Experimental Hematology
Volume 37, Issue 7 , Pages 791-798 , July 2009

Post-transplant immunotherapy with donor-lymphocyte infusion and novel agents to upgrade partial into complete and molecular remission in allografted patients with multiple myeloma

  • Nicolaus Kröger

      Affiliations

    • Department for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg/Germany
    • Corresponding Author InformationOffprint requests to: Nicolaus Kröger, M.D., Department for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany
    • ,
  • Anita Badbaran

      Affiliations

    • Department for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg/Germany
    • ,
  • Michael Lioznov

      Affiliations

    • Department for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg/Germany
    • ,
  • Sabine Schwarz

      Affiliations

    • Department for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg/Germany
    • ,
  • Silke Zeschke

      Affiliations

    • Department for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg/Germany
    • ,
  • York Hildebrand

      Affiliations

    • Department for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg/Germany
    • ,
  • Francis Ayuk

      Affiliations

    • Department for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg/Germany
    • ,
  • Djordje Atanackovic

      Affiliations

    • Department of Hematology/Oncology, University Medical Center Hamburg-Eppendorf, Hamburg/Germany
    • ,
  • Georgia Schilling

      Affiliations

    • Department of Hematology/Oncology, University Medical Center Hamburg-Eppendorf, Hamburg/Germany
    • ,
  • Tatjana Zabelina

      Affiliations

    • Department for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg/Germany
    • ,
  • Ulrike Bacher

      Affiliations

    • Department for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg/Germany
    • ,
  • Evgeny Klyuchnikov

      Affiliations

    • Department for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg/Germany
    • ,
  • Avichai Shimoni

      Affiliations

    • Department of Hematology, Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer/Israel
    • ,
  • Arnon Nagler

      Affiliations

    • Department of Hematology, Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer/Israel
    • ,
  • Paolo Corradini

      Affiliations

    • Department of Hematology, Instituto Nazionale Tumori, University of Milano, Milano/Italy
    • ,
  • Boris Fehse

      Affiliations

    • Department for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg/Germany
    • ,
  • Axel Zander

      Affiliations

    • Department for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg/Germany

Received 7 February 2009 ,Revised 24 March 2009 ,Accepted 26 March 2009.

