellotti M, Bulfamante G, Cobos E, Chiriva-Internati M, Chiaramonte R. Anti-Notch treatment prevents multiple myeloma cells localization to the bone marrow via the chemokine system CXCR4/SDF-1. Leukemia 2013;27:1558-66.
168. Podar K, Tai YT, Davies FE, Lentzsch S, Sattler M, Hideshima T, Lin BK, Gupta D, Shima Y, Chauhan D, Mitsiades C, Raje N, Richardson P, Anderson KC. Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration. Blood 2001;98:428-35.
169. Meads MB, Hazlehurst LA, Dalton WS. The bone marrow microenvironment as a tumor sanctuary and contributor to drug resistance. Clin Cancer Res 2008;14:2519-26.
170. Bianchi G, Kumar S, Ghobrial IM, Roccaro AM. Cell trafficking in multiple myeloma. Open J Hematol 2012;3:4.
171. Bar-Natan M, Stroopinsky D, Luptakova K, Coll MD, Apel A, Rajabi H, Pyzer AR, Palmer K, Reagan MR, Nahas MR, Karp Leaf R, Jain S, Arnason J, Ghobrial IM, Anderson KC, Kufe D, Rosenblatt J, Avigan D. Bone marrow stroma protects myeloma cells from cytotoxic damage via induction of the oncoprotein MUC1. Br J Haematol 2017;176:929-38.
172. Kikuchi J, Kuroda Y, Koyama D, Osada N, Izumi T, Yasui H, Kawase T, Ichinohe T, Furukawa Y. Myeloma cells are activated in bone marrow microenvironment by the CD180/MD-1 complex which senses lipopolysaccharide. Cancer Res 2018;78:1766-78.
173. Gu C, Peng H, Lu Y, Yang H, Tian Z, Yin G, Zhang W, Lu S, Zhang Y, Yang Y. BTK suppresses myeloma cellular senescence through activating AKT/P27/Rb signaling. Oncotarget 2017;8:56858-67.
174. Yang Y, Shi J, Gu Z, Salama ME, Das S, Wendlandt E, Xu H, Huang J, Tao Y, Hao M, Franqui R, Levasseur D, Janz S, Tricot G, Zhan F. Bruton tyrosine kinase is a therapeutic target in stem-like cells from multiple myeloma. Cancer Res 2015;75:594-604.
175. Kobune M, Chiba H, Kato J, Kato K, Nakamura K, Kawano Y, Takada K, Takimoto R, Takayama T, Hamada H, Niitsu Y. Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism. Mol Cancer Ther 2007;6:1774-84.
176. Di Marzo L, Desantis V, Solimando AG, Ruggieri S, Annese T, Nico B, Fumarulo R, Vacca A, Frassanito MA. Microenvironment drug resistance in multiple myeloma: emerging new players. Oncotarget 2016;7:60698-711.
177. Caivano A, Laurenzana I, De Luca L, La Rocca F, Simeon V, Trino S, D'Auria F, Traficante A, Maietti M, Izzo T, D'Arena G, Mansueto G, Pietrantuono G, Laurenti L, Musto P, Del Vecchio L. High serum levels of extracellular vesicles expressing malignancy-related markers are released in patients with various types of hematological neoplastic disorders. Tumour Biol 2015;36:9739-52.
178. Roccaro AM, Sacco A, Maiso P, Azab AK, Tai YT, Reagan M, Azab F, Flores LM, Campigotto F, Weller E, Anderson KC, Scadden DT, Ghobrial IM. BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression. J Clin Invest 2013;123:1542-55.
179. Frassanito MA, Rao L, Moschetta M, Ria R, Di Marzo L, De Luisi A, Racanelli V, Catacchio I, Berardi S, Basile A, Menu E, Ruggieri S, Nico B, Ribatti D, Fumarulo R, Dammacco F, Vanderkerken K, Vacca A. Bone marrow fibroblasts parallel multiple myeloma progression in patients and mice: in vitro and in vivo studies. Leukemia 2014;28:904-16.
