• 1
    Eshaghian S, Berenson JR. Multiple myeloma: improved outcomes with new therapeutic approaches. Curr Opin Support Palliat Care 2012;6:3306.
  • 2
    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;26:14957.
  • 3
    Di Bernardo A, Macor P, Guarnotta C, Franco G, Florena AM, Tedesco F, Tripodo C. Humoral immunotherapy of multiple myeloma: perspectives and perplexities. Expert Opin Biol Ther 2010;10:86373.
  • 4
    Lozanski G, Heerema NA, Flinn IW, Smith L, Harbison J, Webb J, Moran M, Lucas M, Lin T, Hackbarth ML. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood 2004;103:327881.
  • 5
    Bladé J, de Larrea CF, Rosiñol L. Incorporating monoclonal antibodies into the therapy of multiple myeloma. J Clin Oncol 2012;30:19046.
  • 6
    van de Donk NW, Kamps S, Mutis T, Lokhorst HM. Monoclonal antibody-based therapy as a new treatment strategy in multiple myeloma. Leukemia 2012;26:199213.
  • 7
    Weiner LM, Surana R, Wang S. Monoclonal antibodies: versatile platforms for cancer immunotherapy. Nat Rev Immunol 2010;10:31727.
  • 8
    Kastritis E, Charidimou A, Varkaris A, Dimopoulos MA. Targeted therapies in multiple myeloma. Target Oncol 2009;4:2336.
  • 9
    Pilarski LM, Giannakopoulos NV, Szczepek AJ, Masellis AM, Mant MJ, Belch AR. In multiple myeloma, circulating hyper-diploid B cells have clonotypic immunoglobulin heavy chain rearrangements and may mediate spread of disease. Clin Cancer Res 2000;6:58596.
  • 10
    Pilarski LM, Baigorri E, Mant MJ, Pilarski PM, Adamson P, Zola H, Belch AR. Multiple myeloma includes phenotypically defined subsets of clonotypic CD20+ B cells that persist during treatment with rituximab. Clin Med Oncol 2008;2:27587.
  • 11
    Treon SP, Shima Y, Grossbard ML, Preffer FI, Belch AR, Pilarski LM, Anderson KC. Treatment of multiple myeloma by antibody mediated immunotherapy and induction of myeloma selective antigens. Ann Oncol 2000;11:S10711.
  • 12
    Gemmel C, Cremer FW, Weis M, Witzens M, Moldenhauer G, Koniczek KH, Imbach U, Ho AD, Moos M, Goldschmidt H. Anti-CD20 antibody as consolidation therapy in a patient with primary plasma cell leukemia after high-dose therapy and autologous stem cell transplantation. Ann Hematol 2002;81:11923.
  • 13
    Musto P, Carella AM Jr, Greco MM, Falcone A, Sanpaolo G, Bodenizza C, Cascavilla N, Melillo L, Carella AM. Short progression-free survival in myeloma patients receiving rituximab as maintenance therapy after autologous transplantation. Br J Haematol 2003;123:7467.
  • 14
    Ohno H. Long-term response to maintenance treatment with rituximab in CD20(+) multiple myeloma. Leuk Lymphoma 2010;51:21446.
  • 15
    Kapoor P, Greipp PT, Morice WG, Rajkumar SV, Witzig TE, Greipp PR. Anti-CD20 monoclonal antibody therapy in multiple myeloma. Br J Haematol 2008;141:13548.
  • 16
    Zojer N, Kirchbacher K, Vesely M, Hübl W, Ludwig H. Rituximab treatment provides no clinical benefit in patients with pretreated advanced multiple myeloma. Leuk Lymphoma 2006;47:11039.
  • 17
    Robillard N, Avet-Loiseau H, Garand R, Moreau P, Pineau D, Rapp MJ, Harousseau JL, Bataille R. CD20 is associated with a small mature plasma cell morphology and t(11;14) in multiple myeloma. Blood 2003;102:10701.
  • 18
    Gozzetti A, Fabbri A, Lazzi S, Bocchia M, Lauria F. Reply to Rituximab activity in CD20 positive multiple myeloma. Leukemia 2007;21:18423.
  • 19
    Hofer S, Hunziker S, Dirnhofer S, Ludwig C. Rituximab effective in a patient with refractory autoimmune haemolytic anaemia and CD20-negative multiple myeloma. Br J Haematol 2003;122:6901.
  • 20
    Moreau P, Voillat L, Benboukher L, et al. Rituximab in CD20 positive multiple myeloma. Leukemia 2007;21:8356.
  • 21
    Treon SP, Pilarski LM, Belch AR, et al. CD20-directed serotherapy in patients with multiple myeloma: biologic considerations and therapeutic applications. J Immunother 2002;25:7281.
  • 22
    Almeida J, Orfao A, Ocqueteau M, Mateo G, Corral M, Caballero MD, Blade J, Moro MJ, Hernandez J, San Miguel JF. High-sensitive immunophenotyping and DNA ploidy studies for the investigation of minimal residual disease in multiple myeloma. Br J Haematol 1999;107:12131.
  • 23
    Lebovic D, Kaminski MS, Anderson TB, Detweiler-Short K, Griffith KA, Jobkar TL, Kandarpa M, Jakubowiak A. A phase II study of consolidation treatment with iodione-131 tositumomab (Bexxar™) in multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts) 2012;120:1854.
  • 24
    Gisslinger H, Kees M. Therapy strategies for multiple myeloma: current status. Wien Klin Wochenschr 2003;115:45161.
  • 25
    Rossi EA, Rossi DL, Stein R, Goldenberg DM, Chang CH. A bispecific antibody-IFNα2b immunocytokine targeting CD20 and HLA-DR is highly toxic to human lymphoma and multiple myeloma cells. Cancer Res 2010;70:76009.
  • 26
    Tai YT, Dillon M, Song W, et al. Anti-CSl humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood 2008;112:132937.
  • 27
    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;14:277584.
  • 28
    Boles KS, Stepp SE, Bennett M, Kumar V, Mathew PA. 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;181:23449.
  • 29
    Tassi I, Colonna M. The cytotoxicity receptor CRACC (CS-1) recruits EAT-2 and activates the PI3K and phospholipase Cgamma signaling pathways in human NK cells. J Immunol 2005;175:79968002.
  • 30
    Tassi I, Presti R, Kim S, Yokoyama WM, Gilfillan S, Colonna M. Phospholipase C-gamma 2 is a critical signaling mediator for murine NK cell activating receptors. J Immunol 2005;175:74954.
  • 31
    Tai YT, Tonon G, Leiba M. CS1, a new surface target on multiple myeloma (MM) cells, protects myeloma cells from apoptosis via regulation of ERK1/2, AKT and STAT3 signaling cascades. Blood (ASH Annual Meeting Abstracts) 2007;110:40.
  • 32
    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;113:430918.
  • 33
    Bensinger W, Zonder J, Singhal S. Phase I trial of HuLuc63 in multiple myeloma. Blood (ASH Annual Meeting Abstracts) 2007;110:358.
  • 34
    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;8:261624.
  • 35
    Zonder JA, Mohrbacher AF, Singhal S, van Rhee F, Bensinger WI, Ding H, Fry J, Afar DE, Singhal AK. A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Blood 2012;120:5529.
  • 36
    Zonder JA, Singhal S, Bensinger W, Mohrbacher A, Hussein MA, Munshi NC, Caras I, Singhal A, van Rhee F. Phase I study of elotuzumab (HuLuc63) in relapsed/refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts) 2008;112:2773.
  • 37
    Richardson PG, Moreau P, Jakubowiak AJ, et al. Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: interim results of a phase 2 study. Blood (ASH Annual Meeting Abstracts) 2010;116:986.
  • 38
    Rice AG, Dillon MB, Van Abbema AM. HuLuc63 in combination regimens with conventional and targeted therapies has additive and synergistic anti-tumor activity in pre-clinical models of myeloma. Blood (ASH Annual Meeting Abstracts) 2007;110:2517.
  • 39
    Jakubowiak AJ, Bensinger W, Siegel D. Phase 1/2 study of elotuzumab in combination with bortezomib in patients with multiple myeloma with one to three prior therapies: interim results. Blood (ASH Annual Meeting Abstracts) 2009;114:3876.
  • 40
    Lonial S, Vij R, Harousseau J-L. Phase 1/2 study of elotuzumab in combination with lenalidomide and low dose dexamethasone in relapsed or refractory multiple myeloma: interim results. Blood (ASH Annual Meeting Abstracts) 2009;114:432.
  • 41
    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;30:19539.
  • 42
    Jakubowiak AJ, Benson DM, Bensinger W, Siegel DS, Zimmerman TM, Mohrbacher A, Richardson PG, Afar DE, Singhal AK, Anderson KC. 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;30:19605.
  • 43
    Sanderson RD, Lalor P, Bernfield M. B lymphocytes express and lose syndecan at specific stages of differentiation. Cell Regul 1989;1:2735.
  • 44
    Yang Y, Macleod V, Miao HQ, et al. Heparanase enhances syndecan-1 shedding: a novel mechanism for stimulation of tumor growth and metastasis. J Biol Chem 2007;282:1332633.
  • 45
    Wijdenes J, Vooijs WC, Clement C, Post J, Morard F, Vita N, Laurent P, Sun RX, Klein B, Dore JM. A plasmocyte selective monoclonal antibody (B-B4) recognizes syndecan-1. Br J Haematol 1996;94:31823.
  • 46
    Seidel C, Sundan A, Hjorth M, Turesson I, Dahl IM, Abildgaard N, Waage A, Borset M. Serum syndecan-1: a new independent prognostic marker in multiple myeloma. Blood 2000;95:38892.
  • 47
    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;15:402837.
  • 48
    Tassone P, Goldmacher VS, Neri P, et al. Cytotoxic activity of the maytansinoid immunoconjugate B-B4-DM1 against CD138+ multiple myeloma cells. Blood 2004;104:368896.
  • 49
    Lutz RJ, Whiteman KR. Antibody-maytansinoid conjugates for the treatment of myeloma. MAbs 2009;1:54851.
  • 50
    Rousseau C, Ferrer L, Supiot S, et al. Dosimetry results suggest feasibility of radioimmunotherapy using anti-CD138 (B-B4) antibody in multiple myeloma patients. Tumour Biol 2012;33:67988.
  • 51
    Lin P, Owens R, Tricot G, Wilson CS. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. Am J Clin Pathol 2004;121:4828.
  • 52
    Malavasi FA, Funaro S, Roggero A, Horenstein L, Mehta CK. Human CD38: a glycoprotein in search of a function. Immunol Today 1994;15:957.
  • 53
    Deaglio S, Mehta K, Malavasi F. Human CD38: a (r)evolutionary story of enzymes and receptors. Leuk Res 2001;25:112.
  • 54
    Gallay N, Anani L, Lopez A, Colombat P, Binet C, Domenech J, Weksler BB, Malavasi F, Herault O. The role of platelet/endothelial cell adhesion molecule 1 (CD31) and CD38 antigens in marrow microenvironmental retention of acute myelogenous leukemia cells. Cancer Res 2007;67:862432.
  • 55
    Partida-Sanchez S, Cockayne DA, Monard S, et al. Cyclic ADP-ribose production by CD38 regulates intracellular calcium release, extracellular calcium influx and chemotaxis in neutrophils and is required for bacterial clearance in vivo. Nat Med 2001;7:120916.
  • 56
    Santonocito AM, Consoli U, Bagnato S, Milone G, Palumbo GA, Di Raimondo F, Stagno F, Guglielmo P, Giustolisi R. Flow cytometric detection of aneuploid CD38(++) plasmacells and CD19(+) B-lymphocytes in bone marrow, peripheral blood and PBSC harvest in multiple myeloma patients. Leuk Res 2004;28:46977.
  • 57
    Goldmacher VS, Bourret LA, Levine BA, Rasmussen RA, Pourshadi M, Lambert JM, Anderson KC. Anti-CD38-blocked ricin: an immunotoxin for the treatment of multiple myeloma. Blood 1994;84:301725.
  • 58
    Tai YT, de Weers M, Li X. Daratumumab, a novel potent human anti-CD38 monoclonal antibody, induces significant killing of human multiple myeloma cells. Therapeutic Implication. Blood (ASH Annual Meeting Abstracts) 2009;114:608.
  • 59
    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;186:18408.
  • 60
    van der Veer MS, de Weers M, van Kessel B, Bakker JM, Wittebol S, Parren PWHI, Lokhorst HM, Mutis T. Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. Haematologica 2011;96:28490.
  • 61
    Plesner T, Lokhorst H, Gimsing P, Nahi H, Lisby S, Richardson PG. 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;143:654.
  • 62
    Tesar M. Fully human antibody MOR202 against CD38 for the treatment of multiple myeloma and other blood–borne malignancies. J Clin Oncol 2007; 25:article 8106.
  • 63
    Lee BO, Moyron-Quiroz J, Rangel-Moreno J, Kusser KL, Hartson L, Sprague F, Lund FE, Randall TD. CD40, but not CD154, expression on B cells is necessary for optimal primary B cell responses. J Immunol 2003;171:570717.
  • 64
    Pellat-Deceunynck C, Bataille R, Robillard N, Harousseau JL, Rapp MJ, Juge-Morineau N, Wijdenes J, Amiot M. Expression of CD28 and CD40 in human myeloma cells: a comparative study with normal plasma cells. Blood 1994;84:2597603.
  • 65
    Rodrigues-Lima F, Josephs M, Katan M, Cassinat B. Sequence analysis identifies TTRAP, a protein that associates with CD40 and TNF receptor-associated factors, as a member of a superfamily of divalent cation-dependent phosphodiesterases. Biochem Biophys Res Commun 2001;285:12749.
  • 66
    Morel Y, Truneh A, Sweet RW, Olive D, Costello RT. The TNF superfamily members LIGHT and CD154 (CD40 ligand) costimulate induction of dendritic cell maturation and elicit specific CTL activity. J Immunol 2001;167:247986.
  • 67
    Mizuno T, Rothstein TL. B cell receptor (BCR) cross-talk: CD40 engagement creates an alternate pathway for BCR signaling that activates I kappa B kinase/I kappa B alpha/NF-kappa B without the need for PI3K and phospholipase C gamma. J Immunol 2005;174:606270.
  • 68
    Solanilla A, Dechanet J, El Andaloussi A, et al. CD40-ligand stimulates myelopoiesis by regulating flt3-ligand and thrombopoietin production in bone marrow stromal cells. Blood 2000;95:375864.
  • 69
    Futagami S, Hiratsuka T, Shindo T, et al. COX-2 and CCR2 induced by CD40 ligand and MCP-1 are linked to VEGF production in endothelial cells. Prostaglandins Leukot Essent Fatty Acids 2008;78:13746.
  • 70
    Dadgostar H, Zarnegar B, Hoffmann A, Qin XF, Truong U, Rao G, Baltimore D, Cheng G. Cooperation of multiple signaling pathways in CD40-regulated gene expression in B lymphocytes. Proc Natl Acad Sci USA 2002;99:1497502.
  • 71
    Younes A, Snell V, Consoli U, Clodi K, Zhao S, Palmer JL, Thomas EK, Armitage RJ, Andreeff M. Elevated levels of biologically active soluble CD40 ligand in the serum of patients with chronic lymphocytic leukaemia. Br J Haematol 1998;100:13541.
  • 72
    Advani R, Forero-Torres A, Furman RR, Rosenblatt JD, Younes A, Ren H, Harrop K, Whiting N, Drachman JG. Phase I study of the humanized anti-CD40 monoclonal antibody dacetuzumab in refractory or recurrent non-Hodgkin's lymphoma. J Clin Oncol 2009;27:43717.
  • 73
    Tai Y, Li X, Tong X, et al. Human anti-CD40 antagonist antibody triggers significant antitumor activity against human multiple myeloma. Cancer Res 2005;65:5898906.
  • 74
    Long L, Tong X, Patawaran M, Aukerman SL, Jallal B, Luqman M. Antagonist anti-CD40 antibody, CHIR-12.12, induces ADCC, inhibits tumor growth, and prolongs survival in a human multiple myeloma xenograft model. Blood (ASH Annual Meeting Abstracts) 2005;106:3470.
  • 75
    Luqman M, Klabunde S, Lin K, et al. The antileukemia activity of a human anti-CD40 antagonist antibody, HCD122, on human chronic lymphocytic leukemia cells. Blood 2008;112:71120.
  • 76
    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;159:5866.
