Novel Targeted Agents in the Treatment of Multiple Myeloma

Hematology/Oncology Clinics of North America

Volumn 28, Issue 5, 2014, Pages 903-925

  Varga, Cindy ^a   Laubach, Jacob ^a   Hideshima, Teru ^a   Chauhan, Dharminder ^a   Anderson, Kenneth C ^a   Richardson, Paul G ^a  

^a HARVARD MEDICAL SCHOOL   (United States)

Author keywords

BET bromodomain inhibitors; Deubiquitinating enzyme inhibitors; Heat shock protein 90 inhibitors; Histone deacetylase inhibitors; Multiple myeloma; PIK3 Akt mTOR inhibitors; Second generation proteasome inhibitors; Wnt

Indexed keywords

AURORA KINASE INHIBITOR; BROMODOMAIN INHIBITOR; CARRIER PROTEIN; CHEMOKINE RECEPTOR CXCR4; CHROMOSOME REGION MAINTENANCE 1; CYCLIN DEPENDENT KINASE INHIBITOR; CYTOTOXIC AGENT; DARATUMUMAB; ELOTUZUMAB; HEAT SHOCK PROTEIN 90 INHIBITOR; HISTONE DEACETYLASE INHIBITOR; IMMUNOMODULATING AGENT; IXAZOMIB; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MELFLUFEN; MONOCLONAL ANTIBODY; NOTCH RECEPTOR; OPROZOMIB; PROTEASOME INHIBITOR; PROTEIN KINASE B INHIBITOR; RICOLINOSTAT; SALINOSPORAMIDE A; SILTUXIMAB; SONIC HEDGEHOG PROTEIN; UNCLASSIFIED DRUG; VORINOSTAT; WNT PROTEIN; ANTINEOPLASTIC AGENT; IMMUNOLOGIC FACTOR;

CANCER CHEMOTHERAPY; CANCER COMBINATION CHEMOTHERAPY; CANCER PATIENT; DRUG EFFICACY; DRUG TARGETING; HUMAN; HYPOXIA; MULTIPLE MYELOMA; REVIEW; TREATMENT OUTCOME; TUMOR MICROENVIRONMENT; BIOLOGICAL MODEL; DRUG EFFECTS; MOLECULARLY TARGETED THERAPY; PROCEDURES;

ANTIBODIES, MONOCLONAL; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; HUMANS; IMMUNOLOGIC FACTORS; MODELS, BIOLOGICAL; MOLECULAR TARGETED THERAPY; MULTIPLE MYELOMA; TREATMENT OUTCOME; TUMOR MICROENVIRONMENT;

EID: 84912521891     PISSN: 08898588     EISSN: 15581977     Source Type: Journal    
DOI: 10.1016/j.hoc.2014.07.001     Document Type: Review

References (128)

