onmyeloablative Unrelated Donor Hematopoietic Cell ransplantation to Treat Patients with Poor-Risk , elapsed , or Refractory Multiple Myeloma

The purpose of this study was to determine long-term outcome of unrelated donor nonmyeloablative hematopoietic cell transplantation (HCT) in patients with poor-risk multiple myeloma. A total of 24 patients were enrolled; 17 patients (71%) had chemotherapy-refractory disease, and 14 (58%) experienced disease relapse or progression after previous autologous transplantation. Thirteen patients underwent planned autologous transplantation followed 43–135 days later with unrelated transplantation, whereas 11 proceeded directly to unrelated transplantation. All 24 patients were treated with fludarabine (90 mg/m) and 2 Gy of total body irradiation before HLA-matched unrelated peripheral blood stem cell transplantation. Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil. The median follow-up was 3 years after allografting. One patient experienced nonfatal graft rejection. The incidences of acute grades II and III and chronic graft-versus-host disease were 54%, 13%, and 75%, respectively. The 3-year nonrelapse mortality (NRM) was 21%. Complete responses were observed in 10 patients (42%); partial responses, in 4 (17%). At 3 years, overall survival (OS) and progression-free survival (PFS) rates were 61% and 33%, respectively. Patients receiving tandem autologous-unrelated transplantation had superior OS and PFS (77% and 51%) compared with patients proceeding directly to unrelated donor transplantation (44% and 11%) (PFS P value .03). In summary, for patients with poor-risk, relapsed, or refractory multiple myeloma, cytoreductive autologous HCT followed by nonmyeloablative conditioning and unrelated HCT is an effective treatment approach, with low NRM, high complete remission rates, and prolonged disease-free survival. © 2007 American Society for Blood and Marrow Transplantation

[1]  P. Martin.  Documentation of Engraftment and Characterization of Chimerism Following Hematopoietic Cell Transplantation , 2009 .

[2]  K. Sullivan.  Graft‐vs.‐Host Disease , 2007 .

[3]  H. Goldschmidt,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. , 2006, Blood.

[4]  M. Maris,et al.  Unrelated donor granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell transplantation after nonmyeloablative conditioning: the effect of postgrafting mycophenolate mofetil dosing. , 2006, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[5]  P. Loehrer,et al.  International Staging System for Multiple Myeloma , 2006 .

[6]  M. Gordon.  Bortezomib or High-Dose Dexamethasone for Relapsed Multiple Myeloma , 2006 .

[7]  H. Einsele,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. , 2005, Blood.

[8]  C. Kollman,et al.  Outcome of unrelated transplants in patients with multiple myeloma , 2005, Bone Marrow Transplantation.

[9]  B. Barlogie,et al.  Cure of myeloma: hype or reality? , 2005, Bone Marrow Transplantation.

[10]  M. Sorror,et al.  Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning , 2004 .

[11]  N. Kröger,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. , 2004, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[12]  C. Flowers,et al.  Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors. , 2004, Blood.

[13]  C. Flowers,et al.  Comparing morbidity and mortality of HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: influence of pretransplantation comorbidities. , 2004, Blood.

[14]  R. Bataille,et al.  Single versus double autologous stem-cell transplantation for multiple myeloma. , 2003, The New England journal of medicine.

[15]  N. Russell,et al.  The outcome of unrelated donor stem cell transplantation for patients with multiple myeloma , 2003, British journal of haematology.

[16]  R. Storb,et al.  Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. , 2003, Blood.

[17]  S. Heimfeld,et al.  HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. , 2003, Blood.

[18]  M. Maris,et al.  Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. , 2003, Blood.

[19]  Bart Barlogie,et al.  A phase 2 study of bortezomib in relapsed, refractory myeloma. , 2003, The New England journal of medicine.

[20]  G. Morgan,et al.  High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. , 2003, The New England journal of medicine.

[21]  H. Einsele,et al.  Follow‐up of patients with progressive multiple myeloma undergoing allografts after reduced‐intensity conditioning , 2003, British journal of haematology.

[22]  S. Mackinnon,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. , 2003, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[23]  R. Storb,et al.  Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissio , 2003, Blood.

[24]  G. Tricot,et al.  Predicting Long-term Survival in Multiple Myeloma Patients Following Autotransplants , 2003, Leukemia & lymphoma.

[25]  N. Schmitz,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. , 2002, Blood.

[26]  Robert A Kyle,et al.  Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  Richard LeBlanc,et al.  Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. , 2002, Blood.

[28]  B. Barlogie,et al.  Both hypodiploidy and deletion of chromosome 13 independently confer poor prognosis in multiple myeloma , 2002, British journal of haematology.

[29]  R. Bataille,et al.  Long-term results (12 years) of high-dose therapy in 127 patients with de novo multiple myeloma , 2002, Leukemia.

[30]  N. Ueno,et al.  Fludarabine/melphalan conditioning for allogeneic transplantation in patients with multiple myeloma , 2002, Bone Marrow Transplantation.

[31]  N. Kröger,et al.  Autologous stem cell transplantation followed by a dose-reduced allograft induces high complete remission rate in multiple myeloma. , 2002, Blood.

[32]  B. Barlogie,et al.  Improved outcome of allogeneic transplantation in high-risk multiple myeloma patients after nonmyeloablative conditioning. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  C. Craddock,et al.  Limiting transplantation-related mortality following unrelated donor stem cell transplantation by using a nonmyeloablative conditioning regimen. , 2002, Blood.

[34]  B. Barlogie,et al.  Predicting long‐term (≥ 5 years) event‐free survival in multiple myeloma patients following planned tandem autotransplants , 2002, British journal of haematology.

[35]  J. Radich,et al.  Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. , 2001, Blood.

[36]  P. Thall,et al.  Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation. , 2001, Blood.

[37]  R. Fonseca,et al.  Abnormal cytogenetics predict poor survival after high-dose therapy and autologous blood cell transplantation in multiple myeloma , 1999, Bone Marrow Transplantation.

[38]  Anajane G. Smith,et al.  Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and recipient. , 1998, Blood.

[39]  S. Jagannath,et al.  CRITERIA FOR EVALUATING DISEASE RESPONSE AND PROGRESSION IN PATIENTS WITH MULTIPLE MYELOMA TREATED BY HIGH‐DOSE THERAPY AND HAEMOPOIETIC STEM CELL TRANSPLANTATION , 1998, British journal of haematology.

[40]  L. Schwartzberg,et al.  A randomized trial of mobilization of peripheral blood stem cells with cyclophosphamide, etoposide, and granulocyte colony-stimulating factor with or without cisplatin in patients with malignant lymphoma receiving high-dose chemotherapy. , 1998, American journal of clinical oncology.

[41]  N. Ueno,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. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  B. Barlogie,et al.  Salvage autologous or allogeneic transplantation for multiple myeloma refractory to or relapsing after a first-line autograft? , 1998, Bone Marrow Transplantation.

[43]  A. Nagler,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. , 1998, Blood.

[44]  R. Storb,et al.  Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome. , 1996, Blood.

[45]  J. Rossi,et al.  A Prospective, Randomized Trial of Autologous Bone Marrow Transplantation and Chemotherapy in Multiple Myeloma , 1996 .

[46]  B. Barlogie,et al.  Relapse of multiple myeloma after autologous transplantation: survival after salvage therapy. , 1995, Bone marrow transplantation.

[47]  B. Barlogie,et al.  VAD‐based regimens as primary treatment for multiple myeloma , 1990, American journal of hematology.