Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Graft-Versus-Myeloma

Graft-versus-myeloma effect following antithymocyte globulin-based reduced intensity conditioning allogeneic stem cell transplantation

Bone Marrow Transplantation volume 34, pages 77–84 (2004)Cite this article

Summary:

In all, 41 multiple myeloma (MM) patients received an antithymocyte globulin (ATG), fludarabine, and busulfan-based reduced intensity conditioning (RIC) for allogeneic stem cell transplantation (allo-SCT) from HLA-identical siblings. In total, 29 patients (70%) were in partial remission, one patient in complete remission, and 11 (27%) with progressive disease at the time of allo-SCT. Median time between diagnosis and allo-SCT was 24 months. The cumulative incidences of grade II–IV and grade III–IV acute graft-versus-host disease (GVHD) were 36% (95% CI, 21–51%) and 7% (95% CI, 2–20%), respectively. Overall, 10 patients developed limited chronic GVHD, whereas seven developed an extensive form (cumulative incidence, 41% (95% CI, 26–56%) at 2 years). With a median follow-up of 389 days, the overall cumulative incidence of transplant-related mortality (TRM) was 17% (95% CI, 6–28%). In all, 11 patients (27%) are in continuous complete remission, and the Kaplan–Meier estimates of overall survival (OS) and progression-free survival (PFS) at 2 years were 62% (95% CI, 47–76%) and 41% (95% CI, 23–62%), respectively. PFS and OS were significantly higher in patients with chronic GVHD as compared to patients without chronic GVHD (P=0.006 for PFS and P=0.01 for OS). Collectively, these data demonstrate that RIC allo-SCT can mediate a potentially curative graft-versus-myeloma effect with an acceptable incidence of toxicity and TRM.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Hahn T, Wingard JR, Anderson KC et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of multiple myeloma: an evidence-based review. Biol Blood Marrow Transplant 2003; 9: 4–37.

    Article  PubMed  Google Scholar 

  2. 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.

    Article  CAS  PubMed  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. Barlogie B, Jagannath S, Vesole DH et al. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood 1997; 89: 789–793.

    CAS  PubMed  Google Scholar 

  5. Gianni AM, Tarella C, Bregni M et al. High-dose sequential chemoradiotherapy, a widely applicable regimen, confers survival benefit to patients with high-risk multiple myeloma. J Clin Oncol 1994; 12: 503–509.

    Article  CAS  PubMed  Google Scholar 

  6. Lenhoff S, Hjorth M, Holmberg E et al. Impact on survival of high-dose therapy with autologous stem cell support in patients younger than 60 years with newly diagnosed multiple myeloma: a population-based study. Nordic Myeloma Study Group. Blood 2000; 95: 7–11.

    CAS  PubMed  Google Scholar 

  7. Palumbo A, Triolo S, Argentino C et al. Dose-intensive melphalan with stem cell support (MEL100) is superior to standard treatment in elderly myeloma patients. Blood 1999; 94: 1248–1253.

    CAS  PubMed  Google Scholar 

  8. Gertz MA, Lacy MQ, Inwards DJ et al. Early harvest and late transplantation as an effective therapeutic strategy in multiple myeloma. Bone Marrow Transplant 1999; 23: 221–226.

    Article  CAS  PubMed  Google Scholar 

  9. Alexanian R, Weber D, Giralt S et al. Impact of complete remission with intensive therapy in patients with responsive multiple myeloma. Bone Marrow Transplant 2001; 27: 1037–1043.

    Article  CAS  PubMed  Google Scholar 

  10. Bensinger WI . Hematopoietic cell transplantation for multiple myeloma. Cancer Control 1998; 5: 235–242.

    Article  CAS  PubMed  Google Scholar 

  11. Weiden PL, Flournoy N, Thomas ED et al. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med 1979; 300: 1068–1073.

    Article  CAS  PubMed  Google Scholar 

  12. Horowitz MM, Gale RP, Sondel PM et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990; 75: 555–562.

    CAS  PubMed  Google Scholar 

  13. Tricot G, Vesole DH, Jagannath S et al. Graft-versus-myeloma effect: proof of principle. Blood 1996; 87: 1196–1198.

    CAS  PubMed  Google Scholar 

  14. Mehta J, Singhal S . Graft-versus-myeloma. Bone Marrow Transplant 1998; 22: 835–843.

    Article  CAS  PubMed  Google Scholar 

  15. 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.

    Article  CAS  PubMed  Google Scholar 

  16. Salama M, Nevill T, Marcellus D et al. Donor leukocyte infusions for multiple myeloma. Bone Marrow Transplant 2000; 26: 1179–1184.

    Article  CAS  PubMed  Google Scholar 

  17. 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.

    CAS  PubMed  Google Scholar 

  18. 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.

