Biology of Blood and Marrow Transplantation
Volume 15, Issue 12 , Pages 1502-1512 , December 2009

Proteasome Inhibition and Allogeneic Hematopoietic Stem Cell Transplantation: A Review

  • John Koreth

      Affiliations

    • Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachustts
    • ,
  • Edwin P. Alyea

      Affiliations

    • Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachustts
    • ,
  • William J. Murphy

      Affiliations

    • Department of Dermatology, UC Davis School of Medicine, Sacramento, California
    • Corresponding Author InformationCorrespondence and reprint requests: William J. Murphy, MD, PhD, Department of Dermatology, University of California, Davis School of Medicine, Research III, Room 3300, 4645 2nd Avenue, Sacramento, CA 95818.
    • ,
  • Lisbeth A. Welniak

      Affiliations

    • Department of Dermatology, UC Davis School of Medicine, Sacramento, California

Received 15 June 2009 ,Accepted 16 July 2009.

References 

  1. Koreth J, Antin JH. Current and future approaches for control of graft-versus-host disease. Expert Rev Hematol. 2008;1:111–128
  2. Mielcarek M, Martin PJ, Leisenring W, et al. Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood. 2003;102:756–762
  3. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11:945–956
  4. Deeg HJ, Storb R. Acute and chronic graft-versus-host disease: clinical manifestations, prophylaxis, and treatment. J Natl Cancer Inst. 1986;76:1325–1328
  5. Panoskaltsis-Mortari A, Tram KV, Price AP, Wendt CH, Blazar BR. A new murine model for bronchiolitis obliterans post-bone marrow transplant. Am J Respir Crit Care Med. 2007;176:713–723
  6. Blazar B, Taylor P, Vallera D. CD4+ and CD8 + T cells each can utilize a perforin-dependent pathway to mediate lethal graft-versus-host disease in major histocompatibility complex-disparate recipients. Transplantation. 1997;64:571–576
  7. Schmaltz C, Alpdogan O, Horndasch KJ, et al. Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect. Blood. 2001;97:2886–2895
  8. Schmaltz C, Alpdogan O, Kappel BJ, et al. T cells require TRAIL for optimal graft-versus-tumor activity. Nat Med. 2002;8:1433–1437
  9. Korngold R, Marini JC, de Baca ME, Murphy GF, Giles-Komar J. Role of tumor necrosis factor-alpha in graft-versus-host disease and graft-versus-leukemia responses. Biol Blood Marrow Transplant. 2003;9:292–303
  10. Tsukada N, Kobata T, Aizawa Y, Yagita H, Okumura K. Graft-versus-leukemia effect and graft-versus-host disease can be differentiated by cytotoxic mechanisms in a murine model of allogeneic bone marrow transplantation. Blood. 1999;93:2738–2747
  11. Faber LM, van Luxemburg-Heijs SA, Veenhof WF, Willemze R, Falkenburg JH. Generation of CD4+ cytotoxic T-lymphocyte clones from a patient with severe graft-versus-host disease after allogeneic bone marrow transplantation: implications for graft-versus-leukemia reactivity. Blood. 1995;86:2821–2828
  12. Matte CC, Cormier J, Anderson BE, et al. Graft-versus-leukemia in a retrovirally induced murine CML model: mechanisms of T-cell killing. Blood. 2004;103:4353–4361
  13. Pan L, Delmonte J, Jalonen CK, Ferrara JL. Pretreatment of donor mice with granulocyte colony-stimulating factor polarizes donor T lymphocytes toward type-2 cytokine production and reduces severity of experimental graft-versus-host disease. Blood. 1995;86:4422–4429
  14. Reddy P, Teshima T, Hildebrandt G, et al. Pretreatment of donors with interleukin-18 attenuates acute graft-versus-host disease via STAT6 and preserves graft-versus-leukemia effects. Blood. 2003;101:2877–2885
  15. Fowler DH, Gress RE. Th2 and Tc2 cells in the regulation of GVHD, GVL, and graft rejection: considerations for the allogeneic transplantation therapy of leukemia and lymphoma. Leuk Lymphoma. 2000;38:221–234
