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Allogeneic Transplantation for Multiple Myeloma

  • Fengrong Wang
  • Edmund K. Waller
Part of the Contemporary Hematology book series (CH)

Introduction

Autologous hematopoietic stem cell transplantation (HSCT) is currently considered part of the standard care in the management of patients with newly diagnosed multiple myeloma (MM). Autologous transplantation has extended overall survival and progression-free survival by 1–1.5 years compared to conventional dose chemotherapy in randomized clinical studies1, 2, 3in patients up to 65 years of age. Unfortunately, long-term survival for patients treated with autologous HSCT is rare, and virtually all patients relapse. Allogeneic (Allo-) HSCT can induce long-term molecular remission and is possibly the only curative treatment for MM based on the graft-versus-tumor (GVT) or graft-versus-myeloma (GVM) effects mediated by the allogeneic donor immune cells, particularly donor T-cells. Advantages of allogeneic HSCT in comparison to autologous HSCT are a tumor-free stem cell source and the GVM effect. Current clinical research is trying to define the clinical outcomes of patients...

Keywords

Multiple Myeloma Hematopoietic Stem Cell Transplantation Conditioning Regimen Allogeneic Hematopoietic Stem Cell Transplantation Allogeneic Transplantation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myeloma. N Engl J Med 1996; 335:91–97.PubMedCrossRefGoogle Scholar
  2. 2.
    Child JA, Morgan GJ, Davies FC, et al. High-dose chemotherapy with hematopietic stem cell rescue for multiple myeloma. N Engl J Med 2003; 348:1875–1883.PubMedCrossRefGoogle Scholar
  3. 3.
    Palumbo A, Bringhen S, Petrucci MT, et al. Intermediate-dose melphalan improves survival of myeloma patients aged 50–70: results of a randomized controlled trial. Blood 2004; 104:3052–3057.PubMedCrossRefGoogle Scholar
  4. 4.
    Garban F, Attal M, Michallet M, et al. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft(IFM99-03 trial) with tandem autologous stem cell transplantation(IFM99-04 trial) in high-risk de novo multiple myeloma. Blood 2006; 107:3474–3480.PubMedCrossRefGoogle Scholar
  5. 5.
    Bruno B, Rotta M, Patriarca F, et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med 2007; 356:1110–1120.PubMedCrossRefGoogle Scholar
  6. 6.
    McSweeney PA, Niederwieser D, Shizuru JA, et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001; 97:3390–3400.PubMedCrossRefGoogle Scholar
  7. 7.
    Barlogie B, Shaughnessy J, Tricot G, et al. Treatment of multiple myeloma. Blood 2004; 103:20–32.PubMedCrossRefGoogle Scholar
  8. 8.
    Bensiger WI. The current status of reduced-intensity allogeneic hematopoietic stem cell transplantation for multiple myeloma. Leukemia 2006; 20:1683–1689.CrossRefGoogle Scholar
  9. 9.
    Liso A, Stockerl-Goldsteim KE, Auffermann-Gretzinger S, et al. Idiotype vaccination using dendritic cells after autologous peripheral blood progenitor cell transplantation for multiple myeloma. Biol Blood Marrow Transplant 2000; 6:621–627.PubMedCrossRefGoogle Scholar
  10. 10.
    Hansson L, Abdalla AO, Mosfegh A, et al. Long-term idotype vaccination combined with IL-12 or IL-12 and GM-CSF, in early stage multiple myeloma patients. Clin Cancer Res 2007; 13:1503–1510.PubMedCrossRefGoogle Scholar
  11. 11.
    Ruffini PA, Neelapu SS, Kwak L,. Idiotypic vaccination for B-cell malignancies as a model for therapeutic cancer vaccines: from prototype protein to second generation vaccines. Haematologica 2002; 87:989–1001.PubMedGoogle Scholar
  12. 12.
    Harrison SJ, Cook G, Nibbs R. Immunotherapy of multiple myeloma: the start of a long and tortuous journey. Expert Rev Anticancer Ther 2006; 6:1769–1785.PubMedCrossRefGoogle Scholar
  13. 13.