  • 77
    Law CL, Gordon KA, Collier J, et al. Preclinical antilymphoma activity of a humanized anti-CD40 monoclonal antibody, SGN-40. Cancer Res 2005;65:83318.
  • 78
    Lewis TS, McCormick RS, Kissler K, Stone IJ, Jonas M, Sutherland MSK. The humanized anti-CD40 monoclonal antibody, SGN-40, potentiates chemotherapy regimens in NHL Xenograft models via pro-apoptotic signaling. Blood 2007;110:2342.
  • 79
    Tai YT, Catley LP, Mitsiades CS, et al. Mechanisms by which SGN-40, a humanized anti-CD40 antibody, induces cytotoxicity in human multiple myeloma cells: clinical implications. Cancer Res 2004;64:284652.
  • 80
    Bensinger W, Jagannath S, Becker PS, et al. A phase 1 dose escalation study of a fully human, antagonist anti-CD40 antibody, HCD 122 (formerly CHIR-12.12), in patients with relapsed and refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts) 2006;108:3675.
  • 81
    Khubchandani S, Czuczman MS, Hernandez-Ilizaliturri FJ. Dacetuzumab, a humanized mAb against CD40 for the treatment of hematological malignancies. Curr Opin Invest Drugs 2009;10:57987.
  • 82
    Tai YT, Li XF, Catley L, et al. Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications. Cancer Res 2005;65:1171220.
  • 83
    Hussein M, Berenson JR, Niesvizky R, Munshi N, Matous J, Sobecks R, Harrop K, Drachman JG, Whiting N. A phase I multidose study of dacetuzumab (SGN-40; humanized anti-CD40 monoclonal antibody) in patients with multiple myeloma. Haematologica 2010;95:8458.
  • 84
    Agura E, Niesvizky R, Matous J. Dacetuzumab (SGN-40), lenalidomide, and weekly dexamethasone in relapsed or refractory multiple myeloma: multiple responses observed in a phase 1b study. Blood (ASH Annual Meeting Abstracts) 2009;114:2870.
  • 85
    Tassone P, Gozzini A, Goldmacher V, et al. In vitro and in vivo activity of the maytansinoid immunoconjugate huN901-N2′-deacetyl-N2′-(3-mercapto-1-oxopropyl)-maytansine against CD56+ multiple myeloma cells. Cancer Res 2004;64:462936.
  • 86
    Mechtersheimer G, Staudter M, Möller P. Expression of the natural killer (NK) cell-associated antigen CD56(Leu-19), which is identical to the 140-kDa isoform of N-CAM, in neural and skeletal muscle cells and tumors derived therefrom. Ann N Y Acad Sci 1992;650:3116.
  • 87
    Griffin JD, Hercend T, Beveridge R, Schlossman SF. Characterization of an antigen expressed by human natural killer cells. J Immunol 1983;130:294751.
  • 88
    Lanier LL, Le AM, Civin CI, Loken MR, Phillips JH. The relationship of CD16 (Leu-11) and Leu-19 (NKH-1) antigen expression on human peripheral blood NK cells and cytotoxic T lymphocytes. J Immunol 1986;136:44806.
  • 89
    Martín P, Santón A, Bellas C. Neural cell adhesion molecule expression in plasma cells in bone marrow biopsies and aspirates allows discrimination between multiple myeloma, monoclonal gammopathy of uncertain significance and polyclonal plasmacytosis. Histopathology 2004;44:37580.
  • 90
    Harada H, Kawano MM, Huang N, Harada Y, Iwato K, Tanabe O, Tanaka H, Sakai A, Asaoku H, Kuramoto A. Phenotypic difference of normal plasma cells from mature myeloma cells. Blood 1993;81:265863.
  • 91
    Damgaard T, Knudsen LM, Dahl IM, Gimsing P, Lodahl M, Rasmussen T. Regulation of the CD56 promoter and its association with proliferation, anti-apoptosis and clinical factors in multiple myeloma. Leuk Lymphoma 2009;50:23646.
  • 92
    Ely SA, Knowles DM. Expression of CD56/neural cell adhesion molecule correlates with the presence of lytic bone lesions in multiple myeloma and distinguishes myeloma from monoclonal gammopathy of undetermined significance and lymphomas with plasmacytoid differentiation. Am J Pathol 2002;160:12939.
  • 93
    Chanan-Khan AA, Gharibo M, Jagannath S, Munshi NC, Anderson KC, DePaolo D. Phase I study of IMGN901 in patients with relapsed and relapsed/refractory CD56-positive multiple myeloma. Blood (ASH Annual Meeting Abstracts) 2008;112:3689.
  • 94
    Chanan-Khan A, Wolf J, Gharibo M. Phase I study of IMGN901, used as monotherapy, in patients with heavily pre-treated CD56-positive multiple myeloma—a preliminary safety and efficacy analysis. Blood (ASH Annual Meeting Abstracts) 2009;114:2883.
  • 95
    Lutz R, Ab O, Foley K, Goldmacher V, Whiteman K, Xie H. Efficacy of the huN901-DM1 conjugate in combination with antineoplastic agents against multiple myeloma cells in preclinical studies. AACR Meet Abstr 2007;2007:5577.
  • 96
    Whiteman K, Ab O, Bartle L, Foley K, Goldmacher V, Lutz R. Efficacy of IMGN901 (huN901-DM1) in combination with bortezomib and lenalidomide against multiple myeloma cells in preclinical studies. AACR Meet Abstr 2008;2008:2146.
  • 97
    Georgii-Hemming P, Wiklund HJ, Ljunggren O, Nilsson K. Insulin-like growth factor I is a growth and survival factor in human multiple myeloma cell lines. Blood 1996;88:22508.
  • 98
    Jourdan M, De Vos J, Mechti N, Klein B. Regulation of Bcl-2-family proteins in myeloma cells by three myeloma survival factors: interleukin-6, interferon-alpha and insulin-like growth factor 1. Cell Death Differ 2000;7:124452.
  • 99
    Jelinek DF, Witzig TE, Arendt BK. A role for insulin-like growth factor in the regulation of IL-6-responsive human myeloma cell line growth. J Immunol 1997;159:48796.
  • 100
    Heron-Milhavet L, LeRoith D. Insulin-like growth factor I induces MDM2- dependent degradation of p53 via the p38 MAPK pathway in response to DNA damage. J Biol Chem 2002;277:15600.
  • 101
    Ogata A, Chauhan D, Teoh G, Treon SP, Urashima M, Schlossman RL, Anderson KC. IL-6 triggers cell growth via the Ras-dependent mitogen-activated protein kinase cascade. J Immunol 1997;159:221221.
  • 102
    Pene F, Claessens YE, Muller O, Viguie F, Mayeux P, Lacombe C, Bouscary D. Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma. Oncogene 2002;21:658797.
  • 103
    Mitsiades CS, Mitsiades N, Poulaki V, et al. Activation of NF-κB and upregulation of intracellular anti-apoptotic proteins via the IGF 1/Akt signalling in human multiple myeloma cells: therapeutic implications. Oncogene 2002;21:567383.
  • 104
    Cohen BD, Baker DA, Soderstrom C, et al. Combination therapy enhances the inhibition of tumor growth with the fully human anti-type 1 insulin-like growth factor receptor monoclonal antibody CP-751,871. Clin Cancer Res 2005;11:206373.
  • 105
    Tagoug I, Sauty De Chalon A, Dumonte C. Inhibition of IGF-1 signalling enhances the apoptotic effect of AS602868, an IKK2 inhibitor, in multiple myeloma cell lines. PLoS ONE 2011;6:e22641.
  • 106
    Descamps G, Gomez-Bougie P, Venot C, Moreau P, Bataille R, Amiot M. A humanised anti-IGF-1R monoclonal antibody (AVE1642) enhances bortezomib-induced apoptosis in myeloma cells lacking CD45. Br J Cancer 2009;100:3669.
  • 107
    Moreau P, Cavallo F, Leleu X, Hulin C, Amiot M, Descamps G, Facon T, Boccadoro M, Mignard D, Harousseau JL. Phase I study of the anti insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibody, AVE1642, as single agent and in combination with bortezomib in patients with relapsed multiple myeloma. Leukemia 2011;25:8724.