1. Kupperman E., Lee E.C., Cao Y., et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res 2010, 70(5):1970-1980.
2. Chauhan D., Tian Z., Zhou B., et al. Invitro and invivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells. Clin Cancer Res 2011, 17(16):5311-5321.
3. Gupta N., Saleh M., Venkatakrishnan K. Flat-dosing versus BSA-based dosing for MLN9708, an investigational proteasome inhibitor: population pharmacokinetic (PK) analysis of pooled data from 4 phase-1 studies. ASH Annual Meeting Abstracts 2011, 118(21):1433.
4. Kumar S., Bensinger W., Reeder C.B., et al. Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed/refractory multiple myeloma (MM): a phase I study. JClin Oncol 2012, 30(Suppl). [abstract: 8034].
5. Lonial S., Baz R.C., Wang M., et al. Phase I study of twice-weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple myeloma (MM). JClin Oncol 2012, 30(Suppl). [abstract: 8017].
6. Richardson P.G., Hofmeister C.C. Twice-weekly oral MLN9708 (Ixazomib Citrate), an investigational proteasome inhibitor, in combination with lenalidomide (Len) and dexamethasone (Dex) in patients (Pts) with newly diagnosed multiple myeloma (MM): final phase 1 results and phase 2 data. ASH Annual Meeting Abstracts 2013, 122(21). [abstract: 535].
7. Kuhn D.J., Chen Q., Voorhees P.M., et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood 2007, 110(9):3281-3290.
8. Demo S.D., Kirk C.J., Aujay M.A., et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res 2007, 67(13):6383-6391.
9. Chauhan D., Singh A.V., Aujay M., et al. Anovel orally active proteasome inhibitor ONX 0912 triggers invitro and invivo cytotoxicity in multiple myeloma. Blood 2010, 116(23):4906-4915.
10. Zhou J., Geng G., Shi Q., et al. Design and synthesis of androgen receptor antagonists with bulky side chains for overcoming antiandrogen resistance. JMed Chem 2009, 52(17):5546-5550.
11. US National Institute of Health. ClinicalTrial.gov. 2012. Available at:. Accessed July 31, 2012. http://clinicaltrials.gov/.
12. Papadopoulos K.P., Mendelson D.S., Tolcher A.W., et al. Aphase I, open-label, dose-escalation study of the novel oral proteasome inhibitor (PI) ONX 0912 in patients with advanced refractory or recurrent solid tumors. JClin Oncol 2011, 29(Suppl). [abstract: 3075].
13. Chauhan D., Tian Z., Nicholson B., et al. Asmall molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Canc Cell 2012, 22(3):345-358.
14. Chauhan D., Singh A., Brahmandam M., et al. Combination of proteasome inhibitors bortezomib and NPI-0052 trigger invivo synergistic cytotoxicity in multiple myeloma. Blood 2008, 111(3):1654-1664.
15. Chauhan D., Singh A.V., Ciccarelli B., et al. Combination of novel proteasome inhibitor NPI-0052 and lenalidomide trigger invitro and invivo synergistic cytotoxicity in multiple myeloma. Blood 2010, 115(4):834-845.
16. Richardson P.G., Spencer A., Cannell P., et al. Phase 1 clinical evaluation of twice-weekly marizomib (NPI-0052), a novel proteasome inhibitor, in patients with relapsed/refractory multiple myeloma (MM). ASH Annual Meeting Abstracts 2011, 118(21):302.
17. Jaenisch R., Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 2003, 33(Suppl):245-254.
18. Sterner D.E., Berger S.L. Acetylation of histones and transcription-related factors. Microbiol Mol Biol Rev 2000, 64(2):435-459.
19. de Ruijter A.J., van Gennip A.H., Caron H.N., et al. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 2003, 370(Pt 3):737-749.
20. Roth S.Y., Denu J.M., Allis C.D. Histone acetyltransferases. Annu Rev Biochem 2001, 70:81-120.
21. Bolden J.E., Peart M.J., Johnstone R.W. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 2006, 5(9):769-784.