    Article  CAS  PubMed  Google Scholar 

  19. Mohty M, Bay JO, Faucher C et al. Graft-versus-host disease following allogeneic transplantation from HLA-identical sibling with antithymocyte globulin-based reduced-intensity preparative regimen. Blood 2003; 102: 470–476.

    Article  CAS  PubMed  Google Scholar 

  20. Giralt S, Estey E, Albitar M et al. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 1997; 89: 4531–4536.

    CAS  PubMed  Google Scholar 

  21. Slavin S, Nagler A, Naparstek E et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998; 91: 756–763.

    CAS  PubMed  Google Scholar 

  22. Khouri IF, Keating M, Korbling M et al. Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 1998; 16: 2817–2824.

    Article  CAS  PubMed  Google Scholar 

  23. Carella AM, Cavaliere M, Lerma E et al. Autografting followed by nonmyeloablative immunosuppressive chemotherapy and allogeneic peripheral-blood hematopoietic stem-cell transplantation as treatment of resistant Hodgkin's disease and non-Hodgkin's lymphoma. J Clin Oncol 2000; 18: 3918–3924.

    Article  CAS  PubMed  Google Scholar 

  24. Kottaridis PD, Milligan DW, Chopra R et al. In vivo CAMPATH-1 H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation. Blood 2000; 96: 2419–2425.

    CAS  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed  Google Scholar 

  26. Giralt S, Thall PF, Khouri I et al. Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation. Blood 2001; 97: 631–637.

    Article  CAS  PubMed  Google Scholar 

  27. Childs R, Chernoff A, Contentin N et al. Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med 2000; 343: 750–758.

    Article  CAS  PubMed  Google Scholar 

  28. Badros A, Barlogie B, Siegel E et al. Improved outcome of allogeneic transplantation in high-risk multiple myeloma patients after nonmyeloablative conditioning. J Clin Oncol 2002; 20: 1295–1303.

    Article  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

  30. 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.

    Article  CAS  PubMed  Google Scholar 

  31. Maloney DG, Molina AJ, Sahebi F et al. Allografting with non-myeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 2003; First: Edition Paper.

  32. Storb R, Deeg HJ, Whitehead J et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med 1986; 314: 729–735.

    Article  CAS  PubMed  Google Scholar 

  33. Przepiorka D, Weisdorf D, Martin P et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15: 825–828.

    CAS  PubMed  Google Scholar 

  34. Shulman HM, Sullivan KM, Weiden PL et al. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980; 69: 204–217.

    Article  CAS  PubMed  Google Scholar 

  35. Farmer ER . The histopathology of graft-versus-host disease. Adv Dermatol 1986; 1: 173–188.

    CAS  PubMed  Google Scholar 

  36. Sullivan KM, Agura E, Anasetti C et al. Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Semin Hematol 1991; 28: 250–259.

    CAS  PubMed  Google Scholar 

  37. Blade J, Samson D, Reece D et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol 1998; 102: 1115–1123.

    Article  CAS  PubMed  Google Scholar 

  38. Gooley TA, Leisenring W, Crowley J, Storer BE . Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 1999; 18: 695–706.

    Article  CAS  PubMed  Google Scholar 

  39. Kaplan EL, Meier P . Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  40. 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.

    CAS  PubMed  Google Scholar 

  41. 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.

    Article  CAS  PubMed  Google Scholar 

  42. Couban S, Stewart AK, Loach D, Panzarella T, Meharchand J . Autologous and allogeneic transplantation for multiple myeloma at a single centre. Bone Marrow Transplant 1997; 19: 783–789.

    Article  CAS  PubMed  Google Scholar 

  43. Bensinger WI . Recent developments in hematopoietic stem cell transplantation for multiple myeloma. Int J Hematol 2003; 77: 232–238.

    Article  PubMed  Google Scholar 

  44. 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.

    Article  PubMed  Google Scholar 

  45. Djulbegovic B, Seidenfeld J, Bonnell C, Kumar A . Nonmyeloablative allogeneic stem-cell transplantation for hematologic malignancies: a systematic review. Cancer Control 2003; 10: 17–41.

    Article  PubMed  Google Scholar 

  46. Gratwohl A, Baldomero H, Passweg J et al. Hematopoietic stem cell transplantation for hematological malignancies in Europe. Leukemia 2003; 17: 941–959.

    Article  CAS  PubMed  Google Scholar 

  47. 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.

    Article  CAS  PubMed  Google Scholar 

  48. Einsele H, Schafer HJ, Hebart H et al. Follow-up of patients with progressive multiple myeloma undergoing allografts after reduced-intensity conditioning. Br J Haematol 2003; 121: 411–418.

    Article  PubMed  Google Scholar 

  49. 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.

    Article  PubMed  Google Scholar 

  50. Majolino I, Corradini P, Scime R et al. High rate of remission and low rate of disease recurrence in patients with multiple myeloma allografted from their HLA-identical sibling donors. Bone Marrow Transplant 2003; 31: 767–773.

