Allogeneic hematopoietic cell transplantation in multiple myeloma
- S Vincent Rajkumar, MD
S Vincent Rajkumar, MD
- Edward W. and Betty Knight Scripps Professor of Medicine
- Mayo Clinic
Allogeneic hematopoietic cell transplantation (HCT) may be the only treatment for patients with multiple myeloma that has a chance of producing cure. Its use, however, is limited since even ideal candidates who undergo allogeneic HCT have a high rate of treatment-related mortality, and because its efficacy compared with autologous HCT is not fully established. The treatment-related mortality associated with allogeneic HCT is decreasing with the advent of nonmyeloablative preparative regimens. At the same time, new chemotherapeutic agents (eg, bortezomib, thalidomide, lenalidomide) are being incorporated into the initial treatment of multiple myeloma, and survival with chemotherapy alone or with autologous HCT is improving. As such, the role of allogeneic HCT in the treatment of multiple myeloma is not clear.
The use of allogeneic HCT in the management of patients with multiple myeloma will be reviewed here. The process of determining the appropriate initial therapy for patients with multiple myeloma, eligibility guidelines for HCT, and response criteria used to evaluate the treatment of multiple myeloma are discussed separately, as is a comparison of allogeneic HCT to autologous HCT and chemotherapy. (See "Overview of the management of multiple myeloma" and "Selection of initial chemotherapy for symptomatic multiple myeloma" and "Evaluating response to treatment of multiple myeloma".)
The term "hematopoietic cell transplantation" (HCT) will be used throughout this review as a general term to cover transplantation of progenitor (stem) cells from any source (eg, bone marrow, peripheral blood, cord blood). Otherwise, the source of such cells will be specified (eg, autologous peripheral blood progenitor cell transplantation). (See "Sources of hematopoietic stem cells".)
Myeloablative allogeneic HCT requires hematopoietic cells from an HLA-matched donor, which are given after the patient receives high dose chemotherapy and total body radiation. Allogeneic HCT has two advantages over autologous HCT: the graft does not contain tumor cells; and the transplant can produce a graft-versus-myeloma effect [1,2]. Less than 5 to 10 percent of patients with multiple myeloma are candidates for this approach due to its high toxicity. A detailed discussion on eligibility guidelines is presented separately. (See "Overview of the management of multiple myeloma", section on 'Autologous versus allogeneic HCT'.)
In earlier studies, allogeneic HCT for myeloma was associated with an early mortality of at least 20 percent and an overall mortality of 30 to 50 percent, due to fungal infections, interstitial pneumonitis, and graft-versus-host disease [3-8]. This mortality rate limited the use of myeloablative allogeneic HCT . Although there is a suggestion that the mortality rates are lower in more recent years, data are lacking. (See "Overview of the management of multiple myeloma", section on 'Autologous versus allogeneic HCT'.)To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Tricot G, Vesole DH, Jagannath S, et al. Graft-versus-myeloma effect: proof of principle. Blood 1996; 87:1196.
- Mehta J, Singhal S. Graft-versus-myeloma. Bone Marrow Transplant 1998; 22:835.
- Gahrton G, Tura S, Svensson H, et al. Allogeneic bone marrow transplantation in multiple myeloma: an update of the EBMT Registry. VIth International Workshop on Multiple Myeloma, Syllabus, Boston, MA, June 14-18, 1997.
- 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.
- 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.
- Gahrton G, Björkstrand B. Progress in haematopoietic stem cell transplantation for multiple myeloma. J Intern Med 2000; 248:185.
- Bensinger WI, Maloney D, Storb R. Allogeneic hematopoietic cell transplantation for multiple myeloma. Semin Hematol 2001; 38:243.
- Shaw BE, Peggs K, Bird JM, et al. The outcome of unrelated donor stem cell transplantation for patients with multiple myeloma. Br J Haematol 2003; 123:886.
- UK myeloma forum. British Committee for Standards in Haematology. Diagnosis and management of multiple myeloma. Br J Haematol 2001; 115:522.
- Lokhorst H, Einsele H, Vesole D, et al. International Myeloma Working Group consensus statement regarding the current status of allogeneic stem-cell transplantation for multiple myeloma. J Clin Oncol 2010; 28:4521.
- Gahrton G, Svensson H, Björkstrand B, et al. Syngeneic transplantation in multiple myeloma - a case-matched comparison with autologous and allogeneic transplantation. European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 1999; 24:741.
- Fefer A, Cheever MA, Greenberg PD. Identical-twin (syngeneic) marrow transplantation for hematologic cancers. J Natl Cancer Inst 1986; 76:1269.
- D'Sa S, Peggs K, Pizzey A, et al. T- and B-cell immune reconstitution and clinical outcome in patients with multiple myeloma receiving T-cell-depleted, reduced-intensity allogeneic stem cell transplantation with an alemtuzumab-containing conditioning regimen followed by escalated donor lymphocyte infusions. Br J Haematol 2003; 123:309.
- 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.
- 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.
- 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.
- 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.
- Branson K, Chopra R, Kottaridis PD, et al. Role of nonmyeloablative allogeneic stem-cell transplantation after failure of autologous transplantation in patients with lymphoproliferative malignancies. J Clin Oncol 2002; 20:4022.
