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Immunotherapeutic Strategies for Multiple Myeloma

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Cancer Immunology

Abstract

The advent of biologic-based therapies for multiple myeloma has resulted in improved patient outcomes over the last decade. However, curative outcomes remain elusive. There has been an increased appreciation of the critical role host immunity plays in the evolution of disease and the potential therapeutic efficacy of immune-based therapies. These treatment approaches hold the potential promise of selective targeting of the malignant clone, disruption of stromal-plasma cell interactions, and generation of sustained antitumor immunity and durable response. However, the development of clinically efficacious immunotherapy is dependent on achieving greater understanding of the complex interactions between the immunologic milieu and disease. A number of antigens have been identified on malignant plasma cell that may be targeted by both humoral and cell-mediated immunotherapeutic strategies, and encouraging results have been demonstrated both preclinically and in clinical trials. In this chapter we summarize the immunotherapeutic strategies for multiple myeloma together with the most up-to-date clinical trial outcomes.

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References

  1. Pilarski LM, Andrews EJ, Mant MJ, Ruether BA. Humoral immune deficiency in multiple myeloma patients due to compromised B-cell function. J Clin Immunol. 1986;6(6):491–501. PubMed PMID: 3023434.

    CAS  PubMed  Google Scholar 

  2. Savage DG, Lindenbaum J, Garrett TJ. Biphasic pattern of bacterial infection in multiple myeloma. Ann Intern Med. 1982;96(1):47–50. PubMed PMID: 6976144.

    CAS  PubMed  Google Scholar 

  3. Pratt G, Goodyear O, Moss P. Immunodeficiency and immunotherapy in multiple myeloma. Br J Haematol. 2007;138(5):563–79. PubMed PMID: 17686051.

    CAS  PubMed  Google Scholar 

  4. Chauhan D, Singh AV, Brahmandam M, Carrasco R, Bandi M, Hideshima T, et al. Functional interaction of plasmacytoid dendritic cells with multiple myeloma cells: a therapeutic target. Cancer Cell. 2009;16(4):309–23. PubMed PMID: 19800576, Epub 2009/10/06.eng.

    PubMed Central  CAS  PubMed  Google Scholar 

  5. Hayashi T, Hideshima T, Akiyama M, Raje N, Richardson P, Chauhan D, et al. Ex vivo induction of multiple myeloma-specific cytotoxic T lymphocytes. Blood. 2003;102(4):1435–42. PubMed PMID: 12714512, Epub 2003/04/26.eng.

    CAS  PubMed  Google Scholar 

  6. Spisek R, Kukreja A, Chen LC, Matthews P, Mazumder A, Vesole D, et al. Frequent and specific immunity to the embryonal stem cell-associated antigen SOX2 in patients with monoclonal gammopathy. J Exp Med. 2007;204(4):831–40. PubMed PMID: 17389240, Pubmed Central PMCID: 2118551.

    PubMed Central  CAS  PubMed  Google Scholar 

  7. 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 U S A. 2002;99(19):12293–7. PubMed PMID: 12218188, Epub 2002/09/10.eng.

    PubMed Central  CAS  PubMed  Google Scholar 

  8. Liu J, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, Hetuin D, et al. 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(1):296–304. PubMed PMID: 17363736, Epub 2007/03/17.eng.

    CAS  PubMed  Google Scholar 

  9. Rosenblatt J, Glotzbecker B, Mills H, Vasir B, Tzachanis D, Levine JD, et al. PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell/myeloma fusion vaccine. J Immunother. 2011;34(5):409–18. PubMed PMID: 21577144, Epub 2011/05/18.eng.

    PubMed Central  CAS  PubMed  Google Scholar 

  10. Godfrey J, Benson Jr DM. The role of natural killer cells in immunity against multiple myeloma. Leuk Lymphoma. 2012;53(9):1666–76. PubMed PMID: 22423650. Epub 2012/03/20.eng.

    CAS  PubMed  Google Scholar 

  11. Bryceson YT, March ME, Ljunggren HG, Long EO. Activation, coactivation, and costimulation of resting human natural killer cells. Immunol Rev. 2006;214:73–91. PubMed PMID: 17100877, Epub 2006/11/15.eng.

    CAS  PubMed  Google Scholar 

  12. Smyth MJ, Cretney E, Kelly JM, Westwood JA, Street SE, Yagita H, et al. Activation of NK cell cytotoxicity. Mol Immunol. 2005;42(4):501–10. PubMed PMID: 15607806, Epub 2004/12/21.eng.

    CAS  PubMed  Google Scholar 

  13. Jurisic V, Srdic T, Konjevic G, Markovic O, Colovic M. Clinical stage-depending decrease of NK cell activity in multiple myeloma patients. Med Oncol. 2007;24(3):312–7. PubMed PMID: 17873307, Epub 2007/09/18.eng.

    PubMed  Google Scholar 

  14. De Rossi G, De Sanctis G, Bottari V, Tribalto M, Lopez M, Petrucci MT, et al. Surface markers and cytotoxic activities of lymphocytes in monoclonal gammopathy of undetermined significance and untreated multiple myeloma. Increased phytohemagglutinin-induced cellular cytotoxicity and inverted helper/suppressor cell ratio are features common to both diseases. Cancer Immunol Immunother. 1987;25(2):133–6. PubMed PMID: 3664530, Epub 1987/01/01.eng.

    PubMed  Google Scholar 

  15. Garcia-Sanz R, Gonzalez M, Orfao A, Moro MJ, Hernandez JM, Borrego D, et al. Analysis of natural killer-associated antigens in peripheral blood and bone marrow of multiple myeloma patients and prognostic implications. Br J Haematol. 1996;93(1):81–8. PubMed PMID: 8611480, Epub 1996/04/01.eng.

    CAS  PubMed  Google Scholar 

  16. Becknell B, Caligiuri MA. Interleukin-2, interleukin-15, and their roles in human natural killer cells. Adv Immunol. 2005;86:209–39. PubMed PMID: 15705423, Epub 2005/02/12.eng.

    CAS  PubMed  Google Scholar 

  17. Tinhofer I, Marschitz I, Henn T, Egle A, Greil R. Expression of functional interleukin-15 receptor and autocrine production of interleukin-15 as mechanisms of tumor propagation in multiple myeloma. Blood. 2000;95(2):610–8. PubMed PMID: 10627470, Epub 2000/01/11.eng.

    CAS  PubMed  Google Scholar 

  18. Nielsen H, Nielsen HJ, Tvede N, Klarlund K, Mansa B, Moesgaard F, et al. Immune dysfunction in multiple myeloma. Reduced natural killer cell activity and increased levels of soluble interleukin-2 receptors. APMIS. 1991;99(4):340–6. PubMed PMID: 2036217, Epub 1991/04/01.eng.

    CAS  PubMed  Google Scholar 

  19. Carbone E, Neri P, Mesuraca M, Fulciniti MT, Otsuki T, Pende D, et al. HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells. Blood. 2005;105(1):251–8. PubMed PMID: 15328155, Epub 2004/08/26.eng.