180. Tsuyama N, Ishikawa H, Abroun S, Liu S, Li FJ, Otsuyama K, Zheng X, Obata M, Taniguchi O, Kawano MM. The regulatory mechanism of IL-6-dependent proliferation of human myeloma cells. Hematology 2003;8:409-11.
181. Yang H, Du X, Xi Y. Effects of survivin on FVADT chemotherapy for refractory multiple myeloma. Exp Ther Med 2016;12:771-6.
182. Wagner V, Hose D, Seckinger A, Weitz L, Meißner T, Reme T, Rossi JF, Goldschmidt H, Krämer A, Klein B, Raab MS. Survivin in multiple myeloma: prognostic and therapeutic implications. Blood 2011;118:137.
183. Desplanques G, Giuliani N, Delsignore R, Rizzoli V, Bataille R, Barille-Nion S. Impact of XIAP protein levels on the survival of myeloma cells. Haematologica 2009;94:87-93.
184. Abe S, Hasegawa M, Yamamoto K, Kurata M, Nakagawa Y, Suzuki K, Takizawa T, Kitagawa M. Rapid induction of IAP family proteins and Smac/DIABLO expression after proapoptotic stimulation with doxorubicin in RPMI 8226 multiple myeloma cells. Exp Mol Pathol 2007;83:405-12.
185. Nakagawa Y, Abe S, Kurata M, Hasegawa M, Yamamoto K, Inoue M, Takemura T, Suzuki K, Kitagawa M. IAP family protein expression correlates with poor outcome of multiple myeloma patients in association with chemotherapy-induced overexpression of multidrug resistance genes. Am J Hematol 2006;81:824-31.
186. De Veirman K, Van Ginderachter JA, Lub S, De Beule N, Thielemans K, Bautmans I, Oyajobi BO, De Bruyne E, Menu E, Lemaire M, Van Riet I, Vanderkerken K, Van Valckenborgh E. Multiple myeloma induces Mcl-1 expression and survival of myeloid-derived suppressor cells. Oncotarget 2015;6:10532-47.
187. Le Gouill S, Podar K, Amiot M, Hideshima T, Chauhan D, Ishitsuka K, Kumar S, Raje N, Richardson PG, Harousseau JL, Anderson KC. VEGF induces Mcl-1 up-regulation and protects multiple myeloma cells against apoptosis. Blood 2004;104:2886-92.
188. Merz M, Jauch A, Hielscher T, Bochtler T, Schonland SO, Seckinger A, Hose D, Bertsch U, Neben K, Raab MS, Hillengass J, Salwender H, Blau IW, Lindemann HW, Schmidt-Wolf IGH, Scheid C, Haenel M, Weisel KC, Goldschmidt H. Prognostic significance of cytogenetic heterogeneity in patients with newly diagnosed multiple myeloma. Blood Adv 2018;2:1-9.
189. Rasche L, Chavan SS, Stephens OW, Patel PH, Tytarenko R, Ashby C, Bauer M, Stein C, Deshpande S, Wardell C, Buzder T, Molnar G, Zangari M, van Rhee F, Thanendrarajan S, Schinke C, Epstein J, Davies FE, Walker BA, Meissner T, Barlogie B, Morgan GJ, Weinhold N. Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing. Nat Commun 2017;8:268.
190. Hebraud B, Leleu X, Lauwers-Cances V, Roussel M, Caillot D, Marit G, Karlin L, Hulin C, Gentil C, Guilhot F, Garderet L, Lamy T, Brechignac S, Pegourie B, Jaubert J, Dib M, Stoppa AM, Sebban C, Fohrer C, Fontan J, Fruchart C, Macro M, Orsini-Piocelle F, Lepeu G, Sohn C, Corre J, Facon T, Moreau P, Attal M, Avet-Loiseau H. Deletion of the 1p32 region is a major independent prognostic factor in young patients with myeloma: the IFM experience on 1195 patients. Leukemia 2014;28:675-9.
191. Gertz MA, Lacy MQ, Dispenzieri A, Greipp PR, Litzow MR, Henderson KJ, Van Wier SA, Ahmann GJ, Fonseca R. Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy. Blood 2005;106:2837-40.
