The Use of Bortezomib in Autologous Transplantation for Multiple Myeloma

  • Amelia A. Langston
  • Sagar Lonial
Part of the Milestones in Drug Therapy book series (MDT)


High dose therapy and autologous peripheral blood or bone marrow transplantation represents a significant therapeutic advance for patients with multiple myeloma. While patients who undergo autologous transplantation have an improvement in overall survival compared to those who do not, the procedure is not curative. As the practice has become more widely used, it has become clear that methods to enhance the efficacy of transplantation are needed. The use of cytogenetics and FISH as a method by which to identify good or poor risk patients allows for more informed decisions about the durability of HDT and provides useful information to the clinician regarding the potential need of maintenance therapy in the post transplant period. Similarly, the use of more effective induction regimens have also had a significant impact on the depth of pre transplant response, as well as post transplant duration of remission. Finally, modifying the conditioning regimen itself represents yet another method by which the efficacy of autologous transplant can be further enhanced. These strategies to improve the outcomes of the transplant process for patients with multiple myeloma are currently the focus of existing and ongoing trials.


Multiple Myeloma Conditioning Regimen Myeloma Patient Arsenic Trioxide Autologous Transplant 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Attal M, Harousseau JL (1997) Standard therapy versus autologous transplantation in multiple myeloma. Hematol Oncol Clin North Am 11:133–146PubMedCrossRefGoogle Scholar
  2. 2.
    Child JA, Morgan GJ, Davies FE et al (2003) High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 348:1875–1883PubMedCrossRefGoogle Scholar
  3. 3.
    Alexanian R, Weber D, Delasalle K, Handy B, Champlin R, Giralt S (2004) Clinical outcomes with intensive therapy for patients with primary resistant multiple myeloma. Bone Marrow Transplant 34:229–234PubMedCrossRefGoogle Scholar
  4. 4.
    Greipp PR, Katzmann JA, O’Fallon WM, Kyle RA (1988) Value of beta 2-microglobulin level and plasma cell labeling indices as prognostic factors in patients with newly diagnosed myeloma. Blood 72:219–223PubMedGoogle Scholar
  5. 5.
    Greipp PR, Lust JA, O’Fallon WM, Katzmann JA, Witzig TE, Kyle RA (1993) Plasma cell labeling index and beta 2-microglobulin predict survival independent of thymidine kinase and C-reactive protein in multiple myeloma. Blood 81:3382–3387PubMedGoogle Scholar
  6. 6.
    Greipp PR, San Miguel J, Durie BG et al (2005) International staging system for multiple myeloma. J Clin Oncol 23:3412–3420PubMedCrossRefGoogle Scholar
  7. 7.
    Shaughnessy J Jr, Tian E, Sawyer J et al (2003) Prognostic impact of cytogenetic and interphase fluorescence in situ hybridization-defined chromosome 13 deletion in multiple myeloma: early results of total therapy II. Br J Haematol 120:44–52PubMedCrossRefGoogle Scholar
  8. 8.
    Shaughnessy J, Jacobson J, Sawyer J et al (2003) Continuous absence of metaphase-defined cytogenetic abnormalities, especially of chromosome 13 and hypodiploidy, ensures long-term survival in multiple myeloma treated with total therapy I: interpretation in the context of global gene expression. Blood 101:3849–3856PubMedCrossRefGoogle Scholar
  9. 9.
    Avet-Loiseau H (2007) Role of genetics in prognostication in myeloma. Best Pract Res Clin Haematol 20:625–635PubMedCrossRefGoogle Scholar
  10. 10.
    Avet-Loiseau H, Attal M, Moreau P et al (2007) Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myelome. Blood 109(8):3489–3495PubMedCrossRefGoogle Scholar
  11. 11.
    Dispenzieri A, Rajkumar SV, Gertz MA et al (2007) Treatment of newly diagnosed multiple myeloma based on mayo stratification of myeloma and risk-adapted therapy (mSMART): consensus statement. Mayo Clin Proc 82:323–341PubMedGoogle Scholar
  12. 12.
    Lonial S (2007) Designing risk-adapted therapy for multiple myeloma: the mayo perspective. Mayo Clin Proc 82:279–281PubMedGoogle Scholar
  13. 13.
    Harousseau JL, Mathiot C, Attal M, et al. (2008) Bortezomib/dexamethasone versus VAD as induction prior to autologous stem cell transplantion (ASCT) in previously untreated multiple myeloma (MM): Updated data from IFM 2005/01 trial. ASCO, Chicago, Ill: ASCO:8505Google Scholar
  14. 14.
    Cavo M, Tacchetti P, Patriarca F et al (2008) Superior complete response rate and progression-free survival after autologous transplantation with up-front velcade-thalidomide- dexamethasone compared with thalidomide-dexamethasone in newly diagnosed multiple myeloma. ASH Annual Meeting Abstracts 112:158.Google Scholar
  15. 15.
    Mihelic R, Kaufman JL, Lonial S (2007) Maintenance therapy in multiple myeloma. Leukemia 21:1150–1157PubMedCrossRefGoogle Scholar
  16. 16.
    Barlogie B, Tricot G, Anaissie E et al (2006) Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 354:1021–1030PubMedCrossRefGoogle Scholar
  17. 17.
    Attal M, Harousseau JL, Leyvraz S et al (2006) Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood 108:3289–3294PubMedCrossRefGoogle Scholar
  18. 18.
    Brinker BT, Waller EK, Leong T et al (2006) Maintenance therapy with thalidomide improves overall survival after autologous hematopoietic progenitor cell transplantation for multiple myeloma. Cancer 106:2171–2180PubMedCrossRefGoogle Scholar
  19. 19.
    Hoering A, Crowley J, Shaughnessy JD Jr et al (2009) Complete remission in multiple myeloma examined as time-dependent variable in terms of both onset and duration in total therapy protocols. Blood 114:1299–1305PubMedCrossRefGoogle Scholar
  20. 20.
    Moreau P, Facon T, Attal M et al (2002) 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 99:731–735PubMedCrossRefGoogle Scholar
  21. 21.
    Anagnostopoulos A, Aleman A, Ayers G et al (2004) Comparison of high-dose melphalan with a more intensive regimen of thiotepa, busulfan, and cyclophosphamide for patients with multiple myeloma. Cancer 100:2607–2612PubMedCrossRefGoogle Scholar
  22. 22.
    Benson DM Jr, Elder PJ, Lin TS et al (2007) High-dose melphalan versus busulfan, cyclophosphamide, and etoposide as preparative regimens for autologous stem cell transplantation in patients with multiple myeloma. Leuk Res 31:1069–1075PubMedCrossRefGoogle Scholar
  23. 23.
    Blanes M, de la Rubia J, Lahuerta JJ et al (2009) Single daily dose of intravenous busulfan and melphalan as a conditioning regimen for patients with multiple myeloma undergoing autologous stem cell transplantation: a phase II trial. Leuk Lymphoma 50:216–222PubMedCrossRefGoogle Scholar
  24. 24.
    Christoforidou AV, Saliba RM, Williams P et al (2007) Results of a retrospective single institution analysis of targeted skeletal radiotherapy with (166)Holmium-DOTMP as conditioning regimen for autologous stem cell transplant for patients with multiple myeloma. Impact on transplant outcomes. Biol Blood Marrow Transplant 13:543–549PubMedCrossRefGoogle Scholar
  25. 25.
    Giralt S, Bensinger W, Goodman M et al (2003) 166Ho-DOTMP plus melphalan followed by peripheral blood stem cell transplantation in patients with multiple myeloma: results of two phase 1/2 trials. Blood 102:2684–2691PubMedCrossRefGoogle Scholar
  26. 26.
    Mitsiades N, Mitsiades CS, Richardson PG et al (2003) The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 101:2377–2380PubMedCrossRefGoogle Scholar
  27. 27.
    Hideshima T, Hayashi T, Chauhan D, Akiyama M, Richardson P, Anderson K (2003) Biologic sequelae of c-Jun NH(2)-terminal kinase (JNK) activation in multiple myeloma cell lines. Oncogene 22:8797–8801PubMedCrossRefGoogle Scholar
  28. 28.
    Pineda-Roman M, Fox MH, Hollmig KA et al (2006) Retrospective analysis of fractionated high-dose melphalan (F-MEL) and bortezomib-thalidomide-dexamethasone (VTD) with autotransplant (AT) support for advanced and refractory multiple myeloma (AR-MM). ASH Annual Meeting Abstracts. 108:3102Google Scholar
  29. 29.
    Qazilbash MH, Saliba RM, Pelosini M, et al. (2008) A randomized phase II trial of high-dose melphalan, ascorbic acid and arsenic trioxide with or without bortezomib in multiple myeloma. ASH Annual Meeting Abstracts. 112:3320Google Scholar
  30. 30.
    Qazilbash MH, Saliba RM, Nieto Y et al (2008) Arsenic trioxide with ascorbic acid and high-dose melphalan: results of a phase II randomized trial. Biol Blood Marrow Transplant 14:1401–1407PubMedCrossRefGoogle Scholar
  31. 31.
    Zou W, Yue P, Lin N et al (2006) Vitamin C inactivates the proteasome inhibitor PS-341 in human cancer cells. Clin Cancer Res 12:273–280PubMedCrossRefGoogle Scholar
  32. 32.
    Perrone G, Hideshima T, Ikeda H et al (2009) Ascorbic acid inhibits antitumor activity of bortezomib in vivo. Leukemia 23:1679–1686PubMedCrossRefGoogle Scholar
  33. 33.
    Harvey RD, Nettles J, Wang B, Sun SY, Lonial S (2009) Commentary on Perrone et al.: ‘vitamin C: not for breakfast anymore...if you have myeloma’. Leukemia 23:1939–1940PubMedCrossRefGoogle Scholar
  34. 34.
    Roussel M, Moreau P, Huynh A et al (2010) Bortezomib and high dose melphalan as conditioning regimen before autologous stem cell transplantation in patients with de novo multiple myeloma: a phase II study of the Intergroupe Francophone du Myelome (IFM). Blood 115(1):32–7PubMedCrossRefGoogle Scholar
  35. 35.
    Lonial S, Kaufman J, Torre C et al (2008) A randomized phase I trial of melphalan + bortezomib as conditioning for autologous transplant for myeloma: the effect of sequence of administration. ASH Annu Meet Abstr 112:3332Google Scholar
  36. 36.
    Fassas AB, Spencer T, Sawyer J et al (2002) Both hypodiploidy and deletion of chromosome 13 independently confer poor prognosis in multiple myeloma. Br J Haematol 118:1041–1047PubMedCrossRefGoogle Scholar
  37. 37.
    Facon T, Avet-Loiseau H, Guillerm G et al (2001) Chromosome 13 abnormalities identified by FISH analysis and serum beta2-microglobulin produce a powerful myeloma staging system for patients receiving high-dose therapy. Blood 97:1566–1571PubMedCrossRefGoogle Scholar
  38. 38.
    Rasmussen T, Knudsen LM, Dahl IM, Johnsen HE (2003) C-MAF oncogene dysregulation in multiple myeloma: frequency and biological relevance. Leuk Lymphoma 44:1761–1766PubMedCrossRefGoogle Scholar
  39. 39.
    Bergsagel PL, Kuehl WM (2001) Chromosome translocations in multiple myeloma. Oncogene 20:5611–5622PubMedCrossRefGoogle Scholar
  40. 40.