  • 108
    Tolcher AW, Patnaik A, Till E, Daud AI, Patnaik A, Papadopoulos K, Takimoto C, Bartels P, Keating A, Antonia S. A phase I study of AVE1642, a humanized monoclonal antibody IGF-1R (insulin like growth factor1 receptor) antagonist, in patients (pts) with advanced solid tumor(ST). J Clin Oncol 2008;26:3582.
  • 109
    Rothenberg ML, Poplin E, LoRusso P. Pharmacokinetic (PK) and pharmacodynamic (PD) results of Phase I studies of IMC-A12, a fully human insulin like growth factor-I receptor IgG1 monoclonal antibody, in patients with advanced solid malignancies. In: 20th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, 21–24 October. Geneva, Switzerland: Pergamon-Elsevier Science Ltd, 2008:1745.
  • 110
    Higano C, LoRusso P, Gordon M. A phase I study of the recombinant human IgG1 anti-IGF-IR monoclonal antibody (Mab) IMC-A12, administered on a weekly basis to patients with advanced solid tumors: interim analysis. Mol Cancer Ther 2007;6:3439S.
  • 111
    Leong S, Gore L, Benjamin R. A phase I study of R1507, a human monoclonal antibody lGF1R (insulin-like growth factor receptor) antagonist given weekly in patients with advanced solid tumors. Mol Cancer Ther 2007;6:3360S.
  • 112
    Rodon J, Patnaik A, Stein M. A phase I study of q3W R1507, a human monoclonal antibody IGF-1R (insulin-like growth factor receptor) antagonist in patients with advanced solid tumors. Mol Cancer Ther 2007;6:3360S.
  • 113
    Yap TA, Olmos D, Molife LR, de Bono JS. Targeting the insulin-like growth factor signaling pathway: figitumumab and other novel anticancer strategies. Expert Opin Investig Drugs 2011;20:1293304.
  • 114
    Lacy MQ, Alsina M, Fonseca R, et al. Phase I, pharmacokinetic and pharmacodynamic study of the anti-insulinlike growth factor type 1 Receptor monoclonal antibody CP-751,871 in patients with multiple myeloma. J Clin Oncol 2008;26:3196203.
  • 115
    Hidalgo M, Tirado Gomez M, Lewis N. A phase I study of MK-0646, a humanized monoclonal antibody against the insulin-like growth factor receptor type 1 (IGF1R) in advanced solid tumor patients in a q2 wk schedule. ASCO Meet Abstr 2008;26:3520.
  • 116
    Atzori F, Tabernero J, Cervantes A. A phase I, pharmacokinetic (PK) and pharmacodynamic (PD) study of weekly (qW) MK-0646, an insulin-like growth factor-1 receptor (IGF1R) monoclonal antibody (MAb) in patients (pts) with advanced solid tumors. J Clin Oncol 2008;26:3519.
  • 117
    Scartozzi M, Bianconi M, Maccaroni E, Giampieri R, Berardi R, Cascinu S. Dalotuzumab, a recombinant humanized mAb targeted against IGFR1 for the treatment of cancer. Curr Opin Mol Ther 2010;12:36171.
  • 118
    Ohtomo T, Sugamata Y, Ozaki Y, et al. Molecular cloning and characterization of a surface antigen preferentially overexpressed on multiple myeloma cells. Biochem Biophys Res Commun 1999;258:58391.
  • 119
    Ozaki S, Kosaka M, Wakatsuki S, Abe M, Koishihara Y, Matsumoto T. Immunotherapy of multiple myeloma with a monoclonal antibody directed against a plasma cell-specific antigen, HM1.24. Blood 1997;90:317986.
  • 120
    Wang W, Nishioka Y, Ozaki S, Jalili A, Abe S, Kakiuchi S, Kishuku M, Minakuchi K, Matsumoto T, Sone S. HM1.24 (CD317) is a novel target against lung cancer for immunotherapy using anti-HM1.24 antibody. Cancer Immunol Immunother 2009;58:96776.
  • 121
    Kawai S, Yoshimura Y, Iida S, Kinoshita Y, Koishihara Y, Ozaki S, Matsumoto T, Kosaka M, Yamada-Okabe H. Antitumor activity of humanized monoclonal antibody against HM1.24 antigen in human myeloma xenograft models. Oncol Rep 2006;15:3617.
  • 122
    Ono K, Ohtomo T, Yoshida K, Yoshimura Y, Kawai S, Koishihara Y, Ozaki S, Kosaka M, Tsuchiya M. The humanized anti-HM1.24 antibody effectively kills multiple myeloma cells by human effector cell-mediated cytotoxicity. Mol Immunol 1999;36:38795.
  • 123
    Ozaki S, Kosaka M, Wakahara Y, Ozaki Y, Tsuchiya M, Koishihara Y, Goto T, Matsumoto T. Humanized anti-HM1.24 antibody mediates myeloma cell cytotoxicity that is enhanced by cytokine stimulation of effector cells. Blood 1999;93:392230.
  • 124
    Ishiguro T, Kawai S, Habu K, Sugimoto M, Shiraiwa H, Iijima S, Ozaki S, Matsumoto T, Yamada-Okabe H. A defucosylated anti-CD317 antibody exhibited enhanced antibody-dependent cellular cytotoxicity against primary myeloma cells in the presence of effectors from patients. Cancer Sci 2010;101:222733.
  • 125
    Tai YT, Muchhal U, Li X, et al. XmAb®5592 Fc-engineered humanized anti-HM1.24 monoclonal antibody has potent in vitro and in vivo efficacy against multiple myeloma. Blood (ASH Annual Meeting Abstracts) 2009;114:609.
  • 126
    Tai YT, Horton HM, Kong SY, et al. Potent in vitro and in vivo activity of an Fc-engineered humanized anti-HM1.24 antibody against multiple myeloma via augmented effector function. Blood 2012;119:207482.
  • 127
    Amano J, Masuyama N, Hirota Y, Tanaka Y, Igawa Y, Shiokawa R, Okutani T, Miyayama T, Nanami M, Ishigai M. Antigen-dependent internalization is related to rapid elimination from plasma of humanized anti-HM1.24 monoclonal antibody. Drug Metab Dispos 2010;38:233946.
  • 128
    Vaughan HA, Thompson CH, Sparrow RL, McKenzie IF. Hu Ly-M3-a human leukocyte antigen. Transplantation 1983;36:44650.
  • 129
    Hosen N, Ichihara H, Mugitani A, et al. CD48 as a novel molecular target for antibody therapy in multiple myeloma. Br J Haematol 2012;156:21324.
  • 130
    Bjorkman PJ, Burmeister WP. Structures of two classes of MHC molecules elucidated: crucial differences and similarities. Curr Opin Struct Biol 1994;4:8526.
  • 131
    Bataille R, Durie BG, Grenier J. Serum beta2 microglobulin and survival duration in multiple myeloma: a simple reliable marker for staging. Br J Haematol 1983;55:43947.
  • 132
    Alexanian R, Barlogie B, Fritsche H. Beta 2 microglobulin in multiple myeloma. Am J Hematol 1985;20:34551.
  • 133
    Yang J, Qian J, Wezeman M, Wang S, Lin P, Wang M, Yaccoby S, Kwak LW, Barlogie B, Yi Q. Targeting beta2-microglobulin for induction of tumor apoptosis in human hematological malignancies. Cancer Cell 2006;10:295307.
  • 134
    Skov S, Nielsen M, Bregenholt S, Odum N, Claesson MH. Activation of Stat-3 is involved in the induction of apoptosis after ligation of major histocompatibility complex class I molecules on human JurkatT cells. Blood 1998;91:356673.
  • 135
    Pedersen AE, Skov S, Bregenholt S, Ruhwald M, Claesson MH. Signal transduction by the major histocompatibility complex class I molecule. APMIS 1999;107:88795.
  • 136
    Gur H, Geppert TD, Lipsky PE. Structural analysis of class I MHC molecules: the cytoplasmic domain is not required for cytoskeletal association, aggregation and internalization. Mol Immunol 1997;34:12532.
  • 137
    Gur H, Geppert TD, Wacholtz MC, Lipsky PE. The cytoplasmic and the transmembrane domains are not sufficient for class I MHC signal transduction. Cell Immunol 1999;191:10516.
  • 138
    Yang J, Yi Q. Therapeutic monoclonal antibodies for multiple myeloma: an update and future perspectives. Am J Blood Res 2011;1:2233.
  • 139
    Yi Q. Novel immunotherapies. Cancer J 2009;15:50210.
  • 140
    Cao Y, Lan Y, Qian J, et al. Targeting cell surface β2-microglobulin by pentameric IgM antibodies. Br J Haematol 2011;154:11121.
  • 141
    van Gisbergen KP, van Olffen RW, van Beek J, van der Sluijs KF, Arens R, Nolte MA, van Lier RA. Protective CD8 T cell memory is impaired during chronic CD70-driven costimulation. J Immunol 2009;182:535262.
  • 142
    Arens R, Tesselaar K, Baars PA, van Schijndel GM, Hendriks J, Pals ST, Krimpenfort P, Borst J, van Oers MH, van Lier RA. Constitutive CD27/CD70 interaction induces expansion of effector-type T cells and results in IFNgamma-mediated B cell depletion. Immunity 2001;15:80112.
  • 143
    McEarchern JA, Oflazoglu E, Francisco L, et al. Engineered anti-CD70 antibody with multiple effector functions exhibits in vitro and in vivo antitumor activities. Blood 2007;109:118592.
  • 144
    McEarchern JA, Smith LM, McDonagh CF, et al. Preclinical characterization of SGN-70, a humanized antibody directed against CD70. Clin Cancer Res 2008;14:776372.
  • 145
    Long EO, Strubin M, Wake CT, Gross N, Carrel S, Goodfellow P, Accolla RS, Mach B. Isolation of cDNA clones for the p33 invariant chain associated with HLA-DR antigens. Proc Natl Acad Sci USA 1983;80:57148.
  • 146
    Faure-Andre G, Vargas P, Yuseff MI, et al. Regulation of dendritic cell migration by CD74, the MHC class II-associated invariant chain. Science 2008;322:170510.
  • 147
    Veillat V, Carli C, Metz CN, Al-Abed Y, Naccache PH, Akoum A. Macrophage migration inhibitory factor elicits an angiogenic phenotype in human ectopic endometrial cells and triggers the production of major angiogenic factors via CD44, CD74, and MAPK signaling pathways. J Clin Endocrinol Metab 2010;95:E40312.
  • 148
    Burton JD, Ely S, Reddy PK, Stein R, Gold DV, Cardillo TM, Goldenberg DM. CD74 is expressed by multiple myeloma and is a promising target for therapy. Clin Cancer Res 2004;10:660611.
  • 149
    Stein R, Qu Z, Cardillo TM, Chen S, Rosario A, Horak ID, Hansen HJ, Goldenberg DM. Antiproliferative activity of a humanized anti-CD74 monoclonal antibody, hLL1, on B-cell malignancies. Blood 2004;104:370511.
  • 150
    Stein R, Smith MR, Chen S, Zalath M, Goldenberg DM. Combining milatuzumab with bortezomib, doxorubicin, or dexamethasone improves responses in multiple myeloma cell lines. Clin Cancer Res 2009;15:280817.
  • 151
    Berkova Z, Tao RH, Samaniego F. Milatuzumab-a promising new immunotherapeutic agent. Expert Opin Investig Drugs 2010;19:1419.
  • 152
    Kaufman JNR, Stadtmauer E, Chanan-Khan A. First trial of humanized anti-CD-74 monoclonal antibody (Mab), milatuzumab in multiple myeloma. Blood 2008;112:12667.
  • 153
    Carlo-Stella C, Guidetti A, Di Nicola M, et al. IFN-γ enhances the antimyeloma activity of the fully human anti-human leukocyte antigen-DR monoclonal antibody 1D09C3. Cancer Res 2007;67:326975.
  • 154
    Sekimoto E, Ozaki S, Ohshima T, et al. A single-chain Fv diabody against human leukocyte antigen—a molecules specifically induces myeloma cell death in the bone marrow environment. Cancer Res 2007;67:118492.
  • 155
    Johansson SE, Hejdeman B, Hinkula J, Johansson MH, Romagné F, Wahren B, Wagtmann NR, Kärre K, Berg L. NK cell activation by KIR-binding antibody 1-7F9 and response to HIV-infected autologous cells in viremic and controller HIV-infected patients. Clin Immunol 2010;134:15868.
  • 156
    Romagne F, Andre P, Spee P, et al. Preclinical characterization of 1-7F9, a novel human anti-KIR receptor therapeutic antibody that augments natural killer-mediated killing of tumor cells. Blood 2009;114:266777.
  • 157
    Benson DM, Romagne F, Squiban P. Novel monoclonal antibody that enhances natural killer (NK) cell cytotoxicity against multiple myeloma (MM): preclinical data and interim phase I clinical trial results. J Clin Oncol 2009;27:3032.
  • 158
    Campbell KS, Purdy AK. Structure/function of human killer cell immunoglobulin-like receptors: lessons from polymorphisms, evolution, crystal structures and mutations. Immunology 2011;132:31525.
  • 159
    Kimura N, Kawai S, Kinoshita Y, et al. 2D7 diabody bound to the alpha2 domain of HLA class I efficiently induces caspase-independent cell death against malignant and activated lymphoid cells. Biochem Biophys Res Commun 2004;325:12019.
  • 160
    Sandrin MS, Henning MM, Lo MF, Baker E, Sutherland GR, McKenzie IF. Isolation and characterization of cDNA clones for Humly9: the human homologue of mouse Ly9. Immunogenetics 1996;43:139.
  • 161
    Tangye SG, Phillips JH, Lanier LL. The CD2-subset of the Ig superfamily of cell surface molecules: receptor-ligand pairs expressed by NK cells and other immune cells. Semin Immunol 2000;12:14957.
  • 162
    Martin M, Del Valle JM, Saborit I, Engel P. Identification of Grb2 as a novel binding partner of the signaling lymphocytic activation molecule-associated protein binding receptor CD229. J Immunol 2005;174:597786.
  • 163
    Atanackovic D, Panse J, Hildebrandt Y, et al. Surface molecule CD229 as a novel target for the diagnosis and treatment of multiple myeloma. Haematologica 2011;96:151220.
  • 164
    Ishii T, Chanan-Khan A, Jafferjee J, Ersing N, Takahashi H, Mizutani M, Shiotsu Y, Hanai N. A humanized anti-ganglioside GM2 antibody, BIW-8962, exhibits ADCC/CDC activity against multiple myeloma cells and potent anti-tumor activity in mouse xenograft models. Blood (ASH Annual Meeting Abstracts) 2008;112:1718.
  • 165
    Gorczynski RM, Cohen Z, Fu XM, Lei J. Anti-rat OX-2 blocks increased small intestinal transplant survival after portal vein immunization. Transplant Proc 1999;31:5778.
  • 166
    Moreaux J, Hose D, Reme T, et al. CD200 is a new prognostic factor in multiple myeloma. Blood 2006;108:41947.
  • 167
    Zheng Y, Yang J, Qian J, et al. PSGL-1/selectin and ICAM-1/CD18 interactions are involved in macrophage-induced drug resistance in myeloma. Leukemia. 2013;27:70210.
  • 168
    Schmidmaier R, Morsdorf K, Baumann P, Emmerich B, Meinhardt G. Evidence for cell adhesion-mediated drug resistance of multiple myeloma cells in vivo. Int J Biol Markers 2006;21:21822.
  • 169
    Downs JA, Jackson SP. A means to a DNA end: the many roles of Ku. Nat Rev Mol Cell Biol 2004;5:36777.
  • 170
    Difilippantonio MJ, Zhu J, Chen HT, Meffre E, Nussenzweig MC, Max EE, Ried T, Nussenzweig A. DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation. Nature 2000;404:5104.
  • 171
    Gao Y, Ferguson DO, Xie W, Manis JP, Sekiguchi J, Frank KM, Chaudhuri J, Horner J, DePinho RA, Alt FW. Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development. Nature 2000;404:897900.
  • 172
    Khanna KK, Jackson SP. DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet 2001;27:24754.
  • 173
    Gullo C, Au M, Feng G, Teoh G. The biology of Ku and its potential oncogenic role in cancer. Biochim Biophys Acta 2006;1765:22334.
  • 174
    Tuteja R, Tuteja N. Ku autoantigen: a multifunctional DNA-binding protein. Crit Rev Biochem Mol Biol 2000;35:133.
  • 175
    Tai YT, Podar K, Kraeft SK, Wang F, Young G, Lin B, Gupta D, Chen LB, Anderson KC. Translocation of Ku86/Ku70 to the multiple myeloma cell membrane: functional implications. Exp Hematol 2002;30:21220.
