Nonmyeloablative Unrelated Donor (URD) Hematopoietic Cell Transplantation (HCT) for the Treatment of Patients (pts) with Poor-Risk, Relapsed or Refractory Multiple Myeloma.

We carried out HLA-matched URD peripheral blood stem cell (PBSC) transplant in 24 pts with poor-risk multiple myeloma after nonmyeloablative conditioning with fludarabine (90 mg/m2) and 2 Gy total body irradiation. Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil. The median age of the 19 men and 5 women was 53 (23 – 66) years. Conventional metaphase cytogenetics obtained in 14 pts showed Δ13 in 6 pts and complex abnormalities in 9 pts. Stage III disease was present in 83% and 17% had stage II disease. The median time from diagnosis to URD HCT was 25 (range, 8–130) months, and 96% were beyond 1st complete remission (CR) or had never achieved CR1, despite multiple lines of chemotherapy (median 4.5, range 2–10). At study entry, 17 pts (71%) had chemotherapy-refractory disease and 14 pts (58%) had failed autologous HCT. Thirteen pts had planned autologous-URD tandem HCT, while 11 proceeded directly to URD HCT. The median follow-up was 2.5 years after allografting. One pt experienced non-fatal graft rejection. The incidences of acute grades II, III and chronic graft-versus-host disease were 54%, 13% and 75%, respectively. Non-relapse mortality was 22% at 2.5 years. CRs were observed in 11 pts (46%) and partial remissions (PR) in 3 (13%). Best disease responses were seen in pts given tandem autologous-URD HCT with CR in 8 pts and PR in 2 pts (77% CR+PR rate). The estimated overall survival (OS) at 2.5 years for all 24 pts was 65% and progression-free survival (PFS) 41%. Pts receiving tandem autologous-URD HCT had superior OS and PFS, 76% and 63% (Fig. A), compared to pts proceeding directly to URD HCT, 52% and 14% (Fig. B), respectively (PFS p-value=.03). Risk factors for worse OS included pts with significant medical comorbidities (p=.03), chemotherapy-refractory disease prior to HCT (p=.03), and pts who had failed autologous HCT (p=.07). Pts who failed autologous HCT had 48% OS and 30% PFS at 2.5 years. For pts with poor-risk, relapsed or refractory multiple myeloma, cytoreductive autologous HCT followed with nonmyeloablative conditioning and URD HCT is very promising treatment with low non-relapse mortality, high complete remission rates and prolonged PFS. The results also suggest that URD HCT may provide improved graft-versus-myeloma effect compared with HLA-matched sibling HCT without an increase in the risk of non-relapse mortality.

[1]  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.

[2]  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.

[3]  Hartmut Goldschmidt,et al.  Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. , 2005, The New England journal of medicine.

[4]  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.

[5]  J. Crowley,et al.  International staging system for multiple myeloma. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

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

[7]  M. Sorror,et al.  Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

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

[9]  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.

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

[11]  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.

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

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

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

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

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

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

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

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

[20]  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.

[21]  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.

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

[23]  B. Barlogie,et al.  Prognostic factors in allogeneic transplantation for patients with high-risk multiple myeloma after reduced intensity conditioning. , 2003, Experimental hematology.

[24]  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.

[25]  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.

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

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

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

[29]  A. Anagnostopoulos,et al.  Fludarabine/melphalan conditioning for allogeneic transplantation in patients with multiple myeloma , 2002, Bone Marrow Transplantation.

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

[31]  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.

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

[33]  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.

[34]  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.

[35]  G. Gahrton,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 , 2001, British journal of haematology.

[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]  S. Woo,et al.  Graft-vs.-host disease. , 1997, Critical reviews in oral biology and medicine : an official publication of the American Association of Oral Biologists.

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

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

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

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