  16. Fowler DH, Kurasawa K, Smith R, Eckhaus MA, Gress RE. Donor CD4-enriched cells of Th2 cytokine phenotype regulate graft-versus-host disease without impairing allogeneic engraftment in sublethally irradiated mice. Blood. 1994;84:3540–3549
  17. Nikolic B, Lee S, Bronson RT, Grusby MJ, Sykes M. Th1 and Th2 mediate acute graft-versus-host disease, each with distinct end-organ targets. J Clin Invest. 2000;105:1289–1298
  18. Liu J, Anderson BE, Robert ME, et al. Selective T-cell subset ablation demonstrates a role for T1 and T2 cells in ongoing acute graft-versus-host disease: a model system for the reversal of disease. Blood. 2001;98:3367–3375
  19. Yang YG, Qi J, Wang MG, Sykes M. Donor-derived interferon gamma separates graft-versus-leukemia effects and graft-versus-host disease induced by donor CD8 T cells. Blood. 2002;99:4207–4215
  20. Welniak LA, Blazar BR, Anver MR, Wiltrout RH, Murphy WJ. Opposing roles of interferon-gamma on CD4 + T cell-mediated graft-versus-host disease: effects of conditioning. Biol Blood Marrow Transplant. 2000;6:604–612
  21. Murphy WJ, Welniak LA, Taub DD, et al. Differential effects of the absence of interferon-gamma and IL-4 in acute graft-versus-host disease after allogeneic bone marrow transplantation in mice. J Clin Invest. 1998;102:1742–1748
  22. Levine JE, Paczesny S, Mineishi S, et al. Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease. Blood. 2008;111:2470–2475
  23. Busca A, Locatelli F, Marmont F, Ceretto C, Falda M. Recombinant human soluble tumor necrosis factor receptor fusion protein as treatment for steroid refractory graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. Am J Hematol. 2007;82:45–52
  24. Schmaltz C, Alpdogan O, Muriglan SJ, et al. Donor T cell-derived TNF is required for graft-versus-host disease and graft-versus-tumor activity after bone marrow transplantation. Blood. 2003;101:2440–2445
  25. Chen X, Vodanovic-Jankovic S, Johnson B, et al. Absence of regulatory T-cell control of TH1 and TH17 cells is responsible for the autoimmune-mediated pathology in chronic graft-versus-host disease. Blood. 2007;110:3804–3813
  26. Kappel LW, Goldberg GL, King CG, et al. IL-17 contributes to CD4-mediated graft-versus-host disease. Blood. 2009;113:945–952
  27. Yi T, Zhao D, Lin CL, et al. Absence of donor Th17 leads to augmented Th1 differentiation and exacerbated acute graft-versus-host disease. Blood. 2008;112:2101–2110
  28. Shustov A, Luzina I, Nguyen P, et al. Role of perforin in controlling B-cell hyperactivity and humoral autoimmunity. J Clin Invest. 2000;106:R39–R47
  29. Rus V, Svetic A, Nguyen P, Gause WC, Via CS. Kinetics of Th1 and Th2 cytokine production during the early course of acute and chronic murine graft-versus-host disease—regulatory role of donor CD8(+) T-cells. J Immunol. 1995;155:2396–2406
  30. Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S. Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med. 2002;196:389–399
  31. Johnson BD, Konkol MC, Truitt RL. CD25+ immunoregulatory T-cells of donor origin suppress alloreactivity after BMT. Biol Blood Marrow Transplant. 2002;8:525–535
  32. Taylor PA, Lees CJ, Blazar BR. The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood. 2002;99:3493–3499
  33. Anderson BE, McNiff JM, Matte C, et al. Recipient CD4 + T cells that survive irradiation regulate chronic graft-versus-host disease. Blood. 2004;104:1565–1573
  34. Ratanatharathorn V, Ayash L, Reynolds C, et al. Treatment of chronic graft-versus-host disease with anti-CD20 chimeric monoclonal antibody. Biol Blood Marrow Transplant. 2003;9:505–511
  35. Ratanatharathorn V, Carson E, Reynolds C, et al. Anti-CD20 chimeric monoclonal antibody treatment of refractory immune-mediated thrombocytopenia in a patient with chronic graft-versus-host disease. Ann Intern Med. 2000;133:275–279