- Kröger 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.
- Pérez-Simón 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.
- Crawley C, Iacobelli S, Björkstrand B, et al. Reduced-intensity conditioning for myeloma: lower nonrelapse mortality but higher relapse rates compared with myeloablative conditioning. Blood 2007; 109:3588.
- Kumar S, Zhang MJ, Li P, et al. Trends in allogeneic stem cell transplantation for multiple myeloma: a CIBMTR analysis. Blood 2011; 118:1979.
- 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.
- 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.
- 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.
- 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.
- Stewart AK. Reduced-intensity allogeneic transplantation for myeloma: reality bites. Blood 2009; 113:3135.
- Armeson KE, Hill EG, Costa LJ. Tandem autologous vs autologous plus reduced intensity allogeneic transplantation in the upfront management of multiple myeloma: meta-analysis of trials with biological assignment. Bone Marrow Transplant 2013; 48:562.
- Krishnan A, Pasquini MC, Logan B, et al. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol 2011; 12:1195.
- Lokhorst HM, van der Holt B, Cornelissen JJ, et al. Donor versus no-donor comparison of newly diagnosed myeloma patients included in the HOVON-50 multiple myeloma study. Blood 2012; 119:6219.
- 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.
- Rosiñol L, Pérez-Simón JA, Sureda A, et al. A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood 2008; 112:3591.
- Einsele H, Schäfer 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.
- Björkstrand B, Iacobelli S, Hegenbart U, et al. Tandem autologous/reduced-intensity conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: long-term follow-up. J Clin Oncol 2011; 29:3016.
- Gahrton G, Iacobelli S, Björkstrand B, et al. Autologous/reduced-intensity allogeneic stem cell transplantation vs autologous transplantation in multiple myeloma: long-term results of the EBMT-NMAM2000 study. Blood 2013; 121:5055.
- Kneppers E, van der Holt B, Kersten MJ, et al. Lenalidomide maintenance after nonmyeloablative allogeneic stem cell transplantation in multiple myeloma is not feasible: results of the HOVON 76 Trial. Blood 2011; 118:2413.
- 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.
- Kröger N, Schilling G, Einsele H, 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.
- de Lavallade H, El-Cheikh J, Faucher C, et al. Reduced-intensity conditioning allogeneic SCT as salvage treatment for relapsed multiple myeloma. Bone Marrow Transplant 2008; 41:953.
- Kröger N, Shimoni A, Schilling G, et al. Unrelated stem cell transplantation after reduced intensity conditioning for patients with multiple myeloma relapsing after autologous transplantation. Br J Haematol 2010; 148:323.
- Shimoni A, Hardan I, Ayuk F, et al. Allogenic hematopoietic stem-cell transplantation with reduced-intensity conditioning in patients with refractory and recurrent multiple myeloma: long-term follow-up. Cancer 2010; 116:3621.
- Nivison-Smith I, Dodds AJ, Doocey R, et al. Allogeneic hematopoietic cell transplant for multiple myeloma using reduced intensity conditioning therapy, 1998-2006: factors associated with improved survival outcome. Leuk Lymphoma 2011; 52:1727.
- Auner HW, Szydlo R, van Biezen A, et al. Reduced intensity-conditioned allogeneic stem cell transplantation for multiple myeloma relapsing or progressing after autologous transplantation: a study by the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 2013; 48:1395.
- 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.
- Corradini P, Cavo M, Lokhorst H, et al. Molecular remission after myeloablative allogeneic stem cell transplantation predicts a better relapse-free survival in patients with multiple myeloma. Blood 2003; 102:1927.
- Davies FE, Forsyth PD, Rawstron AC, et al. The impact of attaining a minimal disease state after high-dose melphalan and autologous transplantation for multiple myeloma. Br J Haematol 2001; 112:814.
- Rawstron AC, Davies FE, DasGupta R, et al. Flow cytometric disease monitoring in multiple myeloma: the relationship between normal and neoplastic plasma cells predicts outcome after transplantation. Blood 2002; 100:3095.
- Kröger N, Krüger 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.
- 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.
- Bellucci R, Alyea EP, Weller E, et al. Immunologic effects of prophylactic donor lymphocyte infusion after allogeneic marrow transplantation for multiple myeloma. Blood 2002; 99:4610.
- 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.
- Mohty M, Attal M, Marit G, et al. Thalidomide salvage therapy following allogeneic stem cell transplantation for multiple myeloma: a retrospective study from the Intergroupe Francophone du Myélome (IFM) and the Société Française de Greffe de Moelle et Thérapie Cellulaire (SFGM-TC). Bone Marrow Transplant 2005; 35:165.
- MYELOABLATIVE HCT
- SYNGENEIC HCT
- T CELL DEPLETED ALLOGENEIC HCT
- NONMYELOABLATIVE ALLOGENEIC HCT
- Autologous followed by nonmyeloablative allogeneic HCT in newly diagnosed myeloma
- Nonmyeloablative allogeneic HCT in relapsed myeloma
- MONITORING REMISSION POST-ALLOGENEIC HCT
- Allo-HCT and minimal residual disease negative state
- TREATMENT OF RELAPSE AFTER HCT
- Donor lymphocyte infusion
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS