New insights, recent advances, and current challenges in the biological treatment of multiple myeloma

Expert Opinion on Biological Therapy

Volumn 13, Issue SUPPL.1, 2013, Pages

  Vallet, Sonia ^a   Podar, Klaus ^a  

^a UNIVERSITY OF HEIDELBERG   (Germany)

Author keywords

Bone marrow milieu; Carfilzomib; Genetic alterations; Multiple myeloma; Pomalidomide

Indexed keywords

BORTEZOMIB; CARFILZOMIB; CYCLIN D1; CYCLIN D3; CYCLOPHOSPHAMIDE; DARATUMUMAB; DELANZOMIB; DEXAMETHASONE; ELOTUZUMAB; FIBROBLAST GROWTH FACTOR RECEPTOR 3; IXAZOMIB; LENALIDOMIDE; OPROZOMIB; PANOBINOSTAT; PERIFOSINE; POMALIDOMIDE; THALIDOMIDE; VEMURAFENIB; VORINOSTAT;

BIOLOGICAL THERAPY; CANCER CHEMOTHERAPY; CARCINOGENESIS; CLINICAL ASSESSMENT; HUMAN; MULTIPLE CYCLE TREATMENT; MULTIPLE MYELOMA; NONHUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); REVIEW; RISK ASSESSMENT; SYSTEMATIC REVIEW; TUMOR MICROENVIRONMENT;

ANIMALS; ANTINEOPLASTIC AGENTS; HUMANS; MOLECULAR TARGETED THERAPY; MULTIPLE MYELOMA;

EID: 84879571938     PISSN: 14712598     EISSN: None     Source Type: Journal    
DOI: 10.1517/14712598.2013.807337     Document Type: Review

References (169)