  36. Cutler C, Miklos D, Kim HT, et al. Rituximab for steroid-refractory chronic graft-versus-host disease. Blood. 2006;108:756–762
  37. Arai S, Sahaf B, Jones C, et al. Prophylactic rituximab after reduced intensity conditioning transplantation results in low chronic GVHD. ASH Annu Meet Abstr. 2008;112:466
  38. Hakim FT, Rehman N, Dickinson J, et al. Elevated BAFF is correlated with inflammatory processes in chronic graft versus host disease and supports increases in transitional B cells. ASH Annu Meet Abstr. 2008;112:465
  39. Sarantopoulos S, Stevenson KE, Kim HT, et al. High levels of B-cell activating factor in patients with active chronic graft-versus-host disease. Clin Cancer Res. 2007;13:6107–6114
  40. Adams J. Proteasome inhibition in cancer: development of PS-341. Semin Oncol. 2001;28:613–619
  41. Adams J. Proteasome inhibitors as new anticancer drugs. Curr Opin Oncol. 2002;14:628–634
  42. Adams J. Development of the proteasome inhibitor PS-341. Oncologist. 2002;7:9–16
  43. Ciechanover A. The ubiquitin-proteasome proteolytic pathway. Cell. 1994;79:13–21
  44. Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell. 1990;63:1129–1136
  45. Glotzer M, Murray AW, Kirschner MW. Cyclin is degraded by the ubiquitin pathway. Nature. 1991;349:132–138
  46. Pagano M, Tam SW, Theodoras AM, et al. Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science. 1995;269:682–685
  47. Rock KL, Gramm C, Rothstein L, et al. Inhibitors of the proteasome block the egradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell. 1994;78:761–771
  48. Palombella VJ, Rando OJ, Goldberg AL, Maniatis T. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell. 1994;78:773–785
  49. Adams J. Preclinical and clinical evaluation of proteasome inhibitor PS-341 for the treatment of cancer. Curr Opin Chem Biol. 2002;6:493–500
  50. Adams J, Palombella VJ, Elliott PJ. Proteasome inhibition: a new strategy in cancer treatment. Invest New Drugs. 2000;18:109–121
  51. Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem. 1998;67:425–479
  52. Palombella VJ, Conner EM, Fuseler JW, et al. Role of the proteasome and NF-kappaB in streptococcal cell wall-induced polyarthritis. Proc Natl Acad Sci USA. 1998;95:15671–15676
  53. Adams J, Behnke M, Chen S, et al. Potent and selective inhibitors of the proteasome: dipeptidyl boronic acids. Bioorg Med Chem Lett. 1998;8:333–338
  54. Bross PF, Kane R, Farrell AT, et al. Approval summary for bortezomib for injection in the treatment of multiple myeloma. Clin Cancer Res. 2004;10:3954–3964
  55. Kane RC, Farrell AT, Sridhara R, Pazdur R. United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy. Clin Cancer Res. 2006;12:2955–2960
  56. Kane RC, Dagher R, Farrell A, et al. Bortezomib for the treatment of mantle cell lymphoma. Clin Cancer Res. 2007;13:5291–5294
  57. Richardson P, Hofmeister CC, Zimmerman TM, et al. Phase 1 clinical trial of NPI-0052, a novel proteasome inhibitor in patients with multiple myeloma. ASH Annu Meet Abstr. 2008;112:2770
  58. Price T, Padrik P, Townsend A, et al. Clinical trial of NPI-0052 (2nd generation proteasome inhibitor) in patients having advanced malignancies with expanded RP2D cohorts in lymphoma and CLL. ASH Annu Meet Abstr. 2008;112:4934
  59. Hamlin PA, Aghajanian C, Hong D, et al. First-in-human phase 1 dose escalation study of NPI-0052, a novel proteasome inhibitor, in patients with lymphoma and solid tumor. ASH Annu Meet Abstr. 2008;112:4939
  60. Alsina M, Trudel S, Vallone M, et al. Phase 1 single agent antitumor activity of twice weekly consecutive day dosing of the proteasome inhibitor carfilzomib (PR-171) in hematologic malignancies. ASH Annu Meet Abstr. 2007;110:411