    Alyea E, Weller E, Schlossman R, et al. Outcome after autologous and allogeneic stem cell transplantation for patients with multiple myeloma: impact of graft-ver-sus-myeloma effect. Bone Marrow Tansplant 2003; 32:1145–1151.CrossRefGoogle Scholar
  14. 14.
    Huff CA, Fuchs EJ, Noga SJ, et al. Long-term follow-up of T cell-depleted alloge-neic bone marrow transplantation in refractory multiple myeloma: importance of allogeneic T cells. Biol Blood Marrow Transplant 2003; 9:312–319.PubMedCrossRefGoogle Scholar
  15. 15.
    Zeiser R, Bertz H, Spyridonidis A, et al. Donor lymphocyte infusions for multiple myeloma: clinical results and novel perspectives. Bone Marrow Transplant 2004; 34:923–928.PubMedCrossRefGoogle Scholar
  16. 16.
    Bjorkstrand B, Ljungman P, Svensson H, et al. Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma: a retrospective case-matched study form the European group for Blood and Marrow Transplantation. Blood, 1996; 88:4711–4718.PubMedGoogle Scholar
  17. 17.
    Martinelli G, Terragna C, Zamagni E, et al. Molecular remission after allogeneic or autologous transplantation of hematopoietic stem cells for multiple myeloma. J clin Oncol 2000; 18:2273–2281.PubMedGoogle Scholar
  18. 18.
    Lokhorst HM , Schattenberg A , Cornelissen JJ , et al . Donor leukocyte infusions are effective in relapsed multiple myeloma after allogeneic bone marrow transplantation. Blood 1997; 90: 4206–4211 .PubMedGoogle Scholar
  19. 19.
    Lokhorst HM, Wu K, Verdonck LF, 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; 103:4362–4364.PubMedCrossRefGoogle Scholar
  20. 20.
    Salama M, Nevill T, Marcellus T, et al.. Donor leukocyte infusions for multiple myeloma. Bone Marrow Tansplant 2000; 26:1179–1184.CrossRefGoogle Scholar
  21. 21.
    Kroger N, Shimoni A, Zagrivnaja M, et al. Low-dose thalidomide and donor lymphocyte infusions adoptive immunotherapy after allogeneic stem cell transplantation in patients with multiple myeloma. Blood 2004; 104:3361–3363.PubMedCrossRefGoogle Scholar
  22. 22.
    Van de Donk NWCJ, 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.PubMedCrossRefGoogle Scholar
  23. 23.
    Alye E, Weller E, Schlossman R, et al. T-cell depleted allogeneic bone marrow transplantation followed by donor lymphocyte infusion in patients with multiple myeloma: induction of graft-versus-myeloma effect. Blood 2001; 98:934–939.CrossRefGoogle Scholar
  24. 24.
    Badros A, Barlogie B, Morris C, 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; 97:2574–2575.PubMedCrossRefGoogle Scholar
  25. 25.
    Peggs KS, Mackinnon S, Williams CD, et al. Reduced intensity transplantation with in vivo T-cell depletion and adjuvant dose-escalation donor lymphocyte infusions for chemotherapy-sensitive myeloma: limited efficacy of graft-versus-tumor activity. Biol Blood Marrow Transplant 2003; 9:257–265.PubMedCrossRefGoogle Scholar
  26. 26.
    Peggs KS, Thomson K, Hart DP, et al. Dose-escalated donor lymphocyte infusions following reduced intensity transplantation: toxicity, chimerism, and disease responses. Blood 2004; 103:1548–1556.PubMedCrossRefGoogle Scholar
  27. 27.
    Tricot G, Vesole DH, Jagannath S, et al. Graft versus myeloma effect: proof of principle. Blood 1996; 87:1196–1198.PubMedGoogle Scholar
  28. 28.
    Verdonck L, Lokhorst H, Dekker A, et al. Graft-versus-myeloma effect in two cases. Lancet 1996; 347:800–801.PubMedCrossRefGoogle Scholar
  29. 29.
    Bellucci R, Alyea EP, Weller E,. Immunologic effects of prophylactic donor lymphocyte infusion after allogeneic marrow transplantation for multiple myeloma. Blood 2002; 99:4610–4617.PubMedCrossRefGoogle Scholar
  30. 30.