22. Sasakawa Y., Naoe Y., Inoue T., et al. Effects of FK228, a novel histone deacetylase inhibitor, on tumor growth and expression of p21 and c-myc genes invivo. Cancer Lett 2003, 195(2):161-168.
23. Lin H.Y., Chen C.S., Lin S.P., et al. Targeting histone deacetylase in cancer therapy. Med Res Rev 2006, 26(4):397-413.
24. Marks P.A., Richon V.M., Rifkind R.A. Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. JNatl Cancer Inst 2000, 92(15):1210-1216.
25. Fandy T.E., Shankar S., Ross D.D., et al. Interactive effects of HDAC inhibitors and TRAIL on apoptosis are associated with changes in mitochondrial functions and expressions of cell cycle regulatory genes in multiple myeloma. Neoplasia 2005, 7(7):646-657.
26. Qian D.Z., Kato Y., Shabbeer S., et al. Targeting tumor angiogenesis with histone deacetylase inhibitors: the hydroxamic acid derivative LBH589. Clin Cancer Res 2006, 12(2):634-642.
27. Shao W, Growney JD, Feng Y, etal. Potent anticancer activity of the pan-deacetylase inhibitor panobinostat (LBH589) as a single agent in invitro and invivo tumor models. 99th American Association of Cancer Research Annual Meeting [abstract: 6244]. 2008.
28. Atadja P. Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Lett 2009, 280(2):233-241.
29. 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):3441-3449.
30. Ocio E.M., Vilanova D., Atadja P., et al. Invitro and invivo rationale for the triplecombination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma. Haematologica 2010, 95(5):794-803.
31. Wolf J.L., 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):1820-1823.
32. Hideshima T., Richardson P.G., Anderson K.C., et al. Intracellular protein degradation and its therapeutic implications. Clin Cancer Res 2005, 11(24 Pt 1):8530-8533.
33. San-Miguel J.F., Richardson P.G., Gunther A., et al. Phase Ib study of panobinostat and bortezomib in relapsed or relapsed and refractory multiple myeloma. JClin Oncol 2013, 31(29):3696-3703.
34. Richardson P.G., Schlossman R.L., 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):2331-2337.
35. Richardson P.G., Hofmeister C.C. 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. JClin Oncol 2014, 30(Suppl). [abstract: 8017].
36. Xu W.S., Parmigiani R.B., Marks P.A. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 2007, 26(37):5541-5552.
37. Mitsiades C.S., Mitsiades N.S., McMullan C.J., et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci USA 2004, 101(2):540-545.
38. Mitsiades N., Mitsiades C.S., Richardson P.G., et al. Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Blood 2003, 101(10):4055-4062.
39. Kaufman J.L., Shah J.J., Laubach J.P. Lenalidomide, bortezomib, and dexamethasone (RVD) in combination with vorinostat as front-line therapy for patients withmultiple myeloma (MM): results of a phase 1 study. ASH Annual Meeting Abstracts 2012, 120:336.
40. Siegel D.S., 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.
41. Dimopoulos M., Siegel D.S., Lonial S., et al. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. Lancet Oncol 2013, 14(11):1129-1140.
42. Hideshima T., Bradner J.E., Wong J., et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci USA 2005, 102(24):8567-8572.
43. McConkey D. Proteasome and HDAC: who's zooming who?. Blood 2010, 116(3):308-309.
44. Santo L., Hideshima T., Kung A.L., 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):2579-2589.
45. Raje N.S., Vogl D.T., Hari P.N., et al. ACY-1215, a selective histone deacetylase (HDAC) 6 inhibitor: interim results of combination therapy with bortezomib in patients with multiple myeloma (MM). ASH Annual Meeting Abstracts 2013, 122(21). [abstract: 3190].