  61. Jagannath S, Vij R, Stewart AK, et al. Initial results of PX-171-003, an open-label, single-arm, phase ii studyof carfilzomib (CFZ) in patients with relapsed and refractory multiple myeloma (MM). ASH Ann Meet Abstr. 2008;112:864
  62. Orlowski RZ, Stewart K, Vallone M, et al. Safety and antitumor efficacy of the proteasome inhibitor carfilzomib (PR-171) dosed for five consecutive days in hematologic malignancies: phase 1 results. ASH Annu Meet Abstr. 2007;110:409
  63. Vij R, Wang M, Orlowski R, et al. Initial results of PX-171-004, an open-label, single-arm, phase II study of carfilzomib (CFZ) in patients with relapsed myeloma (MM). ASH Annu Meet Abstr. 2008;112:865
  64. Machiels BM, Henfling ME, Gerards WL, et al. Detailed analysis of cell cycle kinetics upon proteasome inhibition. Cytometry. 1997;28:243–252
  65. Brignole C, Marimpietri D, Pastorino F, et al. Effect of bortezomib on human neuroblastoma cell growth, apoptosis, and angiogenesis. J Natl Cancer Inst. 2006;98:1142–1157
  66. Ling YH, Liebes L, Jiang JD, et al. Mechanisms of proteasome inhibitor PS-341-induced G(2)-M-phase arrest and apoptosis in human non-small cell lung cancer cell lines. Clin Cancer Res. 2003;9:1145–1154
  67. Chen Z, Hagler J, Palombella VJ, et al. Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway. Genes Dev. 1995;9:1586–1597
  68. Chu ZL, McKinsey TA, Liu L, et al. Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-kappaB control. Proc Natl Acad Sci USA. 1997;94:10057–10062
  69. Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS. NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science. 1998;281:1680–1683
  70. Wu MX, Ao Z, Prasad KV, Wu R, Schlossman SF. IEX-1L, an apoptosis inhibitor involved in NF-kappaB-mediated cell survival. Science. 1998;281:998–1001
  71. You M, Ku PT, Hrdlickova R, Bose HR. ch-IAP1, a member of the inhibitor-of-apoptosis protein family, is a mediator of the antiapoptotic activity of the v-Rel oncoprotein. Mol Cell Biol. 1997;17:7328–7341
  72. D'Souza BN, Edelstein LC, Pegman PM, et al. Nuclear factor kappa B-dependent activation of the antiapoptotic bfl-1 gene by the Epstein-Barr virus latent membrane protein 1 and activated CD40 receptor. J Virol. 2004;78:1800–1816
  73. Sayers TJ, Brooks AD, Koh CY, et al. The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP. Blood. 2003;102:303–310
  74. Pei XY, Dai Y, Grant S. Synergistic induction of oxidative injury and apoptosis in human multiple myeloma cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitors. Clin Cancer Res. 2004;10:3839–3852
  75. Heider U, von Metzler I, Kaiser M, et al. Synergistic interaction of the histone deacetylase inhibitor SAHA with the proteasome inhibitor bortezomib in mantle cell lymphoma. Eur J Haematol. 2008;80:133–142
  76. Li C, Li R, Grandis JR, Johnson DE. Bortezomib induces apoptosis via Bim and Bik up-regulation and synergizes with cisplatin in the killing of head and neck squamous cell carcinoma cells. Mol Cancer Ther. 2008;7:1647–1655
  77. Takigawa N, Vaziri SA, Grabowski DR, et al. Proteasome inhibition with bortezomib enhances activity of topoisomerase I-targeting drugs by NF-kappaB-independent mechanisms. Anticancer Res. 2006;26:1869–1876
  78. Mitsiades N, Mitsiades CS, Richardson PG, et al. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood. 2003;101:2377–2380
  79. Jacquemont C, Taniguchi T. Proteasome function is required for DNA damage response and fanconi anemia pathway activation. Cancer Res. 2007;67:7395–7405
  80. Fribley AM, Evenchik B, Zeng Q, et al. Proteasome inhibitor PS-341 induces apoptosis in cisplatin-resistant squamous cell carcinoma cells by induction of Noxa. J Biol Chem. 2006;281:31440–31447