References 

  1. Lahuerta JJ, Martinez-Lopez J, Serna JD, et al. Remission status defined by immunofixation vs electrophoresis after autologous transplantation has a major impact on the outcome of multiple myeloma patients. Br J Haematol. 2000;109:438–446
  2. Martinez-Lopez J, Blade J, de la Rubia J, et al. Prognostic impact of posttransplantation complete remission in multiple myeloma. Final results of a prospective study in a series of homogenously treated patients. Haematologica. 2007;92:42
  3. 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
  4. Gahrton G, Svensson H, Cavo M, et al. European Group for Blood and Marrow Transplantation. 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
  5. 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;107:3474–3480Epub 2006 Jan 5
  6. Kröger N, Einsele H, Wolff D, et al. German Study-group Multiple Myeloma (DSMM). 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
  7. Kröger 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
  8. 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;102:3447–3454Epub 2003 Jul 10
  9. 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
  10. Corradini P, Voena C, Tarella C, et al. Molecular and clinical remissions in multiple myeloma: role of autologous and allogeneic transplantation of hematopoietic cells. J Clin Oncol. 1999;17:208–215
  11. 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;18:2273–2781
  12. Corradini P, Cavo M, Lokhorst H, et al. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Molecular remission after myeloablative allogeneic stem cell transplantation predicts a better relapse-free survival in patients with multiple myeloma. Blood. 2003;102:1927–1929Epub 2003 May 08
  13. 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;103:4362–4364Epub 2004 Feb 19
  14. Salama M, Nevill T, Marcellus D, et al. Donor leukocyte infusions for multiple myeloma. Bone Marrow Transplant. 2000;26:1179–1184
  15. Ayuk F, Shimoni A, Nagler A, 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
  16. 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
  17. Kröger N, Kruger W, Renges H, et al. Donor lymphocyte infusion enhances remission status in patients with persistent disease after allografting for multiple myeloma. Br J Haematol. 2001;112:421–423
  18. 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
  19. Byrne JL, Carter GI, Bienz N, et al. Adjuvant alpha-interferon improves complete remission rates following allogeneic transplantation for multiple myeloma. Bone Marrow Transplant. 1998;22:639–643
  20. Kröger N, Shimoni A, Zagrivnaja M, et al. Low-dose thalidomide and donor lymphocyte infusion as adoptive immunotherapy after allogeneic stem cell transplantation in patients with multiple myeloma. Blood. 2004;104:3361–3363Epub 2004 Aug 3
  21. Galustian C, Meyer B, Labarthe MC, et al. The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T-regulatory cells. Cancer Immunol Immunther. 2009;58:1033–1045.
  22. 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;101:8120–8125Epub 2004 May 17
  23. Kröger 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
  24. 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
  25. Alizadeh M, Bernard M, Danic B, et al. Quantitative assessment of hematopoietic chimerism after bone marrow transplantation by real-time quantitative polymerase chain reaction. Blood. 2002;99:4618–4625
  26. Fehse B, Chukhlovin A, Kuhlcke K, et al. Real-time quantitative Y chromosome-specific PCR (QYCS-PCR) for monitoring hematopoietic chimerism after sex-mismatched allogeneic stem cell transplantation. J Hematother Stem Cell Res. 2001;10:419–425
  27. Tögel F, Kröger N, Korioth F, et al. Molecular methods for detection and quantification of myeloma cells after bone marrow transplantation: comparison between realtime quantitative and nested PCR. J Hematother. 2002;11:971–976
  28. Rawstron A, Orfáo A, Beksač M, et al. on behalf of the European Myeloma Network. Report of the European Myeloma Network on multiparametric flow cytometry in multiple myeloma and related disorders. Haematologica. 2008;93:431–438
  29. Voena C, Locatelli G, Castellino C, et al. Qualitative and quantitative polymerase chain reaction detection of the residual myeloma cell contamination after positive selection of CD34+ cells with small-and large-scale Miltenyi cell sorting system. Br J Haematol. 2002;117:642–645
  30. Bladé 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
  31. Fenk R, Ak M, Kobbe G, et al. Levels of minimal residual disease detected by quantitative molecular monitoring herald relapse in patients with multiple myeloma. Haematologica. 2004;89:557–566
  32. Raab MS, Cremer FW, Breitkreutz IN, et al. Molecular monitoring of tumour load kinetics predicts disease progression after non-myeloablative allogeneic stem cell transplantation in multiple myeloma. Ann Oncol. 2005;16:611–617Epub 2005 Feb 28
  33. Paiva B, Vidriales MB, Cervero J, et al. Multiparameter flow cytometry remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood. 2008;112:4017–4023
  34. Martínez-Sánchez P, Montejano L, Sarasquete ME, et al. Evaluation of minimal residual disease in multiple myeloma patients by fluorescent-polymerase chain reaction: the prognostic impact of achieving molecular response. Br J Haematol. 2008;142:766–774Epub 2008 Jul 8
  35. Galimberti S, Benedetti E, Morabito F, et al. Prognostic role of minimal residual disease in multiple myeloma patients after non-myeloablative allogeneic transplantation. Leuk Res. 2005;29:961–966
  36. Lioznov M, Badbaran A, Fehse B, et al. Monitoring of minimal residual disease in multiple myeloma after allo-SCT: flow cytometry vs PCR-based techniques. Bone Marrow Transplant. 2008;41:913–916Epub 2008 Feb 11
  37. Sarasquete ME, García-Sanz R, González D, et al. Minimal residual disease monitoring in multiple myeloma: a comparison between allelic-specific oligonucleotide real-time quantitative polymerase chain reaction and flow cytometry. Haematologica. 2005;90:1365–1372
  38. Kröger N, Zagrivnaja M, Schwartz S, et al. Kinetics of plasma cell chimerism after allogeneic stem cell transplantation by highly-sensitive real-time PCR based on sequence polymorphism and its value to quantify minimal residual disease in patients with multiple myeloma. Exp Hematol. 2006;34:688–694
  39. Kröger N. Mini-midi-maxi? How to harness the graft-versus-myeloma effect and target molecular remission after allogeneic stem cell transplantation. Leukemia. 2007;21:1851–1858Epub 2007 Jun 14

PII: S0301-472X(09)00116-7

doi: 10.1016/j.exphem.2009.03.008

Experimental Hematology
Volume 37, Issue 7 , Pages 791-798 , July 2009

Article Tools

* Image Usage & Resolution