1. Anderson KC, Alsina M, Bensinger W, et al. Multiple myeloma, version 1.2013. J Natl Compr Canc Netw 2013;11:11-17
2. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008;111:2516-20
3. Anderson KC. New insights into therapeutic targets in myeloma. Hematology Am Soc Hematol Educ Program 2011;2011:184-90
4. Lonial S, Vij R, Harousseau JL, et al. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol 2012;30:1953-9
5. Gonzalez D, van der Burg M, Garcia-Sanz R, et al. Immunoglobulin gene rearrangements and the pathogenesis of multiple myeloma. Blood 2007;110:3112-21
6. Fonseca R, Bailey RJ, Ahmann GJ, et al. Genomic abnormalities in monoclonal gammopathy of undetermined significance. Blood 2002;100:1417-24
7. Kaufmann H, Ackermann J, Baldia C, et al. Both IGH translocations and chromosome 13q deletions are early events in monoclonal gammopathy of undetermined significance and do not evolve during transition to multiple myeloma. Leukemia 2004;18:1879-82
8. Rasmussen T, Kuehl M, Lodahl M, et al. Possible roles for activating RAS mutations in the MGUS to MM transition and in the intramedullary to extramedullary transition in some plasma cell tumors. Blood 2005;105:317-23
9. Avet-Loiseau H, Gerson F, Magrangeas F, et al. Rearrangements of the c-myc oncogene are present in 15% of primary human multiple myeloma tumors. Blood 2001;98:3082-6
10. Chiecchio L, Dagrada GP, Protheroe RK, et al. Loss of 1p and rearrangement of MYC are associated with progression of smouldering myeloma to myeloma: sequential analysis of a single case. Haematologica 2009;94:1024-8
11. Munshi NC, Anderson KC, Bergsagel PL, et al. Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. Blood 2011;117:4696-700
12. Avet-Loiseau H, Leleu X, Roussel M, et al. Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol 2010;28:4630-4
13. Klein U, Jauch A, Hielscher T, et al. Chromosomal aberrations +1q21 and del (17p13) predict survival in patients with recurrent multiple myeloma treated with lenalidomide and dexamethasone. Cancer 2011;117:2136-44
14. Boyd KD, Ross FM, Chiecchio L, et al. A novel prognostic model in myeloma based on co-segregating adverse FISH lesions and the ISS: analysis of patients treated in the MRC Myeloma IX trial. Leukemia 2012;26:349-55
15. Kumar S, Flinn I, Richardson PG, et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood 2012;119:4375-82
16. Ludwig H, Viterbo L, Greil R, et al. Randomized phase II study of bortezomib, thalidomide, and dexamethasone with or without cyclophosphamide as induction therapy in previously untreated multiple myeloma. J Clin Oncol 2013;31:247-55
17. Roussel M, Moreau P, Huynh A, et al. Bortezomib and high-dose melphalan as conditioning regimen before autologous stem cell transplantation in patients with de novo multiple myeloma: a phase 2 study of the Intergroupe Francophone du Myelome (IFM). Blood 2010;115:32-7
18. Nishihori T, Alekshun TJ, Shain K, et al. Bortezomib salvage followed by a phase I/II study of bortezomib plus high-dose melphalan and tandem autologous transplantation for patients with primary resistant myeloma. Br J Haematol 2012;157:553-63
19. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366:1782-91
20. Mateos MV, Oriol A, Martinez-Lopez J, et al. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood 2012;120:2581-8
21. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol 2012;30:2946-55
22. Kaufman J, Nooka A, Muppidi S, et al. Survival outcomes of early autologous stem cell transplant (ASCT) followed by lenalidomide, bortezomib, and dexamethasone (RVD) maintenance in patients with high-risk multiple myeloma (MM). J Clin Oncol 2012;30:abstract 8100
23. Corso A, Galli M, Mangiacavalli S, et al. Response-adjusted ISS (RaISS) is a simple and reliable prognostic scoring system for predicting progression-free survival in transplanted patients with multiple myeloma. Am J Hematol 2012;87:150-4
24. Decaux O, Lode L, Magrangeas F, et al. Prediction of survival in multiple myeloma based on gene expression profiles reveals cell cycle and chromosomal instability signatures in high-risk patients and hyperdiploid signatures in low-risk patients: a study of the Intergroupe Francophone du Myelome. J Clin Oncol 2008;26:4798-805
25. Shaughnessy JD Jr, Zhan F, Burington BE, et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood 2007;109:2276-84
26. Kuiper R, Broyl A, de Knegt Y, et al. A gene expression signature for high-risk multiple myeloma. Leukemia 2012;26:2406-13
