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Bortezomib-based strategy with autologous stem cell transplantation for newly diagnosed multiple myeloma: a phase II study by the Japan Study Group for Cell Therapy and Transplantation (JSCT-MM12)

  • Kazutaka SunamiEmail author
  • Morio Matsumoto
  • Shin-ichi Fuchida
  • Eijiro Omoto
  • Hiroyuki Takamatsu
  • Yoko Adachi
  • Ilsong Choi
  • Naohito Fujishima
  • Toru Kiguchi
  • Toshihiro Miyamoto
  • Akio Maeda
  • Junji Suzumiya
  • Ryosuke Yamamura
  • Koji Nagafuji
  • Tomonori Nakazato
  • Yoshiaki Kuroda
  • Toshiaki Yujiri
  • Yasushi Takamatsu
  • Mine Harada
  • Koichi Akashi
Original Article
  • 134 Downloads

Abstract

Background

The Japan Study Group for Cell Therapy and Transplantation (JSCT) organized a phase II study to evaluate the efficacy and safety of a treatment protocol (JSCT-MM12) for multiple myeloma (MM) patients who were previously untreated and transplantation-eligible. Since bortezomib-based therapy is known to be effective for MM, the protocol is intensified more than the previous protocol (JSCT-MM10) and comprised the subsequent treatments: bortezomib + cyclophosphamide + dexamethasone (VCD) induction; bortezomib + high-dose-melphalan (B-HDM) conditioning with autologous stem cell transplantation (ASCT); bortezomib + thalidomide + dexamethasone (VTD) consolidation; and lenalidomide (LEN) maintenance.

Methods

Sixty-four symptomatic patients aged between 20 and 65 years were enrolled for treatment and received three cycles of VCD, followed by cyclophosphamide administration for autologous stem cell harvest and B-HDM/ASCT, and subsequently two cycles of VTD, after that LEN for 1 year.

Results

Complete response (CR)/stringent CR (sCR) rates for induction, ASCT, consolidation, and maintenance therapies were 20, 39, 52, and 56%, respectively. The grade 3/4 toxicities (≥ 10%) with VCD treatment included neutropenia (27%), anemia (19%), and thrombocytopenia (11%). There was no treatment-related mortality. After median follow-up of 41 months, estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 64% and 88%, respectively. The high-risk group revealed lower CR/sCR, PFS, and OS than the standard-risk group.

Conclusions

The study revealed that the treatment protocol consisting of VCD induction, B-HDM/ASCT followed by VTD consolidation, and LEN maintenance could produce highly beneficial responses and favorable tolerability in newly diagnosed MM. However, future study is required for improving treatment in the high-risk group.

Keywords

Bortezomib Thalidomide Lenalidomide Autologous stem cell transplantation Consolidation Maintenance 

Notes

Acknowledgements

We are grateful to Professor Koji Yonemoto (Ryukyu University) for the data analysis. This work was supported by a grant from the Regional Medicine Research Foundation (Tochigi, Japan).

Compliance with ethical standards

Conflict of interest

Kazutaka Sunami received research funding from Ono Pharmaceutical, MSD, Celgene, Abbvie, Takeda pharmaceutical, Sanofi, Bristol-Myers Squibb, Daiichi Sankyo, Janssen, Novartis, Alexion Pharma and GlaxoSmithKline, and received honoraria from Ono Pharmaceutical, Celgene, Takeda Pharmaceutical, and Bristol-Myers Squibb. Morio Matsumoto received honoraria from Janssen, Celgene and Ono Pharmaceutical. Shin-ichi Fuchida received honoraria from Takeda Pharmaceutical. Hiroyuki Takamatsu received honoraria from Janssen and Celgene. Toru Kiguchi received research funding from Daiichi Sankyo, Bristol-Myers Squibb, Otsuka Pharmaceutical, Kyowa Hakko Kirin, MSD, Astellas, Nippon Shinyaku, Novartis, Sumitomo Dainippon, Janssen, Celgene, Symbio Pharmaceutical, Taiho Pharmaceutical, Teijin, Sanofi and Celltrion. Toshihiro Miyamoto received honoraria from Celgene and MSD. Junji Suzumiya received honoraria from Eisai, Celgene, Janssen, Chugai Pharmaceutical, Abbvie and Takeda Pharmaceutical, and research funding from Chugai Pharmaceutical, Eisai, Takeda Pharmaceutical, Kyowa Hakko Kirin, Astellas, Toyama Chemical, Celgene, Celltrion and Symbio Pharmaceutical. Yasushi Takamatsu received honoraria from Ono Pharmaceutical, Kyowa Hakko Kirin and Janssen, and received from research funding from Takeda Pharmaceutical, Ono Pharmaceutical and Celgene. Koichi Akashi received honoraria from Takeda Pharmaceutical, Bristol-Myers Squibb, Novartis, Kyowa Hakko Kirin, Janssen, Pfizer, Chugai Pharmaceutical, Ono Pharmaceutical, Eisai, Astellas and Celgene, and received research funding from Taiho Pharmaceutical, Sanofi, Novartis, MSD, Astellas, Bristol-Myers Squibb, Eli Lilly, Kyowa Hakko Kirin, Chugai Pharmaceutical, Asahi Kasei, Eisai, Otsuka Pharmaceutical, Ono Pharmaceutical, Teijin, Nippon Shinyaku, Shionogi, Mitsubishi Tanabe, Sumitomo Dainippon, Toyama Chemical, Daiichi Sankyo, Takeda Pharmaceutical, Yakult, Taisho Toyama Pharmaceutical, The Chemo-Sero-Therapeutic Research Institute, Alexion Pharma and Merck Serono. The other authors have no conflict of interests to declare.

References

  1. 1.
    Harousseau JL, Attal M, Avet-Loiseau H et al (2010) Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol 28:4621–4629CrossRefGoogle Scholar
  2. 2.
    Cavo M, Tacchetti P, Patriarca F et al (2010) 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 randomized phase 3 study. Lancet 376:2075–2085CrossRefGoogle Scholar
  3. 3.
    Rosiñol L, Oriol A, Teruel AI et al (2012) Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood 120:1589–1596CrossRefGoogle Scholar
  4. 4.
    Reeder CB, Reece DE, Kukreti V et al (2009) Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia 23:1337–1341CrossRefGoogle Scholar
  5. 5.
    Richardson PG, Weller E, Lonial S et al (2010) Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 116:679–686CrossRefGoogle Scholar
  6. 6.
    Palumbo A, Cavallo F, Gay F et al (2014) Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med 371:895–905CrossRefGoogle Scholar
  7. 7.
    Barlogie B, Tricot G, Rasmussen E et al (2006) Total therapy 2 without thalidomide in comparison with total therapy 1: role of intensified induction and posttransplantation consolidation therapies. Blood 107:2633–2638CrossRefGoogle Scholar
  8. 8.
    Attal M, Harousseau JL, Leyvraz S et al (2006) Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood 108:3289–3294CrossRefGoogle Scholar
  9. 9.
    Spencer A, Prince HM, Roberts AW et al (2009) Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol 27:1788–1793CrossRefGoogle Scholar
  10. 10.
    Lokhorst HM, van der Holt B, Zweegman S et al (2010) A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood 115:1113–1120CrossRefGoogle Scholar
  11. 11.
    Morgan GJ, Gregory WM, Davies FE et al (2012) The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood 119:7–15CrossRefGoogle Scholar
  12. 12.
    Stewart AK, Trudel S, Bahlis NJ et al (2013) A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinical Trials Group Myeloma 10 Trial. Blood 121:1517–1523CrossRefGoogle Scholar
  13. 13.
    Attal M, Lauwers-Cances V, Marit G et al (2012) Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 366:1782–1791CrossRefGoogle Scholar
  14. 14.
    McCarthy PL, Owzar K, Hofmeister CC et al (2012) Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 366:1770–1781CrossRefGoogle Scholar
  15. 15.
    Fuchida S, Sunami K, Matsumoto M et al (2018) A phase II study of lenalidomide consolidation and maintenance therapy after autologous PBSCT in patients with multiple myeloma. Int J Hematol 109:107–114CrossRefGoogle Scholar
  16. 16.
    Moreau P, Facon T, Attal M et al (2002) Comparison of 200 mg/m2 melphalan and 8 Gy total body irradiation plus 140 mg/m2 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 99:731–735CrossRefGoogle Scholar
  17. 17.
    Lahuerta JJ, Martinez-Lopez J, Grande C et al (2000) 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 109:138–147CrossRefGoogle Scholar
  18. 18.
    Einsele H, Bamberg M, Budach W et al (2003) A new conditioning regimen involving total marrow irradiation, busulfan and cyclophosphamide followed by autologous PBSCT in patients with advanced multiple myeloma. Bone Marrow Transplant 32:593–599CrossRefGoogle Scholar
  19. 19.
    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 100:2607–2612CrossRefGoogle Scholar
  20. 20.
    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 101:2377–2380CrossRefGoogle Scholar
  21. 21.
    Ma MH, Yang HH, Parker K et al (2003) The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res 9:1136–1144Google Scholar
  22. 22.
    Berenson JR, Yang HH, Sadler K et al (2006) Phase I/II trial assessing bortezomib and melphalan combination therapy for the treatment of patients with relapsed or refractory multiple myeloma. J Clin Oncol 24:937–944CrossRefGoogle Scholar
  23. 23.
    San Miguel JF, Schlag R, Khuageva NK et al (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359:906–917CrossRefGoogle Scholar
  24. 24.
    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 2 study of the Intergroupe Francophone du Myélome (IFM). Blood 115:32–37CrossRefGoogle Scholar
  25. 25.
    Richardson PG, Briemberg H, Jagannath S et al (2006) Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol 24:3113–3120CrossRefGoogle Scholar
  26. 26.
    Sunami K, Shinagawa K, Sawamura M et al (2009) Phase I/II study of tandem high-dose chemotherapy with autologous peripheral blood stem cell transplantation for advanced multiple myeloma. Int J Hematol 90:635–642CrossRefGoogle Scholar
  27. 27.
    Durie BG, Harousseau JL, Miguel JS et al (2006) International uniform response criteria for multiple myeloma. Leukemia 20:1467–1473CrossRefGoogle Scholar
  28. 28.
    Lahuerta JJ, Mateos MV, Martínez-López J et al (2008) Influence of pre- and post-transplantation responses on outcome of patients with multiple myeloma: sequential improvement of response and achievement of complete response are associated with longer survival. J Clin Oncol 26:5775–5782CrossRefGoogle Scholar
  29. 29.
    Reeder CB, Reece DE, Kukreti V et al (2010) Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood 115:3416–3417CrossRefGoogle Scholar
  30. 30.
    Moreau P, Attal M, Pégourié B et al (2011) Achievement of VGPR to induction therapy is an important prognostic factor for longer PFS in the IFM 2005-01 trial. Blood 117:3041–3044CrossRefGoogle Scholar
  31. 31.
    Moreau P, Pylypenko H, Grosicki S et al (2011) Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 12:431–440CrossRefGoogle Scholar
  32. 32.
    Jantunen E, Putkonen M, Nousiainen T et al (2003) Low-dose or intermediate-dose cyclophosphamide plus granulocyte colony-stimulating factor for progenitor cell mobilisation in patients with multiple myeloma. Bone Marrow Transplant 31:347–351CrossRefGoogle Scholar
  33. 33.
    de la Rubia J, Bladé J, Lahuerta JJ et al (2006) Effect of chemotherapy with alkylating agents on the yield of CD34 + cells in patients with multiple myeloma. Results of the Spanish Myeloma Group (GEM) Study. Haematologica 91:621–627Google Scholar
  34. 34.
    Bellido M, Sureda A, Martino R et al (1998) Collection of peripheral blood progenitor cells for autografting with low-dose cyclophosphamide plus granulocyte colony-stimulating factor. Haematologica 83:428–431Google Scholar
  35. 35.
    Niesvizky R, Mark TM, Ward M et al (2013) Overcoming the response plateau in multiple myeloma: a novel bortezomib-based strategy for secondary induction and high-yield CD34 + stem cell mobilization. Clin Cancer Res 19:1534–1546CrossRefGoogle Scholar
  36. 36.
    Leleu X, Fouquet G, Hebraud B et al (2013) Consolidation with VTd significantly improves the complete remission rate and time to progression following VTd induction and single autologous stem cell transplantation in multiple myeloma. Leukemia 27:2242–2244CrossRefGoogle Scholar
  37. 37.
    McCarthy PL, Holstein SA, Petrucci MT et al (2017) Lenalidomide maintenance after autologous stem cell transplantation in newly diagnosed multiple myeloma: a meta-analysis. J Clin Oncol 35:3279–3289CrossRefGoogle Scholar
  38. 38.
    Fonseca R, Blood E, Rue M et al (2003) Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 101:4569–4575CrossRefGoogle Scholar
  39. 39.
    Avet-Loiseau H, Attal M, Moreau P et al (2007) Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. Blood 109:3489–3495CrossRefGoogle Scholar
  40. 40.
    Avet-Loiseau H, Leleu X, Roussel M et al (2010) Bortezomib plus dexamethasone induction improves outcome of patients with t (4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol 28:4621–4635CrossRefGoogle Scholar
  41. 41.
    Cavo M, Pantani L, Petrucci MT et al (2012) Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood 120:9–19CrossRefGoogle Scholar
  42. 42.
    Neben K, Lokhorst HM, Jauch A et al (2012) Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood 119:940–948CrossRefGoogle Scholar
  43. 43.
    Hebraud B, Leleu X, Lauwers-Cances V et al (2014) Deletion of the 1p32 region is a major independent prognostic factor in young patients with myeloma: the IFM experience on 1195 patients. Leukemia 28:675–679CrossRefGoogle Scholar
  44. 44.
    Nooka AK, Kaufman JL, Muppidi S et al (2014) Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia 28:690–693CrossRefGoogle Scholar
  45. 45.
    Roussel M, Lauwers-Cances V, Robillard N et al (2014) Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol 32:2712–2717CrossRefGoogle Scholar
  46. 46.
    Chng WJ, Goldschmidt H, Dimopoulos MA et al (2017) Carfilzomib–dexamethasone vs bortezomib–dexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study ENDEAVOR. Leukemia 31:1368–1374CrossRefGoogle Scholar
  47. 47.
    Avet-Loiseau H, Bahlis NJ, Chng WJ et al (2017) Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients. Blood 130:2610–2618CrossRefGoogle Scholar
  48. 48.
    Dimopoulos MA, Lonial S, White D et al (2017) Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT-2 follow-up and post hoc analyses on progression-free survival and tumour growth. Br J Haematol 178:896–905CrossRefGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2019

Authors and Affiliations

  • Kazutaka Sunami
    • 1
    Email author
  • Morio Matsumoto
    • 2
  • Shin-ichi Fuchida
    • 3
  • Eijiro Omoto
    • 4
  • Hiroyuki Takamatsu
    • 5
  • Yoko Adachi
    • 6
  • Ilsong Choi
    • 7
  • Naohito Fujishima
    • 8
  • Toru Kiguchi
    • 9
  • Toshihiro Miyamoto
    • 10
  • Akio Maeda
    • 11
  • Junji Suzumiya
    • 12
  • Ryosuke Yamamura
    • 13
  • Koji Nagafuji
    • 14
  • Tomonori Nakazato
    • 15
  • Yoshiaki Kuroda
    • 16
  • Toshiaki Yujiri
    • 17
  • Yasushi Takamatsu
    • 18
  • Mine Harada
    • 19
  • Koichi Akashi
    • 10
  1. 1.Department of HematologyNational Hospital Organization Okayama Medical CenterOkayamaJapan
  2. 2.Department of HematologyNational Hospital Organization Shibukawa Medical CenterShibukawaJapan
  3. 3.Department of HematologyJapan Community Health Care Organization Kyoto Kuramaguchi Medical CenterKyotoJapan
  4. 4.Department of HematologyYamagata Prefectural Central HospitalYamagataJapan
  5. 5.Department of Hematology/Respiratory Medicine, Faculty of Medicine, Institute of MedicalPharmaceutical and Health Sciences, Kanazawa UniversityKanazawaJapan
  6. 6.Department of Internal MedicineJapan Community Health Care Organization Kobe Central HospitalKobeJapan
  7. 7.Department of HematologyNational Hospital Organization Kyushu Cancer CenterFukuokaJapan
  8. 8.Division of Blood TransfusionAkita University HospitalAkitaJapan
  9. 9.Department of HematologyChugoku Central HospitalFukuyamaJapan
  10. 10.Medicine and Biosystemic Science, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
  11. 11.Department of HematologyHyogo Cancer CenterAkashiJapan
  12. 12.Innovative Cancer Center/Oncology-HematologyShimane University HospitalIzumoJapan
  13. 13.Department of HematologyOsaka Saiseikai Nakatsu HospitalKitakuJapan
  14. 14.Division of Hematology and Oncology, Department of MedicineKurume University School of MedicineKurumeJapan
  15. 15.Department of HematologyYokohama Municipal Citizen’s HospitalYokohamaJapan
  16. 16.Department of Hematology and Oncology, Research Institute for Radiation Biology and MedicineHiroshima UniversityMinami-kuJapan
  17. 17.Third Department of Internal MedicineYamaguchi University School of MedicineUbeJapan
  18. 18.Division of Medical Oncology, Hematology and Infectious Diseases, Department of MedicineFukuoka UniversityFukuokaJapan
  19. 19.Karatsu Higashimatsuura Medical AssociationKaratsuJapan

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