    CAS  PubMed  Google Scholar 

  20. Benson Jr DM, Bakan CE, Mishra A, Hofmeister CC, Efebera Y, Becknell B, et al. The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood. 2010;116(13):2286–94. PubMed PMID: 20460501. Epub 2010/05/13.eng.

    PubMed Central  CAS  PubMed  Google Scholar 

  21. Fauriat C, Mallet F, Olive D, Costello RT. Impaired activating receptor expression pattern in natural killer cells from patients with multiple myeloma. Leukemia. 2006;20(4):732–3. PubMed PMID: 16437151, Epub 2006/01/27.eng.

    CAS  PubMed  Google Scholar 

  22. El-Sherbiny YM, Meade JL, Holmes TD, McGonagle D, Mackie SL, Morgan AW, et al. The requirement for DNAM-1, NKG2D, and NKp46 in the natural killer cell-mediated killing of myeloma cells. Cancer Res. 2007;67(18):8444–9. PubMed PMID: 17875681, Epub 2007/09/19.eng.

    CAS  PubMed  Google Scholar 

  23. Soriani A, Zingoni A, Cerboni C, Iannitto ML, Ricciardi MR, Di Gialleonardo V, et al. ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Blood. 2009;113(15):3503–11. PubMed PMID: 19098271, Epub 2008/12/23.eng.

    CAS  PubMed  Google Scholar 

  24. von Lilienfeld-Toal M, Frank S, Leyendecker C, Feyler S, Jarmin S, Morgan R, et al. Reduced immune effector cell NKG2D expression and increased levels of soluble NKG2D ligands in multiple myeloma may not be causally linked. Cancer Immunol Immunother. 2010;59(6):829–39. PubMed PMID: 20024547. Epub 2009/12/22.eng.

    CAS  Google Scholar 

  25. Costello RT, Boehrer A, Sanchez C, Mercier D, Baier C, Le Treut T, et al. Differential expression of natural killer cell activating receptors in blood versus bone marrow in patients with monoclonal gammopathy. Immunology. 2013;139(3):338–41. PubMed PMID: 23360454. Epub 2013/01/31.eng.

    PubMed Central  CAS  PubMed  Google Scholar 

  26. 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(2):199–213. PubMed PMID: 21852787. Epub 2011/08/20.eng.

    PubMed  Google Scholar 

  27. Weiner LM, Surana R, Wang S. Monoclonal antibodies: versatile platforms for cancer immunotherapy. Nat Rev Immunol. 2010;10(5):317–27. PubMed PMID: 20414205. Epub 2010/04/24.eng.

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Albert ML, Sauter B, Bhardwaj N. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature. 1998;392(6671):86–9. PubMed PMID: 9510252, Epub 1998/03/24.eng.

    CAS  PubMed  Google Scholar 

  29. Dhodapkar KM, Krasovsky J, Williamson B, Dhodapkar MV. Antitumor monoclonal antibodies enhance cross-presentation of cellular antigens and the generation of myeloma-specific killer T cells by dendritic cells. J Exp Med. 2002;195(1):125–33. PubMed PMID: 11781371, Epub 2002/01/10.eng.

    PubMed Central  CAS  PubMed  Google Scholar 

  30. Tai YT, Dillon M, Song W, Leiba M, Li XF, Burger P, et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood. 2008;112(4):1329–37. PubMed PMID: 17906076, Epub 2007/10/02.eng.

    PubMed Central  CAS  PubMed  Google Scholar 

  31. Hsi ED, Steinle R, Balasa B, Szmania S, Draksharapu A, Shum BP, et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res. 2008;14(9):2775–84. PubMed PMID: 18451245, Epub 2008/05/03.eng.

    CAS  PubMed  Google Scholar 

  32. Zonder JA, Mohrbacher AF, Singhal S, van Rhee F, Bensinger WI, Ding H, et al. A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Blood. 2012;120(3):552–9. PubMed PMID: 22184404. Epub 2011/12/21.eng.

    CAS  PubMed  Google Scholar 

  33. van Rhee F, Szmania SM, Dillon M, van Abbema AM, Li X, Stone MK, et al. Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma. Mol Cancer Ther. 2009;8(9):2616–24. PubMed PMID: 19723891, Epub 2009/09/03.eng.

    PubMed Central  PubMed  Google Scholar 

  34. Jakubowiak AJ, Benson DM, Bensinger W, Siegel DS, Zimmerman TM, Mohrbacher A, 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(16):1960–5. PubMed PMID: 22291084. Epub 2012/02/01.eng.

    CAS  PubMed  Google Scholar 

  35. Lonial S, Vij R, Harousseau JL, Facon T, Moreau P, Mazumder A, et al. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012;30(16):1953–9.

    CAS  PubMed  Google Scholar 

  36. Richardson PG, Jagannath S, Moreau P, Jakubowiak A, Raab MS, Facon T, Vij R, White DJ, Reece D, Benboubker L, Zonder JA, Deng W, Kroog G, Singhal AK, Lonial S, editors. 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. ASH annual meeting abstracts; 2012; Atlanta: Blood. 2012;120:202.

    Google Scholar 

  37. de Weers M, Tai YT, van der Veer MS, Bakker JM, Vink T, Jacobs DC, et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011;186(3):1840–8. PubMed PMID: 21187443.

    PubMed  Google Scholar 

  38. van der Veer MS, de Weers M, van Kessel B, Bakker JM, Wittebol S, Parren PW, et al. Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. Haematologica. 2011;96(2):284–90. PubMed PMID: 21109694, Pubmed Central PMCID: 3031697.

    PubMed Central  PubMed  Google Scholar 

  39. Plesner T, Lokhorst H, Gimsing P, Nahi H, Lisby S, Richardson PG, editors. Daratumumab, a CD38 monoclonal antibody in patients with multiple myeloma – data from a dose-escalation phase I/II study. ASH annual meeting; 2012; Atlanta: Blood. 2012;120:73.

    Google Scholar 

  40. Mahindra A, Hideshima T, Anderson KC. Multiple myeloma: biology of the disease. Blood Rev. 2010;24 Suppl 1:S5–11. PubMed PMID: 21126636. Epub 2010/12/04.eng.

    PubMed  Google Scholar 

  41. van de Donk NW, Lokhorst HM, Bloem AC. Growth factors and antiapoptotic signaling pathways in multiple myeloma. Leukemia. 2005;19(12):2177–85. PubMed PMID: 16239913, Epub 2005/10/22.eng.

    PubMed  Google Scholar 

  42. Hideshima T, Podar K, Chauhan D, Anderson KC. Cytokines and signal transduction. Best Pract Res Clin Haematol. 2005;18(4):509–24. PubMed PMID: 16026734.

    CAS  PubMed  Google Scholar 

  43. Voorhees PM, Chen Q, Kuhn DJ, Small GW, Hunsucker SA, Strader JS, et al. Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in preclinical models of multiple myeloma. Clin Cancer Res. 2007;13(21):6469–78. PubMed PMID: 17975159, Epub 2007/11/03.eng.

    CAS  PubMed  Google Scholar 

  44. van Zaanen HC, Lokhorst HM, Aarden LA, Rensink HJ, Warnaar SO, van der Lelie J, et al. Chimaeric anti-interleukin 6 monoclonal antibodies in the treatment of advanced multiple myeloma: a phase I dose-escalating study. Br J Haematol. 1998;102(3):783–90. PubMed PMID: 9722307, Epub 1998/08/29.eng.