    Bethge WA, Hegenbart U, Stuart M, et al. Adoptive immunotherapy with donor lymphocyte infusions after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning. Blood 2004; 103:790–795.PubMedCrossRefGoogle Scholar
  31. 31.
    Coscia M, Mariani S, Battaglio S, et al. Long-term follow-up of idiotype vaccination in human myeloma as a maintenance therapy after high-dose chemotherapy. Leukemia 2004; 18:138–145.CrossRefGoogle Scholar
  32. 32.
    Kofler DM, Mayr C and Wendtner CM. Current status of immunotherapy in B cell malignancies. Current Drug Targests 2006; 7:1372–1374.Google Scholar
  33. 33.
    Kwak LW, Taub DD, Duffey PL,. Transfer of myeloma idiotype-specific immunity from an actively immunized marrow donor. Lancet 1995; 345:1016.PubMedCrossRefGoogle Scholar
  34. 34.
    Rosenberg SA. A new era for cancer immunotherapy based on the genes that encode cancer antigens. Immunity 1999; 10:282–287.CrossRefGoogle Scholar
  35. 35.
    Wang RF. The role of MHC class II-restricted tumor antigens and CD4+ T cells in antitumor immunity. Trends Immunol 2001; 22:269–276.PubMedCrossRefGoogle Scholar
  36. 36.
    Barratt-Boyes SM. Making the most of mucin: a novel target for tumor immuno-therapy. Cancer Immunol Immunother 1996; 43:142–151.CrossRefGoogle Scholar
  37. 37.
    Takahashi T, Makiguchi Y, Hinoda Y, et al. Expression of MUC-1 on myeloma cells and induction of HLA-unrestricted CTL against MUC-1 form a multiple myeloma patient. J Immunol 1994; 152:2102–2112.Google Scholar
  38. 38.
    Zeiser R, Bertz H, Spyridonidis A, et al. Donor lymphocyte infusions for multiple myeloma: clinical results and novel perspectives. Bone Marrow Transplant 2004; 34:923–928.PubMedCrossRefGoogle Scholar
  39. 39.
    Szmania SM, Pomtree M, Batchu RB, Pre-existent humoral and cellular immunity to NY-ESO-1. Blood 2003; 102(suppl 1):3464a.CrossRefGoogle Scholar
  40. 40.
    van Rhee F, Szmania SM, Zhan F, NY-ESO-1 is highly expressed in poor-prognosis multiple myeloma and induces spontaneous humoral and cellular immune responses. Blood 2005; 106; 3939e–3944e.CrossRefGoogle Scholar
  41. 41.
    Chen Y, Scanlan MJ, Sahin U, et al. A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening. Proc Natl Acad Sci 1997; 94:1914–1918.PubMedCrossRefGoogle Scholar
  42. 42.
    Bellucci R, Wu CJ, Chiaretti S, et al. Completed response to donor lymphocyte infusion in multiple myeloma is associated with antibody responses to highly expressed antigens. Blood 2004; 103:656–663.PubMedCrossRefGoogle Scholar
  43. 43.
    Bellucci R, Alyea EP, Chiaretti S, et al. Graft-versus-tumor response in patients with multiple myeloma is associated with antibody responses to BCMA, a plasma-cell membrane receptor. Blood 2005; 105:3945–3950.PubMedCrossRefGoogle Scholar
  44. 44.
    Gahrton G, Tura S, Ljungman P, et al. Prognostic factors in allogeneic bone marrow transplantation for multiple myeloma. J Clin Oncol 1995; 13:1312–1322.PubMedGoogle Scholar
  45. 45.
    Bensinger WI, Buckner CD, Nansetti C, et al. Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome. Blood 1996; 88:2787–2793.PubMedGoogle Scholar
  46. 46.
    Mehta J, Tricot G, Jagannath S, et al. Salvage autologous or allogeneic transplantation for multiple myeloma refractory to or relapsing after a first-line autograft? Bone Marrow Transplant 1998; 21:887–892.PubMedCrossRefGoogle Scholar
  47. 47.