192. Avet-Loiseau H, Gerson F, Magrangeas F, Minvielle S, Harousseau JL, Bataille R; Intergroupe Francophone du Myélome. Rearrangements of the c-myc oncogene are present in 15% of primary human multiple myeloma tumors. Blood 2001;98:3082-6.
193. Bolli N, Avet-Loiseau H, Wedge DC, Van Loo P, Alexandrov LB, Martincorena I, Dawson KJ, Iorio F, Nik-Zainal S, Bignell GR, Hinton JW, Li Y, Tubio JM, McLaren S, S OM, Butler AP, Teague JW, Mudie L, Anderson E, Rashid N, Tai YT, Shammas MA, Sperling AS, Fulciniti M, Richardson PG, Parmigiani G, Magrangeas F, Minvielle S, Moreau P, Attal M, Facon T, Futreal PA, Anderson KC, Campbell PJ, Munshi NC. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat Commun 2014;5:2997.
194. Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC, Harview CL, Brunet JP, Ahmann GJ, Adli M, Anderson KC, Ardlie KG, Auclair D, Baker A, Bergsagel PL, Bernstein BE, Drier Y, Fonseca R, Gabriel SB, Hofmeister CC, Jagannath S, Jakubowiak AJ, Krishnan A, Levy J, Liefeld T, Lonial S, Mahan S, Mfuko B, Monti S, Perkins LM, Onofrio R, Pugh TJ, Rajkumar SV, Ramos AH, Siegel DS, Sivachenko A, Stewart AK, Trudel S, Vij R, Voet D, Winckler W, Zimmerman T, Carpten J, Trent J, Hahn WC, Garraway LA, Meyerson M, Lander ES, Getz G, Golub TR. Initial genome sequencing and analysis of multiple myeloma. Nature 2011;471:467-72.
195. Kortuem KM, Braggio E, Bruins L, Barrio S, Shi CS, Zhu YX, Tibes R, Viswanatha D, Votruba P, Ahmann G, Fonseca R, Jedlowski P, Schlam I, Kumar S, Bergsagel PL, Stewart AK. Panel sequencing for clinically oriented variant screening and copy number detection in 142 untreated multiple myeloma patients. Blood Cancer J 2016;6:e397.
196. Johnson DC, Weinhold N, Mitchell JS, Chen B, Kaiser M, Begum DB, Hillengass J, Bertsch U, Gregory WA, Cairns D, Jackson GH, Forsti A, Nickel J, Hoffmann P, Noethen MM, Stephens OW, Barlogie B, Davis FE, Hemminki K, Goldschmidt H, Houlston RS, Morgan GJ. Genome-wide association study identifies variation at 6q25.1 associated with survival in multiple myeloma. Nat Commun 2016;7:10290.
197. Shah V, Boyd KD, Houlston RS, Kaiser MF. Constitutional mutation in CDKN2A is associated with long term survivorship in multiple myeloma: a case report. BMC Cancer 2017;17:718.
198. Basmaci C, Pehlivan M, Tomatir A, Sever T, Okan V, Yilmaz M, Oguzkan-Balci S, Pehlivan S. Effects of TNFalpha, NOS3, MDR1 gene polymorphisms on clinical parameters, prognosis and survival of multiple myeloma cases. Asian Pac J Cancer Prev 2016;17:1009-14.
199. Corre J, Munshi N, Avet-Loiseau H. Genetics of multiple myeloma: another heterogeneity level? Blood 2015;125:1870-6.
200. Andrulis M, Lehners N, Capper D, Penzel R, Heining C, Huellein J, Zenz T, von Deimling A, Schirmacher P, Ho AD, Goldschmidt H, Neben K, Raab MS. Targeting the BRAF V600E mutation in multiple myeloma. Cancer Discov 2013;3:862-9.
201. Lu S, Yang J, Chen Z, Gong S, Zhou H, Xu X, Wang J. Different mutants of PSMB5 confer varying bortezomib resistance in T lymphoblastic lymphoma/leukemia cells derived from the Jurkat cell line. Exp Hematol 2009;37:831-7.
