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.

  • Spotlight
  • Published:

The current status of reduced-intensity allogeneic hematopoietic stem cell transplantation for multiple myeloma

Leukemia volume 20, pages 1683–1689 (2006)Cite this article

Abstract

Of all the treatment modalities employed to control multiple myeloma, only allogeneic hematopoetic stem cell transplantation is potentially curative, due in large part to a graft-versus-myeloma (GVM) effect. Whereas patients who receive either allogeneic or autologous stem cell transplants for multiple myeloma have similar 3–5-year survival, only allograft recipients appear to enjoy long-term disease-free survival. High transplant-related mortality (TRM) associated with allogeneic stem cell transplantation is currently the major limitation to wider use of this potentially curative modality. This high mortality has been the major impetus for exploration of reduced intensity conditioning (RIC) regimens designed to allow engraftment of allogeneic stem cells. With follow-up now extending to 7 years, it is clear that when compared to myeloablative transplants, RIC allografts are associated with lower TRM; however, reduced mortality comes at a cost of higher rates of disease progression and relapse. Strategies designed to improve the therapeutic index of allografts include the use of more intensive, yet still non-myeloablative conditioning regimens, tandem autologous plus RIC allografts, peripheral blood cells rather than bone marrow, graft engineering to improve the GVM activity while reducing graft-versus-host disease, post-transplant maintenance and targeted conditioning therapies such as bone-seeking radioisotopes.

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

Relevant articles

Open Access articles citing this article.

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

References

  1. Kumar S, Anderson KC . Drug insight: thalidomide as a treatment for multiple myeloma (review). Nat Clin Pract Oncol 2005; 2: 262–270.

    Article  CAS  PubMed  Google Scholar 

  2. Anderson KC, Shaughnessy Jr JD, Barlogie B, Harousseau J-L, Roodman GD . Multiple myeloma. In: Broudy VC, Abkowitz JL, Vose JM (eds). Hematology 2002: American Society of Hematology Education Program Book. American Society of Hemtology: Washington, DC, 2002, pp 214–240.

    Google Scholar 

  3. Tricot G, Vesole DH, Jagannath S, Hilton J, Munshi N, Barlogie B . Graft-versus-myeloma effect: proof of principle. Blood 1996; 87: 1196–1198.

    CAS  PubMed  Google Scholar 

  4. Verdonck LF, Lokhorst HM, Dekker AW, Nieuwenhuis HK, Petersen EJ . Graft-versus-myeloma effect in two cases. Lancet 1996; 347: 800–801.

    Article  CAS  PubMed  Google Scholar 

  5. Aschan J, Lonnqvist B, Ringden O, Kumlien G, Gahrton G . Graft-versus-myeloma effect (letter). Lancet 1996; 348: 346.

    Article  CAS  PubMed  Google Scholar 

  6. Le Blanc R, Montminy-Métivier S, Bélanger R, Busque L, Fish D, Roy D-C et al. Allogeneic transplantation for multiple myeloma: further evidence for a GVHD-associated graft-versus-myeloma effect. Bone Marrow Transplant 2001; 28: 841–848.

    Article  CAS  PubMed  Google Scholar 

  7. Libura J, Hoffmann T, Passweg J, Gregor M, Favre G, Tichelli A et al. Graft-versus-myeloma after withdrawal of immunosuppression following allogeneic peripheral stem cell transplantation. Bone Marrow Transplant 1999; 24: 925–927.

    Article  CAS  PubMed  Google Scholar 

  8. Bertz H, Burger JA, Kunzmann R, Mertelsmann R, Finke J . adoptive immunotherapy for relapsed multiple myeloma after allogeniec bone marrow transplantation (BMT): evidence for a graft-versus-myeloma effect. Leukemia 1997; 11: 281–283.

    Article  CAS  PubMed  Google Scholar 

  9. Salama M, Nevill T, Marcellus D, Parker P, Johnson M, Kirk A et al. donor leukocyte infusions for multiple myeloma. Bone Marrow Transplant 2000; 26: 1179–1184.

    Article  CAS  PubMed  Google Scholar 

  10. Collins Jr RH, Shpilberg O, Drobyski WR, Porter DL, Giralt S, Champlin R et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 1997; 15: 433–444.

    Article  PubMed  Google Scholar 

  11. Alyea E, Ritz J . Induction of graft versus myeloma by donor lymphocyte infusions following allogeneic bone marrow transplant. In: Anderson KC (ed). VI International Workshop on Multiple Myeloma 1997, 1997.

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

    Article  CAS  PubMed  Google Scholar 

  13. Kroger N, Perez-Simon JA, Myint H, Klingemann H, Shimoni A, Nagler A, 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.

