Biology of Blood and Marrow Transplantation
Volume 14, Issue 12 , Pages 1401-1407 , December 2008

Arsenic Trioxide with Ascorbic Acid and High-Dose Melphalan: Results of a Phase II Randomized Trial

  • Muzaffar H. Qazilbash

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy
    • Corresponding Author InformationCorrespondence and reprint requests: Muzaffar H. Qazilbash, MD, Department of Blood and Marrow Transplantation, UT-M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 423, Houston, TX 77030.
  • ,
  • Rima M. Saliba

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy
  • ,
  • Yago Nieto

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy
  • ,
  • Gaurav Parikh

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy
  • ,
  • Matteo Pelosini

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy
  • ,
  • Fatima B. Khan

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy
  • ,
  • Roy B. Jones

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy
  • ,
  • Chitra Hosing

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy
  • ,
  • Floralyn Mendoza

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy
  • ,
  • Donna M. Weber

      Affiliations

    • Department of Lymphoma and Myeloma, UT M.D. Anderson Cancer Center, Houston, Texas
  • ,
  • Michael Wang

      Affiliations

    • Department of Lymphoma and Myeloma, UT M.D. Anderson Cancer Center, Houston, Texas
  • ,
  • Uday Popat

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy
  • ,
  • Amin Alousi

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy
  • ,
  • Paolo Anderlini

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy
  • ,
  • Richard E. Champlin

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy
  • ,
  • Sergio Giralt, MD

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy

Received 30 August 2008 ,Accepted 23 September 2008.

