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International Journal of Hematology

, Volume 98, Issue 3, pp 337–345 | Cite as

Combination of high-dose melphalan and bortezomib as conditioning regimen for autologous peripheral blood stem cell transplantation in multiple myeloma

  • Toshihiro MiyamotoEmail author
  • Goichi Yoshimoto
  • Tomohiko Kamimura
  • Tsuyoshi Muta
  • Shuichiro Takashima
  • Yoshikiyo Ito
  • Motoaki Shiratsuchi
  • Ilseung Choi
  • Koji Kato
  • Katsuto Takenaka
  • Hiromi Iwasaki
  • Yasushi Takamatsu
  • Takanori Teshima
  • Koichi Akashi
Original Article

Abstract

Bortezomib and melphalan have synergistic effects against multiple myeloma (MM) cells. We conducted a pilot study on the combination of bortezomib and high-dose melphalan (Bor-HDM) as a conditioning regimen followed by autologous stem cell transplant (ASCT) in 17 Japanese patients with newly diagnosed MM, in comparison with a historical control of patients who received high-dose melphalan (HDM) only followed by ASCT. Nine patients received a single dose of bortezomib 1.3 mg/m2 on day −1 in combination with melphalan 100 mg/m2 on days −3 and −2 (Bor1-HDM), and eight received two doses of bortezomib 1.3 mg/m2 on days −4 and −1 (Bor2-HDM) in combination with HDM. Engraftment of autologous peripheral blood stem cells and regimen-related toxicities (RRT) were comparable among the HDM and Bor-HDM groups. Probability of upgrading from a less than very good partial response (VGPR) to VGPR after ASCT was approximately two times higher in the Bor-HDM group than in the HDM group. However, we observed no significant differences in engraftment, RRT, and response rates between the Bor1-HDM and Bor2-HDM groups. The present study showed that concurrent administration of at least two doses of bortezomib in combination with HDM can be safe in Japanese patients. Additional large prospective randomized trials are required to address the optimal dosages and schedules of bortezomib administration, as well as the efficacy of the Bor-HDM conditioning regimen for ASCT.

Keywords

Bortezomib Melphalan Multiple myeloma Autologous Stem cell transplantation 

Notes

Acknowledgments

We thank the nursing staff who cared for the patients at the Fukuoka BMT group. This work was supported, in part, by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology in Japan (23390254 & 24659462 to T.M.).

Conflict of interest

None.