    Anagnostopoulos A, Gika D, Symeonidis A et al (2005) Multiple myeloma in elderly patients: prognostic factors and outcome. Eur J Haematol 75:370–375PubMedCrossRefGoogle Scholar
  41. 41.
    Jurisic V, Colovic M (2002) Correlation of sera TNF-alpha with percentage of bone marrow plasma cells, LDH, beta2-microglobulin, and clinical stage in multiple myeloma. Med Oncol 19:133–139PubMedCrossRefGoogle Scholar
  42. 42.
    Kurabayashi H, Kubota K, Tsuchiya J, Murakami H, Tamura J, Naruse T (1999) Prognostic value of morphological classifications and clinical variables in elderly and young patients with multiple myeloma. Ann Hematol 78:19–23PubMedCrossRefGoogle Scholar
  43. 43.
    Suguro M, Kanda Y, Yamamoto R et al (2000) High serum lactate dehydrogenase level predicts short survival after vincristine-doxorubicin-dexamethasone (VAD) salvage for refractory multiple myeloma. Am J Hematol 65:132–135PubMedCrossRefGoogle Scholar
  44. 44.
    Kumar S, Rajkumar SV, Kyle RA et al (2005) Prognostic value of circulating plasma cells in monoclonal gammopathy of undetermined significance. J Clin Oncol 23:5668–5674PubMedCrossRefGoogle Scholar
  45. 45.
    Nowakowski GS, Witzig TE, Dingli D et al (2005) Circulating plasma cells detected by flow cytometry as a predictor of survival in 302 patients with newly diagnosed multiple myeloma. Blood 106:2276–2279PubMedCrossRefGoogle Scholar
  46. 46.
    Desikan KR, Tricot G, Dhodapkar M et al (2000) Melphalan plus total body irradiation (MEL-TBI) or cyclophosphamide (MEL-CY) as a conditioning regimen with second autotransplant in responding patients with myeloma is inferior compared to historical controls receiving tandem transplants with melphalan alone. Bone Marrow Transplant 25:483–487PubMedCrossRefGoogle Scholar
  47. 47.
    Talamo G, Claxton DF, Dougherty DW et al (2009) BU and CY as conditioning regimen for autologous transplant in patients with multiple myeloma. Bone Marrow Transplant 44: 157–161PubMedCrossRefGoogle Scholar
  48. 48.
    Toor AA, Ayers J, Strupeck J et al (2004) Favourable results with a single autologous stem cell transplant following conditioning with busulphan and cyclophosphamide in patients with multiple myeloma. Br J Haematol 124:769–776PubMedCrossRefGoogle Scholar
  49. 49.
    Wong JY, Rosenthal J, Liu A, Schultheiss T, Forman S, Somlo G (2009) Image-guided total-marrow irradiation using helical tomotherapy in patients with multiple myeloma and acute leukemia undergoing hematopoietic cell transplantation. Int J Radiat Oncol Biol Phys 73:273–279PubMedCrossRefGoogle Scholar
  50. 50.
    Attal M, Harousseau JL, Facon T et al (2003) Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 349:2495–2502PubMedCrossRefGoogle Scholar
  51. 51.
    Moreau P, Hullin C, Garban F et al (2006) Tandem autologous stem cell transplantation in high-risk de novo multiple myeloma: final results of the prospective and randomized IFM 99-04 protocol. Blood 107:397–403PubMedCrossRefGoogle Scholar
  52. 52.
    Kumar A, Kharfan-Dabaja MA, Glasmacher A, Djulbegovic B (2009) Tandem versus single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: a systematic review and meta-analysis. J Natl Cancer Inst 101:100–106PubMedCrossRefGoogle Scholar
  53. 53.
    Cavo M, Tosi P, Zamagni E et al (2007) Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol 25:2434–2441PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2011

Authors and Affiliations

  1. 1.Winship Cancer InstituteEmory University School of MedicineAtlantaUSA

Personalised recommendations