International Journal of Hematology

, Volume 92, Issue 3, pp 503–509

A phase I study of bortezomib in combination with doxorubicin and intermediate-dose dexamethasone (iPAD therapy) for relapsed or refractory multiple myeloma

  • Yasushi Takamatsu
  • Kazutaka Sunami
  • Hiroyuki Hata
  • Koji Nagafuji
  • Ilseung Choi
  • Masakazu Higuchi
  • Kimiharu Uozumi
  • Yasufumi Masaki
  • Kazuo Tamura
  • The Kyushu Hematology Organization for Treatment Study Group (K-HOT)
Original Article


Bortezomib and doxorubicin have synergistic activity against myeloma cells in vitro. We underwent a dose finding study of bortezomib in combination with a fixed dose of doxorubicin and intermediate-dose dexamethasone (iPAD therapy) in patients with relapsed or refractory myeloma. Bortezomib was administered on days 1, 4, 8 and 11 at a dose of 1.0 and 1.3 mg/m2 in cohorts 1 and 2, respectively. Doxorubicin 9 mg/m2 was given by rapid intravenous infusion on days 1–4, and dexamethasone 20 mg on days 1–2, 4–5, 8–9 and 11–12. Treatment was repeated at a 3-week interval and the dose-limiting toxicity (DLT), defined as grade 4 hematological toxicity lasting more than 5 days and/or grade 3 or higher non-hematological toxicity, was evaluated. In cohort 1, 2 of 6 patients developed DLTs including grade 4 hyponatremia and grade 3 infection with appropriate neutrophil counts. No DLT was observed in the remaining 4 patients, indicating this dose was tolerable. In cohort 2, 3 of 5 patients developed DLTs including grade 4 thrombocytopenia lasting more than 5 days, grade 3 hepatic transaminase elevation and grade 3 ileus, indicating this dose was intolerable. It is concluded that bortezomib at the dose of 1.0 mg/m2 is recommended in combination with doxorubicin and intermediate-dose dexamethasone.


Bortezomib Doxorubicin Myeloma Phase 1 trial 


  1. 1.
    Adams J. The proteasome: a suitable antineoplastic target. Nat Rev Cancer. 2004;4:349–60.CrossRefPubMedGoogle Scholar
  2. 2.
    Hideshima T, Richardson P, Chauhan D, et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res. 2001;61:3071–6.PubMedGoogle Scholar
  3. 3.
    Jagannath S, Barlogie B, Berenson J, et al. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol. 2004;127:165–72.CrossRefPubMedGoogle Scholar
  4. 4.
    Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348:2609–17.CrossRefPubMedGoogle Scholar
  5. 5.
    Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487–98.CrossRefPubMedGoogle Scholar
  6. 6.
    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.CrossRefPubMedGoogle Scholar
  7. 7.
    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
  8. 8.
    Oakervee HE, Popat R, Curry N, et al. PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol. 2005;129:755–62.CrossRefPubMedGoogle Scholar
  9. 9.
    Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007;25:3892–901.CrossRefPubMedGoogle Scholar
  10. 10.
    Berenson JR, Yang HH, Sadler K, et al. Phase I/II trial assessing bortezomib and melphalan combination therapy for the treatment of patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2006;24:937–44.CrossRefPubMedGoogle Scholar
  11. 11.
    Mateos MV, Hernandez JM, Hernández MT, et al. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study. Blood. 2006;108:2165–72.CrossRefPubMedGoogle Scholar
  12. 12.
    Kropff M, Bisping G, Schuck E, et al. Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma. Br J Haematol. 2007;138:330–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996;335:91–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Pineda-Roman M, Zangari M, van Rhee F, et al. VTD combination therapy with bortezomib-thalidomide-dexamethasone is highly effective in advanced and refractory multiple myeloma. Leukemia. 2008;22:1419–27.CrossRefPubMedGoogle Scholar
  15. 15.
    Popat R, Oakervee HE, Hallam S, et al. Bortezomib, doxorubicin and dexamethasone (PAD) front-line treatment of multiple myeloma: updated results after long-term follow-up. Br J Haematol. 2008;141:512–6.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2010

Authors and Affiliations

  • Yasushi Takamatsu
    • 1
  • Kazutaka Sunami
    • 2
  • Hiroyuki Hata
    • 3
  • Koji Nagafuji
    • 4
  • Ilseung Choi
    • 5
  • Masakazu Higuchi
    • 6
  • Kimiharu Uozumi
    • 7
  • Yasufumi Masaki
    • 8
  • Kazuo Tamura
    • 1
  • The Kyushu Hematology Organization for Treatment Study Group (K-HOT)
  1. 1.Division of Medical Oncology, Hematology and Infectious Diseases, Department of MedicineFukuoka UniversityFukuokaJapan
  2. 2.Department of HematologyNational Hospital Organization Okayama Medical CenterOkayamaJapan
  3. 3.Department of HematologyKumamoto University of MedicineKumamotoJapan
  4. 4.Department of Medicine and Biosystemic ScienceKyushu University Graduate School of Medical SciencesFukuokaJapan
  5. 5.Department of HematologyNational Kyushu Cancer CenterFukuokaJapan
  6. 6.Department of Internal MedicineKyushu Kosei-Nenkin HospitalKitakyushuJapan
  7. 7.Department of Hematology and ImmunologyKagoshima UniversityKagoshimaJapan
  8. 8.Department of Hematology and ImmunologyKanazawa Medical UniversityKanazawaJapan

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