Role of allogeneic stem cell transplantation in multiple myeloma



Multiple myeloma remains incurable despite the use of high-dose therapy and autologous stem cell transplantation and the introduction of novel agents with high response rates. The use of an uncontaminated stem cell graft and the presence of a graft-versus-myeloma effect led to the use of allogeneic stem cell transplantation in myeloma, and it has been part of the therapeutic armamentarium for more than a decade. Early results were discouraging due to high transplantation-related mortality and high rates of graft-versus-host disease. More recently, better supportive care, increasing experience with this modality and its complications, use of reduced-intensity conditioning regimens, and its use earlier in the course of disease have led to improved outcomes. Patients with high-risk genetic and biochemical features do poorly with conventional therapies, and allogeneic transplantation offers the potential for long-term disease control.

References and Recommended Reading

  1. 1.
    Jemal A, Siegel R, Ward E, et al.: Cancer statistics, 2007. CA Cancer J Clin 2007, 57:43–66.PubMedGoogle Scholar
  2. 2.
    Myeloma Trialists’ Collaborative Group: Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. J Clin Oncol 1998, 16:3832–3842.Google Scholar
  3. 3.
    McElwain TJ, Powles RL: High-dose intravenous melphalan for plasma-cell leukaemia and myeloma. Lancet 1983, 8:822–824.CrossRefGoogle Scholar
  4. 4.
    Barlogie B, Alexanian R, Dicke KA, et al.: High-dose chemoradiotherapy and autologous bone marrow transplantation for resistant multiple myeloma. Blood 1987, 70:869–872.PubMedGoogle Scholar
  5. 5.
    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 Myelome. N Engl J Med 1996, 335:91–97.PubMedCrossRefGoogle Scholar
  6. 6.
    Child JA, Morgan GJ, Davies FE, et al.: High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 2003, 348:1875–1883.PubMedCrossRefGoogle Scholar
  7. 7.
    Attal M, Harousseau JL, Facon T, et al.: Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 2003, 349:2495–2502.PubMedCrossRefGoogle Scholar
  8. 8.
    Kumar S, Rajkumar SV: Thalidomide and lenalidomide in the treatment of multiple myeloma. Eur J Cancer 2006, 42:1612–1622.PubMedCrossRefGoogle Scholar
  9. 9.
    Rajkumar SV, Blood E, Vesole D, et al.: Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2006, 24:431–436.PubMedCrossRefGoogle Scholar
  10. 10.
    Rajkumar SV, Hayman SR, Lacy MQ, et al.: Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 2005, 106:4050–4053.PubMedCrossRefGoogle Scholar
  11. 11.
    Singhal S, Mehta J, Desikan R, et al.: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999, 341:1565–1571.PubMedCrossRefGoogle Scholar
  12. 12.
    Richardson PG, Sonneveld P, Schuster MW, et al.: Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005, 352:2487–2498.PubMedCrossRefGoogle Scholar
  13. 13.
    Kumar SK, Rajkumar SV, Dispenzieri A, et al.: Improved survival in multiple myeloma and the impact of novel therapies. Blood 2007 [Epub ahead of print].Google Scholar
  14. 14.
    Bergsagel PL, Kuehl WM: Molecular pathogenesis and a consequent classification of multiple myeloma. J Clin Oncol 2005, 23:6333–6338.PubMedCrossRefGoogle Scholar
  15. 15.
    Dispenzieri A, Rajkumar SV, Gertz MA, et al.: Treatment of newly diagnosed multiple myeloma based on Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART): consensus statement. Mayo Clin Proc 2007, 82:323–341.PubMedCrossRefGoogle Scholar
  16. 16.
    Tricot G, Vesole DH, Jagannath S, et al.: Graft-versus-myeloma effect: proof of principle. Blood 1996, 87:1196–1198.PubMedGoogle Scholar
  17. 17.
    Alyea E, Weller E, Schlossman R, et al.: Outcome after autologous and allogeneic stem cell transplantation for patients with multiple myeloma: impact of graft-versus-myeloma effect. Bone Marrow Transplant 2003, 32:1145–1151.PubMedCrossRefGoogle Scholar
  18. 18.
    Huff CA, Fuchs EJ, Noga SJ, et al.: Long-term follow-up of T cell-depleted allogeneic bone marrow transplantation in refractory multiple myeloma: importance of allogeneic T cells. Biol Blood Marrow Transplant 2003, 9:312–319.PubMedCrossRefGoogle Scholar
  19. 19.
    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
  20. 20.
    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
  21. 21.
    Alyea 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.PubMedCrossRefGoogle Scholar
  22. 22.
    Crawley C, Lalancette M, Szydlo R, 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, 105:4532–4539.PubMedCrossRefGoogle Scholar
  23. 23.
    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, 97:2574–2579.PubMedCrossRefGoogle Scholar
  24. 24.
    Peggs KS, Mackinnon S, Williams CD, et al.: Reduced-intensity transplantation with in vivo T-cell depletion and adjuvant dose-escalating donor lymphocyte infusions for chemotherapy-sensitive myeloma: limited efficacy of graft-versus-tumor activity. Biol Blood Marrow Transplant 2003, 9:257–265.PubMedCrossRefGoogle Scholar
  25. 25.
    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
  26. 26.
    Bensinger WI, Buckner CD, Anasetti C, et al.: Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome. Blood 1996, 88:2787–2793.PubMedGoogle Scholar
  27. 27.