27. Mulligan G, Mitsiades C, Bryant B, et al. Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib. Blood 2007;109:3177-88
28. Kumar SK, Uno H, Jacobus SJ, et al. Impact of gene expression profiling-based risk stratification in patients with myeloma receiving initial therapy with lenalidomide and dexamethasone. Blood 2011;118:4359-62
29. Morgan GJ, Kaiser MF. How to use new biology to guide therapy in multiple myeloma. Hematology Am Soc Hematol Educ Program 2012;2012:342-9
30. Chapman MA, Lawrence MS, Keats JJ, et al. Initial genome sequencing and analysis of multiple myeloma. Nature 2011;471:467-72
31. Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 2011;146:904-17
32. Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci USA 2004;101:540-5
33. 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;117:211-20
34. Hideshima T, Bradner JE, 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;102:8567-72
35. 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;119:2579-89
36. 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; [Epub ahead of print]
37. Rajan P, Elliott DJ, Robson CN, Leung HY. Alternative splicing and biological heterogeneity in prostate cancer. Nat Rev Urol 2009;6:454-60
38. Munshi N, Li C, Minvielle S, et al. Alternate splicing is a frequent event and impacts clinical outcome in myeloma: a high-density exon array analysis of uniformly treated newly-diagnosed myeloma patients. Blood 2008;112:abstract 498
39. Egan JB, Shi CX, Tembe W, et al. Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. Blood 2012;120:1060-6
40. Keats JJ, Chesi M, Egan JB, et al. Clonal competition with alternating dominance in multiple myeloma. Blood 2012;120:1067-76
41. Magrangeas F, Avet-Loiseau H, Gouraud W, et al. Minor clone provides a reservoir for relapse in multiple myeloma. Leukemia 2012;27(2):473-81
42. Schmitz R, Young RM, Ceribelli M, et al. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature 2012;490:116-20
43. Yu M, Ting DT, Stott SL, et al. RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis. Nature 2012;487:510-13
44. Gupta D, Treon SP, Shima Y, et al. Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia 2001;15:1950-61
45. Abe M, Hiura K, Wilde J, et al. Osteoclasts enhance myeloma cell growth and survival via cell-cell contact: a vicious cycle between bone destruction and myeloma expansion. Blood 2004;104:2484-91
46. Podar K, Anderson KC. The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications. Blood 2005;105:1383-95
47. Bruns I, Cadeddu RP, Brueckmann I, et al. Multiple myeloma-related deregulation of bone marrow-derived CD34(+) hematopoietic stem and progenitor cells. Blood 2012;120:2620-30
48. Pene F, Claessens YE, Muller O, et al. Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma. Oncogene 2002;21:6587-97
49. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med 2011;364:1046-60
50. 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. N Engl J Med 2003;349:2483-94
51. Roodman GD. Treatment strategies for bone disease. Bone Marrow Transplant 2007;40:1139-46
52. Kong YY, Yoshida H, Sarosi I, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 1999;397:315-23
53. Enomoto H, Shiojiri S, Hoshi K, et al. Induction of osteoclast differentiation by Runx2 through receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin regulation and partial rescue of osteoclastogenesis in Runx2-/-mice by RANKL transgene. J Biol Chem 2003;278:23971-7
54. Sezer O, Heider U, Zavrski I, et al. RANK ligand and osteoprotegerin in myeloma bone disease. Blood 2003;101:2094-8
55. Lee JW, Chung HY, Ehrlich LA, et al. IL-3 expression by myeloma cells increases both osteoclast formation and growth of myeloma cells. Blood 2004;103:2308-15
56. Ehrlich LA, Chung HY, Ghobrial I, et al. IL-3 is a potential inhibitor of osteoblast differentiation in multiple myeloma. Blood 2005;106:1407-14
57. Choi SJ, Oba Y, Gazitt Y, et al. Antisense inhibition of macrophage inflammatory protein 1-alpha blocks bone destruction in a model of myeloma bone disease. J Clin Invest 2001;108:1833-41
58. Masih-Khan E, Trudel S, Heise C, et al. MIP-1alpha (CCL3) is a downstream target of FGFR3 and RAS-MAPK signaling in multiple myeloma. Blood 2006;108:3465-71
59. Vallet S, Raje N, Ishitsuka K, et al. MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts. Blood 2007;110:3744-52
60. Vallet S, Pozzi S, Patel K, et al. A novel role for CCL3 (MIP-1alpha) in myeloma-induced bone disease via osteocalcin downregulation and inhibition of osteoblast function. Leukemia 2011;25:1174-81