    PubMed  Google Scholar 

  45. Kurzrock R, Voorhees PM, Casper C, Furman RR, Fayad L, Lonial S, et al. A phase I, open-label study of siltuximab, an anti-IL-6 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma, multiple myeloma, or Castleman disease. Clin Cancer Res. 2013;19(13):3659–70. PubMed PMID: 23659971. Epub 2013/05/11.eng.

    CAS  PubMed  Google Scholar 

  46. Orlowski RZ, Gercheva L, Williams C, Sutherland HJ, Robak T, Masszi T, Goranova-Marinova V, Dimopoulos MA, Cavenagh JD, Spicka I, Maiolino A, Suvorov A, Blade J, Samoilova OS, Van De Velde H, Bandekar R, Kranenburg R, Xie H, Jean-Francois R, editors. Phase II, randomized, double blind, placebo-controlled study comparing siltuximab plus bortezomib versus bortezomib alone in pts with relapsed/refractory multiple myeloma. ASCO annual meeting; 2012; Chicago: Journal of Clinical Oncology. 2012;30:8018

    Google Scholar 

  47. Luptakova K, Rosenblatt J, Glotzbecker B, Mills H, Stroopinsky D, Kufe T, et al. Lenalidomide enhances anti-myeloma cellular immunity. Cancer Immunol Immunother. 2013;62(1):39–49. PubMed PMID: 22733396. Epub 2012/06/27. Eng.

    PubMed Central  CAS  PubMed  Google Scholar 

  48. Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14(10):3044–51. PubMed PMID: 18483370, Epub 2008/05/17. eng.

    CAS  PubMed  Google Scholar 

  49. Rosenblatt J, Avivi I, Vasir B, Uhl L, Katz T, Somaiya P, Mills H, Joyce R, Levine JD, Tzachanis D, Boussiotis VA, Luptakova K, Arnason JE, Drummy N, Delaney C, Breault E, Held V, Bisharat L, Giallombardo N, Conway K, Mortellite J, Wagoner J, Schickler M, Rotem-Yehudar R, Richardson PG, Laubach JP, Munshi NC, Anderson KC, Rowe JM, Kufe D, Avigan D, editors. Blockade of PD-1 in combination with dendritic cell/myeloma fusion cell vaccination following autologous stem cell transplantation. ASH annual meeting; 2012; Atlanta: Blood. 2012:120:578.

    Google Scholar 

  50. Bird JM, Russell NH, Samson D. Minimal residual disease after bone marrow transplantation for multiple myeloma: evidence for cure in long-term survivors. Bone Marrow Transplant. 1993;12(6):651–4. PubMed PMID: 8136748, Epub 1993/12/01. eng.

    CAS  PubMed  Google Scholar 

  51. Seiden MV, Schlossman R, Andersen J, Freeman A, Robertson M, Soiffer R, et al. Monoclonal antibody-purged bone marrow transplantation therapy for multiple myeloma. Leuk Lymphoma. 1995;17(1–2):87–93. PubMed PMID: 7773166, Epub 1995/03/01. eng.

    CAS  PubMed  Google Scholar 

  52. Bensinger WI, Buckner CD, Anasetti C, Clift R, Storb R, Barnett T, et al. Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome. Blood. 1996;88(7):2787–93. PubMed PMID: 8839877, Epub 1996/10/01. eng.

    CAS  PubMed  Google Scholar 

  53. Russell NH, Miflin G, Stainer C, McQuaker JG, Bienz N, Haynes AP, et al. Allogeneic bone marrow transplant for multiple myeloma. Blood. 1997;89(7):2610–1. PubMed PMID: 9116309, Epub 1997/04/01. eng.

    CAS  PubMed  Google Scholar 

  54. Gahrton G, Tura S, Ljungman P, Blade J, Brandt L, Cavo M, et al. Prognostic factors in allogeneic bone marrow transplantation for multiple myeloma. J Clin Oncol Off J Am Soc Clin Oncol. 1995;13(6):1312–22. PubMed PMID: 7751876, Epub 1995/06/01. eng.

    CAS  Google Scholar 

  55. Kuruvilla J, Shepherd JD, Sutherland HJ, Nevill TJ, Nitta J, Le A, et al. Long-term outcome of myeloablative allogeneic stem cell transplantation for multiple myeloma. Biol Blood Marrow Transplant. 2007;13(8):925–31. PubMed PMID: 17640596, Epub 2007/07/21. eng.

    PubMed  Google Scholar 

  56. Crawley C, Lalancette M, Szydlo R, Gilleece M, Peggs K, Mackinnon S, et al. Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic Leukaemia Working Party of the EBMT. Blood. 2005;105(11):4532–9. PubMed PMID: 15731182, Epub 2005/02/26. eng.

    CAS  PubMed  Google Scholar 

  57. Bellucci R, Alyea EP, Weller E, Chillemi A, Hochberg E, Wu CJ, et al. Immunologic effects of prophylactic donor lymphocyte infusion after allogeneic marrow transplantation for multiple myeloma. Blood. 2002;99(12):4610–7. PubMed PMID: 12036895, Epub 2002/05/31. eng.

    CAS  PubMed  Google Scholar 

  58. Kroger N, Kruger W, Renges H, Zabelina T, Stute N, Jung R, et al. Donor lymphocyte infusion enhances remission status in patients with persistent disease after allografting for multiple myeloma. Br J Haematol. 2001;112(2):421–3. PubMed PMID: 11167841, Epub 2001/02/13. eng.

    CAS  PubMed  Google Scholar 

  59. Badros A, Barlogie B, Morris C, Desikan R, Martin SR, Munshi N, et al. High response rate in refractory and poor-risk multiple myeloma after allotransplantation using a nonmyeloablative conditioning regimen and donor lymphocyte infusions. Blood. 2001;97(9):2574–9. PubMed PMID: 11313244, Epub 2001/04/21. eng.

    CAS  PubMed  Google Scholar 

  60. Orsini E, Alyea EP, Schlossman R, Canning C, Soiffer RJ, Chillemi A, et al. Changes in T cell receptor repertoire associated with graft-versus-tumor effect and graft-versus-host disease in patients with relapsed multiple myeloma after donor lymphocyte infusion. Bone Marrow Transplant. 2000;25(6):623–32. PubMed PMID: 10734296, Epub 2000/03/29. eng.

    CAS  PubMed  Google Scholar 

  61. Lokhorst HM, Wu K, Verdonck LF, Laterveer LL, van de Donk NW, van Oers MH, et al. The occurrence of graft-versus-host disease is the major predictive factor for response to donor lymphocyte infusions in multiple myeloma. Blood. 2004;103(11):4362–4. PubMed PMID: 14976044, Epub 2004/02/21. eng.

    CAS  PubMed  Google Scholar 

  62. Qian J, Wang S, Yang J, Xie J, Lin P, Freeman 3rd ME, et al. Targeting heat shock proteins for immunotherapy in multiple myeloma: generation of myeloma-specific CTLs using dendritic cells pulsed with tumor-derived gp96. Clin Cancer Res. 2005;11(24 Pt 1):8808–15. PubMed PMID: 16361569, Epub 2005/12/20. eng.

