title: Experimental approaches in the treatment of multiple myeloma.
abstract: Myeloma therapy has undergone significant advances in recent years resulting in a marked improvement in survival. Knowledge of the active pathways involved in myeloma pathogenesis has led to the discovery of novel agents and greatly expanded the potential armamentarium available for treatment. This better understanding of the disease and resistance mechanisms has resulted in new agent classes that are being evaluated in preclinical and early clinical studies. In addition, dosing for existing agents is being optimized, and they are being given in new combinations. In this article, we review experimental agents that are showing promise in multiple myeloma treatment. New biological agents in clinical trials hold the promise of efficacy through novel mechanisms of action, with a significant reduction of dose-limiting toxicities compared with classic cytotoxic chemotherapeutics. Second-generation proteasome inhibitors and immunomodulatory agents are furthest along in clinical development, and histone deacetylase inhibitors, heat shock protein 90 inhibitors, Akt inhibitors and monoclonal antibodies are some of the other agents entering later-phase clinical trials. We also review developments in targeting the myeloma stem cell as an exciting new treatment direction.
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Saad A
authors.initials: SA
authors.lastname: Khan
authors.forename: Adam D
authors.initials: AD
authors.lastname: Cohen
keywords: immunomodulatory agent; myeloma; novel therapies; proteasome inhibitor
references.citation: Chem Pharm Bull (Tokyo). 2004 Jan;52(1):1-26
references.pmid: 14709862
references.citation: Br J Haematol. 2011 Feb;152(4):367-79
references.pmid: 21219297
references.citation: Br J Haematol. 2005 Jun;129(6):776-83
references.pmid: 15953004
references.citation: Clin Cancer Res. 2008 May 1;14(9):2775-84
references.pmid: 18451245
references.citation: Cancer Res. 2006 Apr 15;66(8):4426-33
references.pmid: 16618769
references.citation: Exp Hematol. 2010 Feb;38(2):124-31
references.pmid: 19948206
references.citation: Blood. 2009 May 7;113(19):4667-76
references.pmid: 19050304
references.citation: Eur J Haematol. 2010 Mar;84(3):201-11
references.pmid: 19929977
references.citation: Blood. 2003 May 15;101(10):4055-62
references.pmid: 12531799
references.citation: Clin Cancer Res. 2010 May 15;16(10):2792-802
references.pmid: 20406843
references.citation: Future Oncol. 2007 Dec;3(6):639-47
references.pmid: 18041916
references.citation: Mol Cancer Ther. 2010 Oct;9(10):2689-99
references.pmid: 20937594
references.citation: Blood. 2007 May 1;109(9):3915-21
references.pmid: 17213289
references.citation: Invest New Drugs. 2012 Apr;30(2):480-9
references.pmid: 21080211
references.citation: Cancer Cell. 2005 Nov;8(5):407-19
references.pmid: 16286248
references.citation: Blood. 2008 Mar 1;111(5):2516-20
references.pmid: 17975015
references.citation: Cancer Lett. 2009 May 8;277(1):1-7
references.pmid: 18809245
references.citation: J Clin Oncol. 2004 Aug 15;22(16):3269-76
references.pmid: 15249589
references.citation: N Engl J Med. 2003 Jun 26;348(26):2609-17
references.pmid: 12826635
references.citation: Blood. 2010 Dec 2;116(23):4745-53
references.pmid: 20807892
references.citation: Cancer Res. 2008 Jul 15;68(14):5519-23
references.pmid: 18632601
references.citation: Cancer Res. 2007 Jul 1;67(13):6383-91
references.pmid: 17616698
references.citation: Haematologica. 2010 May;95(5):845-8
references.pmid: 20133895
references.citation: Leuk Lymphoma. 2008 Mar;49(3):502-7
references.pmid: 18297527
references.citation: Clin Lymphoma Myeloma Leuk. 2010 Apr;10(2):149-51
references.pmid: 20371450
references.citation: N Engl J Med. 2005 Jun 16;352(24):2487-98
references.pmid: 15958804
references.citation: Blood. 2010 Oct 28;116(17):3227-37
references.pmid: 20651070
references.citation: Clin Cancer Res. 2009 Aug 15;15(16):5250-7
references.pmid: 19671864
references.citation: Cancer Res. 2008 Jan 1;68(1):190-7
references.pmid: 18172311
references.citation: N Engl J Med. 2008 Aug 28;359(9):906-17
references.pmid: 18753647
references.citation: Blood. 2010 Aug 5;116(5):679-86
references.pmid: 20385792
references.citation: Blood. 2006 Nov 15;108(10):3441-9
references.pmid: 16728695
references.citation: J Clin Oncol. 2012 Jun 1;30(16):1953-9
references.pmid: 22547589
references.citation: Curr Opin Drug Discov Devel. 2008 Sep;11(5):616-25
references.pmid: 18729013
references.citation: Br J Haematol. 2008 May;141(4):470-82
references.pmid: 18341634
references.citation: Clin Cancer Res. 2004 Jun 1;10(11):3839-52