    Article  PubMed  Google Scholar 

  14. Dazzi F, Szydlo RM, Cross NC, Craddock C, Kaeda J, Kanfer E et al. Durability of responses following donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood 2000; 96: 2712–2716.

    CAS  PubMed  Google Scholar 

  15. Helg C, Starobinski M, Jeannet M, Chapuis B . Donor lymphocyte infusion for the treatment of relapse after allogeneic hematopoietic stem cell transplantation (review). Leukemia Lymph 1998; 29: 301–313.

    Article  CAS  Google Scholar 

  16. Storb R, Yu C, Sandmaier B, McSweeney P, Georges G, Nash R, Woolfrey A . Mixed hematopoietic chimerism after hematopoietic stem cell allografts. Transplant Proc 1999; 31: 677–678.

    Article  CAS  PubMed  Google Scholar 

  17. McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG 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 

  18. Maloney DG, Molina AJ, Sahebi F, Stockerl-Goldstein KE, Sandmaier BM, Bensinger W et al. Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 2003; 102: 3447–3454.

    Article  CAS  PubMed  Google Scholar 

  19. Lee C-K, Badros A, Barlogie B, Morris C, Zangari M, Fassas A 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 

  20. Giralt S, Bensinger W, Goodman M, Podoloff D, Eary J, Wendt R . 166Ho-DOTMP plus melphalan followed by peripheral blood stem cell transplantation in patients with multiple myeloma: results of two phase 1/2 trials. Blood 2003; 102: 2684–2691.

    Article  CAS  PubMed  Google Scholar 

  21. Einsele H, Schafer HJ, Hebart H, Bader P, Meisner C, Plasswilm L 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 

  22. Qazilbash MH, Saliba R, de Lima M, Hosing C, Couriel D, Aleman A et al. Second autologous or allogeneic transplantation after the failure of first autograft in patients with multiple myeloma. Cancer 2006; 106: 1084–1089.

    Article  PubMed  Google Scholar 

  23. Elice F, Raimondi R, Tosetto A, D’Emilio A, Di Bona E, Piccin A et al. Prolonged overall survival with second on-demand autologous transplant in multiple myeloma. Am J Hematol 2006; 81: 426–431.

    Article  PubMed  Google Scholar 

  24. Kroger N, Schwerdtfeger R, Kiehl M, Sayer HG, Renges H, Zabelina T et al. Autologous stem cell transplantation followed by a dose-reduced allograft induces high complete remission rate in multiple myeloma. 2002; 100: 755–760.

  25. Kroger N, Sayer HG, Schwerdtfeger R, Kiehl M, Nagler A, Renges H 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 

  26. Galimberti S, Benedetti E, Morabito F, Papineschi F, Callea V, Fazzi R et al. Prognostic role of minimal residual disease in multiple myeloma patients after non-myeloablative allogeneic transplantation. Leuk Res 2005; 29: 961–966.

    Article  CAS  PubMed  Google Scholar 

  27. Peggs KS, Mackinnon S, Williams CD, D’Sa S, Thuraisundaram D, Kyriakou C 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.

    Article  PubMed  Google Scholar 

  28. Mohty M, Boiron JM, Damaj G, Michallet AS, Bay JO, Faucher C et al. Graft-versus-myeloma effect following antithymocyte globulin-based reduced intensity conditioning allogeneic stem cell transplantation. Bone Marrow Transplant 2004; 34: 77–84.

    Article  CAS  PubMed  Google Scholar 

  29. 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 Leukemia Working Party of the EBMT. Blood 2005; 105: 4532–4539.

    Article  CAS  PubMed  Google Scholar 

  30. Garban F, Attal M, Michallet M, Hulin C, Bourhis JH, Yakoub-Agha I 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.

    Article  CAS  PubMed  Google Scholar 

  31. Kroger N, Schilling G, Einsele H, Liebisch P, Shimoni A, Nagler A et al. Deletion of chromosome band 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.

    Article  PubMed  Google Scholar 

  32. Ayuk F, Shimoni A, Nagler A, Schwerdtfeger R, Kiehl M, Sayer HG et al. Efficacy and toxicity of low-dose escalating donor lymphocyte infusion given after reduced intensity conditioning allograft for multiple myeloma. Leukemia 2004; 18: 659–662.

    Article  CAS  PubMed  Google Scholar 

  33. Kroger N, Shimoni A, Zagrivnaja M, Ayuk F, Lioznov M, Schieder H et al. Low-dose thalidomide and donor lymphocyte infusion as adoptive immunotherapy after allogeneic stem cell transplantation in patients with multiple myeloma. Blood 2004; 104: 3361–3363.

    Article  PubMed  Google Scholar 

  34. van de Donk NW, Kröger N, Hegenbart U, Corradini P, Miguel JF, Goldschmidt H 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.