  81. Noborio-Hatano K, Kikuchi J, Takatoku M, et al. Bortezomib overcomes cell adhesion-mediated drug resistance through downregulation of VLA-4 expression in multiple myeloma. Oncogene. 2009;28:231–242
  82. Hallett WH, Ames E, Motarjemi M, et al. Sensitization of tumor cells to NK cell-mediated killing by proteasome inhibition. J Immunol. 2008;180:163–170
  83. Yong AS, Keyvanfar K, Hensel N, et al. Primitive quiescent CD34+ cells in chronic myeloid leukemia are targeted by in vitro expanded natural killer cells, which are functionally enhanced by bortezomib. Blood. 2008;113:875–882
  84. Liu X, Yue P, Chen S, et al. The proteasome inhibitor PS-341 (bortezomib) up-regulates DR5 expression leading to induction of apoptosis and enhancement of TRAIL-induced apoptosis despite up-regulation of c-FLIP and survivin expression in human NSCLC cells. Cancer Res. 2007;67:4981–4988
  85. Schumacher LY, Vo DD, Garban HJ, et al. Immunosensitization of tumor cells to dendritic cell-activated immune responses with the proteasome inhibitor bortezomib (PS-341, Velcade). J Immunol. 2006;176:4757–4765
  86. Lundqvist A, Abrams SI, Schrump DS, et al. Bortezomib and depsipeptide sensitize tumors to tumor necrosis factor-related apoptosis-inducing ligand: a novel method to potentiate natural killer cell tumor cytotoxicity. Cancer Res. 2006;66:7317–7325
  87. Spisek R, Charalambous A, Mazumder A, et al. Bortezomib enhances dendritic cell (DC)-mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications. Blood. 2007;109:4839–4845
  88. Straube C, Wehner R, Wendisch M, et al. Bortezomib significantly impairs the immunostimulatory capacity of human myeloid blood dendritic cells. Leukemia. 2007;21:1464–1471
  89. Subklewe M, Sebelin-Wulf K, Beier C, et al. Dendritic cell maturation stage determines susceptibility to the proteasome inhibitor bortezomib. Hum Immunol. 2007;68:147–155
  90. Nencioni A, Schwarzenberg K, Brauer KM, et al. Proteasome inhibitor bortezomib modulates TLR4-induced dendritic cell activation. Blood. 2006;108:551–558
  91. Nencioni A, Garuti A, Schwarzenberg K, et al. Proteasome inhibitor-induced apoptosis in human monocyte-derived dendritic cells. Eur J Immunol. 2006;36:681–689
  92. Arpinati M, Chirumbolo G, Nicolini B, Agostinelli C, Rondelli D. Selective apoptosis of monocytes and monocyte-derived DCs induced by Bortezomib (Velcade). Bone Marrow Transplant. 2008;43:253–259
  93. Meister S, Schubert U, Neubert K, et al. Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition. Cancer Res. 2007;67:1783–1792
  94. Neubert K, Meister S, Moser K, et al. The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat Med. 2008;14:748–755
  95. Sun K, Welniak LA, Panoskaltsis-Mortari A, et al. Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib. Proc Natl Acad Sci USA. 2004;101:8120–8125
  96. Blanco B, Perez-Simon JA, Sanchez-Abarca LI, et al. Treatment with bortezomib of human CD4 + T cells preserves natural regulatory T cells and allows the emergence of a distinct suppressor T-cell population. Haematologica. 2009;94:975–983
  97. Lee SW, Kim JH, Park YB, Lee SK. Bortezomib attenuates murine collagen-induced arthritis. Ann Rheum Dis. 2008 Dec. 3;[E-pub ahead of print]
  98. Sun K, Li M, Sayers TJ, Welniak LA, Murphy WJ. Differential effects of donor T-cell cytokines on outcome with continuous bortezomib administration after allogeneic bone marrow transplantation. Blood. 2008;112:1522–1529
  99. Sun K, Wilkins DE, Anver MR, et al. Differential effects of proteasome inhibition by bortezomib on murine acute graft-versus-host disease (GVHD): delayed administration of bortezomib results in increased GVHD-dependent gastrointestinal toxicity. Blood. 2005;106:3293–3299