    CAS  PubMed  Google Scholar 

  63. Takahashi T, Makiguchi Y, Hinoda Y, Kakiuchi H, Nakagawa N, Imai K, et al. Expression of MUC1 on myeloma cells and induction of HLA-unrestricted CTL against MUC1 from a multiple myeloma patient. J Immunol. 1994;153(5):2102–9. PubMed PMID: 8051415, Epub 1994/09/01. eng.

    CAS  PubMed  Google Scholar 

  64. Brossart P, Schneider A, Dill P, Schammann T, Grunebach F, Wirths S, et al. The epithelial tumor antigen MUC1 is expressed in hematological malignancies and is recognized by MUC1-specific cytotoxic T-lymphocytes. Cancer Res. 2001;61(18):6846–50. PubMed PMID: 11559560.

    CAS  PubMed  Google Scholar 

  65. Lim SH, Wang Z, Chiriva-Internati M, Xue Y. Sperm protein 17 is a novel cancer-testis antigen in multiple myeloma. Blood. 2001;97(5):1508–10. PubMed PMID: 11222401, Epub 2001/02/27. eng.

    CAS  PubMed  Google Scholar 

  66. Szmania S, Tricot G, van Rhee F. NY-ESO-1 immunotherapy for multiple myeloma. Leuk Lymphoma. 2006;47(10):2037–48. PubMed PMID: 17071474, Epub 2006/10/31. eng.

    CAS  PubMed  Google Scholar 

  67. Atanackovic D, Arfsten J, Cao Y, Gnjatic S, Schnieders F, Bartels K, et al. Cancer-testis antigens are commonly expressed in multiple myeloma and induce systemic immunity following allogeneic stem cell transplantation. Blood. 2007;109(3):1103–12. PubMed PMID: 17023585, Epub 2006/10/07. eng.

    CAS  PubMed  Google Scholar 

  68. Hundemer M, Schmidt S, Condomines M, Lupu A, Hose D, Moos M, et al. Identification of a new HLA-A2-restricted T-cell epitope within HM1.24 as immunotherapy target for multiple myeloma. Exp Hematol. 2006;34(4):486–96. PubMed PMID: 16569595, Epub 2006/03/30. eng.

    PubMed Central  CAS  PubMed  Google Scholar 

  69. Pellat-Deceunynck C, Mellerin MP, Labarriere N, Jego G, Moreau-Aubry A, Harousseau JL, et al. The cancer germ-line genes MAGE-1, MAGE-3 and PRAME are commonly expressed by human myeloma cells. Eur J Immunol. 2000;30(3):803–9. PubMed PMID: 10741395, Epub 2000/03/31. eng.

    CAS  PubMed  Google Scholar 

  70. Avigan D. Dendritic cells: development, function and potential use for cancer immunotherapy. Blood Rev. 1999;13(1):51–64.

    CAS  PubMed  Google Scholar 

  71. Wen YJ, Min R, Tricot G, Barlogie B, Yi Q. Tumor lysate-specific cytotoxic T lymphocytes in multiple myeloma: promising effector cells for immunotherapy. Blood. 2002;99(9):3280–5. PubMed PMID: 11964294, Epub 2002/04/20. eng.

    CAS  PubMed  Google Scholar 

  72. Dembic Z, Schenck K, Bogen B. Dendritic cells purified from myeloma are primed with tumor-specific antigen (idiotype) and activate CD4+ T cells. Proc Natl Acad Sci U S A. 2000;97(6):2697–702. PubMed PMID: 10706628, Epub 2000/03/08. eng.

    PubMed Central  CAS  PubMed  Google Scholar 

  73. O’Neill DW, Adams S, Bhardwaj N. Manipulating dendritic cell biology for the active immunotherapy of cancer. Blood. 2004;104(8):2235–46. PubMed PMID: 15231572, Epub 2004/07/03. eng.

    PubMed  Google Scholar 

  74. Szabolcs P, Moore MA, Young JW. Expansion of immunostimulatory dendritic cells among the myeloid progeny of human CD34+ bone marrow precursors cultured with c-kit ligand, granulocyte-macrophage colony-stimulating factor, and TNF-alpha. J Immunol. 1995;154(11):5851–61.

    CAS  PubMed  Google Scholar 

  75. Racanelli V, Leone P, Frassanito MA, Brunetti C, Perosa F, Ferrone S, et al. Alterations in the antigen processing-presenting machinery of transformed plasma cells are associated with reduced recognition by CD8+ T cells and characterize the progression of MGUS to multiple myeloma. Blood. 2011;115(6):1185–93. PubMed PMID: 20008301, Epub 2009/12/17. eng.

    Google Scholar 

  76. Lee JJ, Choi BH, Kang HK, Park MS, Park JS, Kim SK, et al. Induction of multiple myeloma-specific cytotoxic T lymphocyte stimulation by dendritic cell pulsing with purified and optimized myeloma cell lysates. Leuk Lymphoma. 2007;48(10):2022–31. PubMed PMID: 17917970, Epub 2007/10/06. eng.

    CAS  PubMed  Google Scholar 

  77. Signori E, Iurescia S, Massi E, Fioretti D, Chiarella P, De Robertis M, et al. DNA vaccination strategies for anti-tumour effective gene therapy protocols. Cancer Immunol Immunother. 2010;59(10):1583–91. PubMed PMID: 20390416. Epub 2010/04/15. eng.

    CAS  PubMed  Google Scholar 

  78. Fioretti D, Iurescia S, Fazio VM, Rinaldi M. DNA vaccines: developing new strategies against cancer. J Biomed Biotechnol. 2010;2010:174378. PubMed PMID: 20368780, Epub 2010/04/07.eng.

    PubMed Central  PubMed  Google Scholar 

  79. Spisek R, Chevallier P, Morineau N, Milpied N, Avet-Loiseau H, Harousseau JL, et al. Induction of leukemia-specific cytotoxic response by cross-presentation of late-apoptotic leukemic blasts by autologous dendritic cells of nonleukemic origin. Cancer Res. 2002;62(10):2861–8. PubMed PMID: 12019165.

    CAS  PubMed  Google Scholar 

  80. Gulley JL, Arlen PM, Tsang KY, Yokokawa J, Palena C, Poole DJ, et al. Pilot study of vaccination with recombinant CEA-MUC-1-TRICOM poxviral-based vaccines in patients with metastatic carcinoma. Clin Cancer Res. 2008;14(10):3060–9. PubMed PMID: 18483372, Epub 2008/05/17.eng.

    PubMed Central  CAS  PubMed  Google Scholar 

  81. Kaufman HL, Kim-Schulze S, Manson K, DeRaffele G, Mitcham J, Seo KS, et al. Poxvirus-based vaccine therapy for patients with advanced pancreatic cancer. J Transl Med. 2007;5:60. PubMed PMID: 18039393, Epub 2007/11/28.eng.