    Article  CAS  PubMed  Google Scholar 

  51. Kroger N, Zabelina T, Kruger W et al. In vivo T cell depletion with pretransplant anti-thymocyte globulin reduces graft-versus-host disease without increasing relapse in good risk myeloid leukemia patients after stem cell transplantation from matched related donors. Bone Marrow Transplant 2002; 29: 683–689.

    Article  CAS  PubMed  Google Scholar 

  52. Orsini E, Bellucci R, Alyea EP et al. Expansion of tumor-specific CD8+ T cell clones in patients with relapsed myeloma after donor lymphocyte infusion. Cancer Res 2003; 63: 2561–2568.

    CAS  PubMed  Google Scholar 

  53. Lim SH, Badros A, Lue C, Barlogie B . Distinct T-cell clonal expansion in the vicinity of tumor cells in plasmacytoma. Cancer 2001; 91: 900–908.

    Article  CAS  PubMed  Google Scholar 

  54. Chiriva-Internati M, Du J, Cannon M, Barlogie B, Yi Q . Myeloma-reactive allospecific cytotoxic T lymphocytes lyse target cells via the granule exocytosis pathway. Br J Haematol 2001; 112: 410–420.

    Article  CAS  PubMed  Google Scholar 

  55. Kolb HJ, Schattenberg A, Goldman JM et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Blood 1995; 86: 2041–2050.

    CAS  PubMed  Google Scholar 

  56. Slavin S, Naparstek E, Nagler A et al. Allogeneic cell therapy with donor peripheral blood cells and recombinant human interleukin-2 to treat leukemia relapse after allogeneic bone marrow transplantation. Blood 1996; 87: 2195–2204.

    CAS  PubMed  Google Scholar 

  57. Kersey JH, Weisdorf D, Nesbit ME et al. Comparison of autologous and allogeneic bone marrow transplantation for treatment of high-risk refractory acute lymphoblastic leukemia. N Engl J Med 1987; 317: 461–467.

    Article  CAS  PubMed  Google Scholar 

  58. Sullivan KM, Weiden PL, Storb R et al. Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood 1989; 73: 1720–1728.

    CAS  PubMed  Google Scholar 

  59. Gratwohl A, Hermans J, Apperley J et al. Acute graft-versus-host disease: grade and outcome in patients with chronic myelogenous leukemia. Working Party Chronic Leukemia of the European Group for Blood and Marrow Transplantation. Blood 1995; 86: 813–818.

    CAS  PubMed  Google Scholar 

  60. Mohty M, Kuentz M, Michallet M et al. Chronic graft versus host disease after allogeneic blood stem cell transplantation: long term results of a randomized study. Blood 2002; 100: 3128–3134.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

M Mohty was supported by grants from the ‘Association Méditerranéenne pour le Développement, de la Transplantation’ (Marseille, France) and from the ‘Ligue contre le Cancer du Gard’ (Nimes, France). We thank FB Petersen, MD (University of Utah Health Sciences Center, Salt Lake City, Utah) for critical reading of the manuscript. We thank the nursing staff for providing excellent care for our patients. We also thank the following physicians for their dedicated patient care and important study contributions: N Vey, RT Costello, R Bouabdallah, A Charbonnier, JM Schiano de Collela, C Chabannon, P Ladaique (Institut Paoli-Calmettes); and B Choufi, O Tournilhac (Centre Jean Perrin).

Author information

Authors and Affiliations

  1. Unité de Transplantation et de Thérapie Cellulaire (UTTC), Institut Paoli-Calmettes, Marseille, France

    M Mohty, C Faucher, K Bilger & D Blaise

  2. Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France

    J M Boiron, V Perreau & R Tabrizi

  3. Département d'Hématologie, Institut Paoli-Calmettes, Marseille, France

    G Damaj, D Coso, A M Stoppa, J A Gastaut, D Maraninchi & D Blaise

  4. CHU Edouard Herriot, Lyon, France

    A S Michallet & M Michallet

  5. Centre Jean-Perrin, Clermont-Ferrand, Marseille, France

    J O Bay

  6. Université de la Méditerranée, Marseille, France

    J A Gastaut, D Maraninchi & D Blaise

Authors
  1. M Mohty
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J M Boiron
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G Damaj
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A S Michallet
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J O Bay
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Faucher
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. V Perreau
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. K Bilger
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. D Coso
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A M Stoppa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. R Tabrizi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. J A Gastaut
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. M Michallet
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. D Maraninchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. D Blaise
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Mohty.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mohty, M., Boiron, J., Damaj, G. et al. Graft-versus-myeloma effect following antithymocyte globulin-based reduced intensity conditioning allogeneic stem cell transplantation. Bone Marrow Transplant 34, 77–84 (2004). https://doi.org/10.1038/sj.bmt.1704531

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1704531

Keywords

This article is cited by

Search

Advanced search

Quick links