46. Yee A.J., Vorhees P., Bensinger W.I., et al. ACY-1215, a selective histone deacetylase (HDAC) 6 inhibitor, in combination with lenalidomide and dexamethasone (dex), is well tolerated without dose limiting toxicity (DLT) in patients (Pts) with multiple myeloma (MM) at doses demonstrating biologic activity: interim results of a phase 1b Trial. ASH Annual Meeting Abstracts 2013, 122(21). [abstract: 3190].
47. Drysdale M.J., Brough P.A., Massey A., et al. Targeting Hsp90 for the treatment of cancer. Curr Opin Drug Discov Dev 2006, 9(4):483-495.
48. Richardson P.G., Chanan-Khan A.A., Lonial S., et al. Tanespimycin and bortezomib combination treatment in patients with relapsed or relapsed and refractory multiple myeloma: results of a phase 1/2 study. Br J Haematol 2011, 153(6):729-740.
49. Liu P., Cheng H., Roberts T.M., et al. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009, 8(8):627-644.
50. Hsu J., Shi Y., Krajewski S., et al. The AKT kinase is activated in multiple myeloma tumor cells. Blood 2001, 98(9):2853-2855.
51. Hideshima T., Catley L., Raje N., et al. Inhibition of Akt induces significant downregulation of survivin and cytotoxicity in human multiple myeloma cells. Br J Haematol 2007, 138(6):783-791.
52. Richardson P.G., Wolf J., Jakubowiak A., et al. Perifosine plus bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma previously treated with bortezomib: results of a multicenter phase I/II trial. JClin Oncol 2011, 29(32):4243-4249.
53. Mimura N., Hideshima T., Shimomura T., et al. Selective and potent Akt inhibition triggers anti-myeloma activities and enhances fatal endoplasmic reticulum stress induced by proteasome inhibition. Cancer Res 2014, [Epub ahead of print]. Accessed June 16, 2014.
54. Dang C.V., Le A., Gao P. MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res 2009, 15(21):6479-6483.
55. Delmore J.E., Issa G.C., Lemieux M.E., et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 2011, 146(6):904-917.
56. Glickman M.H., Ciechanover A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 2002, 82(2):373-428.
57. Schnell J.D., Hicke L. Non-traditional functions of ubiquitin and ubiquitin-binding proteins. JBiol Chem 2003, 278(38):35857-35860.
58. Reyes-Turcu F.E., Ventii K.H., Wilkinson K.D. Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annu Rev Biochem 2009, 78:363-397.
59. Menendez-Benito V., Verhoef L.G., Masucci M.G., et al. Endoplasmic reticulum stress compromises the ubiquitin-proteasome system. Hum Mol Genet 2005, 14(19):2787-2799.
60. Tian Z., D'Arcy P., Wang X., et al. Anovel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance. Blood 2014, 123(5):706-716.
61. Takebe N., Harris P.J., Warren R.Q., et al. Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nat Rev Clin Oncol 2011, 8(2):97-106.
62. Tian E., Zhan F., Walker R., et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. NEngl J Med 2003, 349(26):2483-2494.
63. Fulciniti M., Tassone P., Hideshima T., et al. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood 2009, 114(2):371-379.
64. Padmanabhan S., Beck J.T., Kelly K.R., et al. Aphase I/II study of BHQ880, a novel osteoblast activating, anti-dkk1 human monoclonal antibody, in relapsed and refractory multiple myeloma (MM) patients treated with zoledronic acid (Zol) and anti-myeloma therapy (MM Tx). Blood (ASH Annual Meeting Abstracts) 2009, 114(21):750.
65. Munshi N., Abonour R., Beck J.T., et al. Early evidence of anabolic bone activity of BHQ880, a fully human anti-DKK1 neutralizing antibody: results of a phase 2 study in previously untreated patients with smoldering multiple myeloma at risk for progression. Blood (ASH Annual Meeting Abstracts) 2012, 120(21):331.
66. Mirandola L., Comi P., Cobos E., et al. Notch-ing from T-cell to B-cell lymphoid malignancies. Cancer Lett 2011, 308(1):1-13.
67. Ramakrishnan V., Ansell S., Haug J., et al. MRK003, a gamma-secretase inhibitor exhibits promising invitro pre-clinical activity in multiple myeloma and non-Hodgkin's lymphoma. Leukemia 2012, 26(2):340-348.