    PubMed Central  PubMed  Google Scholar 

  82. Lou E, Marshall J, Aklilu M, Cole D, Chang D, Morse M. A phase II study of active immunotherapy with PANVAC or autologous, cultured dendritic cells infected with PANVAC after complete resection of hepatic metastases of colorectal carcinoma. Clin Colorectal Cancer. 2006;5(5):368–71. PubMed PMID: 16512998, Epub 2006/03/04.eng.

    PubMed  Google Scholar 

  83. Litzinger MT, Foon KA, Tsang KY, Schlom J, Palena C. Comparative analysis of MVA-CD40L and MVA-TRICOM vectors for enhancing the immunogenicity of chronic lymphocytic leukemia (CLL) cells. Leuk Res. 2010;34(10):1351–7. PubMed PMID: 20122733, Epub 2010/02/04.eng.

    PubMed Central  CAS  PubMed  Google Scholar 

  84. Rosenblatt J, Kufe D, Avigan D. Dendritic cell fusion vaccines for cancer immunotherapy. Expert Opin Biol Ther. 2005;5(5):703–15. PubMed PMID: 15934845, Epub 2005/06/07.eng.

    CAS  PubMed  Google Scholar 

  85. Gong J, Chen D, Kashiwaba M, Kufe D. Induction of antitumor activity by immunization with fusions of dendritic and carcinoma cells. Nat Med. 1997;3(5):558–61.

    CAS  PubMed  Google Scholar 

  86. Vasir B, Borges V, Wu Z, Grosman D, Rosenblatt J, Irie M, et al. Fusion of dendritic cells with multiple myeloma cells results in maturation and enhanced antigen presentation. Br J Haematol. 2005;129(5):687–700. PubMed PMID: 15916692.

    CAS  PubMed  Google Scholar 

  87. Lynch RG, Graff RJ, Sirisinha S, Simms ES, Eisen HN. Myeloma proteins as tumor-specific transplantation antigens. Proc Natl Acad Sci U S A. 1972;69(6):1540–4. PubMed PMID: 4113870, Epub 1972/06/01.eng.

    PubMed Central  CAS  PubMed  Google Scholar 

  88. Osterborg A, Yi Q, Henriksson L, Fagerberg J, Bergenbrant S, Jeddi-Tehrani M, et al. Idiotype immunization combined with granulocyte-macrophage colony-stimulating factor in myeloma patients induced type I, major histocompatibility complex-restricted, CD8- and CD4-specific T-cell responses. Blood. 1998;91(7):2459–66. PubMed PMID: 9516146.

    CAS  PubMed  Google Scholar 

  89. Wen YJ, Ling M, Bailey-Wood R, Lim SH. Idiotypic protein-pulsed adherent peripheral blood mononuclear cell-derived dendritic cells prime immune system in multiple myeloma. Clin Cancer Res. 1998;4(4):957–62. PubMed PMID: 9563890, Epub 1998/05/14.eng.

    CAS  PubMed  Google Scholar 

  90. Lim SH, Bailey-Wood R. Idiotypic protein-pulsed dendritic cell vaccination in multiple myeloma. Int J Cancer. 1999;83(2):215–22. PubMed PMID: 10471530, Epub 1999/09/02.eng.

    CAS  PubMed  Google Scholar 

  91. Cull G, Durrant L, Stainer C, Haynes A, Russell N. Generation of anti-idiotype immune responses following vaccination with idiotype-protein pulsed dendritic cells in myeloma. Br J Haematol. 1999;107(3):648–55. PubMed PMID: 10583271, Epub 1999/12/03.eng.

    CAS  PubMed  Google Scholar 

  92. Titzer S, Christensen O, Manzke O, Tesch H, Wolf J, Emmerich B, et al. Vaccination of multiple myeloma patients with idiotype-pulsed dendritic cells: immunological and clinical aspects. Br J Haematol. 2000;108(4):805–16. PubMed PMID: 10792287, Epub 2000/05/03.eng.

    CAS  PubMed  Google Scholar 

  93. Reichardt VL, Okada CY, Liso A, Benike CJ, Stockerl-Goldstein KE, Engleman EG, et al. Idiotype vaccination using dendritic cells after autologous peripheral blood stem cell transplantation for multiple myeloma–a feasibility study. Blood. 1999;93(7):2411–9. PubMed PMID: 10090953.

    CAS  PubMed  Google Scholar 

  94. Yasukawa M, Fujiwara H, Ochi T, Suemori K, Narumi H, Azuma T, et al. Clinical efficacy of WT1 peptide vaccination in patients with acute myelogenous leukemia and myelodysplastic syndrome. Am J Hematol. 2009;84(5):314–5. PubMed PMID: 19338044, Epub 2009/04/02.eng.

    PubMed  Google Scholar 

  95. Ochsenreither S, Fusi A, Geikowski A, Stather D, Busse A, Stroux A, et al. Wilms’ tumor protein 1 (WT1) peptide vaccination in AML patients: predominant TCR CDR3beta sequence associated with remission in one patient is detectable in other vaccinated patients. Cancer Immunol Immunother. 2012;61(3):313–22. PubMed PMID: 21898091, Epub 2011/09/08.eng.

    CAS  PubMed  Google Scholar 

  96. van Rhee F, Szmania SM, Zhan F, Gupta SK, Pomtree M, Lin P, et al. NY-ESO-1 is highly expressed in poor-prognosis multiple myeloma and induces spontaneous humoral and cellular immune responses. Blood. 2005;105(10):3939–44. PubMed PMID: 15671442, Epub 2005/01/27.eng.

    PubMed Central  PubMed  Google Scholar 

  97. Batchu RB, Moreno AM, Szmania SM, Bennett G, Spagnoli GC, Ponnazhagan S, et al. Protein transduction of dendritic cells for NY-ESO-1-based immunotherapy of myeloma. Cancer Res. 2005;65(21):10041–9. PubMed PMID: 16267030, Epub 2005/11/04.eng.

    CAS  PubMed  Google Scholar 

  98. Bae J, Smith R, Daley J, Mimura N, Tai YT, Anderson KC, et al. Myeloma-specific multiple peptides able to generate cytotoxic T lymphocytes: a potential therapeutic application in multiple myeloma and other plasma cell disorders. Clin Cancer Res. 2012;18(17):4850–60. PubMed PMID: 22753586.

    CAS  PubMed  Google Scholar 

  99. Bae J, Song W, Smith R, Daley J, Tai YT, Anderson KC, et al. A novel immunogenic CS1-specific peptide inducing antigen-specific cytotoxic T lymphocytes targeting multiple myeloma. Br J Haematol. 2012;157(6):687–701. PubMed PMID: 22533610.

    CAS  PubMed  Google Scholar 

  100. Bae J, Tai YT, Anderson KC, Munshi NC. Novel epitope evoking CD138 antigen-specific cytotoxic T lymphocytes targeting multiple myeloma and other plasma cell disorders. Br J Haematol. 2011;155(3):349–61. PubMed PMID: 21902685.

    PubMed Central  CAS  PubMed  Google Scholar 

  101. Bae J, Carrasco R, Lee AH, Prabhala R, Tai YT, Anderson KC, et al. Identification of novel myeloma-specific XBP1 peptides able to generate cytotoxic T lymphocytes: a potential therapeutic application in multiple myeloma. Leukemia. 2011;25(10):1610–9. PubMed PMID: 21660045, Pubmed Central PMCID: 3483794.