  • 176
    Teoh G, Urashima M, Greenfield EA, Nguyen KA, Lee JF, Chauhan D, Ogata A, Treon SP, Anderson KC. The 86-kD subunit of Ku autoantigen mediates homotypic and heterotypic adhesion of multiple myeloma cells. J Clin Invest 1998;101:137988.
  • 177
    Liew PX, Ge F, Gullo C, Teoh GKH, Hwang WYK. Use of phage display to isolate specific human monoclonal antibody fragments against a potential target for multiple myeloma. Ann Acad Med Singapore 2009;38:6219.
  • 178
    Klein B, Zhang XG, Jourdan M, Content J, Houssiau F, Aarden L, Piechaczyk M, Bataille R. Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6. Blood 1989;73:51726.
  • 179
    Podar K, Gouill SL, Zhang J, et al. A pivotal role for Mcl-1 in Bortezomib-induced apoptosis. Oncogene 2008;27:72131.
  • 180
    Voorhees PM, Chen Q, Kuhn DJ, Small GW, Hunsucker SA, Strader JS, Corringham RE, Zaki MH, Nemeth JA, Orlowski RZ. Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in preclinical models of multiple myeloma. Clin Cancer Res 2007;13:646978.
  • 181
    Mundy GR, Raisz LG, Cooper RA, Schechter GP, Salmon SE. Evidence for the secretion of an osteoclast stimulating factor in myeloma. N Engl J Med 1974;291:10416.
  • 182
    Kurihara N, Bertolini D, Suda T, Akiyama Y, Roodman GD. IL-6 stimulates osteoclast-like multinucleated cell formation in long term human marrow cultures by inducing IL-1 release. J Immunol 1990;144:422630.
  • 183
    Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC. Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer 2007;7:58598.
  • 184
    Greipp PR, Leong T, Bennett JM, Gaillard JP, Klein B, Stewart JA, Oken MM, Kay NE, Van Ness B, Kyle RA. Plasmablastic morphology – an independent prognostic factor with clinical and laboratory correlates: Eastern Cooperative Oncology Group (ECOG) myeloma trial E9486 report by the ECOG Myeloma Laboratory Group. Blood 1998;91:25017.
  • 185
    Stasi R, Brunetti M, Parma A, Di Giulio C, Terzoli E, Pagano A. The prognostic value of soluble interleukin-6 receptor in patients with multiple myeloma. Cancer 1998;82:18606.
  • 186
    Wierzbowska A, Urbanska-Rys H, Robak T. Circulating IL-6-type cytokines and sIL-6R in patients with multiple myeloma. Br J Haematol 1999;105:4129.
  • 187
    Guo Y, Xu F, Lu T, Duan Z, Zhang Z. Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treat Rev 2012;38:90410.
  • 188
    van Zaanen HC, Lokhorst HM, Aarden LA, Rensink HJ, Warnaar SO, van der Lelie J, van Oers MH. Chimaeric anti-interleukin 6 monoclonal antibodies in the treatment of advanced multiple myeloma: a phase I dose-escalating study. Br J Haematol 1998;102:78390.
  • 189
    Trikha M, Corringham R, Klein B, Rossi JF. Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence. Clin Cancer Res 2003;9:465365.
  • 190
    Gu ZJ, De Vos J, Rebouissou C, Jourdan M, Zhang XG, Rossi JF, Wijdenes J, Klein B. Agonist anti-gp130 transducer monoclonal antibodies are human myeloma cell survival and growth factors. Leukemia 2000;14:18897.
  • 191
    Rossi JF, Manges RF, Sutherland HJ, et al. Preliminary results of CNTO 328, an anti-interleukin-6 monoclonal antibody, in combination with bortezomib in the treatment of relapsed or refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts) 2008;112:867.
  • 192
    Voorhees PM, Chen Q, Small GW, Kuhn DJ, Hunsucker SA, Nemeth JA, Orlowski RZ. Targeted inhibition of interleukin-6 with CNTO 328 sensitizes pre-clinical models of multiple myeloma to dexamethasone-mediated cell death. Br J Haematol 2009;145:48190.
  • 193
    van Zaanen HCT, Lokhorst HM, Aarden LA, Rensink HJAM, Warnaar SO, van Oers MHJ. Blocking interleukin-6 activity with chimeric anti-IL6 monoclonal antibodies in multiple myeloma: effects on soluble IL6 receptor and soluble gp130. Leuk Lymphoma 1998;3:5518.
  • 194
    Hunsucker SA, Magarotto V, Kuhn DJ, et al. Blockade of interleukin-6 signalling with siltuximab enhances melphalan cytotoxicity in preclinical models of multiple myeloma. Br J Haematol 2011;152:57992.
  • 195
    Hirata T, Shimazaki C, Sumikuma T, Ashihara E, Goto H, Inaba T, Koishihara Y, Nakagawa M. Humanized anti-interleukin-6 receptor monoclonal antibody induced apoptosis of fresh and cloned human myeloma cells in vitro. Leuk Res 2003;27:3439.
  • 196
    Nishimoto N, Shima Y, Sasai M, Danno N, Yoshizaki K. Clinical application of interleukin-6 receptor antibody. Nihon Rinsho Meneki Gakkai Kaishi 1997;20:8794. (In Japanese, Abstract in English.)
  • 197
    Matsuyama Y, Nagashima T, Honne K, Kamata Y, Iwamoto M, Okazaki H, Sato K, Ozawa K, Minota S. Successful treatment of a patient with rheumatoid arthritis and IgA-kappa multiple myeloma with tocilizumab. Intern Med 2011;50:63942.
  • 198
    Yoshio-Hoshino N, Adachi Y, Aoki C, Pereboev A, Curiel DT, Nishimoto N. Establishment of a new interleukin-6 (IL-6) receptor inhibitor applicable to the gene therapy for IL-6-dependent tumor. Cancer Res 2007;67:8715.
  • 199
    Bataille R, Barlogie B, Lu ZY, Rossi JF, Lavabre-Bertrand T, Beck T, Wijdenes J, Brochier J, Klein B. Biologic effects of anti-interleukin-6 murine monoclonal antibody in advanced multiple myeloma. Blood 1995;86:68591.
  • 200
    Emilie D, Wijdenes J, Gisselbrecht C, Jarrousse B, Billaud E, Blay JY, Gabarre J, Gaillard JP, Brochier J, Raphael M. Administration of an anti-interleukin-6 monoclonal antibody to patients with acquired immunodeficiency syndrome and lymphoma: effect on lymphoma growth and on B clinical symptoms. Blood 1994;84:24729.
  • 201
    Rossi JF, Fegueux N, Lu ZY, et al. Optimizing the use of anti-interleukin-6 monoclonal antibody with dexamethasone and 140 mg/m2 of melphalan in multiple myeloma: results of a pilot study including biological aspects. Bone Marrow Transplant 2005;36:7719.
  • 202
    Moreau P, Harousseau JL, Wijdenes J, Morineau N, Milpied N, Bataille R. A combination of anti-interleukin 6 murine monoclonal antibody with dexamethasone and high-dose melphalan induces high complete response rates in advanced multiple myeloma. Br J Haematol 2000;109:6614.
  • 203
    Fulciniti M, Hideshima T, Vermot-Desroches C, et al. A high-affinity fully human anti-IL-6 mAb (OP-R003-1, 1339) for the treatment of Multiple Myeloma. Clin Cancer Res 2009;15:714452.
  • 204
    Honemann D, Chatterjee M, Savino R, Bommert K, Burger R, Gramatzki M, Dörken B, Bargou RC. The IL-6 receptor antagonist SANT-7 overcomes bone marrow stromal cell-mediated drug resistance of multiple myeloma cells. Int J Cancer 2001;93:67480.
  • 205
    Tassone P, Forciniti S, Galea E, Savino R, Turco MC, Iacopino P, Tagliaferri P, Morrone G, Ciliberto G, Venuta S. Synergistic induction of growth arrest and apoptosis of human myeloma cells by the IL-6 super-antagonist Sant7 and Dexamethasone. Cell Death Differ 2000;7:3278.