68. Xu D., Hu J., De Bruyne E., et al. Dll1/notch activation contributes to bortezomib resistance by upregulating CYP1A1 in multiple myeloma. Biochem Biophys Res Commun 2012, 428(4):518-524.
69. Davies F.E., Dring A.M., Li C., et al. Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis. Blood 2003, 102(13):4504-4511.
70. Blotta S., Jakubikova J., Calimeri T., et al. Canonical and noncanonical Hedgehog pathway in the pathogenesis of multiple myeloma. Blood 2012, 120(25):5002-5013.
71. Kapoor T.M., Mayer T.U., Coughlin M.L., et al. Probing spindle assembly mechanisms with monastrol, a small molecule inhibitor of the mitotic kinesin, Eg5. JCell Biol 2000, 150(5):975-988.
72. Woessner R., Tunquist B.J., Cox A., et al. Combination of the KSP inhibitor ARRY-520 with bortezomib or revlimid causes sustained tumor regressions and significantly increased time to regrowth in models of multiple myeloma. ASH Annual Meeting Abstracts 2011 2009, 114:2858.
73. Tunquist B.J., Woessner R.D., Walker D.H. Mcl-1 stability determines mitotic cell fate of human multiple myeloma tumor cells treated with the kinesin spindle protein inhibitor ARRY-520. Mol Cancer Ther 2010, 9(7):2046-2056.
74. Shah J.J., Zonder J., Cohen A., et al. ARRY-520 shows durable responses in patients with relapsed/refractory multiple myeloma in a phase 1 dose-escalation study. ASH Annual Meeting Abstracts 2011 2011, 118:1860.
75. Shah J.J., Zonder J., Cohen A., et al. The novel KSP inhibitor ARRY-520 is active both with and without low-dose dexamethasone in patients with multiple myeloma refractory to bortezomib and lenalidomide: results from a phase 2 study. ASH Annual Meeting Abstracts 2012, 120(449).
76. Xu D., Grishin N.V., Chook Y.M. NESdb: a database of NES-containing CRM1 cargoes. Mol Biol Cell 2012, 23(18):3673-3676.
77. Turner J.G., Dawson J., Sullivan D.M. Nuclear export of proteins and drug resistance in cancer. Biochem Pharmacol 2012, 83(8):1021-1032.
78. Brodie K.M., Henderson B.R. Characterization of BRCA1 protein targeting, dynamics, and function at the centrosome: a role for the nuclear export signal, CRM1, and Aurora A kinase. JBiol Chem 2012, 287(10):7701-7716.
79. Yao Y., Dong Y., Lin F., et al. The expression of CRM1 is associated with prognosis in human osteosarcoma. Oncol Rep 2009, 21(1):229-235.
80. Huang W.Y., Yue L., Qiu W.S., et al. Prognostic value of CRM1 in pancreas cancer. Clin Invest Med 2009, 32(6):E315.
81. Tai Y.T., Landesman Y., Acharya C., et al. CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications. Leukemia 2014, 28(1):155-165.
82. Azab A.K., Hu J., Quang P., et al. Hypoxia promotes dissemination of multiple myeloma through acquisition of epithelial to mesenchymal transition-like features. Blood 2012, 119(24):5782-5794.
83. Hu J., Van Valckenborgh E., Xu D., et al. Synergistic induction of apoptosis in multiple myeloma cells by bortezomib and hypoxia-activated prodrug TH-302, invivo and invitro. Mol Cancer Ther 2013, 12(9):1763-1773.
84. de la Puente P., Muz B., Azab F., et al. Cell trafficking of endothelial progenitor cells in tumor progression. Clin Cancer Res 2013, 19(13):3360-3368.
85. Prince H.M., Honemann D., Spencer A., et al. Vascular endothelial growth factor inhibition is not an effective therapeutic strategy for relapsed or refractory multiple myeloma: a phase 2 study of pazopanib (GW786034). Blood 2009, 113(19):4819-4820.
86. Kovacs M.J., Reece D.E., Marcellus D., et al. Aphase II study of ZD6474 Zactima, a selective inhibitor of VEGFR and EGFR tyrosine kinase in patients with relapsed multiple myeloma-NCIC CTG IND.145. Invest New Drugs 2006, 24(6):529-535.
