Panobinostat: A review of trial results and future prospects in multiple myeloma

Expert Review of Hematology

Volumn 8, Issue 1, 2015, Pages 9-18

  Libby, Edward N ^a   Becker, Pamela S ^a   Burwick, Nicholas ^b   Green, Damian J ^a   Holmberg, Leona ^c   Bensinger, William Ira ^c  

^a UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF WASHINGTON   (United States)

^c Fred Hutchinson Cancer Research Center   (United States)

Author keywords

epigenetics; histone deacetylase inhibitors; immunomodulatory drugs; LBH589; multiple myeloma; panobinostat; proteasome inhibitors

Indexed keywords

HISTONE DEACETYLASE INHIBITOR; IMMUNOMODULATING AGENT; PANOBINOSTAT; PROTEASOME INHIBITOR; ANTINEOPLASTIC AGENT; HYDROXAMIC ACID; INDOLE DERIVATIVE;

AREA UNDER THE CURVE; CANCER PATIENT; CANCER SURVIVAL; DRUG EFFICACY; DRUG HALF LIFE; DRUG METABOLISM; EPIGENETICS; HISTONE ACETYLATION; HISTONE CODE; HUMAN; MAXIMUM PLASMA CONCENTRATION; METHYLATION; MULTIPLE MYELOMA; NUCLEOSOME; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; REVIEW; GENETICS; METABOLISM;

ANTINEOPLASTIC AGENTS; HUMANS; HYDROXAMIC ACIDS; INDOLES; MULTIPLE MYELOMA;

EID: 84920843408     PISSN: 17474086     EISSN: 17474094     Source Type: Journal    
DOI: 10.1586/17474086.2015.983065     Document Type: Review

References (74)

1. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008;111(5):2516-20
2. American Cancer Society. Cancer Facts and Statistics. Availble from: http://www.cancer. org/cancer/multiplemyeloma/detailedguide/multiple-myeloma-key-statistics [Accessed 2014]
3. Libby E, Garcia D, Quintana D, et al. Disease-specific survival for patients with multiple myeloma: significant improvements over time in all age groups. Leuk Lymphoma 2014. [Epub ahead of print]
4. Kumar SK, Therneau TM, Gertz MA, et al. Clinical course of patients with relapsed multiple myeloma. Mayo Clin Proc 2004; 79(7):867-74
5. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia 2012;26(1): 149-57
6. Butler JS, Dent SY. The role of chromatin modifiers in normal and malignant hematopoiesis. Blood 2013;121(16):3076-84
7. Jiang Y, Hatzi K, Shaknovich R Mechanisms of epigenetic deregulation in lymphoid neoplasms. Blood 2013;121(21): 4271-9
8. Goodell MA, Godley LA. Perspectives and future directions for epigenetics in hematology. Blood 2013;121(26):5131-7
9. Zhu B, Reinberg D. Epigenetic inheritance: uncontested? Cell Res 2011;21(3):435-41
10. Timmermann S, Lehrmann H, Polesskaya A, et al. Histone acetylation and disease. Cellular and molecular life sciences: CMLS 2001;58(5-6):728-36
11. Marks P, Rifkind RA, Richon VM, et al. Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 2001;1(3): 194-202
12. Felsenfeld G. A brief history of epigenetics. Cold Spring Harb Perspect Biol 2014; 6(1):pii: a018200
13. Grunstein M. Histone acetylation in chromatin structure and transcription. Nature 1997;389(6649):349-52
14. New M, Olzscha H, La Thangue NB. HDAC inhibitor-based therapies: can we interpret the code? Mol Oncol 2012;6(6): 637-56
15. Hideshima T, Anderson KC. Histone deacetylase inhibitors in the treatment for multiple myeloma. Int J Hematol 2013; 97(3):324-32
16. Drummond DC, Noble CO, Kirpotin DB, et al. Clinical development of histone deacetylase inhibitors as anticancer agents. Annu Rev Pharmacol Toxicol 2005;45: 495-528
17. Cress WD, Seto E. Histone deacetylases, transcriptional control, and cancer. J Cell Physiol 2000;184(1):1-16
18. Mielcarek M, Landles C, Weiss A, et al. HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration. PLoS Biol 2013;11(11):e1001717
19. Pipalia NH, Cosner CC, Huang A, et al. Histone deacetylase inhibitor treatment dramatically reduces cholesterol accumulation in Niemann-Pick type C1 mutant human fibroblasts. Proc Natl Acad Sci USA 2011;108(14):5620-5
20. Markopoulou A, Kyttaris VC. Small molecules in the treatment of systemic lupus erythematosus. Clinical immunology 2013; 148(3):359-68
21. Meinke PT, Liberator P. Histone deacetylase: a target for antiproliferative and antiprotozoal agents. Curr Med Chem 2001;8(2):211-35
22. Jung M. Inhibitors of histone deacetylase as new anticancer agents. Curr Med Chem 2001;8(12): 1505-11
23. Miller TA, Witter DJ, Belvedere S. Histone deacetylase inhibitors. J Med Chem 2003; 46(24):5097-116
24. Norris KL, Lee JY, Yao TP. Acetylation goes global: the emergence of acetylation biology. Sci Signal 2009;2(97):pe76
25. Kavanaugh SM, White LA, Kolesar JM. Vorinostat: a novel therapy for the treatment of cutaneous T-cell lymphoma. Am J Health Syst Pharm 2010;67(10): 793-7
26. Coiffier B, Pro B, Prince HM, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol 2012;30(6): 631-6
27. Rajkumar SV. MGUS and smoldering multiple myeloma: update on pathogenesis, natural history, and management. Hematology Am Soc Hematol Educ Program 2005;340-5
28. Schmidt-Hieber M, Gutierrez ML, Perez-Andres M, et al. Cytogenetic profiles in multiple myeloma and monoclonal gammopathy of undetermined significance: a study in highly purified aberrant plasma cells. Haematologica 2013;98(2):279-87
29. Heller G, Schmidt WM, Ziegler B, et al. Genome-wide transcriptional response to 5-aza-2'-deoxycytidine and trichostatin a in multiple myeloma cells. Cancer Res 2008; 68(1):44-54
30. Gkotzamanidou M, Terpos E, Bamia C, et al. Progressive changes in chromatin structure and DNA damage response signals in bone marrow and peripheral blood during myelomagenesis. Leukemia 2014; 28(5):1113-21
31. Davies FE, Dring AM, Li C, et al. Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis. Blood 2003;102(13):4504-11
32. Richardson PG, Mitsiades CS, Laubach JP, et al. Preclinical data and early clinical experience supporting the use of histone deacetylase inhibitors in multiple myeloma. Leuk Res 2013;37(7):829-37
33. Maes K, Menu E, Van Valckenborgh E, et al. Epigenetic modulating agents as a new therapeutic approach in multiple myeloma. Cancers 2013;5(2):430-61
34. Martinez-Garcia E, Popovic R, Min DJ, 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(1):211-20
35. Todoerti K, Ronchetti D, Agnelli L, et al. Transcription repression activity is associated with the type I isoform of the MMSET gene involved in t(4;14) in multiple myeloma. Br J Haematol 2005;131(2): 214-18
36. Mitsiades N, Mitsiades CS, Richardson PG, et al. Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Blood 2003;101(10):4055-62
37. Lentzsch S, Ehrlich LA, Roodman GD. Pathophysiology of multiple myeloma bone disease. Hematol Oncol Clin North Am 2007;21(6):1035-49
38. Jin Z, Wei W, Dechow PC, et al. HDAC7 inhibits osteoclastogenesis by reversing RANKL-triggered beta-catenin switch. Mol Endocrinol 2013;27(2):325-35
39. Cantley MD, Fairlie DP, Bartold PM, et al. Inhibitors of histone deacetylases in class I and class II suppress human osteoclasts in vitro. J Cell Physiol 2011;226(12):3233-41
40. Kane RC, Farrell AT, Sridhara R, et al. United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy. Clin Cancer Res 2006;12(10):2955-60