  • 206
    Tassone P, Galea E, Forciniti S, Tagliaferri P, Venuta S. The IL-6 receptor super-antagonist Sant7 enhances antiproliferative and apoptotic effects induced by dexamethasone and zoledronic acid on multiple myeloma cells. Int J Oncol 2002;2:86773.
  • 207
    Ribatti D, Vacca A. The role of microenvironment in tumor angiogenesis. Genes Nutr 2008;3:2934.
  • 208
    Podar K, Hideshima T, Chauhan D, Anderson KC. Targeting signalling pathways for the treatment of multiple myeloma. Expert Opin Ther Targets 2005;9:35981.
  • 209
    Jakob C, Sterz J, Zavrski I, Heider U, Kleeberg L, Fleissner C, Kaiser M, Sezer O. Angiogenesis in multiple myeloma. Eur J Cancer 2006;42:158190.
  • 210
    Fan F, Schimming A, Jaeger D, Podar K. Targeting the tumor microenvironment: focus on angiogenesis. J Oncol 2012;2012:281261.
  • 211
    Ferrara N, Hillan KJ, Novotny W. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 2005;333:32835.
  • 212
    Gorski DH, Beckett MA, Jaskowiak NT, et al. Blockade of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res 1999;59:33748.
  • 213
    Hoyer RJ, Leung N, Witzig TE, Lacy MQ. Treatment of diuretic refractory pleural effusions with bevacizumab in four patients with primary systemic amyloidosis. Am J Hematol 2007;82:40913.
  • 214
    Goldman B. For investigational targeted drugs, combination trials pose challenges. J Natl Cancer Inst 2003;95:17446.
  • 215
    Attar-Schneider O, Drucker L, Zismanov V, Tartakover-Matalon S, Rashid G, Lishner M. Bevacizumab attenuates major signaling cascades and eIF4E translation initiation factor in multiple myeloma cells. Lab Invest 2012;92:17890.
  • 216
    Somlo G, Lashkari A, Bellamy W, et al. Phase II randomized trial of bevacizumab versus bevacizumab and thalidomide for relapsed/refractory multiple myeloma: a California Cancer Consortium trial. Br J Haematol 2011;154:5335.
  • 217
    Martinelli E, De Palma R, Orditura M, De Vita F, Ciardiello F. Anti-epidermal growth factor receptor monoclonal antibodies in cancer therapy. Clin Exp Immunol 2009;158:19.
  • 218
    Mendelsohn J, Baselga J. Epidermal growth factor receptor targeting in cancer. Semin Oncol 2006;33:36985.
  • 219
    Harding J, Burtness B. Cetuximab: an epidermal growth factor receptor chimeric human-murine monoclonal antibody. Drugs Today 2005;41:10727.
  • 220
    Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:56778.
  • 221
    VanCutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360:140817.
  • 222
    Mahtouk K, Hose D, Reme T, et al. Expression of EGF-family receptors and amphiregulin in multiple myeloma. Amphiregulin is a growth factor for myeloma cells. Oncogene 2005;24:351224.
  • 223
    Mahtouk K, Jourdan M, De Vos J, Hertogh C, Fiol G, Jourdan E, Rossi JF, Klein B. An inhibitor of the EGF receptor family blocks myeloma cell growth factor activity of HB-EGF and potentiates dexamethasone or anti- IL-6 antibody-induced apoptosis. Blood 2004;103:182937.
  • 224
    Böll B, Eichenauer DA, Von Tresckow B, Peine D, Hallek M, Engert A, Hübel K. Activity of cetuximab as single agent in a patient with relapsed multiple myeloma. Leuk Lymphoma 2010;51:5624.
  • 225
    Chapman MA, Lawrence MS, Keats JJ, et al. Initial genome sequencing and analysis of multiple myeloma. Nature 2011;471:46772.
  • 226
    Brito JL, Walker B, Jenner M, et al. MMSET deregulation affects cell cycle progression and adhesion regulons in t(4;14) myeloma plasma cells. Haematologica 2009;94:7886.
  • 227
    Morgan GJ, Kaiser MF. How to use new biology to guide therapy in multiple myeloma. Hematology Am Soc Hematol Educ Program 2012;2012:3429.
  • 228
    Kamath AV, Lu D, Gupta P, et al. Preclinical pharmacokinetics of MFGR1877A, a human monoclonal antibody to FGFR3, and prediction of its efficacious clinical dose for the treatment of t(4;14)-positive multiple myeloma. Cancer Chemother Pharmacol 2012;69:10718.
  • 229
    Burkiewicz JS, Scarpace SL, Bruce SP. Denosumab in osteoporosis and oncology. Ann Pharmacother 2009;43:144555.
  • 230
    Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 2012;379:3946.
  • 231
    Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011;3779768:81322.
  • 232
    Body JJ, Facon T, Coleman RE, Lipton A, Geurs F, Fan M, Holloway D, Peterson MC, Bekker PJ. A study of the biological receptor activator of nuclear factor-κB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin Cancer Res 2006;12:12218.
  • 233
    Vij R, Horvath N, Spencer A, Taylor K, Vadhan-Raj S, Vescio R, Smith J, Qian Y, Yeh H, Jun S. An open-label, phase 2 trial of denosumab in the treatment of relapsed or plateau-phase multiple myeloma. Am J Hematol 2009;8410:6506.
  • 234
    Aghaloo TL, Felsenfeld AL, Tetradis S. Osteonecrosis of the jaw in a patient on Denosumab. J Oral Maxillofac Surg 2010;685:95963.
  • 235
    Santini D, Fratto ME, Vincenzi B, Napoli N, Galluzzo S, Tantardini M, Abbruzzese A, Caraglia M, Tonini G. Denosumab: the era of targeted therapies in bone metastatic diseases. Curr Cancer Drug Targets 2009;9:83442.
  • 236
    Wang Y, Lin B. In silico investigations of the anti-catabolic effects of pamidronate and denosumab on multiple myeloma-induced bone disease. PLoS ONE 2012;7:e44868.
  • 237
    Pinzone JJ, Hall BM, Thudi NK, Vonau M, Qiang YW, Rosol TJ, Shaughnessy JD Jr. The role of Dickkopf-1 in bone development, homeostasis, and disease. Blood 2009;113:51725.
  • 238
    Yaccoby S, Ling W, Zhan F, Walker R, Barlogie B, Shaughnessy JD. Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood 2007;109:210611.
  • 239
    Heath DJ, Chantry AD, Buckle CH, Coulton L, Shaughnessy JD Jr, Evans HR, Snowden JA, Stover DR, Vanderkerken K, Croucher PI. Inhibiting dickkopf-1 (Dkkl) removes suppression of bone formation and prevents the development of osteolytic bone disease in multiple myeloma. J Bone Miner Res 2009;24:42536.
  • 240
    Fulciniti M, Tassone P, Hideshima T, et al. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood 2009;114:3719.
  • 241
    Qian J, Zheng Y, Zheng C, et al. Active vaccination with Dickkopf-1 induces protective and therapeutic antitumor immunity in murine multiple myeloma. Blood 2012;119:1619.
  • 242
    Woodruff TK. Regulation of cellular and system function by activin. Biochem Pharmacol 1998;55:95363.
  • 243
    Fuller K, Bayley KE, Chambers TJ. Activin A is an essential cofactor for osteoclast induction. Biochem Biophys Res Commun 2000;268:27.
  • 244
    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;107:51249.
  • 245
    Abdulkadyrov KM, Salogub GN, Khuazheva NK. 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 (ASH Annual Meeting Abstracts) 2009;114:749.
  • 246
    Novak AJ, Darce JR, Arendt BK, Harder B, Henderson K, Kindsvogel W, Gross JA, Greipp PR, Jelinek DF. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood 2004;103:68994.
  • 247
    Moreaux J, Cremer FW, Reme T, et al. The level of TACI gene expression in myeloma cells is associated with a signature of microenvironment dependence versus a plasmablastic signature. Blood 2005;106:102130.
  • 248
    Neri P, Kumar S, Fulciniti MT, et al. Neutralizing B-cell activating factor antibody improves survival and inhibits osteoclastogenesis in a severe combined immunodeficient human multiple myeloma model. Clin Cancer Res 2007;13:59039.
  • 249
    Moreaux J, Legouffe E, Jourdan E, Quittet P, Reme T, Lugagne C, Moine P, Rossi JF, Klein B, Tarte K. BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood 2004;103:314857.