References 

  1. Hari P, Pasquini MC, Vesole DH. Cure of multiple myeloma—more hype, less reality. Bone Marrow Transplant. 2006;37:1–18
  2. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med. 2004;351:1860–1873
  3. Barlogie B, Jagannath S, Vesole DH, et al. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood. 1997;89:789–793
  4. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996;335:91–97
  5. Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348:1875–1883
  6. Fermand JP, Katsahian S, Divine M, et al. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol. 2005;23:9227–9233
  7. Blade J, Rosinol L, Sureda A, et al. High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood. 2005;106:3755–3759
  8. Fassas A, Tricot G. Results of high-dose treatment with autologous stem cell support in patients with multiple myeloma. Semin Hematol. 2001;38:231–242
  9. Mehta J, Tricot G, Jagannath S, et al. Salvage autologous or allogeneic transplantation for multiple myeloma refractory to or relapsing after a first-line autograft?. Bone Marrow Transplant. 1998;21:887–892
  10. Qazilbash MH, Saliba R, De Lima M, et al. Second autologous or allogeneic transplantation after the failure of first autograft in patients with multiple myeloma. Cancer. 2006;106:1084–1089
  11. Badros A, Barlogie B, Siegel E, et al. Results of autologous stem cell transplant in multiple myeloma patients with renal failure. Br J Haematol. 2001;114:822–829
  12. Moreau P, Facon T, Attal M, et al. Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myelome 9502 randomized trial. Blood. 2002;99:731–735
  13. Badros A, Barlogie B, Siegel E, et al. Autologous stem cell transplantation in elderly multiple myeloma patients over the age of 70 years. Br J Haematol. 2001;114:600–607
  14. Lahuerta JJ, Martinez-Lopez J, Grande C, et al. Conditioning regimens in autologous stem cell transplantation for multiple myeloma: a comparative study of efficacy and toxicity from the Spanish Registry for Transplantation in Multiple Myeloma. Br J Haematol. 2000;109:138–147
  15. Anagnostopoulos A, Aleman A, Ayers G, et al. Comparison of high-dose melphalan with a more intensive regimen of thiotepa, busulfan, and cyclophosphamide for patients with multiple myeloma. Cancer. 2004;100:2607–2612
  16. Fenk R, Schneider P, Kropff M, et al. High-dose idarubicin, cyclophosphamide and melphalan as conditioning for autologous stem cell transplantation increases treatment-related mortality in patients with multiple myeloma: results of a randomised study. Br J Haematol. 2005;130:588–594
  17. Niu C, Yan H, Yu T, et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood. 1999;94:3315–3324
  18. Soignet SL, Frankel SR, Douer D, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;19:3852–3860
  19. Park WH, Seol JG, Kim ES, et al. Arsenic trioxide-mediated growth inhibition in MC/CAR myeloma cells via cell cycle arrest in association with induction of cyclin-dependent kinase inhibitor, p21, and apoptosis. Cancer Res. 2000;60:3065–3071
  20. Perkins C, Kim CN, Fang G, Bhalla KN. Arsenic induces apoptosis of multidrug-resistant human myeloid leukemia cells that express Bcr-Abl or overexpress MDR, MRP, Bcl-2, or Bcl-x(L). Blood. 2000;95:1014–1022
  21. Hideshima T, Chauhan D, Richardson P, et al. NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem. 2002;277:16639–16647
  22. Bahlis NJ, McCafferty-Grad J, Jordan-McMurry I, et al. Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of relapsed/refractory multiple myeloma. Clin Cancer Res. 2002;8:3658–3668
  23. Campbell RA, Sanchez E, Steinberg JA, et al. Antimyeloma effects of arsenic trioxide are enhanced by melphalan, bortezomib and ascorbic acid. Br J Haematol. 2007;138:467–478
  24. Munshi NC, Tricot G, Desikan R, et al. Clinical activity of arsenic trioxide for the treatment of multiple myeloma. Leukemia. 2002;16:1835–1837
  25. Hussein MA, Saleh M, Ravandi F, Mason J, Rifkin RM, Ellison R. Phase 2 study of arsenic trioxide in patients with relapsed or refractory multiple myeloma. Br J Haematol. 2004;125:470–476
  26. Berenson JR, Boccia R, Siegel D, et al. Efficacy and safety of melphalan, arsenic trioxide and ascorbic acid combination therapy in patients with relapsed or refractory multiple myeloma: a prospective, multicentre, phase II, single-arm study. Br J Haematol. 2006;135:174–183
  27. Kaplan EL, Meier P. Nonparametric estimator from incomplete observations. J Am Stat Assoc. 1958;53:457–481
  28. Blade 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
  29. Fox E, Razzouk BI, Widemann BC, et al. Phase 1 trial and pharmacokinetic study of arsenic trioxide in children and adolescents with refractory or relapsed acute leukemia, including acute promyelocytic leukemia or lymphoma. Blood. 2008;111:566–573
  30. Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol. 1994;47:1245–1251
  31. Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106:2912–2919
  32. Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23:3412–3420
  33. Dimopoulos MA, Weber D, Kantarjian H, Delasalle KB, Alexanian R. HyperCVAD for VAD-resistant multiple myeloma. Am J Hematol. 1996;52:77–81
  34. Palumbo A, Bringhen S, Caravita T, et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet. 2006;367:825–831
  35. Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003;349:2495–2502
  36. Cavo M, Tosi P, Zamagni E, et al. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol. 2007;25:2434–2441
  37. Attal M, Harousseau JL, Leyvraz S, et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006;108:3289–3294
  38. 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
  39. Barbey JT, Pezzullo JC, Soignet SL. Effect of arsenic trioxide on QT interval in patients with advanced malignancies. J Clin Oncol. 2003;21:3609–3615
  40. Qazilbash MH, Saliba RM, Aleman A, et al. Risk factors for relapse after complete remission with high-dose therapy for multiple myeloma. Leuk Lymphoma. 2006;47:1360–1364
  41. Qazilbash MH, Saliba RM, Hosing C, et al. Autologous stem cell transplantation is safe and feasible in elderly patients with multiple myeloma. Bone Marrow Transplant. 2007;39:279–283

 Financial disclosure: See Acknowledgments on page 1406.

PII: S1083-8791(08)00418-7

doi: 10.1016/j.bbmt.2008.09.019

Biology of Blood and Marrow Transplantation
Volume 14, Issue 12 , Pages 1401-1407 , December 2008