41. Herndon TM, Deisseroth A, Kaminskas E, et al. U.S. Food and Drug Administration approval: carfilzomib for the treatment of multiple myeloma. Clin Cancer Res 2013; 19(17):4559-63
42. Khan RZ, Badros A. Role of carfilzomib in the treatment of multiple myeloma. Expert Rev Hematol 2012;5(4):361-72
43. Catley L, Weisberg E, Kiziltepe T, et al. Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood 2006;108(10): 3441-9
44. Pei XY, Dai Y, Grant S. Synergistic induction of oxidative injury and apoptosis in human multiple myeloma cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitors. Clin Cancer Res 2004;10(11):3839-52
45. Simms-Waldrip T, Rodriguez-Gonzalez A, Lin T, et al. The aggresome pathway as a target for therapy in hematologic malignancies. Mol Genet Metab 2008; 94(3):283-6
46. Hideshima T, Richardson PG, Anderson KC. Mechanism of action of proteasome inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple myeloma. Mol Cancer Ther 2011;10(11):2034-42
47. 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(4): 683-7
48. Cortes M, Georgopoulos K. Aiolos is required for the generation of high affinity bone marrow plasma cells responsible for long-term immunity. J Exp Med 2004; 199(2):209-19
49. Zhu YX, Braggio E, Shi CX, et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood 2011;118(18):4771-9
50. Lu G, Middleton RE, Sun H, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 2014;343(6168):305-9
51. Stewart AK. Medicine. How thalidomide works against cancer. Science 2014; 343(6168):256-7
52. Ocio EM, Vilanova D, Atadja P, et al. In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma. Haematologica 2010;95(5):794-803
53. Giles F, Fischer T, Cortes J, et al. A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clin Cancer Res 2006;12(15):4628-35
54. DeAngelo DJ, Spencer A, Bhalla KN, et al. Phase Ia/II, two-arm, open-label, dose-escalation study of oral panobinostat administered via two dosing schedules in patients with advanced hematologic malignancies. Leukemia 2013;27(8):1628-36
55. Clive S, Woo MM, Nydam T, et al. Characterizing the disposition, metabolism, and excretion of an orally active pan-deacetylase inhibitor, panobinostat, via trace radiolabeled 14C material in advanced cancer patients. Cancer Chemother Pharmacol 2012;70(4):513-22
56. Maiso P, Carvajal-Vergara X, Ocio EM, et al. The histone deacetylase inhibitor LBH589 is a potent antimyeloma agent that overcomes drug resistance. Cancer Res 2006;66(11):5781-9
57. Bishton MJ, Harrison SJ, Martin BP, et al. Deciphering the molecular and biologic processes that mediate histone deacetylase inhibitor-induced thrombocytopenia. Blood 2011;117(13):3658-68
58. San-Miguel JF, Richardson PG, Gunther A, et al. Phase Ib study of panobinostat and bortezomib in relapsed or relapsed and refractory multiple myeloma. J Clin Oncol 2013;31(29):3696-703
59. Berdeja J SM, Mace JR, Hart L, et al. A Single-Arm, Open-Label, Multi-Center Phase I/II Study Of The Combination Of Panobinostat and Carfilzomib In Patients (pts) With Relapsed Or Relapse/Refractory Multiple Myeloma (MM). Blood (ASH Annual Meeting Abstracts) 2013;122:21
60. M Mateos AS, Taylor K, Lonial S, et al. Phase Ib study of oral panobinostat (LBH589) plus lenalidomide (LEN) plus dexamethasone (DEX) in patients (Pts) with relapsed (Rel) or Rel and refractory (Ref) multiple myeloma (MM). J Clin Oncol 2010;28(15 Suppl):abstr 8030
61. Biran N, Shahnaz S, Jagannath S, et al. A Phase II, single-center, open-label study of oral panobinostat in combination with lenalidomide and weekly dexamethasone in patients with multiple myeloma. Blood 2013;122(21):5392
62. Wolf JL, Siegel D, Goldschmidt H, et al. Phase II trial of the pan-deacetylase inhibitor panobinostat as a single agent in advanced relapsed/refractory multiple myeloma. Leuk Lymphoma 2012;53(9): 1820-3
63. Richardson PG, Schlossman RL, Alsina M, et al. PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood 2013;122(14):2331-7
64. Berenson JR, Hilger JD, Yellin O, et al. A phase 1/2 study of oral panobinostat combined with melphalan for patients with relapsed or refractory multiple myeloma. Ann Hematol 2014;93(1):89-98
65. Offidani M, Polloni C, Cavallo F, et al. Phase II study of melphalan, thalidomide and prednisone combined with oral panobinostat in patients with relapsed/refractory multiple myeloma. Leuk Lymphoma 2012;53(9):1722-7
66. Palumbo A, Bringhen S, Caravita T, et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet 2006; 367(9513):825-31
67. Dimopoulos M, Siegel DS, Lonial S, et al. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. Lancet Oncol 2013;14(11):1129-40
68. Panorama 1: A randomized, double-blind, phase 3 study of panobinostat or placebo plus bortezomib and dexamethasone in relapsed or relapsed and refractory multiple myeloma. ASCO; Chicago, Illinois. J Clin Oncol 2014
69. San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 2014;15(11):1195-206
70. Siegel DS, Richardson P, Dimopoulos M, et al. Vorinostat in combination with lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. Blood Cancer J 2014;4:e202
71. West AC, Johnstone RW. New and emerging HDAC inhibitors for cancer treatment. J Clin Invest 2014;124(1):30-9
72. Santo L, Hideshima T, Kung AL, et al. Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood 2012;119(11):2579-89
73. Raje N VD, Bensinger W, Voorhees P, et al. Ricolinostat (ACY-1215), the First Selective Histone Decetylase 6 Inhibitor, is active and well tolerated in combination with lenalidomide or bortezomib in patients with refractory myeloma. In: European Haematology Association 2014
74. Shustov A. Novel therapies for peripheral T-cell lymphomas. Ther Adv Hematol 2013;4(3):173-87