    PubMed Central  CAS  PubMed  Google Scholar 

  102. Cohen S, Haimovich J, Hollander N. Dendritic cell-based therapeutic vaccination against myeloma: vaccine formulation determines efficacy against light chain myeloma. J Immunol. 2009;182(3):1667–73. PubMed PMID: 19155516.

    CAS  PubMed  Google Scholar 

  103. Gong J, Koido S, Chen D, Tanaka Y, Huang L, Avigan D, et al. Immunization against murine multiple myeloma with fusions of dendritic and plasmacytoma cells is potentiated by interleukin 12. Blood. 2002;99(7):2512–7.

    CAS  PubMed  Google Scholar 

  104. Rosenblatt J, Vasir B, Uhl L, Blotta S, Macnamara C, Somaiya P, 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(2):393–402. PubMed PMID: 21030562, Epub 2010/10/30.eng.

    PubMed Central  CAS  PubMed  Google Scholar 

  105. Hayashi T, Hideshima T, Akiyama M, Podar K, Yasui H, Raje N, et al. Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells: clinical application. Br J Haematol. 2005;128(2):192–203. PubMed PMID: 15638853, Epub 2005/01/11.eng.

    CAS  PubMed  Google Scholar 

  106. Tai YT, Li XF, Catley L, Coffey R, Breitkreutz I, Bae J, 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(24):11712–20. PubMed PMID: 16357183, Epub 2005/12/17.eng.

    CAS  PubMed  Google Scholar 

  107. Benson Jr DM, Bakan CE, Zhang S, Collins SM, Liang J, Srivastava S, et al. IPH2101, a novel anti-inhibitory KIR antibody, and lenalidomide combine to enhance the natural killer cell versus multiple myeloma effect. Blood. 2011;118(24):6387–91. PubMed PMID: 22031859. Epub 2011/10/28.eng.

    PubMed Central  CAS  PubMed  Google Scholar 

  108. Shi J, Tricot GJ, Garg TK, Malaviarachchi PA, Szmania SM, Kellum RE, et al. Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell-mediated lysis of myeloma. Blood. 2008;111(3):1309–17. PubMed PMID: 17947507, Epub 2007/10/20.eng.

    PubMed Central  CAS  PubMed  Google Scholar 

  109. Porrata LF, Gastineau DA, Padley D, Bundy K, Markovic SN. Re-infused autologous graft natural killer cells correlates with absolute lymphocyte count recovery after autologous stem cell transplantation. Leuk Lymphoma. 2003;44(6):997–1000. PubMed PMID: 12854901, Epub 2003/07/12.eng.

    CAS  PubMed  Google Scholar 

  110. Siddiqui MA, Svetomir NM, Nevala WK, Uhl CB, Morice WG, Porrata LF, editors. Day 15 natural killer (NK) cell recovery predicts progression free survival after autologous stem cell transplantation in non-hodgkin’s lymphoma. ASH annual meeting; 2006; Orlando: Blood. 2006;108:2914.

    Google Scholar 

  111. Kroger N, Shaw B, Iacobelli S, Zabelina T, Peggs K, Shimoni A, et al. Comparison between antithymocyte globulin and alemtuzumab and the possible impact of KIR-ligand mismatch after dose-reduced conditioning and unrelated stem cell transplantation in patients with multiple myeloma. Br J Haematol. 2005;129(5):631–43. PubMed PMID: 15916686, Epub 2005/05/27.Eng.

    PubMed  Google Scholar 

  112. Shi J, Tricot G, Szmania S, Rosen N, Garg TK, Malaviarachchi PA, et al. Infusion of haplo-identical killer immunoglobulin-like receptor ligand mismatched NK cells for relapsed myeloma in the setting of autologous stem cell transplantation. Br J Haematol. 2008;143(5):641–53. PubMed PMID: 18950462, Epub 2008/10/28.eng.

    PubMed Central  PubMed  Google Scholar 

  113. Kroger N, Zabelina T, Berger J, Duske H, Klyuchnikov E, Binder T, et al. Donor KIR haplotype B improves progression-free and overall survival after allogeneic hematopoietic stem cell transplantation for multiple myeloma. Leukemia. 2011;25(10):1657–61. PubMed PMID: 21647155. Epub 2011/06/08.eng.

    CAS  PubMed  Google Scholar 

  114. Lioznov M, El-Cheikh Jr J, Hoffmann F, Hildebrandt Y, Ayuk F, Wolschke C, et al. Lenalidomide as salvage therapy after allo-SCT for multiple myeloma is effective and leads to an increase of activated NK (NKp44(+)) and T (HLA-DR(+)) cells. Bone Marrow Transplant. 2010;45(2):349–53. PubMed PMID: 19584825. Epub 2009/07/09.eng.

    CAS  PubMed  Google Scholar 

  115. Wolschke C, Stubig T, Hegenbart U, Schonland S, Heinzelmann M, Hildebrandt Y, et al. Postallograft lenalidomide induces strong NK cell-mediated antimyeloma activity and risk for T cell-mediated GvHD: Results from a phase I/II dose-finding study. Exp Hematol. 2013;41(2):134–42 e3. PubMed PMID: 23085463. Epub 2012/10/23.eng.

    CAS  PubMed  Google Scholar 

  116. Romagne F, Andre P, Spee P, Zahn S, Anfossi N, Gauthier L, 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(13):2667–77. PubMed PMID: 19553639, Epub 2009/06/26.eng.

    PubMed Central  CAS  PubMed  Google Scholar 

  117. Benson Jr DM, Hofmeister CC, Padmanabhan S, Suvannasankha A, Jagannath S, Abonour R, et al. A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma. Blood. 2012;120(22):4324–33. PubMed PMID: 23033266. Epub 2012/10/04.eng.

    PubMed Central  CAS  PubMed  Google Scholar 

  118. Schmudde M, Braun A, Pende D, Sonnemann J, Klier U, Beck JF, et al. Histone deacetylase inhibitors sensitize tumour cells for cytotoxic effects of natural killer cells. Cancer Lett. 2008;272(1):110–21. PubMed PMID: 18718708, Epub 2008/08/23.eng.

    CAS  PubMed  Google Scholar 

  119. Wu X, Tao Y, Hou J, Meng X, Shi J. Valproic acid upregulates NKG2D ligand expression through an ERK-dependent mechanism and potentially enhances NK cell-mediated lysis of myeloma. Neoplasia. 2012;14(12):1178–89. PubMed PMID: 23308050. Epub 2013/01/12.eng.

    PubMed Central  CAS  PubMed  Google Scholar 

  120. Alici E, Sutlu T, Bjorkstrand B, Gilljam M, Stellan B, Nahi H, et al. Autologous antitumor activity by NK cells expanded from myeloma patients using GMP-compliant components. Blood. 2008;111(6):3155–62. PubMed PMID: 18192509, Epub 2008/01/15.eng.