202. Balsas P, Galan-Malo P, Marzo I, Naval J. Bortezomib resistance in a myeloma cell line is associated to PSMbeta5 overexpression and polyploidy. Leuk Res 2012;36:212-8.
203. Niewerth D, Jansen G, Assaraf YG, Zweegman S, Kaspers GJ, Cloos J. Molecular basis of resistance to proteasome inhibitors in hematological malignancies. Drug Resist Updat 2015;18:18-35.
204. Pichiorri F, Suh SS, Ladetto M, Kuehl M, Palumbo T, Drandi D, Taccioli C, Zanesi N, Alder H, Hagan JP, Munker R, Volinia S, Boccadoro M, Garzon R, Palumbo A, Aqeilan RI, Croce CM. MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis. Proc Natl Acad Sci U S A 2008;105:12885-90.
205. 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;9:1511-20.
206. Abedin SM, Boddy CS, Munshi HG. BET inhibitors in the treatment of hematologic malignancies: current insights and future prospects. Onco Targets Ther 2016;9:5943-53.
208. Sive JI, Feber A, Smith D, Quinn J, Beck S, Yong K. Global hypomethylation in myeloma is associated with poor prognosis. Br J Haematol 2016;172:473-5.
209. Zhang W, Wang YE, Zhang Y, Leleu X, Reagan M, Zhang Y, Mishima Y, Glavey S, Manier S, Sacco A, Jiang B, Roccaro AM, Ghobrial IM. Global epigenetic regulation of microRNAs in multiple myeloma. PLoS One 2014;9:e110973.
210. Bi C, Chung TH, Huang G, Zhou J, Yan J, Ahmann GJ, Fonseca R, Chng WJ. Genome-wide pharmacologic unmasking identifies tumor suppressive microRNAs in multiple myeloma. Oncotarget 2015;6:26508-18.
211. Dupere-Richer D, Licht JD. Epigenetic regulatory mutations and epigenetic therapy for multiple myeloma. Curr Opin Hematol 2017;24:336-44.
212. Pawlyn C, Kaiser MF, Heuck C, Melchor L, Wardell CP, Murison A, Chavan SS, Johnson DC, Begum DB, Dahir NM, Proszek PZ, Cairns DA, Boyle EM, Jones JR, Cook G, Drayson MT, Owen RG, Gregory WM, Jackson GH, Barlogie B, Davies FE, Walker BA, Morgan GJ. The spectrum and clinical impact of epigenetic modifier mutations in myeloma. Clin Cancer Res 2016;22:5783-94.
213. Chim CS, Kumar SK, Orlowski RZ, Cook G, Richardson PG, Gertz MA, Giralt S, Mateos MV, Leleu X, Anderson KC. Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond. Leukemia 2018;32:252-62.
214. Sonneveld P, Broijl A. Treatment of relapsed and refractory multiple myeloma. Haematologica 2016;101:396-406.
215. Cornell RF, Kassim AA. Evolving paradigms in the treatment of relapsed/refractory multiple myeloma: increased options and increased complexity. Bone Marrow Transplant 2016;51:479-91.
216. Dimopoulos M, Alegre A, Stadtmauer EA, Goldschmidt H, Zonder JA, de Castro CM, Masliak Z, Reece D, Olesnyckyj M, Yu Z, Weber DM. The efficacy and safety of lenalidomide plus dexamethasone in relapsed and/or refractory multiple myeloma patients with impaired renal function. Cancer 2010;116:3807-14.
217. Dimopoulos M, Siegel DS, Lonial S, Qi J, Hajek R, Facon T, Rosinol L, Williams C, Blacklock H, Goldschmidt H, Hungria V, Spencer A, Palumbo A, Graef T, Eid JE, Houp J, Sun L, Vuocolo S, Anderson KC. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. Lancet Oncol 2013;14:1129-40.