References

  1. 1.
    Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364:1046–60.PubMedCrossRefGoogle Scholar
  2. 2.
    Watanabe R, Tokuhira M, Kizaki M. Current approaches for the treatment of multiple myeloma. Int J Hematol. 2013;97:333–44.PubMedCrossRefGoogle Scholar
  3. 3.
    Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol. 2012;30:2946–55.PubMedCrossRefGoogle Scholar
  4. 4.
    Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:2075–85.PubMedCrossRefGoogle Scholar
  5. 5.
    McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1770–81.PubMedCrossRefGoogle Scholar
  6. 6.
    Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782–91.PubMedCrossRefGoogle Scholar
  7. 7.
    Ueda T, Iino R, Yokoyama K, et al. Post-transplant consolidation therapy using thalidomide alone for the patients with multiple myeloma: a feasibility study in Japanese population. Int J Hematol. 2012;96:477–84.PubMedCrossRefGoogle Scholar
  8. 8.
    Takamatsu Y, Sunami K, Hata H, et al. A phase I study of bortezomib in combination with doxorubicin and intermediate-dose dexamethasone (iPAD therapy) for relapsed or refractory multiple myeloma. Int J Hematol. 2010;92:503–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Reeder CB, Reece DE, Kukreti V, et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2010;115:3416–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Kumar S, Flinn I, Richardson PG, et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012;119:4375–82.PubMedCrossRefGoogle Scholar
  11. 11.
    Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679–86.PubMedCrossRefGoogle Scholar
  12. 12.
    San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906–17.PubMedCrossRefGoogle Scholar
  13. 13.
    Palumbo A, Cavallo F, Hardan I, et al. Melphalan/Prednisone/Lenalidomide (MPR) Versus High-Dose Melphalan and Autologous Transplantation (MEL200) in Newly Diagnosed Multiple Myeloma (MM) Patients <65 years: Results of a Randomized Phase III Study. Blood (ASH Annual Meeting Abstracts). 2011;118:3069.Google Scholar
  14. 14.
    Mitsiades N, Mitsiades CS, Richardson PG, et al. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood. 2003;101:2377–80.PubMedCrossRefGoogle Scholar
  15. 15.
    Ma MH, Yang HH, Parker K, et al. The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res. 2003;9:1136–44.PubMedGoogle Scholar
  16. 16.
    Roussel M, Moreau P, Huynh A, et al. Bortezomib and high-dose melphalan as conditioning regimen before autologous stem cell transplantation in patients with de novo multiple myeloma: a phase 2 study of the Intergroupe Francophone du Myelome (IFM). Blood. 2010;115:32–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Lonial S, Kaufman J, Tighiouart M, et al. A phase I/II trial combining high-dose melphalan and autologous transplant with bortezomib for multiple myeloma: a dose- and schedule-finding study. Clin Cancer Res. 2010;16:5079–86.PubMedCrossRefGoogle Scholar
  18. 18.
    Rowley S, Siegel D, Donato M, et al. Combination melphalan and bortezomib conditioning with autologous hematopoietic stem cell support in patients with advanced multiple myeloma. A phase I/II study. Blood (ASH Annual Meeting Abstracts). 2009;114:1214.Google Scholar
  19. 19.
    Wong Doo N, Thompson PA, Prince HM, et al. Bortezomib with high dose melphalan conditioning for autologous transplant is safe and effective in patients with heavily pretreated and high risk multiple myeloma. Leuk Lymphoma. 2012.Google Scholar
  20. 20.
    Nishihori T, Alekshun TJ, Shain K, et al. Bortezomib salvage followed by a Phase I/II study of bortezomib plus high-dose melphalan and tandem autologous transplantation for patients with primary resistant myeloma. Br J Haematol. 2012;157:553–63.PubMedCrossRefGoogle Scholar
  21. 21.
    Lee SR, Kim SJ, Park Y, Sung HJ, Choi CW, Kim BS. Bortezomib and melphalan as a conditioning regimen for autologous stem cell transplantation in multiple myeloma. Korean J Hematol. 2010;45:183–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Lahuerta JJ, Mateos MV, Martinez-Lopez J, et al. Busulfan 12 mg/kg plus melphalan 140 mg/m2 versus melphalan 200 mg/m2 as conditioning regimens for autologous transplantation in newly diagnosed multiple myeloma patients included in the PETHEMA/GEM2000 study. Haematologica. 2010;95:1913–20.PubMedCrossRefGoogle Scholar
  24. 24.
    Blanes M, Lahuerta JJ, Gonzalez JD, et al. Intravenous busulfan and melphalan as a conditioning regimen for autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: a matched comparison to a melphalan-only approach. Biol Blood Marrow Transplant. 2013;19:69–74.PubMedCrossRefGoogle Scholar
  25. 25.
    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;99:731–5.PubMedCrossRefGoogle Scholar
  26. 26.
    Einsele H, Bamberg M, Budach W, et al. A new conditioning regimen involving total marrow irradiation, busulfan and cyclophosphamide followed by autologous PBSCT in patients with advanced multiple myeloma. Bone Marrow Transplant. 2003;32:593–9.PubMedCrossRefGoogle Scholar
  27. 27.
    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;100:2607–12.PubMedCrossRefGoogle Scholar
  28. 28.
    Takezako N, Sekiguchi N, Nagata A, Noto S, Miwa A. Conditioning for autlogous stem cell transplantation by combining bortezomib and dexamethasone with high-dose melphalan (BD-HDM) is feasible in young japanese multiple myeloma patients. Haematologica (13th IMW Abstracts). 2011;96:s93.Google Scholar
  29. 29.
    Huang W, Li J, Li H, et al. High-dose melphalan with bortezomib as conditioning regimen for autologous stem cell transplant in patients with newly diagnosed multiple myeloma who exhibited at least very good partial response to bortezomib-based induction therapy. Leuk Lymphoma. 2012;53:2507–10.PubMedCrossRefGoogle Scholar
  30. 30.
    Thompson PA, Prince HM, Seymour JF, et al. Bortezomib added to high-dose melphalan as pre-transplant conditioning is safe in patients with heavily pre-treated multiple myeloma. Bone Marrow Transplant. 2011;46:764–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Yarde DN, Oliveira V, Mathews L, et al. Targeting the Fanconi anemia/BRCA pathway circumvents drug resistance in multiple myeloma. Cancer Res. 2009;69:9367–75.PubMedCrossRefGoogle Scholar
  32. 32.
    Popat R, Maharaj L, Oakervee H, Cavenagh J, Joel S. Schedule dependent cytotoxicity of bortezomib and melphalan in multiple myeloma. Br J Haematol. 2013;160:111–4.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2013

Authors and Affiliations

  • Toshihiro Miyamoto
    • 1
    Email author
  • Goichi Yoshimoto
    • 1
    • 2
  • Tomohiko Kamimura
    • 3
  • Tsuyoshi Muta
    • 1
  • Shuichiro Takashima
    • 1
  • Yoshikiyo Ito
    • 3
  • Motoaki Shiratsuchi
    • 4
  • Ilseung Choi
    • 5
  • Koji Kato
    • 1
  • Katsuto Takenaka
    • 6
  • Hiromi Iwasaki
    • 6
  • Yasushi Takamatsu
    • 7
  • Takanori Teshima
    • 6
    • 8
  • Koichi Akashi
    • 1
    • 6
  1. 1.Department of Medicine and Biosystemic ScienceKyushu University Graduate School of Medical ScienceFukuokaJapan
  2. 2.Department of HematologyNational Kyushu Medical CenterFukuokaJapan
  3. 3.Department of HematologyHarasanshin HospitalFukuokaJapan
  4. 4.Department of Medicine and Bioregulatory ScienceKyushu University Graduate School of Medical ScienceFukuokaJapan
  5. 5.Department of HematologyNational Hospital Organization Kyushu Cancer CenterFukuokaJapan
  6. 6.Center for Cellular and Molecular MedicineKyushu University Graduate School of Medical ScienceFukuokaJapan
  7. 7.Division of Medical Oncology, Hematology and Infectious Diseases, Department of MedicineFukuoka UniversityFukuokaJapan
  8. 8.Department of Hematology and OncologyHokkaido University Graduate School of MedicineSapporoJapan

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