87. Alsayed Y., Ngo H., Runnels J., et al. Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma. Blood 2007, 109(7):2708-2717.
88. Azab A.K., Runnels J.M., Pitsillides C., et al. CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy. Blood 2009, 113(18):4341-4351.
89. Ghobrial I., Shain K., Hanlon C., et al. Phase I/II trial of plerixafor and bortezomib as a chemosensitization strategy in relapsed or relapsed/refractory multiple myeloma. ASH Annual Meeting Abstracts 2013, 120:336.
90. Barr A.R., Gergely F. Aurora-A: the maker and breaker of spindle poles. JCell Sci 2007, 120(Pt 17):2987-2996.
91. Fu J., Bian M., Jiang Q., et al. Roles of Aurora kinases in mitosis and tumorigenesis. Mol Canc Res 2007, 5(1):1-10.
92. Marumoto T., Honda S., Hara T., et al. Aurora-A kinase maintains the fidelity ofearly and late mitotic events in HeLa cells. JBiol Chem 2003, 278(51):51786-51795.
93. Evans R., Naber C., Steffler T., et al. Aurora A kinase RNAi and small molecule inhibition of Aurora kinases with VE-465 induce apoptotic death in multiple myeloma cells. Leuk Lymphoma 2008, 49(3):559-569.
94. Dutta-Simmons J., Zhang Y., Gorgun G., et al. Aurora kinase A is a target of Wnt/beta-catenin involved in multiple myeloma disease progression. Blood 2009, 114(13):2699-2708.
95. Gorgun G., Calabrese E., Hideshima T., et al. Anovel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma. Blood 2010, 115(25):5202-5213.
96. Greipp P.R., Witzig T.E., Gonchoroff N.J., et al. Immunofluorescence labeling indices in myeloma and related monoclonal gammopathies. Mayo Clin Proc 1987, 62(11):969-977.
97. Sherr C.J., Roberts J.M. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999, 13(12):1501-1512.
98. Ely S., Di Liberto M., Niesvizky R., et al. Mutually exclusive cyclin-dependent kinase 4/cyclin D1 and cyclin-dependent kinase 6/cyclin D2 pairing inactivates retinoblastoma protein and promotes cell cycle dysregulation in multiple myeloma. Cancer Res 2005, 65(24):11345-11353.
99. Baughn L.B., Di Liberto M., Wu K., et al. Anovel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6. Cancer Res 2006, 66(15):7661-7667.
100. Raje N., Kumar S., Hideshima T., et al. Seliciclib (CYC202 or R-roscovitine), a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of Mcl-1 in multiple myeloma. Blood 2005, 106(3):1042-1047.
101. Kumaresan P.R., Lai W.C., Chuang S.S., et al. CS1, a novel member of the CD2 family, is homophilic and regulates NK cell function. Mol Immunol 2002, 39(1-2):1-8.
102. Hsi E.D., Steinle R., Balasa B., et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res 2008, 14(9):2775-2784.
103. Tai Y.T., Dillon M., Song W., et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood 2008, 112(4):1329-1337.
104. Rice AG, Balasa B, Yun R, etal. Natural killer cell activation, cytokine production, and cytotoxicity in human PBMC/myeloma cell co-cultures exposed to elotuzumab alone or in combination with lenalidomide. 17th Congress of the European Hematology Association. 2013.
105. van Rhee F., Szmania S.M., Dillon M., et al. Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma. Mol Cancer Ther 2009, 8(9):2616-2624.
106. Richardson P., Jagannath S., Moreau P., et al. Aphase 2 study of elotuzumab (Elo) in combination with lenalidomide and low-dose dexamethasone (Ld) in patients (pts) with relapsed/refractory multiple myeloma (R/R MM): updated results. Blood (ASH Annual Meeting Abstracts) 2012, 120(21):202.
107. Malavasi F., Funaro A., Roggero S., et al. Human CD38: a glycoprotein in search of a function. Immunol Today 1994, 15(3):95-97.
108. Mehta K., Malavasi F. Human CD38 and related molecules 2000, Karger, Switzerland.
109. Lin P., Owens R., Tricot G., et al. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. Am J Clin Pathol 2004, 121(4):482-488.