references.pmid: 15173093
references.citation: Blood. 2006 Feb 1;107(3):1092-100
references.pmid: 16234364
references.citation: J Mol Med (Berl). 2009 Nov;87(11):1079-85
references.pmid: 19760278
references.citation: Clin Cancer Res. 2010 Jun 15;16(12):3260-9
references.pmid: 20530693
references.citation: Clin Cancer Res. 2007 Oct 1;13(19):5903-9
references.pmid: 17908986
references.citation: Blood. 2009 May 7;113(19):4614-26
references.pmid: 19228610
references.citation: Clin Cancer Res. 2007 Nov 1;13(21):6469-78
references.pmid: 17975159
references.citation: Br J Haematol. 1998 Aug;102(3):783-90
references.pmid: 9722307
references.citation: J Clin Oncol. 2006 Jul 1;24(19):3113-20
references.pmid: 16754936
references.citation: Blood. 2008 Mar 1;111(5):2765-75
references.pmid: 18057228
references.citation: Nat Rev Drug Discov. 2009 Jan;8(1):33-40
references.pmid: 19116625
references.citation: Br J Haematol. 2003 May;121(4):592-6
references.pmid: 12752100
references.citation: Blood. 2006 May 15;107(10):4053-62
references.pmid: 16418332
references.citation: Int J Hematol. 2010 Mar;91(2):267-75
references.pmid: 20049565
references.citation: Leukemia. 2008 Aug;22(8):1604-12
references.pmid: 18480838
references.citation: Leukemia. 2010 Nov;24(11):1934-9
references.pmid: 20827286
references.citation: Blood. 2011 Sep 15;118(11):2970-5
references.pmid: 21690557
references.citation: Mol Cancer Ther. 2009 Dec;8(12):3341-9
references.pmid: 19996272
references.citation: Cancer Res. 2006 Jul 1;66(13):6675-82
references.pmid: 16818641
references.citation: Blood. 2010 Apr 22;115(16):3416-7
references.pmid: 20413666
references.citation: Blood. 2010 Dec 2;116(23):4906-15
references.pmid: 20805366
references.citation: Cancer Res. 2006 Aug 1;66(15):7661-7
references.pmid: 16885367
references.citation: J Clin Oncol. 2009 Oct 20;27(30):5008-14
references.pmid: 19720894
references.citation: Cancer Res. 2010 Mar 1;70(5):1970-80
references.pmid: 20160034
references.citation: Mol Cancer Ther. 2010 Jul;9(7):2046-56
references.pmid: 20571074
references.citation: Blood. 2003 Aug 1;102(3):1070-1
references.pmid: 12702507
references.citation: CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300
references.pmid: 20610543
references.citation: Cancer. 2011 Jan 15;117(2):336-42
references.pmid: 20862746
references.citation: Br J Haematol. 2007 Sep;138(6):783-91
references.pmid: 17760810
references.citation: Blood. 2009 Apr 30;113(18):4331-40
references.pmid: 19171872
references.citation: Haematologica. 2005 May;90(5):706-7
references.pmid: 15921396
references.citation: Blood. 2006 Apr 15;107(8):3098-105
references.pmid: 16373662
references.citation: Blood. 2005 Jul 1;106(1):296-303
references.pmid: 15755896
references.citation: N Engl J Med. 1999 Nov 18;341(21):1565-71
references.pmid: 10564685
references.citation: Blood. 2007 Nov 1;110(9):3281-90
references.pmid: 17591945
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4048-53
references.pmid: 17360475
references.citation: J Clin Oncol. 2005 Jan 20;23(3):630-9
references.pmid: 15659509
references.citation: Cancer Res. 2006 Apr 1;66(7):3773-81
references.pmid: 16585204
references.citation: Blood. 2010 Nov 11;116(19):3743-50
references.pmid: 20628153
references.citation: Br J Haematol. 2009 May;145(4):481-90
references.pmid: 19344406
references.citation: Br J Haematol. 2013 Nov;163(4):478-86
references.pmid: 24112026
references.citation: Br J Haematol. 2008 Apr;141(2):135-48
references.pmid: 18318769
references.citation: Blood. 1994 Oct 15;84(8):2597-603
references.pmid: 7522634
references.citation: J Immunother. 2002 Jan-Feb;25(1):72-81
references.pmid: 11924912
references.citation: J Immunol. 2005 Nov 1;175(9):6163-8
references.pmid: 16237113
references.citation: Cancer Res. 2005 Dec 15;65(24):11712-20
references.pmid: 16357183
references.citation: Clin Cancer Res. 2009 Nov 15;15(22):7085-91
references.pmid: 19903785
references.citation: Cancer Res. 2008 Jul 1;68(13):5216-25
references.pmid: 18593922
references.citation: Cancer Cell. 2003 Mar;3(3):213-7
references.pmid: 12676580
references.citation: Cancer Res. 2004 Jul 1;64(13):4629-36
references.pmid: 15231675
references.citation: Blood. 2010 Oct 21;116(16):3004-12
references.pmid: 20616215
references.citation: Nat Rev Cancer. 2004 May;4(5):349-60
references.pmid: 15122206
references.citation: Cell Stress Chaperones. 1996 Jun;1(2):97-8
references.pmid: 9222594
references.citation: Br J Haematol. 2006 Feb;132(4):385-97
references.pmid: 16412014
references.citation: Cancer Res. 2009 Jul 15;69(14):5835-42
references.pmid: 19584292
references.citation: Blood. 2000 Nov 1;96(9):2943-50
references.pmid: 11049970