218. Laubach J, Garderet L, Mahindra A, Gahrton G, Caers J, Sezer O, Voorhees P, Leleu X, Johnsen HE, Streetly M, Jurczyszyn A, Ludwig H, Mellqvist UH, Chng WJ, Pilarski L, Einsele H, Hou J, Turesson I, Zamagni E, Chim CS, Mazumder A, Westin J, Lu J, Reiman T, Kristinsson S, Joshua D, Roussel M, O'Gorman P, Terpos E, McCarthy P, Dimopoulos M, Moreau P, Orlowski RZ, Miguel JS, Anderson KC, Palumbo A, Kumar S, Rajkumar V, Durie B, Richardson PG. Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group. Leukemia 2016;30:1005-17.
219. Matsui W, Borrello I, Mitsiades C. Autologous stem cell transplantation and multiple myeloma cancer stem cells. Biol Blood Marrow Transplant 2012;18:S27-32.
220. Byrne M, Salmasinia D, Leather H, Cogle CR, Davis A, Hsu JW, Wiggins L, Chang MN, An Q, Wingard JR, Moreb JS. Tandem autologous stem cell transplantation for multiple myeloma patients based on response to their first transplant-a prospective phase II study. Clin Med Insights Oncol 2014;8:101-5.
221. Cowan AJ, Stevenson PA, Libby EN, Becker PS, Coffey DG, Green DJ, Hyun TS, Fromm JR, Gopal AK, Holmberg LA. Circulating plasma cells at the time of collection of autologous PBSC for transplant in multiple myeloma patients is a negative prognostic factor even in the age of post-transplant maintenance therapy. Biol Blood Marrow Transplant 2018; doi: 10.1016/j.bbmt.2018.02.017. doi: 10.1016/j.bbmt.2018.02.017.
222. Lee SE, Lim JY, Ryu DB, Kim TW, Jeon YW, Yoon JH, Cho BS, Eom KS, Kim YJ, Kim HJ, Lee S, Cho SG, Kim DW, Lee JW, Min WS, Min CK. Circulating CD3(+)CD4(+)CD161(+) cells are associated with early complications after autologous stem cell transplantation in multiple myeloma. Biomed Res Int 2018;2018:5097325.
223. Pulte ED, Dmytrijuk A, Nie L, Goldberg KB, McKee AE, Farrell AT, Pazdur R. FDA approval summary: lenalidomide as maintenance therapy after autologous stem cell transplant in newly diagnosed multiple myeloma. Oncologist 2018; doi: 10.1634/theoncologist.2017-0440. doi: 10.1634/theoncologist.2017-0440.
224. Micallef IN, Stiff PJ, Nademanee AP, Maziarz RT, Horwitz ME, Stadtmauer EA, Kaufman JL, McCarty JM, Vargo R, Cheverton PD, Struijs M, Bolwell B, DiPersio JF. Plerixafor plus granulocyte colony-stimulating factor for patients with non-Hodgkin lymphoma and multiple myeloma: long-term follow-up report. Biol Blood Marrow Transplant ; doi: 10.1016/j.bbmt.2018.01.039.
225. Gossi U, Jeker B, Mansouri Taleghani B, Bacher U, Novak U, Betticher D, Egger T, Zander T, Pabst T. Prolonged survival after second autologous transplantation and lenalidomide maintenance for salvage treatment of myeloma patients at first relapse after prior autograft. Hematol Oncol 2018;36:436-44.
226. Sonneveld P, Marie JP, Huisman C, Vekhoff A, Schoester M, Faussat AM, van Kapel J, Groenewegen A, Charnick S, Zittoun R, Lowenberg B. Reversal of multidrug resistance by SDZ PSC 833, combined with VAD (vincristine, doxorubicin, dexamethasone) in refractory multiple myeloma. A phase I study. Leukemia 1996;10:1741-50.
227. Dalton WS, Crowley JJ, Salmon SS, Grogan TM, Laufman LR, Weiss GR, Bonnet JD. A phase III randomized study of oral verapamil as a chemosensitizer to reverse drug resistance in patients with refractory myeloma. A Southwest Oncology Group study. Cancer 1995;75:815-20.
228. Friedenberg WR, Rue M, Blood EA, Dalton WS, Shustik C, Larson RA, Sonneveld P, Greipp PR. Phase III study of PSC-833 (valspodar) in combination with vincristine, doxorubicin, and dexamethasone (valspodar/VAD) versus VAD alone in patients with recurring or refractory multiple myeloma (E1A95): a trial of the Eastern Cooperative Oncology Group. Cancer 2006;106:830-8.
