Summary:
Donor lymphocyte infusions (DLIs) provide effective therapy for patients with various hematological malignancies who have relapsed after allogeneic hematopoietic stem cell transplantation (HSCT). In patients with multiple myeloma (MM), DLIs can induce response rates of 40–52%. DLIs were employed as treatment for MM relapse or as prophylaxis for relapse in MM patients undergoing allo-HSCT. The clinically most relevant treatment-related morbidity with DLIs is the occurrence of graft-versus-host disease (GVHD). Secondly, graft failure and the immune escape of extramedullary plasmocytoma have been reported. The fact that previous clinical reports have documented graft-versus-myeloma (GVM) activity without GVHD suggests that at least two distinct immunocompetent cell populations mediating GVHD and/or GVM may exist. Further characterization of the effector cells such as T cells and/or NK cells and their targets may help to clarify the immune response that mediates the GVM effect. This review considers the results of clinical approaches with DLI for MM, with emphasis on strategies to prevent GVHD while preserving the GVM effect. Furthermore, currently investigated molecular antigenic targets for the GVM effect such as MM-specific idiotypic determinant of immunglobulin variable regions, several PRAME epitopes and antigenic structures encoded by cancer germline-specific genes as candidates for immunotherapy trials are discussed.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
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.
Gahrton G, Tura S, Ljungman P et al. Prognostic factors in allogeneic bone marrow transplantation for multiple myeloma. J Clin Oncol 1995; 13: 1312–1320.
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.
Reece DE, Shepherd JD, Klingemann HG et al. Treatment of myeloma using intensive therapy and allogeneic bone marrow transplantation. Bone Marrow Transplant 1995; 15: 117–123.
Majolino I, Corradini P, Scime R et al. High rate of remission and low rate of disease recurrence in patients with multiple myeloma allografted with PBSC from their HLA-identical sibling donors. Bone Marrow Transplant 2003; 31: 767–773.
Bensinger WI, Buckner CD, Clift RA et al. Phase I study of busulfan and cyclophosphamide in preparation for allogeneic marrow transplant for patients with multiple myeloma. J Clin Oncol 1992; 10: 1492–1497.
Bellucci R, Ritz J . Allogeneic stem cell transplantation for multiple myeloma. Rev Clin Exp Hematol 2002; 6: 205–224.
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.
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.
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.
Peggs KS, Mackinnon S, Williams CD et al. Reduced intensity transplantation with in vivo T-cell depletion and adjuvant dose-escalating donor lymphocyte infusios for chemotherapy-sensitive myeloma: limited efficacy of graft-versus-tumor activity. Biol Blood Marrow Transplant 2003; 9: 257–265.
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.
Tricot G, Vesole DH, Jagannath S et al. Graft versus myeloma effect: proof of principle. Blood 1996; 87: 1196–1198.
Verdonck L, Lokhorst H, Dekker A et al. Graft-versus-myeloma effect in two cases. Lancet 1996; 347: 800–801.
Bertz H, Burger JA, Kunzmann R et al. Adoptive immunotherapy for relapsed multiple myeloma after allogeneic BMT: evidence of a graft-versus-myeloma effect. Leukemia 1997; 11: 281–283.
Orsini E, Alyea EP, Schlossmann R et al. Expansion of preexisting clonal populations following donor lymphocyte infusion for relapsed multiple myeloma after allogeneic bone marrow transplantation. Blood 1997; 90 (Suppl 1): 549a.
Munshi NC, Govindarajan R, Drake R et al. Thymidine kinase (TK) gene-transduced human lymphocytes can be highly purified, remain fully functional, and are killed efficiently with ganciclovir. Blood 1997; 89: 1334–1340.
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.
Salama M, Nevill T, Marcellus T et al. Donor leukocyte infusions for multiple myeloma. Bone Marrow Transplant 2000; 26: 1179–1184.
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.
Balkwill FR . Interferons. Lancet 1989; 1: 1060–1063.
Upadhyaya G, Guba SC, Sih SA et al. Interferon alpha restores the deficient expression of the cytoadhesion molecule lymphocyte function antigen-3 by chronic myelogenous leukemia progenitor cells. J Clin Invest 1991; 88: 2131–2136.
MacKinnon S . Who may benefit from donor leukocyte infusions after allogeneic stem cell transplantation? Br J Haematol 2000; 110: 12–17.
Zomas A, Stefanoudaki K, Fisfis M et al. Graft-versus-myeloma after donor leukocyte infusion: maintenance of marrow remission but extramedullary relapse with plasmocytomas. Bone Marrow Transplant 1998; 21: 1163–1165.
Yang YG, Sergio JJ, Pearson DA et al. Interleukin-12 preserves the graft-versus-leukemia effect of allogeneic CD8T cells while inhibiting CD4-dependent graft-versus-host disease in mice. Blood 1997; 90: 4651–4660.
Anderson LD, Savary CA, Mullen CA . Immunization of allogeneic bone marrow transplant recipients with tumor cell vaccines enhances graft-versus-tumor activity without exacerbating graft-versus-host disease. Blood 2000; 95: 2426–2433.
Tsukada N, Kobata T, Aizawa Y et al. Graft-versus-leukemia effect and graft-versus-host disease can be differentiated by cytotoxic mechanisms in a murine model of allogeneic bone marrow transplantation. Blood 1999; 93: 2738–2747.