61. D'Souza S, Kurihara N, Shiozawa Y, et al. Annexin II interactions with the annexin II receptor enhance multiple myeloma cell adhesion and growth in the bone marrow microenvironment. Blood 2012;119:1888-96
62. Vallet S, Smith MR, Raje N. Novel bone-targeted strategies in oncology. Clin Cancer Res 2010;16:4084-93
63. 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;61:3071-6
64. Davies FE, Raje N, Hideshima T, et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 2001;98:210-16
65. Lee AH, Iwakoshi NN, Anderson KC, Glimcher LH. Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc Natl Acad Sci USA 2003;100:9946-51
66. Roccaro AM, Hideshima T, Raje N, et al. Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells. Cancer Res 2006;66:184-91
67. Munemasa S, Sakai A, Kuroda Y, et al. Osteoprogenitor differentiation is not affected by immunomodulatory thalidomide analogs but is promoted by low bortezomib concentration, while both agents suppress osteoclast differentiation. Int J Oncol 2008;33:129-36
68. Breitkreutz I, Raab MS, Vallet S, et al. Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma. Leukemia 2008;22:1925-32
69. Gorgun G, Calabrese E, Soydan E, et al. Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma. Blood 2010;116:3227-37
70. De Luisi A, Ferrucci A, Coluccia AM, et al. Lenalidomide restrains motility and overangiogenic potential of bone marrow endothelial cells in patients with active multiple myeloma. Clin Cancer Res 2011;17:1935-46
71. Bolzoni M, Storti P, Bonomini S, et al. Immunomodulatory drugs lenalidomide and pomalidomide inhibit multiple myeloma-induced osteoclast formation and the RANKL/OPG ratio in the myeloma microenvironment targeting the expression of adhesion molecules. Exp Hematol 2012
72. Zhu YX, Braggio E, Shi CX, et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood 2011;118:4771-9
73. Lopez-Girona A, Mendy D, Ito T, et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia 2012;26:2326-35
74. Heintel D, Rocci A, Ludwig H, et al. High expression of cereblon (CRBN) is associated with improved clinical response in patients with multiple myeloma treated with lenalidomide and dexamethasone. Br J Haematol 2013;161(5):695-700
75. Broyl A, Kuiper R, van Duin M, et al. High cereblon expression is associated with better survival in patients with newly diagnosed multiple myeloma treated with thalidomide maintenance. Blood 2013;121:624-7
76. Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity. Science 2010;327:1345-50
77. Ling SC, Lau EK, Al-Shabeeb A, et al. Response of myeloma to the proteasome inhibitor bortezomib is correlated with the unfolded protein response regulator XBP-1. Haematologica 2012;97:64-72
78. McMillin DW, Delmore J, Weisberg E, et al. Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity. Nat Med 2010;16:483-9
79. McMillin DW, Delmore J, Negri JM, et al. Compartment-Specific Bioluminescence Imaging platform for the high-throughput evaluation of antitumor immune function. Blood 2012;119:e131-8
80. Chattopadhyay S, Stewart AL, Mukherjee S, et al. Niche-based screening identifies novel small molecules that overcome stromal effects in multiple myeloma. Blood 2012;120:abstract 571
81. Asosingh K, Radl J, Van Riet I, et al. The 5TMM series: a useful in vivo mouse model of human multiple myeloma. Hematol J 2000;1:351-6
82. Carrasco DR, Sukhdeo K, Protopopova M, et al. The differentiation and stress response factor XBP-1 drives multiple myeloma pathogenesis. Cancer cell 2007;11:349-60
83. Chesi M, Matthews GM, Garbitt VM, et al. Drug response in a genetically engineered mouse model of multiple myeloma is predictive of clinical efficacy. Blood 2012;120:376-85
84. Yaccoby S, Johnson CL, Mahaffey SC, et al. Antimyeloma efficacy of thalidomide in the SCID-hu model. Blood 2002;100:4162-8
85. Mitsiades CS, Mitsiades NS, Bronson RT, et al. Fluorescence imaging of multiple myeloma cells in a clinically relevant SCID/NOD in vivo model: biologic and clinical implications. Cancer Res 2003;63:6689-96
86. Calimeri T, Battista E, Conforti F, et al. A unique three-dimensional SCID-polymeric scaffold (SCID-synth-hu) model for in vivo expansion of human primary multiple myeloma cells. Leukemia 2011;25:707-11
87. Croucher PI, De Hendrik R, Perry MJ, et al. Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival. J Bone Miner Res 2003;18:482-92