  • 250
    Tai YT, Li XF, Breitkreutz I, et al. Role of B-cell-activating factor in adhesion and growth of human multiple myeloma cells in the bone marrow microenvironment. Cancer Res 2006;66:667582.
  • 251
    Rossi JF, Moreaux J, Hose D, et al. Atacicept in relapsed/refractory multiple myeloma or active Waldenstrom's macroglobulinemia: a phase I study. Br J Cancer 2009;101:10518.
  • 252
    Rossi JF, Phase I. study of atacicept in relapsed/refractory multiple myeloma (MM) and Waldenström's macroglobulinemia. Clin Lymphoma Myeloma Leuk 2011;11:1368.
  • 253
    Yaccoby S, Pennisi A, Li X, Dillon SR, Zhan F, Barlogie B, Shaughnessy JD Jr. Atacicept (TACI-Ig) inhibits growth of TACI primary myeloma cells in SCID-hu mice and in coculture with osteoclasts. Leukemia 2008;22:40613.
  • 254
    Ryan MC, Hering M, Peckham D, McDonagh CF, Brown L, Kim KM, Meyer DL, Zabinski RF, Grewal IS, Carter PJ. Antibody targeting of B-cell maturation antigen on malignant plasma cells. Mol Cancer Ther 2007;6:300918.
  • 255
    Kimberley FC, Screaton GR. Following a TRAIL: update on a ligand and its five receptors. Cell Res 2004;14:35972.
  • 256
    Bouralexis S, Findlay DM, Evdokiou A. Death to the bad guys: targeting cancer via APO2L/TRAIL. Apoptosis 2005;10:3551.
  • 257
    Van Geelen CM, de Vries EG, de Jong S. Lessons from TRAIL-resistance mechanisms in colorectal cancer cells: paving the road to patient-tailored therapy. Drug Resist Updat 2004;7:34558.
  • 258
    Pukac L, Kanakaraj P, Humphreys R, et al. HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo. Br J Cancer 2005;92:143041.
  • 259
    Menoret E, Gomez-Bougie P, Geffroy-Luseau A, Daniels S, Moreau P, Le Gouill S, Harousseau JL, Bataille R, Amiot M, Pellat-Deceunynck C. Mcl-1L cleavage is involved in TRAIL-R1- and TRAIL-R2-mediated apoptosis induced by HGS-ETR1 and HGS-ETR2 human mAbs in myeloma cells. Blood 2006;108:134652.
  • 260
    Locklin RM, Croucher PI, Russell RG, Edwards CM. Agonists of TRAIL death receptors induce myeloma cell apoptosis that is not prevented by cells of the bone marrow microenvironment. Leukemia 2007;21:80512.
  • 261
    Kabore AF, Sun J, Hu X, McCrea K, Johnston JB, Gibson SB. The TRAIL apoptotic pathway mediates proteasome inhibitor induced apoptosis in primary chronic lymphocytic leukemia cells. Apoptosis 2006;11:117593.
  • 262
    Smith MR, Jin F, Joshi I. Bortezomib sensitizes non-Hodgkin's lymphoma cells to apoptosis induced by antibodies to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors TRAIL-R1 and TRAIL-R2. Clin Cancer Res 2007;13:5528s34s.
  • 263
    Ghoshal P, Chitta K, Vujcic S, Gaddy J, Miles KM, Stein L. Mapatumumab, a TRAIL receptor 1 agonist antibody, induces apoptosis in bortezomib resistant multiple myeloma. Blood (ASH Annual Meeting Abstracts) 2009;114:2832.
  • 264
    Belch A, Sharma A, Spencer A, Tarantolo S, Bahlis NJ, Doval D. A multicenter randomized phase II trial of mapatumumab, a TRAIL-R1 agonist monoclonal antibody, in combination with bortezomib in patients with relapsed/refractory multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts) 2010;116:2321.
  • 265
    Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revised. Annu Rev Immunol 2005;23:51548.
  • 266
    Liu J, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, Hetuin D, Saudemont A, Quesnel B. Plasma cells from multiple myeloma patients express B7–H1 (PD-L1) and increase expression after stimulation with IFN-{gamma} and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood 2007;110:296304.
  • 267
    Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA 2002;99:122937.
  • 268
    Rosenblatt J, Glotzbecker B, Mills H, et al. CT-011, anti-PD-1 antibody, enhances ex-vivo T cell responses to autologous dendritic/myeloma fusion vaccine developed for the treatment of multiple myeloma. Blood (ASH Annual Meeting Abstracts) 2009;114:781.
  • 269
    Uchiyama H, Barut BA, Chauhan D, Cannistra SA, Anderson KC. Characterization of adhesion molecules on human myeloma cell lines. Blood 1992;80:230614.
  • 270
    Noborio-Hatano K, Kikuchi J, Takatoku M, et al. Bortezomib overcomes cell-adhesion-mediated drug resistance through down-regulation of VLA-4 expression in multiple myeloma. Oncogene 2009;28:23142.
  • 271
    Mori Y, Shimizu N, Dallas M, Niewolna M, Story B, Williams PJ, Mundy GR, Yoneda T. Anti-alpha4 integrin antibody suppresses the development of multiple myeloma and associated osteoclastic osteolysis. Blood 2004;104:214954.
  • 272
    Olson DL, Burkly LC, Leone DR, Dolinski BM, Lobb RR. Anti-alpha4 integrin monoclonal antibody inhibits multiple myeloma growth in a murine model. Mol Cancer Ther 2005;4:919.
  • 273
    Podar K, Zimmerhackl A, Fulciniti M, et al. The selective adhesion molecule inhibitor Natalizumab decreases multiple myeloma cell growth in the bone marrow microenvironment: therapeutic implications. Br J Haematol 2011;155:43848.
  • 274
    Sainz IM, Isordia-Salas I, Espinola RG, Long WK, Pixley RA, Colman RW. Multiple myeloma in a murine syngeneic model: modulation of growth and angiogenesis by a monoclonal antibody to kininogen. Cancer Immunol Immunother 2006;55:797807.
  • 275
    Matsui W, Huff CA, Wang Q, Malehorn MT, Barber J, Tanhehco Y, Smith BD, Civin CI, Jones RJ. Characterization of clonogenic multiple myeloma cells. Blood 2004;103:23326.
  • 276
    Treon SP, Mitsiades C, Mitsiades N, Young G, Doss D, Schlossman R, Anderson KC. Tumor cell expression of CD59 is associated with resistance to CD20 serotherapy in patients with B-cell malignancies. J Immunother 2001;24:26371.
  • 277
    Rozenfeld-Granot G, Toren A, Amariglio N, Brok-Simoni F, Rechavi G. Mutation analysis of the FAS and TNFR apoptotic cascade genes in hematological malignancies. Exp Hematol 2001;29:22833.
  • 278
    Matsui W, Huff CA, Vala M, Barber J, Smith BD, Jones RJ. Anti-tumour activity of interferon-alpha in multiple myeloma: role of interleukin 6 and tumor cell differentiation. Br J Haematol 2003;121:2518.
  • 279
    Zand MS, Vo T, Pellegrin T, Felgar R, Liesveld JL, Ifthikharuddin JJ, Abboud CN, Sanz I, Huggins J. Apoptosis and complement-mediated lysis of myeloma cells by polyclonal rabbit antithymocyte globulin. Blood 2006;107:2895903.
  • 280
    Richardson PG, Lonial S, Jakubowiak AJ, Harousseau JL, Anderson KC. Monoclonal antibodies in the treatment of multiple myeloma. Br J Haematol 2011; July 21, doi:10.1111/j.1365-2141.2011.08790.x.
  • 281
    Lambert JM. Drug-conjugated monoclonal antibodies for the treatment of cancer. Curr Opin Pharmacol 2005;5:5439.
  • 282
    Senter PD. Potent antibody drug conjugates for cancer therapy. Curr Opin Chem Biol 2009;13:23544.
  • 283
    Berardi S, Caivano A, Ria R, et al. Four proteins governing overangiogenic endothelial cell phenotype in patients with multiple myeloma are plausible therapeutic targets. Oncogene 2012;31:225869.
  • 284
    Tai YT, Anderson KC. Antibody-based therapies in multiple myeloma. Bone Marrow Res 2011;2011:924058.
  • 285
    Morgan G. Future drug developments in multiple myeloma: an overview of novel lenalidomide-based combination therapies. Blood Rev 2010;24:2732.