229. Gulla A, Di Martino MT, Gallo Cantafio ME, Morelli E, Amodio N, Botta C, Pitari MR, Lio SG, Britti D, Stamato MA, Hideshima T, Munshi NC, Anderson KC, Tagliaferri P, Tassone P. A 13 mer LNA-i-miR-221 inhibitor restores drug sensitivity in melphalan-refractory multiple myeloma cells. Clin Cancer Res 2016;22:1222-33.
230. Jones RJ, Gu D, Bjorklund CC, Kuiatse I, Remaley AT, Bashir T, Vreys V, Orlowski RZ. The novel anticancer agent JNJ-26854165 induces cell death through inhibition of cholesterol transport and degradation of ABCA1. J Pharmacol Exp Ther 2013;346:381-92.
231. Mark E, Issa MC. Withaferin A induces cell death and differentiation in multiple myeloma cancer stem cells. Med Chem Commun 2016;8:10.
232. Issa ME, Wijeratne EMK, Gunatilaka AAL, Cuendet M. Withanolide D exhibits similar cytostatic effect in drug-resistant and drug-sensitive multiple myeloma cells. Front Pharmacol 2017;8:610.
233. Matsui W, Wang Q, Brennan S, Meeker A, Tressler R, Harley C, Huff CA, Smith BD, Jones R. The novel telomerase inhibitor GRN163L targets drug-resistant cancer stem cells in multiple myeloma. Mol Cancer Ther 2007;6 Suppl 11:A97.
234. Richardson PG, Bensinger WI, Huff CA, Costello CL, Lendvai N, Berdeja JG, Anderson LD, Siegel DS, Lebovic D, Jagannath S, Laubach JP, Stockerl-Goldstein KE, Kwei L, Clow F, Elias L, Salman Z, Graef T, Bilotti E, Vij R. Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: phase 2 trial results. Br J Haematol 2018;180:821-30.
235. Rius M, Lyko F. Epigenetic cancer therapy: rationales, targets and drugs. Oncogene 2012;31:4257-65.
236. Amorim S, Stathis A, Gleeson M, Iyengar S, Magarotto V, Leleu X, Morschhauser F, Karlin L, Broussais F, Rezai K, Herait P, Kahatt C, Lokiec F, Salles G, Facon T, Palumbo A, Cunningham D, Zucca E, Thieblemont C. Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study. Lancet Haematol 2016;3:e196-204.
237. Drew AE, Moradei O, Jacques SL, Rioux N, Boriack-Sjodin AP, Allain C, Scott MP, Jin L, Raimondi A, Handler JL, Ott HM, Kruger RG, McCabe MT, Sneeringer C, Riera T, Shapiro G, Waters NJ, Mitchell LH, Duncan KW, Moyer MP, Copeland RA, Smith J, Chesworth R, Ribich SA. Identification of a CARM1 inhibitor with potent in vitro and in vivo activity in preclinical models of multiple myeloma. Sci Rep 2017;7:17993.
238. Sonneveld P, Suciu S, Weijermans P, Beksac M, Neuwirtova R, Solbu G, Lokhorst H, van der Lelie J, Dohner H, Gerhartz H, Segeren CM, Willemze R, Lowenberg B; European Organization for Research and Treatment of Cancer (EORTC); Leukaemia Cooperative Group (LCG); Dutch Haemato-Oncology Cooperative Study Group (HOVON). Cyclosporin A combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma: an EORTC-HOVON randomized phase III study (06914). Br J Haematol 2001;115:895-902.
239. Dimopoulos K, Sogaard Helbo A, Fibiger Munch-Petersen H, Sjo L, Christensen J, Sommer Kristensen L, Asmar F, Hermansen NEU, O'Connel C, Gimsing P, Liang G, Gronbaek K. Dual inhibition of DNMTs and EZH2 can overcome both intrinsic and acquired resistance of myeloma cells to IMiDs in a cereblon-independent manner. Mol Oncol 2018;12:180-95.