88. Menu E, De Leenheer E, De Raeve H, et al. Role of CCR1 and CCR5 in homing and growth of multiple myeloma and in the development of osteolytic lesions: a study in the 5TMM model. Clin Exp Metastasis 2006;23:291-300
89. Neben K, Lokhorst HM, Jauch A, et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood 2012;119:940-8
90. San Miguel JF, Schlag R, Khuageva NK, et al. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan- prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol 2013;31:448-55
91. Arastu-Kapur S, Anderl JL, Kraus M, et al. Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events. Clin Cancer Res 2011;17:2734-43
92. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 2011;12:431-40
93. Chauhan D, Li G, Shringarpure R, et al. Blockade of Hsp27 overcomes Bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res 2003;63:6174-7
94. Kuhn DJ, Berkova Z, Jones RJ, et al. Targeting the insulin-like growth factor-1 receptor to overcome bortezomib resistance in preclinical models of multiple myeloma. Blood 2012;120:3260-70
95. Stessman HA, Baughn LB, Sarver A, et al. Profiling bortezomib resistance identifies secondary therapies in a mouse myeloma model. Mol Cancer Ther 2013; Epub ahead of print
96. Kuhn DJ, Chen Q, Voorhees PM, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood 2007;110:3281-90
97. Parlati F, Lee SJ, Aujay M, et al. Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome. Blood 2009;114:3439-47
98. O'Connor OA, Stewart AK, Vallone M, et al. A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. Clin Cancer Res 2009;15:7085-91
99. Alsina M, Trudel S, Furman RR, et al. A phase I single-agent study of twice-weekly consecutive-day dosing of the proteasome inhibitor carfilzomib in patients with relapsed or refractory multiple myeloma or lymphoma. Clin Cancer Res 2012;18:4830-40
100. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood 2012;120:2817-25
101. Vij R, Wang M, Kaufman JL, et al. An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood 2012;119:5661-70
102. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 2012;120:1801-9
103. Sonneveld P, Asselbergs E, Zweegman S, et al. Carfilzomib combined with thalidomide and dexamethasone (CTD) is an highly effective induction and consolidation treatment in newly diagnosed patients with multiple myeloma (MM) who are transplant candidate. Blood 2012;120:abstract 333
104. Mikhael J, Reeder C, Libby E, et al. Results from the phase II dose expansion of cyclophosphamide, carfilzomib, thalidomide and dexamethasone (CYCLONE) in patients with newly diagnosed multiple myeloma. Blood 2012;120:abstract 445
105. Zhou HJ, Aujay MA, Bennett MK, et al. Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor (PR-047). J Med Chem 2009;52:3028-38
106. Chauhan D, Singh AV, Aujay M, et al. A novel orally active proteasome inhibitor ONX 0912 triggers in vitro and in vivo cytotoxicity in multiple myeloma. Blood 2010;116:4906-15
107. Piva R, Ruggeri B, Williams M, et al. CEP-18770: a novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib. Blood 2008;111:2765-75
108. Dorsey BD, Iqbal M, Chatterjee S, et al. Discovery of a potent, selective, and orally active proteasome inhibitor for the treatment of cancer. J Med Chem 2008;51:1068-72
109. Gallerani E, Zucchetti M, Brunelli D, et al. A first in human phase I study of the proteasome inhibitor CEP-18770 in patients with advanced solid tumours and multiple myeloma. Eur J Cancer 2013;49:290-6
110. Chauhan D, Tian Z, Zhou B, et al. In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells. Clin Cancer Res 2011;17:5311-21
111. Kumar SK, Berdeja JG, Niesvizky R, et al. A phase 1/2 study of weekly MLN9708, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (MM). Blood 2012;120:abstract 332
112. Chauhan D, Catley L, Li G, et al. A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell 2005;8:407-19
113. Chauhan D, Singh A, Brahmandam M, et al. Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma. Blood 2008;111:1654-64
114. Richardson PG, 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). Blood 2011;118:abstract 302
115. Singh AV, Bandi M, Aujay MA, et al. PR-924, a selective inhibitor of the immunoproteasome subunit LMP-7, blocks multiple myeloma cell growth both in vitro and in vivo. Br J Haematol 2011;152:155-63
116. Chauhan D, Tian Z, Nicholson B, et al. A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Cancer Cell 2012;22:345-58
117. Palumbo A, Hajek R, Delforge M, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 2012;366:1759-69