    Hunter HM, Peggs K, Powles R, et al.: Analysis of outcome following allogeneic haemopoietic 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
  28. 28.
    Lokhorst HM, Segeren 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
  29. 29.
    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
  30. 30.
    Bjorkstrand BB, Ljungman P, Svensson H, et al.: Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma: a retrospective case-matched study from the European Group for Blood and Marrow Transplantation. Blood 1996, 88:4711–4718.PubMedGoogle Scholar
  31. 31.
    Gahrton G, Svensson H, Cavo M, et al.: Progress in allogenic bone marrow and peripheral blood stem cell transplantation for multiple myeloma: a comparison between transplants performed 1983–93 and 1994–8 at European Group for Blood and Marrow Transplantation centres. Br J Haematol 2001, 113:209–216.PubMedCrossRefGoogle Scholar
  32. 32.
    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
  33. 33.
    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
  34. 34.
    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
  35. 35.
    Kroger N, Sayer HG, Schwerdtfeger R, et al.: Unrelated stem cell transplantation in multiple myeloma after a reduced-intensity conditioning with pretransplantation antithymocyte globulin is highly effective with low transplantation-related mortality. Blood 2002, 100:3919–3924.PubMedCrossRefGoogle Scholar
  36. 36.
    Crawley C, Iacobelli 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
  37. 37.
    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
  38. 38.
    Bruno B, Sorasio R, Patriarca F, et al.: Unrelated donor haematopoietic cell transplantation after non-myeloablative conditioning for patients with high-risk multiple myeloma. Eur J Haematol 2007, 78:330–337.PubMedCrossRefGoogle Scholar
  39. 39.
    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
  40. 40.
    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
  41. 41.
    Salama M, Nevill T, Marcellus D, et al.: Donor leukocyte infusions for multiple myeloma. Bone Marrow Transplant 2000, 26:1179–1184.PubMedCrossRefGoogle Scholar
  42. 42.
    Lokhorst HM, Schattenberg A, Cornelissen JJ, et al.: Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stem-cell transplantation: predictive factors for response and long-term outcome. J Clin Oncol 2000, 18:3031–3037.PubMedGoogle Scholar
  43. 43.
    Levenga H, Levison-Keating S, Schattenberg AV, et al.: Multiple myeloma patients receiving pre-emptive donor lymphocyte infusion after partial T-cell-depleted allogeneic stem cell transplantation show a long progression-free survival. Bone Marrow Transplant 2007, 40:355–359.PubMedCrossRefGoogle Scholar
  44. 44.
    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
  45. 45.
    Arora M, McGlave PB, Burns LJ, et al.: Results of autologous and allogeneic hematopoietic cell transplant therapy for multiple myeloma. Bone Marrow Transplant 2005, 35:1133–1140.PubMedCrossRefGoogle Scholar
  46. 46.
    Lokhorst HM, Sonneveld P, Cornelissen JJ, et al.: Induction therapy with vincristine, adriamycin, dexamethasone (VAD) and intermediate-dose melphalan (IDM) followed by autologous or allogeneic stem cell transplantation in newly diagnosed multiple myeloma. Bone Marrow Transplant 1999, 23:317–322.PubMedCrossRefGoogle Scholar
  47. 47.
    Varterasian M, Janakiraman N, Karanes C, et al.: Transplantation in patients with multiple myeloma: a multicenter comparative analysis of peripheral blood stem cell and allogeneic transplant. Am J Clin Oncol 1997, 20:462–466.PubMedCrossRefGoogle Scholar
  48. 48.
    Couban S, Stewart AK, Loach D, et al.: Autologous and allogeneic transplantation for multiple myeloma at a single centre. Bone Marrow Transplant 1997, 19:783–789.PubMedCrossRefGoogle Scholar
  49. 49.
    Reynolds C, Ratanatharathorn V, Adams P, et al.: Allogeneic stem cell transplantation reduces disease progression compared to autologous transplantation in patients with multiple myeloma. Bone Marrow Transplant 2001, 27:801–807.PubMedCrossRefGoogle Scholar
  50. 50.
    Kuruvilla J, Shepherd JD, Sutherland HJ, et al.: Long-term outcome of myeloablative allogeneic stem cell transplantation for multiple myeloma. Biol Blood Marrow Transplant 2007, 13:925–931.PubMedCrossRefGoogle Scholar
  51. 51.
    Perez-Simon JA, Martino R, Alegre A, et al.: Chronic but not acute graft-versus-host disease improves outcome in multiple myeloma patients after non-myeloablative allogeneic transplantation. Br J Haematol 2003, 121:104–108.PubMedCrossRefGoogle Scholar
  52. 52.
    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
  53. 53.
    Majolino I, Davoli M, Carnevalli E, et al.: Reduced intensity conditioning with thiotepa, fludarabine, and melphalan is effective in advanced multiple myeloma. Leuk Lymphoma 2007, 48:759–766.PubMedCrossRefGoogle Scholar
  54. 54.
    Shimazaki C, Fujii H, Yoshida T, et al.: Reduced-intensity conditioning allogeneic stem cell transplantation for multiple myeloma: results from the Japan Myeloma Study Group. Int J Hematol 2005, 81:342–348.PubMedCrossRefGoogle Scholar
  55. 55.
    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

Copyright information

© Current Medicine Group LLC 2008

Authors and Affiliations

  1. 1.Division of HematologyMayo ClinicRochesterUSA

Personalised recommendations