    Kulkarni S, Powles RL, Treleaven JG, et al. Impact of previous high-dose therapy on outcome after allografting for multiple myeloma. Bone Marrow Transplant 1999; 23:675–680.PubMedCrossRefGoogle Scholar
  48. 48.
    Le Blanc R, Montminy-Métivier S, Bélanger R, et al. Allogeneic transplantation for multiple myeloma: further evidence for a GVHD-associated graft-versus-myeloma effect. Bone Marrow Transplant 2001; 28:841–848.PubMedCrossRefGoogle Scholar
  49. 49.
    Gahrton G, Svensson H, Cava M, et al. Progress in allogeneic bone marrow and peripheral blood stem cell transplantation for multiple myeloma: a comparison between transplants performed 1983–93 and 1994–98 at European Group for Blood and Marrow Transplantation centres. Br J Haematol 2001; 113:209–216.PubMedCrossRefGoogle Scholar
  50. 50.
    Kroger N, Einsele H, Wloff D, et al. Myeloablative intensified conditioning regimen with in vivo T-cell depletion(ATG) followed by allografting in patients with advanced multiple myeloma. A phase I/II study of the German Study-group Multiple Myeloma(DSMM). Bone Marrow Transplant 2003; 31:973–979.PubMedCrossRefGoogle Scholar
  51. 51.
    Lokhorst HM, Segeen CM, Verdonck LF, et al. Partially T-cell depleted allogeneic stem-cell transplantation for first-line treatment of multiple myeloma: a prospective evaluation of patients treated in the phase III study Hovon 24 MM. J Clin Oncol 2003; 21:1728–1733.PubMedCrossRefGoogle Scholar
  52. 52.
    Ballen KK, King R, Carston M, et al. Outcome of unrelated transplants in patients with multiple myeloma. Bone Marrow Transplant 2005; 35:675–681.PubMedCrossRefGoogle Scholar
  53. 53.
    Hunter HM, Peggs K, Powles R, Analysis of outcome following allogeneic haemo-poietic stem cell transplantation for myeloma using myeloablative conditioning--evidence for a superior outcome using melphalan combined with total body irradiation. Br. J Haematol 2005; 128:496–502.PubMedCrossRefGoogle Scholar
  54. 54.
    Kuruvilla J, Shepherd JD, Sutberland HJ, et al. Long-term outcome of myeloabla-tive allogeneic stem cell transplantation for multiple myeloma. Biol Blood Marrow Transplant 2007; 9:257–265.Google Scholar
  55. 55.
    Crawley C, Lacobelli S, Bjorkstrand B, et al. Reduced-intensity conditioning for myeloma: lower nonrelapse mortality but higher relapse rates compared with myeloablative conditioning. Blood 2007; 109:3588–3594.PubMedCrossRefGoogle Scholar
  56. 56.
    Badros A, Barlogie B, Spegel E, et al. Improved outcome of allogeneic transplantation in high-risk multiple myeloma patients after non myeloablative conditioning. J Clin Oncol 2002; 20:1295–1303.PubMedCrossRefGoogle Scholar
  57. 57.
    Einsele H, Shafer HJ, Hebart H, et al. Follow-up of patients with multiple myeloma undergoing allografts after reduced-intensity conditioning. Br J Haematol 2003; 121:411–418.PubMedCrossRefGoogle Scholar
  58. 58.
    Giralt S, Aleman A, Anagnostopoulos A, et al. Fludarabine/melphalan conditioning for allogeneic transplantation in patients with multiple myeloma. Bone Marrow Transplant 2002;30:367–373.PubMedCrossRefGoogle Scholar
  59. 59.
    Kroger N, Sayer HG, Schwerdtfeger R, et al. Unrelated stem cell transplantation in multiple myeloma after reduced intensity conditioning with pretransplantation antithymocyte globulin is highly effective with low transplantation-related mortality. Blood 2002; 100:3919–3924.PubMedCrossRefGoogle Scholar
  60. 60.
    Storb R, Yu C, Zaucha JM, et al. Stable mixed hematopoietic chimerism in dog given antigen, CTLA4Ig and 100 cGy total body irradiation before and pharmaco-logic immunosuppression after marrow transplant. Blood 1999; 94:2523–2529.PubMedGoogle Scholar
  61. 61.