118. Dimopoulos MA, Richardson PG, Brandenburg N, et al. A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide. Blood 2012;119:2764-7
119. Richardson PG, Siegel DS, Vij R, et al. Randomized, open label phase 1/2 study of pomalidomide (POM) alone or in combination with low-dose dexamethasone (LoDex) in patients (Pts) with relapsed and refractory multiple myeloma who have received prior treatment that includes lenalidomide (LEN) and bortezomib (BORT): phase 2 results. Blood 2011;118:abstract 634
120. Richardson PG, Siegel D, Baz R, et al. Phase I study of pomalidomide MTD, safety and efficacy in patients with refractory multiple myeloma who have received lenalidomide and bortezomib. Blood 2013;121(11):1961-7
121. Lacy MQ, Allred JB, Gertz MA, et al. Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood 2011;118:2970-5
122. Leleu X, Attal M, Arnulf B, et al. Pomalidomide plus low dose dexamethasone is active and well tolerated in bortezomib and lenalidomide refractory multiple myeloma: IFM 2009-02. Blood 2013
123. Dimopoulos MA, Lacy MQ, Moreau P, et al. Pomalidomide in combination with low-dose dexamethasone: demonstrates a significant progression free survival and overall survival advantage, in relapsed/refractory MM: a phase 3, multicenter, randomized, open-label study. Blood 2012;120:abstract LBA-6
124. Palumbo A, Larocca A, Montefusco V, et al. Pomalidomide cyclophosphamide and prednisone (PCP) treatment for relapsed/refractory multiple myeloma. Blood 2012;120:abstract 446
125. Mark TM, Boyer A, Rossi AC, et al. ClaPD (Clarithromycin, Pomalidomide, Dexamethasone) therapy in relapsed or refractory multiple myeloma. Blood 2012;120:abstract 77
126. Boles KS, Stepp SE, Bennett M, et al. 2B4 (CD244) and CS1: novel members of the CD2 subset of the immunoglobulin superfamily molecules expressed on natural killer cells and other leukocytes. Immunol Rev 2001;181:234-49
127. Tai YT, 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;112:1329-37
128. Hsi ED, Steinle R, Balasa B, et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res 2008;14:2775-84
129. van Rhee F, Szmania SM, Dillon M, et al. Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma. Mol Cancer Ther 2009;8:2616-24
130. Tai YT, Soydan E, Song W, et al. CS1 promotes multiple myeloma cell adhesion, clonogenic growth, and tumorigenicity via c-maf-mediated interactions with bone marrow stromal cells. Blood 2009;113:4309-18
131. Zonder JA, Mohrbacher AF, Singhal S, et al. A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Blood 2012;120:552-9
132. Jakubowiak AJ, Benson DM, Bensinger W, et al. Phase I trial of anti-CS1 monoclonal antibody elotuzumab in combination with bortezomib in the treatment of relapsed/refractory multiple myeloma. J Clin Oncol 2012;30:1960-5
133. Richardson P, Jagannath S, Moreau P, et al. A phase 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 2012;120:abstract 202
134. van der Veer MS, 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;96:284-90
135. de Weers M, Tai YT, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol 2011;186:1840-8
136. 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 2012;120:abstract 73
137. Hussein M, Berenson JR, Niesvizky R, et al. A phase I multidose study of dacetuzumab (SGN-40; humanized anti-CD40 monoclonal antibody) in patients with multiple myeloma. Haematologica 2010;95:845-8
138. Bensinger W, Maziarz RT, Jagannath S, et al. A phase 1 study of lucatumumab, a fully human anti-CD40 antagonist monoclonal antibody administered intravenously to patients with relapsed or refractory multiple myeloma. Br J Haematol 2012;159:58-66
139. Ikeda H, Hideshima T, Fulciniti M, et al. The monoclonal antibody nBT062 conjugated to cytotoxic Maytansinoids has selective cytotoxicity against CD138-positive multiple myeloma cells in vitro and in vivo. Clin Cancer Res 2009;15:4028-37
140. Heffner LT, Jagannath S, Zimmerman TM, et al. BT062, an antibody-drug conjugate directed against CD138, given weekly for 3 weeks in each 4 week cycle: safety and further evidence of clinical activity. Blood 2012;120:abstract 4042
141. Pessoa de Magalhaes RJ, Vidriales MB, Paiva B, et al. Analysis of the immune system of multiple myeloma patients achieving long-term disease control by multidimensional flow cytometry. Haematologica 2013;98:79-86
142. Rosenblatt J, Vasir B, Uhl L, et al. Vaccination with dendritic cell/tumor fusion cells results in cellular and humoral antitumor immune responses in patients with multiple myeloma. Blood 2011;117:393-402