    CAS  PubMed  Google Scholar 

  121. Garg TK, Szmania SM, Khan JA, Hoering A, Malbrough PA, Moreno-Bost A, et al. Highly activated and expanded natural killer cells for multiple myeloma immunotherapy. Haematologica. 2012;97(9):1348–56. PubMed PMID: 22419581. Epub 2012/03/16.eng.

    PubMed Central  CAS  PubMed  Google Scholar 

  122. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725–33. PubMed PMID: 21830940, Pubmed Central PMCID: 3387277.

    PubMed Central  CAS  PubMed  Google Scholar 

  123. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509–18. PubMed PMID: 23527958.

    PubMed Central  CAS  PubMed  Google Scholar 

  124. Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5(177):177ra38. PubMed PMID: 23515080. Pubmed Central PMCID: 3742551.

    PubMed Central  PubMed  Google Scholar 

  125. Carpenter RO, Evbuomwan MO, Pittaluga S, Rose JJ, Raffeld M, Yang S, et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res. 2013;19(8):2048–60. PubMed PMID: 23344265. Epub 2013/01/25.eng.

    PubMed Central  CAS  PubMed  Google Scholar 

  126. Schuberth PC, Jakka G, Jensen SM, Wadle A, Gautschi F, Haley D, et al. Effector memory and central memory NY-ESO-1-specific re-directed T cells for treatment of multiple myeloma. Gene Ther. 2013;20(4):386–95. PubMed PMID: 22739387. Epub 2012/06/29.eng.

    CAS  PubMed  Google Scholar 

  127. Dhodapkar MV, Abe E, Theus A, Lacy M, Langford JK, Barlogie B, et al. Syndecan-1 is a multifunctional regulator of myeloma pathobiology: control of tumor cell survival, growth, and bone cell differentiation. Blood. 1998;91(8):2679–88. PubMed PMID: 9531576.

    CAS  PubMed  Google Scholar 

  128. Jagannath SA, Chanan-Khan A, Heffner LT, Avigan D, Lutz RJ, Uherek C, Osterroth F, Ruehle M, Haeder, Niemann G, Wartenberg-Demand A, Munshi NC, Anderson KC, editors. BT062, An antibody-drug conjugate directed against CD138, shows clinical activity in a phase I study in patients with relapsed or relapsed/refractory multiple myeloma. ASH annual meeting; 2010; Orlando: Blood. 2010;116:3060.

    Google Scholar 

  129. Chanan-Khan A, Wolf JL, Garcia J, Gharibo M, Jagannath S, Manfredi D, Sher T, Martin C, Zildjian SH, O’Leary J, Vescio R, editors. Efficacy analysis from phase I study of lorvotuzumab mertansine (IMGN901), used as monotherapy, in patients with heavily pre-treated CD56-positive multiple myeloma – a preliminary efficacy analysis. ASH annual meeting; 2010; Orlando: Blood. 2010;116:1962.

    Google Scholar 

  130. Berdeja JG, Hernandez-Ilizaliturri F, Chanan-Khan A, Patel M, Kelly KR, Running KL, Murphy M, Guild R, Carrigan C, Ladd S, Wolf BB, O’Leary JJ, Ailawadhi S, editors. Phase I study of Lorvotuzumab Mertansine (LM, IMGN901) in combination with lenalidomide (Len) and dexamethasone (Dex) in patients with CD56-positive relapsed or relapsed/refractory multiple myeloma (MM). ASH annual meeting; 2012; Atlanta: Blood. 2012;120;728.

    Google Scholar 

  131. Qiang YW, Kopantzev E, Rudikoff S. Insulinlike growth factor-I signaling in multiple myeloma: downstream elements, functional correlates, and pathway cross-talk. Blood. 2002;99(11):4138–46. PubMed PMID: 12010818.

    CAS  PubMed  Google Scholar 

  132. Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Akiyama M, et al. Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Cancer Cell. 2004;5(3):221–30. PubMed PMID: 15050914.

    CAS  PubMed  Google Scholar 

  133. Bataille R, Robillard N, Avet-Loiseau H, Harousseau JL, Moreau P. CD221 (IGF-1R) is aberrantly expressed in multiple myeloma, in relation to disease severity. Haematologica. 2005;90(5):706–7. PubMed PMID: 15921396.

    CAS  PubMed  Google Scholar 

  134. Moreau P, Cavallo F, Leleu X, Hulin C, Amiot M, Descamps G, et al. 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(5):872–4. PubMed PMID: 21321571.

    CAS  PubMed  Google Scholar 

  135. Lacy MQ, Alsina M, Fonseca R, Paccagnella ML, Melvin CL, Yin D, 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(19):3196–203. PubMed PMID: 18474873.

    CAS  PubMed  Google Scholar 

  136. Somlo G, Lashkari A, Bellamy W, Zimmerman TM, Tuscano JM, O’Donnell MR, 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(4):533–5. PubMed PMID: 21517811, Pubmed Central PMCID: 3272081.

    PubMed Central  PubMed  Google Scholar 

  137. White D, Kassim A, Bhaskar B, Yi J, Wamstad K, Paton VE. Results from AMBER, a randomized phase 2 study of bevacizumab and bortezomib versus bortezomib in relapsed or refractory multiple myeloma. Cancer. 2013;119(2):339–47. PubMed PMID: 22811009.

    CAS  PubMed  Google Scholar 

  138. Humbert AT, RC, McFarland T, Go R, Markovina S, Miyamoto S, Williams EC, Asimakopoulos F, Kolesar J, Thompson MA, Kim K, Callander N, editors. Angiogenic blockade with bevacizumab does not increase response to lenalidomide and low dose dexamethasone in relapsed or refractory myeloma. ASH annual meeting; 2012; Atlanta: Blood. 2012;120:5041.

    Google Scholar 

  139. Moreaux J, Cremer FW, Reme T, Raab M, Mahtouk K, Kaukel P, 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(3):1021–30. PubMed PMID: 15827134, Pubmed Central PMCID: 2408610.

    PubMed Central  CAS  PubMed  Google Scholar 

  140. Moreaux J, Legouffe E, Jourdan E, Quittet P, Reme T, Lugagne C, et al. BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood. 2004;103(8):3148–57. PubMed PMID: 15070697, Pubmed Central PMCID: 2387243.

    PubMed Central  CAS  PubMed  Google Scholar 

  141. Tai YT, Li XF, Breitkreutz I, Song W, Neri P, Catley L, 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(13):6675–82. PubMed PMID: 16818641.

    CAS  PubMed  Google Scholar 

  142. Leng L, Metz CN, Fang Y, Xu J, Donnelly S, Baugh J, et al. MIF signal transduction initiated by binding to CD74. J Exp Med. 2003;197(11):1467–76. PubMed PMID: 12782713, Pubmed Central PMCID: 2193907.

    PubMed Central  CAS  PubMed  Google Scholar 

  143. Lantner F, Starlets D, Gore Y, Flaishon L, Yamit-Hezi A, Dikstein R, et al. CD74 induces TAp63 expression leading to B-cell survival. Blood. 2007;110(13):4303–11. PubMed PMID: 17846227.