  100. Zou P, Kawada J, Pesnicak L, Cohen JI. Bortezomib induces apoptosis of Epstein-Barr virus (EBV)-transformed B cells and prolongs survival of mice inoculated with EBV-transformed B cells. J Virol. 2007;81:10029–10036
  101. Fu DX, Tanhehco YC, Chen J, et al. Virus-associated tumor imaging by induction of viral gene expression. Clin Cancer Res. 2007;13:1453–1458
  102. Chanan-Khan A, Sonneveld P, Schuster MW, et al. Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study. J Clin Oncol. 2008;26:4784–4790
  103. Tong Y, Qian J, Li Y, Meng H, Jin J. The high incidence of varicella herpes zoster with the use of bortezomib in 10 patients. Am J Hematol. 2007;82:403–404
  104. Fitzgerald M, Fraser C, Webb I, et al. Normal hematopoietic stem cell function in mice following treatment with bortezomib. Biol Blood Marrow Transplant. 2003;9:121
  105. Orlowski RZ, Stinchcombe TE, Mitchell BS, et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol. 2002;20:4420–4427
  106. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348:2609–2617
  107. Cottler-Fox M, Holley D, Whigham L, et al. Hematopoietic progenitor cell (HPC) mobilization after initial therapy of multiple myeloma including velcade: ability to collect HPC as a function of velcade dosing. ASH Annu Meet Abstr. 2004;104:2884
  108. Hollmig K, Stover J, Talamo G, et al. Addition of bortezomib (VelcadeTM) to high dose melphalan (Vel-Mel) as an effective conditioning regimen with autologous stem cell support in multiple myeloma (MM). ASH Annu Meet Abstr. 2004;104:929
  109. Oakervee HE, Popat R, Curry N, et al. PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol. 2005;129:755–762
  110. Harousseau JL, Attal M, Leleu X, et al. Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of an IFM phase II study. Haematologica. 2006;91:1498–1505
  111. Uy GL, Fisher NM, Devine SM, et al. Bortezomib given in sequence with anthracycline and thalidomide-containing regimens does not adversely affect stem cell mobilization and engraftment in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation. ASH Annu Meet Abstr. 2004;104:541
  112. Jagannath S, Durie BG, Wolf J, et al. Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol. 2005;129:776–783
  113. Barlogie B, Tricot G, Rasmussen E, et al. Total therapy 3 (TT3) incorporating velcadeR (V) intro upfront management of multiple myeloma (MM): comparison with TT2 + thalidomide (T). ASH Annu Meet Abstr. 2005;106:1154
  114. Wang LM, Weber DM, Delasalle KB, Alexanian RVTD. (Velcade, Thalidomide, Dexamethasone) as primary therapy for newly-diagnosed multiple myeloma. ASH Annu. Meet. Abstr. 2004;104:210
  115. Vodanovic-Jankovic S, Hari P, Jacobs P, Komorowski R, Drobyski WR. NF-kappaB as a target for the prevention of graft-versus-host disease: comparative efficacy of bortezomib and PS-1145. Blood. 2006;107:827–834
  116. Arastu-Kapur S, Shenk K, Parlati F, Bennett MK. Non-proteasomal targets of proteasome inhibitors bortezomib and carfilzomib. ASH Annu Meet Abstr. 2008;112:2657
  117. 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;13:5528s–5534s
  118. Balsas P, Lopez-Royuela N, Galan-Malo P, et al. Cooperation between Apo2L/TRAIL and bortezomib in multiple myeloma apoptosis. Biochem Pharmacol. 2009;77:804–812
  119. Conticello C, Adamo L, Vicari L, et al. Antitumor activity of bortezomib alone and in combination with TRAIL in human acute myeloid leukemia. Acta Haematol. 2008;120:19–30
  120. Lu G, Punj V, Chaudhary PM. Proteasome inhibitor Bortezomib induces cell cycle arrest and apoptosis in cell lines derived from Ewing's sarcoma family of tumors and synergizes with TRAIL. Cancer Biol Ther. 2008;7:603–608
  121. Shanker A, Brooks AD, Tristan CA, et al. Treating metastatic solid tumors with bortezomib and a tumor necrosis factor-related apoptosis-inducing ligand receptor agonist antibody. J Natl Cancer Inst. 2008;100:649–662
