Skip to main content

Advertisement

SpringerLink
Log in

Phase I dose-escalation study of cyclophosphamide combined with bortezomib and dexamethasone in Japanese patients with relapsed and/or refractory multiple myeloma

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

The present study was conducted to determine the recommended dose (RD) of cyclophosphamide (CPM) in the CBD regimen, a triplet combination of CPM, bortezomib (BTZ), and dexamethasone (Dex), for relapsed and/or refractory multiple myeloma (RRMM). Patients received intravenous CPM on days 1 and 8 at one of three dose levels: 300, 400, or 500 mg/m2, with dose escalation in a 3 + 3 design. BTZ at 1.3 mg/m2 was given twice weekly in 3-week cycles, with Dex at 20 mg/m2 on the day of and day after BTZ. Of 16 patients enrolled, 15 eligible patients were allocated to the study. Dose-limiting toxicities (DLTs) were seen in two patients: one in dose level 1 with increased γ-GTP and the other in dose level 3 with increased γ-GTP and ALT. Both patients spontaneously recovered from DLT. Neither therapy-related mortality nor severe adverse events were reported during the study. Therefore, the RD of CPM was determined as 500 mg/m2. Overall, 2 (13.3 %), 1 (6.7 %), and 8 (53.3 %) patients achieved CR, VGPR, and PR, respectively. The regimen was well tolerated and showed promising activity in patients with RRMM.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Harousseau J-L, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M, et al. 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. 2010;28:4621–9.

    Article  CAS  PubMed  Google Scholar 

  2. Sonneveld P, Schmidt-Wolf IGH, van der Holt B, el Jarari L, Bertsch U, Salwender H, 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.

    Article  CAS  PubMed  Google Scholar 

  3. Barlogie B, Tricot G, Anaissie E, Shaughnessy J, Rasmussen E, van Rhee F, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med. 2006;354:1021–30.

    Article  CAS  PubMed  Google Scholar 

  4. Lokhorst HM, Schmidt-Wolf I, Sonneveld P, van der Holt B, Martin H, Barge R, et al. Thalidomide in induction treatment increases the very good partial response rate before and after high-dose therapy in previously untreated multiple myeloma. Haematologica. 2008;93:124–7.

    Article  CAS  PubMed  Google Scholar 

  5. Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679–86.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Nooka AK, Kaufman JL, Behera M, Langston A, Waller EK, Flowers CR, et al. Bortezomib-containing induction regimens in transplant-eligible myeloma patients: a meta-analysis of phase 3 randomized clinical trials. Cancer. 2013;119:4119–28.

    Article  CAS  PubMed  Google Scholar 

  7. Sonneveld P, Goldschmidt H, Rosiñol L, Bladé J, Lahuerta JJ, Cavo M, et al. Bortezomib-Based versus nonbortezomib-based induction treatment before autologous stem-cell transplantation in patients with previously untreated multiple myeloma: a meta-analysis of phase III randomized controlled trials. J Clin Oncol. 2013;31:3279–87.

    Article  CAS  PubMed  Google Scholar 

  8. Palumbo A, Cavallo F. Have drug combinations supplanted stem cell transplantation in myeloma? ASH Edu Prog Book. 2012;2012:335–41.

    Google Scholar 

  9. Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, 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.

    Article  CAS  PubMed  Google Scholar 

  10. Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, 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.

    Article  CAS  PubMed  Google Scholar 

  11. Davies FE, Wu P, Jenner M, Srikanth M, Saso R, Morgan GJ. The combination of cyclophosphamide, velcade and dexamethasone (CVD) induces high response rates with comparable toxicity to velcade alone (V) and velcade plus dexamethasone (VD). Haematologica. 2007;92:1149–50.

    Article  CAS  PubMed  Google Scholar 

  12. Kropff M, Bisping G, Schuck E, Liebisch P, Lang N, Hentrich M, 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.

    Article  CAS  PubMed  Google Scholar 

  13. Reece DE, Rodriguez GP, Chen C, Trudel S, Kukreti V, Mikhael J, et al. Phase I-II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory multiple myeloma. J Clin Oncol. 2008;26:4777–83.

    Article  CAS  PubMed  Google Scholar 

  14. Khan ML, Reeder CB, Kumar SK, Lacy MQ, Reece DE, Dispenzieri A, et al. A comparison of lenalidomide/dexamethasone versus cyclophosphamide/lenalidomide/dexamethasone versus cyclophosphamide/bortezomib/dexamethasone in newly diagnosed multiple myeloma. Br J Haematol. 2012;156:326–33.

    Article  CAS  PubMed  Google Scholar 

  15. Kropff M, Liebisch P, Knop S, Weisel K, Wand H, Gann C-N, et al. DSMM XI study: dose definition for intravenous cyclophosphamide in combination with bortezomib/dexamethasone for remission induction in patients with newly diagnosed myeloma. Ann Hematol. 2009;88:1125–30.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Hentz J, et al. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009;23:1337–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Durie BGM, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467–73.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the Center for Supporting Hematology-Oncology Trials (C-SHOT). The authors would like to thank Shizuka Kobayashi for assisting as a data manager.

Author information

Authors and Affiliations

  1. Division of Hematology and Oncology, Toyohashi Municipal Hospital, 50 Hachiken-nishi, Aotake-cho, Toyohashi, 441-8570, Japan

    Isamu Sugiura & Satomi Terabe

  2. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Tomohiro Kinoshita

  3. Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital, Nagoya, Japan

    Kazuhito Yamamoto

  4. Department of Hematology, Anjo Kosei Hospital, Anjo, Japan

    Masashi Sawa

  5. Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

    Yukiyasu Ozawa

  6. Department of Hematopoietic Stem Cell Transplantation Data Management/Biostatistics, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Yoshiko Atsuta & Ritsuro Suzuki

  7. Tokai Central Hospital, Kakamigahara, Japan

    Kazuyuki Shimizu

Authors
  1. Isamu Sugiura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Satomi Terabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tomohiro Kinoshita
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kazuhito Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masashi Sawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yukiyasu Ozawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshiko Atsuta
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ritsuro Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kazuyuki Shimizu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Isamu Sugiura.

Ethics declarations

Conflict of interest

K. Yamamoto has received honoraria from Takeda Pharmaceutical Company Limited, and Janssen Pharmaceutical Company Limited, and research funding from Takeda Pharmaceutical Company Limited. K. Shimizu is a speaker’s bureau of Janssen Pharmaceutical Company Limited. I. Sugiura, S. Terabe, T. Kinoshita, M. Sawa, Y. Ozawa, Y. Atsuta, and R. Suzuki declare that they have no conflict of interest.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sugiura, I., Terabe, S., Kinoshita, T. et al. Phase I dose-escalation study of cyclophosphamide combined with bortezomib and dexamethasone in Japanese patients with relapsed and/or refractory multiple myeloma. Int J Hematol 102, 434–440 (2015). https://doi.org/10.1007/s12185-015-1846-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-015-1846-5

Keywords

Search

Navigation