    CAS  PubMed  Google Scholar 

  144. Kaufman JL, RN, Stadtmauer EA, Chanan-Khan A, Siegel D, Horne H, Teoh N, Wegener WA, Goldenberg DM, editors. Dose-escalation trial of milatuzumab (humanized anti-CD74 monoclonal antibody) in multiple myeloma. ASCO annual meeting; 2009; Orlando: Journal of Clinical Oncology. 2009;27:8593.

    Google Scholar 

  145. Tai YT, Podar K, Gupta D, Lin B, Young G, Akiyama M, et al. CD40 activation induces p53-dependent vascular endothelial growth factor secretion in human multiple myeloma cells. Blood. 2002;99(4):1419–27. PubMed PMID: 11830495.

    CAS  PubMed  Google Scholar 

  146. Tai YT, Podar K, Mitsiades N, Lin B, Mitsiades C, Gupta D, et al. CD40 induces human multiple myeloma cell migration via phosphatidylinositol 3-kinase/AKT/NF-kappa B signaling. Blood. 2003;101(7):2762–9. PubMed PMID: 12433678.

    CAS  PubMed  Google Scholar 

  147. Urashima M, Chauhan D, Uchiyama H, Freeman GJ, Anderson KC. CD40 ligand triggered interleukin-6 secretion in multiple myeloma. Blood. 1995;85(7):1903–12. PubMed PMID: 7535594.

    CAS  PubMed  Google Scholar 

  148. Gupta D, Treon SP, Shima Y, Hideshima T, Podar K, Tai YT, et al. Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia. 2001;15(12):1950–61. PubMed PMID: 11753617.

    CAS  PubMed  Google Scholar 

  149. Hussein M, Berenson JR, Niesvizky R, Munshi N, Matous J, Sobecks 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(5):845–8. PubMed PMID: 20133895, Pubmed Central PMCID: 2864394.

    PubMed Central  CAS  PubMed  Google Scholar 

  150. Agura E, Niesvizky R, Matous J, Munshi N, Hussein M, Parameswaran RV, Tarantolo S, Whiting NC, Drachman JG, Zonder JA, editors. Dacetuzumab (SGN-40), lenalidomide, and weekly dexamethasone in relapsed or refractory multiple myeloma: multiple responses observed in a phase 1b study. ASH annual meeting; 2009; New Orleans: Blood. 2009;114:2870.

    Google Scholar 

  151. Bensinger W, Maziarz RT, Jagannath S, Spencer A, Durrant S, Becker PS, 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(1):58–66. PubMed PMID: 22861192.

    CAS  PubMed  Google Scholar 

  152. Dimberg LY, Anderson CK, Camidge R, Behbakht K, Thorburn A, Ford HL. On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics. Oncogene. 2013;32(11):1341–50. PubMed PMID: 22580613.

    CAS  PubMed  Google Scholar 

  153. Belch A, Sharma A, Spencer A, Tarantolo A, Bahlis NJ, Doval D, Gallant G, Kumm E, Klein J, Chanan-Khan AA, editors. 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). ASH annual meeting; 2010; Orlando: Blood. 2010;116:5031.

    Google Scholar 

  154. Campbell KS, Purdy AK. Structure/function of human killer cell immunoglobulin-like receptors: lessons from polymorphisms, evolution, crystal structures and mutations. Immunology. 2011;132(3):315–25. PubMed PMID: 21214544, Pubmed Central PMCID: 3044898.

    PubMed Central  CAS  PubMed  Google Scholar 

  155. Benson DM Jr., Cohen AD, Munshi NC, Jagannath S, Spitzer G, Hofmeister CC, Zerbib R, Andre P, Efebera YA, Oxier S, Caligiuri MA, editors. A phase I trial of the anti-inhibitory KIR antibody, IPH2101, and lenalidomide in multiple myeloma: interim results. ASH annual meeting; 2012; Atlanta: Blood. 2012;120:4058.

    Google Scholar 

  156. Moreaux J, Hose D, Reme T, Jourdan E, Hundemer M, Legouffe E, et al. CD200 is a new prognostic factor in multiple myeloma. Blood. 2006;108(13):4194–7. PubMed PMID: 16946299.

    CAS  PubMed  Google Scholar 

  157. Mahadevan D, Lanasa MC, Whelden M, Faas SJ, Ulery TL, Kukreja A, Li L, MS, Bedrosian CL, Heffner LT, editor. First-in-human phase I dose escalation study of a humanized anti-CD200 antibody (Samalizumab) in patients with advanced stage B cell chronic lymphocytic leukemia (B-CLL) or multiple myeloma (MM). ASH annual meeting; 2010; Orlando: Blood. 2010;116:2465.

    Google Scholar 

  158. Hofbauer LC, Neubauer A, Heufelder AE. Receptor activator of nuclear factor-kappaB ligand and osteoprotegerin: potential implications for the pathogenesis and treatment of malignant bone diseases. Cancer. 2001;92(3):460–70. PubMed PMID: 11505389.

    CAS  PubMed  Google Scholar 

  159. Vij R, Horvath N, Spencer A, Taylor K, Vadhan-Raj S, Vescio R, et al. An open-label, phase 2 trial of denosumab in the treatment of relapsed or plateau-phase multiple myeloma. Am J Hematol. 2009;84(10):650–6. PubMed PMID: 19714603.

    CAS  PubMed  Google Scholar 

  160. Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol. 2011;29(9):1125–32. PubMed PMID: 21343556.

    CAS  PubMed  Google Scholar 

  161. Qiang YW, Barlogie B, Rudikoff S, Shaughnessy Jr JD. Dkk1-induced inhibition of Wnt signaling in osteoblast differentiation is an underlying mechanism of bone loss in multiple myeloma. Bone. 2008;42(4):669–80. PubMed PMID: 18294945.

    CAS  PubMed  Google Scholar 

  162. Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, 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(26):2483–94. PubMed PMID: 14695408.

    CAS  PubMed  Google Scholar 

  163. Padmanabhan S, Beck JT, Kelly KR, Munshi NC, Dzik-Jurasz A, Gangolli E, Ettenberg S, Miner K, Bilic S, Whyte W, Mehdi F, Lu-May C, Rae PL, Spencer A, Shah J, Anderson KC, Giles FJ, Stewart AK, editors. A phase I/II study of BHQ880, a novel osteoblast activating, anti-DKK1 human monoclonal antibody, in relapsed and refractory multiple myeloma (MM) patients treated with zoledronic acid (Zol) and anti-myeloma therapy (MM Tx). ASH annual meeting; 2009; New Orleans: Blood. 2009;114:750.

    Google Scholar 

  164. Munshi NC, Abonour R, Beck JT MD, Bensinger W, Facon T, Stockerl-Goldstein K, Baz R, Siegel DS, Neben K, Lonial S, Suvannasankha A, Bilic S, Chica S, Mukhopadhyay S, Isaacs R, Jagannath S, editors. 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. ASH annual meeting; 2012; Atlanta: Blood. 2012;120:331.

    Google Scholar 

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Correspondence to David E. Avigan MD .

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Bar-Natan, M., Anderson, K.C., Avigan, D.E. (2015). Immunotherapeutic Strategies for Multiple Myeloma. In: Rezaei, N. (eds) Cancer Immunology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-46410-6_4

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