  122. Thorpe JA, Christian PA, Schwarze SR. Proteasome inhibition blocks caspase-8 degradation and sensitizes prostate cancer cells to death receptor-mediated apoptosis. Prostate. 2008;68:200–209
  123. Kandasamy K, Kraft AS. Proteasome inhibitor PS-341 (VELCADE) induces stabilization of the TRAIL receptor DR5 mRNA through the 3′-untranslated region. Mol Cancer Ther. 2008;7:1091–1100
  124. Nikrad M, Johnson T, Puthalalath H, et al. The proteasome inhibitor bortezomib sensitizes cells to killing by death receptor ligand TRAIL via BH3-only proteins Bik and Bim. Mol Cancer Ther. 2005;4:443–449
  125. Liu FT, Agrawal SG, Gribben JG, et al. Bortezomib blocks Bax degradation in malignant B cells during treatment with TRAIL. Blood. 2008;111:2797–2805
  126. Oldenhuis CN, Stegehuis JH, Walenkamp AM, de Jong S, de Vries EG. Targeting TRAIL death receptors. Curr Opin Pharmacol. 2008;8:433–439
  127. Lundqvist A, Yokoyama H, Smith A, Berg M, Childs R. Bortezomib treatment and regulatory T-cell depletion enhance the antitumor effects of adoptively infused NK cells. Blood. 2009;113:6120–6127
  128. Zweegman S, Janssen JJ, Lokhorst HM. Immune-modulatory effects of bortezomib in GVHD. Leuk Lymphoma. 2007;48:853–854
  129. Giralt S, Aleman A, Lei X, et al. Results of bortezomib (BTZ) therapy for myeloma (MM) patients relapsing after an allogeneic transplant. Preliminary results show efficacy without induction of GVHD. ASH Annu Meet Abstr. 2004;104:1651
  130. El-Cheikh J, Michallet M, Nagler A, et al. High response rate and improved graft-versus-host disease following bortezomib as salvage therapy after reduced intensity conditioning allogeneic stem cell transplantation for multiple myeloma. Haematologica. 2008;93:455–458
  131. van de Donk NW, Kroger N, Hegenbart U, et al. Remarkable activity of novel agents bortezomib and thalidomide in patients not responding to donor lymphocyte infusions following nonmyeloablative allogeneic stem cell transplantation in multiple myeloma. Blood. 2006;107:3415–3416
  132. Collins RH, Shpilberg O, Drobyski WR, et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol. 1997;15:433–444
  133. Kroger N, Badbaran A, Lioznov M, et al. Post-transplant immunotherapy with donor-lymphocyte infusion and novel agents to upgrade partial into complete and molecular remission in allografted patients with multiple myeloma. Exp Hematol. 2009;37:791–798
  134. Koreth J, Stevenson K, Kim HT, et al. A phase I/II trial of bortezomib, tacrolimus and methotrexate for prophylaxis of acute graft versus host disease after HLA mismatched reduced intensity transplantation. ASH Annu Meet Abstr. 2008;112:1158
  135. Todisco E, Sarina B, Castagna L, et al. Inhibition of chronic graft-vs-host disease with retention of anti-myeloma effects by the proteasome inhibitor bortezomib. Leuk Lymphoma. 2007;48:1015–1018
  136. Mateos-Mazon J, Perez-Simon JA, Lopez O, et al. Use of bortezomib in the management of chronic graft-versus-host disease among multiple myeloma patients relapsing after allogeneic transplantation. Haematologica. 2007;92:1295–1296
  137. Pavletic SZ, Martin P, Lee SJ, et al. Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. Response Criteria Working Group report. Biol Blood Marrow Transplant. 2006;12:252–266
  138. Kroger N, Zabelina T, Ayuk F, et al. Bortezomib after dose-reduced allogeneic stem cell transplantation for multiple myeloma to enhance or maintain remission status. Exp Hematol. 2006;34:770–775

 Financial disclosure: See Acknowledgments on page 1509.

PII: S1083-8791(09)00344-9

doi: 10.1016/j.bbmt.2009.07.016

Biology of Blood and Marrow Transplantation
Volume 15, Issue 12 , Pages 1502-1512 , December 2009

Article Tools

* Image Usage & Resolution