143. Rosenblatt J, Avivi I, Vasir B, et al. Blockade of PD-1 in combination with dendritic cell/myeloma fusion cell vaccination following autologous stem cell transplantation. Blood 2012;120:abstract 578
144. Brown R, Kabani K, Favaloro J, et al. CD86+ or HLA-G+ can be transferred via trogocytosis from myeloma cells to T cells and are associated with poor prognosis. Blood 2012;120:2055-63
145. Choudhary C, Kumar C, Gnad F, et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 2009;325:834-40
146. Catley L, Weisberg E, Tai YT, et al. NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma. Blood 2003;102:2615-22
147. Richardson P, Mitsiades C, Colson K, et al. Phase I trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced multiple myeloma. Leuk Lymphoma 2008;49:502-7
148. Badros A, Burger AM, Philip S, et al. Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Clin Cancer Res 2009;15:5250-7
149. Weber DM, Graef T, Hussein M, et al. Phase I trial of vorinostat combined with bortezomib for the treatment of relapsing and/or refractory multiple myeloma. Clin Lymphoma Myeloma Leuk 2012;12:319-24
150. Dimopoulos M, Jagannath S, Yoon S, et al. Vantage 088: vorinostat in combination with bortezomib in patients with relapsed/refractory multiple myeloma: results of a global, randomized phase 3 trial. Blood 2011;118:abstract 811
151. Kaufman JL, Shah JJ, Laubach JP, et al. Lenalidomide, bortezomib, and dexamethasone (RVD) in combination with vorinostat as front-line therapy for patients with multiple myeloma (MM): results of a phase 1 study. Blood 2012;120:abstract 336
152. 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;53:1722-7
153. Nawrocki ST, Carew JS, Pino MS, et al. Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. Cancer Res 2006;66:3773-81
154. Peterson TR, Laplante M, Thoreen CC, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 2009;137:873-86
155. Frost P, Moatamed F, Hoang B, et al. In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model. Blood 2004;104:4181-7
156. McMillin DW, Ooi M, Delmore J, et al. Antimyeloma activity of the orally bioavailable dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. Cancer Res 2009;69:5835-42
157. Cirstea D, Hideshima T, Rodig S, et al. Dual inhibition of akt/mammalian target of rapamycin pathway by nanoparticle albumin-bound-rapamycin and perifosine induces antitumor activity in multiple myeloma. Mol Cancer Ther 2010;9:963-75
158. Richardson PG, 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. J Clin Oncol 2011;29:4243-9
159. Jakubowiak AJ, Richardson PG, Zimmerman T, et al. Perifosine plus lenalidomide and dexamethasone in relapsed and relapsed/refractory multiple myeloma: a Phase I Multiple Myeloma Research Consortium study. Br J Haematol 2012;158:472-80
160. Farag SS, Zhang S, Jansak BS, et al. Phase II trial of temsirolimus in
161. Ghobrial IM, Weller E, Vij R, et al. Weekly bortezomib in combination with temsirolimus in relapsed or relapsed and refractory multiple myeloma: a multicentre, phase 1/2, open-label, dose-escalation study. Lancet Oncol 2011;12:263-72
162. Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 2013;31:88-94
163. Tai YT, Chang BY, Kong SY, et al. Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma. Blood 2012;120:1877-87
164. Morgan GJ, Davies FE, Gregory WM, et al. Effects of induction and maintenance plus long-term bisphosphonates on bone disease in patients with multiple myeloma: the Medical Research Council Myeloma IX Trial. Blood 2012;119:5374-83
165. Vallet S, Mukherjee S, Vaghela N, et al. Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease. Proc Natl Acad Sci USA 2010;107:5124-9
166. Abdulkadyrov KM, Salogub GN, Khuazheva NK, et al. ACE-011, a soluble activin receptor type Iia IgG-Fc fusion protein, increases hemoglobin (Hb) and improves bone lesions in multiple myeloma patients receiving myelosuppressive chemotherapy: preliminary analysis. Blood 2009;114:abstract 749
167. Scullen T, Santo L, Vallet S, et al. Lenalidomide in combination with an activin A neutralizing antibody; preclinical rationale for a novel anti-myeloma strategy. Leukemia 2013
168. Munshi NC, Abonour R, Beck JT, 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 2012;120:abstract 331
169. Richardson P, Alsina M, Weber D, et al. PANORAMA 2: panobinostat combined with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma. Blood 2012;218:abstract 1852