Alyea EP, Soiffer RJ, Canning C et al. Toxicity and efficacy of defined doses of CD4(+) donor lymphocytes for treatment of relapse after allogeneic bone marrow transplant. Blood 1998; 91: 3671–3680.
Giralt S, Hester J, Huh Y et al. CD8-depleted donor lymphocyte infusion as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation. Blood 1995; 86: 4337–4343.
Mackinnon S, Papadopoulos EB, Carabasi MH et al. Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-leukemia responses from graft-versus-host disease. Blood 1995; 86: 1261–1268.
Kwak LW, Campbell MJ, Czerwinski DK et al. Induction of immune responses in patients with B-cell lymphoma against the surface-immunglobulin idiotype expressed by their tumors. N Engl J Med 1992; 237: 1209–1215.
Hsu FJ, Caspar CB, Czervinski D et al. Tumor-specific idiotype vaccines in the treatment of patients with B-cell lymphoma – long-term results of a clinical trial. Blood 1997; 98: 3129–3135.
Bogen B . Peripheral T cell tolerance as a tumor escape mechanism: deletion of CD4+ T cells specific for a monoclonal immunglobulin idiotype secreted by a plasmacytoma. Eur J Immunol 1996; 26: 2671–2679.
Kwak LW, Taub DD, Duffey PL et al. Transfer of myeloma idiotype-specific immunity from an actively immunized marrow donor. Lancet 1995; 345: 1016.
Barratt-Boyes SM . Making the most of mucin: a novel target for tumor immunotherapy. Cancer Immunol Immunother 1996; 43: 142–148.
Takahashi T, Makiguchi Y, Hinoda Y et al. Expression of MUC1 on myeloma cells and induction of HLA-unrestricted cytotoxic T lymphocytes against MUC1 from a multiple myeloma patient. J Immunol 1994; 152: 2102–2112.
Brossart P, Schneider A, Dill P et al. The epithelial tumor antigen MUC1 is expressed in hematological malignancies and is recognized by MUC1-specific cytotoxic T-lymphocytes. Cancer Res 2001; 61: 6846–6851.
Ikeda H, Lethe B, Lehmann F et al. Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor. Immunity 1997; 6: 199–204.
van Baren N, Chambost H, Ferrant A et al. PRAME, a gene encoding an antigen recognized on a human melanoma by cytolytic T cells, is expressed in acute leukemia cells. Br J Haematol 1998; 102: 1376–1381.
van Baren N, Brasseur F, Godelaine D et al. Genes encoding tumor-specific antigens are expressed in human myeloma cells. Blood 1999; 94: 1156–1164.
Kessler JH, Beekman NJ, Bres-Vloemans SA et al. Efficient identification of novel HLA-A*0201-presented cytotoxic T lymphocyte epitopes in the widely expressed tumor antigen PRAME by proteasome-mediated digestion analysis. J Exp Med 2001; 193: 73–79.
Boon T, van der Bruggen P . Human Tumor antigens recognized by T lymphocytes. J Exp Med 1996; 183: 725–729.
Szmania SM, Pomtree M, Batchu RB et al. Pre-existent humoral and cellular immunity to NY-ESO-1. Blood 2003; 102 (Suppl 1): 3464a.
Pellat-Deceunynck C, Mellerin M-P, Labarriere N et al. The cancer germ-line genes MAGE-1, MAGE-3 and PRAME are commonly expressed by human myeloma cells. Eur J Immunol 2000; 30: 803–809.
Tarte K, de Vos J, Thykjaer T et al. Generation of polyclonal plasmablasts from peripheral blood B cells: a normal counterpart of malignant plasmablasts. Blood 2002; 100: 1113–1122.
Chesi M, Bergsagel PL, Brents LA et al. Dysregulation of Cyclin D1 by translocation into an IgH gamma switch region in two multiple myeloma cell lines. Blood 1996; 88: 674–681.
Chesi M, Nardini E, Lim RS et al. The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel geen, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood 1998; 92: 3025–3032.
Zhan F, Hardin J, Kordsmeier B et al. Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells. Blood 2002; 99: 1745–1751.
Bellucci R, Wu CJ, Chiaretti S et al. Complete response to donor lymphocyte infusion in multiple myeloma is associated with antibody responses to highly expressed antigens. Blood 2004; 103: 656–663.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zeiser, R., Bertz, H., Spyridonidis, A. et al. Donor lymphocyte infusions for multiple myeloma: clinical results and novel perspectives. Bone Marrow Transplant 34, 923–928 (2004). https://doi.org/10.1038/sj.bmt.1704670
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bmt.1704670
Keywords
This article is cited by
-
Factors influencing extramedullary relapse after allogeneic transplantation for multiple myeloma
Blood Cancer Journal (2015)
-
Reply to ‘Allogeneic hematopoietic cell transplantation for concurrent multiple myeloma and myelodysplastic syndrome’
Bone Marrow Transplantation (2015)
-
A prospective study of lenalidomide monotherapy for relapse after Allo-SCT for multiple myeloma
Bone Marrow Transplantation (2014)
-
Induction of multiple myeloma-reactive T cells during post-transplantation immunotherapy with donor lymphocytes and recipient DCs
Bone Marrow Transplantation (2012)
-
Bortezomib and donor lymphocyte infusion in multiple myeloma relapsed after allo-SCT does not result in durable remissions
Bone Marrow Transplantation (2011)