    Mohty M, Boiron JM, Damaj G, et al. Graft-versus-myeloma effect following antithymocyte globulin-based reduced intensity conditioning allogeneic stem cell transplantation. Bone Marrow Transplant 2004; 34:77–84.PubMedCrossRefGoogle Scholar
  62. 62.
    Crawley C, Lalancette M, Szydlo R, et al. Outcomes for reduced-intensity alloge-neic transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT. Blood 2005; 105:4532–4539.PubMedCrossRefGoogle Scholar
  63. 63.
    Maloney DG, Molina AJ, Sahebi F, et al. Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 2003; 102:3447–3454.PubMedCrossRefGoogle Scholar
  64. 64.
    Kroger N, Perez-Simon JS, Myint H, et al. Relapse to prior autograft and chronic graft-versus-host disease are the strongest prognostic factors for outcome of melphalan/fludarabine-based dose-reduced allogeneic stem cell transplantation in patients with multiple myeloma. Biol Blood Marrow Transplant 2004; 10:698–708.PubMedCrossRefGoogle Scholar
  65. 65.
    Gerull S, Goerner M, Benner A, et al. Long-term outcome of nonmyeloablative allogeneic transplantation in patients with high-risk multiple myeloma. Bone Marrow Transplant 2005; 36:963–969.PubMedCrossRefGoogle Scholar
  66. 66.
    High-dose therapy and autologous peripheral blood stem cells transplantation followed by a very low reduced intensity regimen with fludarabine+cyclophospha mide and allograft improve complete remission rate in de novo multiple myeloma patients. Am J Hematol 2006; 81:973–978.Google Scholar
  67. 67.
    Majolino I, Davoli M, Carnevalli E, et al. Reduced intensity conditioning with thiopa, fludarabine and melphalan is effective in advanced multiple myeloma. Leuk Lymphoma 2007; 48:759–766.PubMedCrossRefGoogle Scholar
  68. 68.
    Georges GE, Maris MB, Maloney DG, et al. Nonmyeloablative unrelated donor hematopoietic cell transplantation to treat patients with poor-risk, relapsed, or refractory multiple myeloma. Biol Blood Marrow Transplant 2007; 13:423–432.PubMedCrossRefGoogle Scholar
  69. 69.
    Qazilbash MH, Saliba R, De Lima M, et al. Second autologous or allogeneic transplantation after the failure of first autograft in patients with multiple myeloma. Cancer 2006; 106:1084–1089.PubMedCrossRefGoogle Scholar
  70. 70.
    Kroger N, Schwerdtfeger R, Kiehl M, et al. Autologous stem cell transplantation followed by a dose-reduced allograft induces high complete remission rate in multiple myeloma. Blood 2002; 100:755–760.PubMedCrossRefGoogle Scholar
  71. 71.
    Lee CK, Badros A, Barlogie B, et al. Prognostic factors in allogeneic transplantation for patients with high-risk multiple myeloma after reduced intensity conditioning. Exp Hematol 2003; 31:73–80.PubMedCrossRefGoogle Scholar
  72. 72.
    Fassas ABT, Spencer R, Sawyer J, et al. Both hypodipliody or deletion of chromosome 13 independently confer post prognosis in multiple myeloma. Br J Haematol 2002; 118:1041–1047.PubMedCrossRefGoogle Scholar
  73. 73.
    Kroger N, Schilling G, Einsele H, et al. Deletion of chromosome b and 13q14 as detected by fluorescence in situ hybridization is a prognostic factor in patients with multiple myeloma who are receiving allogeneic dose-reduced stem cell transplantation. Blood 2004; 103:4056–4061.PubMedCrossRefGoogle Scholar
  74. 74.
    Waller EK, Langston AA, Lonial S, et al. Pharmacokinetics and pharmacody-namics of anti-thymocyte globulin in recipients of partially HLA-matched blood hematopoietic progenitor cell transplantation. Biol Blood Marrow Transplant 2003; 9:460–471.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Fengrong Wang
    • 1
  • Edmund K. Waller
    • 1
  1. 1.Bone Marrow and Stem Cell Transplant Center, Winship Cancer InstituteEmory University School of MedicineAtlantaUSA

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