110. de Weers M., Tai Y.T., van der Veer M.S., et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. JImmunol 2011, 186(3):1840-1848.
111. van der Veer M.S., de Weers M., van Kessel B., et al. Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. Haematologica 2011, 96(2):284-290.
112. Plesner T., Lokhorst H., Gimsing P., et al. Daratumumab, a CD38 monoclonal antibody in patients with multiple myeloma - data from a dose-escalation phase I/II study. Blood (ASH Annual Meeting Abstracts) 2012, 120(21):73.
113. Plesner T., Lokhorst H., Gimsing P., et al. Daratumumab, a CD38 mab, for the treatment of relapsed/refractory multiple myeloma patients: preliminary efficacy data from a multicenter phase I/II study. ASCO Meeting Abstr 2012, 30(Suppl 15):8019.
114. Lokhorst H.M., Plesner T., Gimsing P., et al. Phase I/II dose-escalation study of daratumumab in patients with relapsed or refractory multiple myeloma. ASCO Meeting Abstr 2013, 31(Suppl):8512.
115. Plesner T., Arkenau T., Lokhorst H., et al. Preliminary safety and efficacy data of daratumumab in combination with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma. ASH Annual Meeting Abstracts 2013, 122(21). [abstract:1986].
116. Martin T.G., Strickland S.A., Glenn M., et al. SAR650984, a CD38 monoclonal antibody in patients with selected CD38+ hematological malignancies- data from a dose-escalation phase i study. ASH Annual Meeting Abstracts 2013, 122(21). [abstract: 1986].
117. Klein B., Zhang X.G., Jourdan M., et al. Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6. Blood 1989, 73(2):517-526.
118. Voorhees P.M., Chen Q., Kuhn D.J., et al. Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in preclinical models of multiple myeloma. Clin Cancer Res 2007, 13(21):6469-6478.
119. Voorhees P.M., Chen Q., Small G.W., et al. Targeted inhibition of interleukin-6 withCNTO 328 sensitizes pre-clinical models of multiple myeloma to dexamethasone-mediated cell death. Br J Haematol 2009, 145(4):481-490.
120. van Zaanen H.C., Lokhorst H.M., Aarden L.A., et al. Chimaeric anti-interleukin 6 monoclonal antibodies in the treatment of advanced multiple myeloma: a phase I dose-escalating study. Br J Haematol 1998, 102(3):783-790.
121. Voorhees P.M., Manges R.F., Sonneveld P., et al. Aphase 2 multicentre study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with relapsed or refractory multiple myeloma. Br J Haematol 2013, 161(3):357-366.
122. San Miguel J., Bladé J., Samoilova O.S., et al. Randomized, open label, phase 2 study of siltuximab (an anti-IL6 mab) and bortezomib-melphalan-prednisone versus bortezomib-melphalan-prednisone in patients with previously untreated multiple myeloma. EHA Abstracts 2013, 98(Suppl l):97.
123. Gullbo J., Wallinder C., Tullberg M., et al. Antitumor activity of the novel melphalan containing tripeptide J3 (L-prolyl-L-melphalanyl-p-L-fluorophenylalanine ethyl ester): comparison with its m-L-sarcolysin analogue P2. Mol Cancer Ther 2003, 2(12):1331-1339.
124. Gullbo J., Lindhagen E., Bashir-Hassan S., et al. Antitumor efficacy and acute toxicity of the novel dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) invivo. Invest New Drugs 2004, 22(4):411-420.
125. Wickstrom M., Johnsen J.I., Ponthan F., et al. The novel melphalan prodrug J1 inhibits neuroblastoma growth invitro and invivo. Mol Cancer Ther 2007, 6(9):2409-2417.
126. Chauhan D., Ray A., Viktorsson K., et al. Invitro and invivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells. Clin Cancer Res 2013, 19(11):3019-3031.
127. Chauhan D., Catley L., Li G., et al. Anovel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell 2005, 8(5):407-419.
128. Hideshima T., Richardson P., Chauhan D., et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 2001, 61(7):3071-3076.