240. Alzrigat M, Parraga AA, Majumder MM, Ma A, Jin J, Osterborg A, Nahi H, Nilsson K, Heckman CA, Oberg F, Kalushkova A, Jernberg-Wiklund H. The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomains. Oncotarget 2017;8:103731-43.
241. Jakubowiak A, Offidani M, Pegourie B, De La Rubia J, Garderet L, Laribi K, Bosi A, Marasca R, Laubach J, Mohrbacher A, Carella AM, Singhal AK, Tsao LC, Lynch M, Bleickardt E, Jou YM, Robbins M, Palumbo A. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood 2016;127:2833-40.
242. Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, Belch A, Krishnan A, Vescio RA, Mateos MV, Mazumder A, Orlowski RZ, Sutherland HJ, Blade J, Scott EC, Oriol A, Berdeja J, Gharibo M, Stevens DA, LeBlanc R, Sebag M, Callander N, Jakubowiak A, White D, de la Rubia J, Richardson PG, Lisby S, Feng H, Uhlar CM, Khan I, Ahmadi T, Voorhees PM. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet 2016;387:1551-60.
243. Schonfeld K, Zuber C, Pinkas J, Hader T, Bernoster K, Uherek C. Indatuximab ravtansine (BT062) combination treatment in multiple myeloma: pre-clinical studies. J Hematol Oncol 2017;10:13.
244. Karadimitris A, Chaidos A, Caputo V, Goudevenou K, Ponnusamy K, Xiao X. Myeloma propagating cells, drug resistance and relapse. Stem Cells 2015;33:3205-11.
245. Ritchie JP, Ramani VC, Ren Y, Naggi A, Torri G, Casu B, Penco S, Pisano C, Carminati P, Tortoreto M, Zunino F, Vlodavsky I, Sanderson RD, Yang Y. SST0001, a chemically modified heparin, inhibits myeloma growth and angiogenesis via disruption of the heparanase/syndecan-1 axis. Clin Cancer Res 2011;17:1382-93.
246. Vasuthasawat A, Yoo EM, Trinh KR, Lichtenstein A, Timmerman JM, Morrison SL. Targeted immunotherapy using anti-CD138-interferon alpha fusion proteins and bortezomib results in synergistic protection against multiple myeloma. MAbs 2016;8:1386-97.
247. Kulkarni U, Karsten CM, Kohler T, Hammerschmidt S, Bommert K, Tiburzy B, Meng L, Thieme L, Recke A, Ludwig RJ, Pollok K, Kalies K, Bogen B, Boettcher M, Kamradt T, Hauser AE, Langer C, Huber-Lang M, Finkelman FD, Kohl J, Wong DM, Manz RA. IL-10 mediates plasmacytosis-associated immunodeficiency by inhibiting complement-mediated neutrophil migration. J Allergy Clin Immunol 2016;137:1487-97.e6.
248. Muthu Raja KR, Rihova L, Zahradova L, Klincova M, Penka M, Hajek R. Increased T regulatory cells are associated with adverse clinical features and predict progression in multiple myeloma. PLoS One 2012;7:e47077.
249. Comeau JM, Kelly K, Jean GW. The role of elotuzumab in the treatment of relapsed or refractory multiple myeloma. Am J Health Syst Pharm 2018;75:55-66.
250. Frerichs KA, Nagy NA, Lindenbergh PL, Bosman P, Marin Soto J, Broekmans M, Groen RWJ, Themeli M, Nieuwenhuis L, Stege C, Nijhof IS, Mutis T, Zweegman S, Lokhorst HM, van de Donk N. CD38-targeting antibodies in multiple myeloma: mechanisms of action and clinical experience. Expert Rev Clin Immunol 2018;14:197-206.
251. Qin H, Wei G, Sakamaki I, Dong Z, Cheng WA, Smith DL, Wen F, Sun H, Kim K, Cha S, Bover L, Neelapu SS, Kwak LW. Novel BAFF-receptor antibody to natively folded recombinant protein eliminates drug-resistant human B-cell malignancies in vivo. Clin Cancer Res 2018;24:1114-23.