    Article  CAS  PubMed  Google Scholar 

  35. Barlogie B, Kyle RA, Anderson KC, Greipp PR, Lazarus HM, Hurd DD et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of Phase III US Intergroup Trial S9321. J Clin Oncol 2006; 24: 929–936.

    Article  CAS  PubMed  Google Scholar 

  36. Gahrton G, Svensson H, Cavo M, Apperley J, Bacigalupo A, Björkstand B 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.

    Article  CAS  PubMed  Google Scholar 

  37. Majolino I, Corradini P, Scim R, Santoro A, Tarella C, Cavallaro AM et al. Allogeneic transplantation of unmanipulated peripheral blood stem cells in patients with multiple myeloma. Bone Marrow Transplant 1998; 22: 449–455.

    Article  CAS  PubMed  Google Scholar 

  38. Giralt S, Bensinger W, Goodman M, Podoloff D, Eary J, Wendt R et al. 166HO-DOTMP plus melphalan followed by peripheral blood stem cell transplantation in patients with multiple myeloma: results of two phase 1/2 trials. Blood 2003; 102: 2684–2691.

    Article  CAS  PubMed  Google Scholar 

  39. Dispenzieri A, Wiseman GA, Lacy MQ, Litzow MR, Anderson PM, Gastineau DA et al. A Phase I study of 153Sm-EDTMP with fixed high-dose melphalan as a peripheral blood stem cell conditioning regimen in patients with multiple myeloma. Leukemia 2005; 19: 118–125.

    Article  CAS  PubMed  Google Scholar 

  40. Kennedy GA, Durrant S, Butler J, Morton J, Western R, Bartlett ML et al. Outcome of myeloablative allogeneic stem cell transplantation in multiple myeloma with a 153Sm-EDTMP-based preparative regimen. Leukemia 2005; 19: 879–880.

    Article  CAS  PubMed  Google Scholar 

  41. Bensinger WI, Martin PJ, Storer B, Clift R, Forman SJ, Negrin R et al. Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med 2001; 344: 175–181.

    Article  CAS  PubMed  Google Scholar 

  42. Macfarlane DJ, Durrant S, Bartlett ML, Allison R, Morton AJ . 153Sm EDTMP for bone marrow ablation prior to stem cell transplantation for haematological malignancies. Nucl Med Commun 2002; 23: 1099–1106.

    Article  CAS  PubMed  Google Scholar 

  43. Deeg HJ, Storer B, Slattery JT, Anasetti C, Doney KC, Hansen JA et al. Conditioning with targeted busulfan and cyclophosphamide for hemopoietic stem cell transplantation from related and unrelated donors in patients with myelodysplastic syndrome. Blood 2002; 100: 1201–1207.

    Article  CAS  PubMed  Google Scholar 

  44. Champlin R, Giralt S, Gajewski J, Hester J, Körbling M, Deisseroth A . CD8 depleted donor lymphocytes for CML relapsing post BMT. Int Soc Exp Hematol 1995; 23: 939.

    Google Scholar 

  45. Kroger N, Shaw B, Iacobelli S, Zabelina T, Peggs K, Shimoni A et al. Comparison between antithymocyte globulin, alemtuzumab, the possible impact of KIR-ligand mismatch after dose-reduced conditioning, unrelated stem cell transplantation in patients with multiple myeloma. Br J Haematol 2005; 129: 631–643.

    Article  PubMed  Google Scholar 

  46. Gerull S, Goerner M, Benner A, Hegenbart U, Klein U, Schaefer H et al. Long-term outcome of nonmyeloablative allogeneic transplantation in patients with high-risk multiple myeloma. Bone Marrow Transplant 2005; 36: 963–969.

    Article  CAS  PubMed  Google Scholar 

  47. Ma SY, Lie AK, Au WY, Chim CS, Kwong YL, Liang R . Non-myeloablative allogeneic peripheral stem cell transplantation for multiple myeloma. Hong Kong Med J 2004; 10: 77–83.

    CAS  PubMed  Google Scholar 

  48. Perez-Simon J, Martino R, Alegre A, Tomas J, De Leon A, Caballero D 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.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by Grants CA-18029, CA-47748, CA-18221, CA-15704 from the National Cancer Institute, and HL 36444 from the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, The Jose Carreras Foundation Against Leukemia, Barcelona, Spain.

Author information

Authors and Affiliations

  1. Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA

    W I Bensinger

Authors
  1. W I Bensinger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to W I Bensinger.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bensinger, W. The current status of reduced-intensity allogeneic hematopoietic stem cell transplantation for multiple myeloma. Leukemia 20, 1683–1689 (2006). https://doi.org/10.1038/sj.leu.2404333

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404333

Keywords

This article is cited by

Search

Advanced search

Quick links