252. Yang C, Xiong F, Wang J, Dou J, Chen J, Chen D, Zhang Y, Luo S, Gu N. Anti-ABCG2 monoclonal antibody in combination with paclitaxel nanoparticles against cancer stem-like cell activity in multiple myeloma. Nanomedicine (Lond) 2014;9:45-60.
253. Study of Natalizumab in Relapsed/Refractory Multiple Myeloma. In: U.S. National Library of Medicine; 2008. ClinicalTrials.gov Identifier: NCT00675428. .
254. Podar K, Zimmerhackl A, Fulciniti M, Tonon G, Hainz U, Tai YT, Vallet S, Halama N, Jager D, Olson DL, Sattler M, Chauhan D, Anderson KC. The selective adhesion molecule inhibitor natalizumab decreases multiple myeloma cell growth in the bone marrow microenvironment: therapeutic implications. Br J Haematol 2011;155:438-48.
255. Sherbenou DW, Mark TM, Forsberg P. Monoclonal antibodies in multiple myeloma: a new wave of the future. Clin Lymphoma Myeloma Leuk 2017;17:545-54.
257. Fernandez-Poma SM, Salas-Benito D, Lozano T, Casares N, Riezu-Boj JI, Mancheno U, Elizalde E, Alignani D, Zubeldia N, Otano I, Conde E, Sarobe P, Lasarte JJ, Hervas-Stubbs S. Expansion of tumor-infiltrating CD8(+) T cells expressing PD-1 improves the efficacy of adoptive t-cell therapy. Cancer Res 2017;77:3672-84.
258. Chu J, Deng Y, Benson DM, He S, Hughes T, Zhang J, Peng Y, Mao H, Yi L, Ghoshal K, He X, Devine SM, Zhang X, Caligiuri MA, Hofmeister CC, Yu J. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. Leukemia 2014;28:917-27.
259. Larocca A, Palumbo A. Optimizing treatment for elderly patients with newly diagnosed multiple myeloma: a personalized approach. J Clin Oncol 2016; doi: 10.1200/JCO.2016.68.6113. doi: 10.1200/JCO.2016.68.6113.
260. Hari PN, Zhang MJ, Roy V, Perez WS, Bashey A, To LB, Elfenbein G, Freytes CO, Gale RP, Gibson J, Kyle RA, Lazarus HM, McCarthy PL, Milone GA, Pavlovsky S, Reece DE, Schiller G, Vela-Ojeda J, Weisdorf D, Vesole D. Is the international staging system superior to the Durie-Salmon staging system? A comparison in multiple myeloma patients undergoing autologous transplant. Leukemia 2009;23:1528-34.
261. Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Migkou M, Eleutherakis-Papaiakovou E, Fotiou D, Ziogas D, Panagiotidis I, Kafantari E, Giannouli S, Zomas A, Konstantopoulos K, Dimopoulos MA. Evaluation of the revised international staging system in an independent cohort of unselected patients with multiple myeloma. Haematologica 2017;102:593-9.
262. Agarwal MB. Multiple myeloma: treatment is getting individualized. Indian J Hematol Blood Transfus 2016;32:3-9.
263. van Rhee F, Szymonifka J, Anaissie E, Nair B, Waheed S, Alsayed Y, Petty N, Shaughnessy JD Jr, Hoering A, Crowley J, Barlogie B. Total therapy 3 for multiple myeloma: prognostic implications of cumulative dosing and premature discontinuation of VTD maintenance components, bortezomib, thalidomide, and dexamethasone, relevant to all phases of therapy. Blood 2010;116:1220-7.
264. Keats JJ, Chesi M, Egan JB, Garbitt VM, Palmer SE, Braggio E, Van Wier S, Blackburn PR, Baker AS, Dispenzieri A, Kumar S, Rajkumar SV, Carpten JD, Barrett M, Fonseca R, Stewart AK, Bergsagel PL. Clonal competition with alternating dominance in multiple myeloma. Blood 2012;120:1067-76.
265. Sikic BI. Modulation of multidrug resistance: a paradigm for translational clinical research. Oncology (Williston Park) 1999;13:183-7.
