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Bortezomib and low-dose dexamethasone with or without continuous low-dose oral cyclophosphamide for primary refractory or relapsed multiple myeloma: a randomized phase III study

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Abstract

This phase III, open-label, randomized, controlled study aimed to evaluate the benefit of adding continuous low-dose oral cyclophosphamide to bortezomib-dexamethasone in patients with primary relapsed/refractory multiple myeloma. Patients were randomized 1:1 to receive up to eight 3-week cycles of bortezomib (1.3 mg/m2) and dexamethasone (20 mg; VD; n = 48) or bortezomib-dexamethasone plus oral cyclophosphamide (50 mg; VCD; n = 48). Median time to progression (primary endpoint) was slightly longer in the VD versus VCD group (12.6 vs 9.9 months, P = 0.192), and the hazard ratio for disease progression was in favor of VD (hazard ratio = 0.71, 95% confidence interval = 0.43–1.19, P = 0.196). The overall response rate was 74% with VD and 70% with VCD. Most adverse events were similar in frequency between arms; however, grade ≥ 3 peripheral neuropathy was more frequent in the VCD versus VD arm (15 vs 4%). Infection rate was higher in the VCD arm (64 vs 52%); however, grade ≥3 infection rates were comparable (19 vs 17%). Further trials are needed to determine whether addition of cyclophosphamide to VD at a different dose/schedule confers clinical benefit. This study was terminated prematurely, with insufficient sample size to adequately compare the arms; the results should, therefore, be considered descriptive. This trial is registered: EudraCT Number 2008-003213-27; ClinicalTrials.gov NCT00813150.

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Acknowledgements

The authors would like to acknowledge the contribution of Astrid Kruse as study coordinator for the majority of the patients. The authors would also like to acknowledge the writing assistance of Helen Johns of FireKite, an Ashfield company, part of UDG Healthcare plc during the development of this publication, which was funded by Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, and Janssen Global Services, LLC. This study was supported by research funding from Janssen Research & Development and Millennium Pharmaceuticals, Inc.

Authorship contribution statements

MK was the principal investigator and takes primary responsibility for the paper; MK, GB, RS, LM, RW, WK, TD, HF, GK, SK, and WEB collected data and/or recruited patients; MK and WEB designed the study. MV co-ordinated preparation and analysis of the dataset; MK and WEB interpreted the data. MK, WEB, and MV prepared the manuscript. All authors reviewed and approved the manuscript.

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Authors and Affiliations

  1. Department of Medicine A, University Hospital Muenster, Muenster, Germany

    Martin Kropff, Guido Bisping & Wolfgang E. Berdel

  2. Department of Medicine III, Oncology, Hematology, and Stem Cell Transplantation, Osnabrück, Germany

    Martin Kropff

  3. Janssen-Cilag GmbH, Neuss, Germany

    Martin Vogel

  4. Private Practice for Hematology/Oncology, Würzburg, Germany

    Rudolf Schlag

  5. Private Practice and Clinic for Hematology/Oncology, Koblenz, Germany

    Rudolf Weide

  6. Private Practice for Hematology and Oncology, Frankfurt, Germany

    Wolfgang Knauf

  7. Private Practice for Hematology, Oncology and Palliative Medicine, Stuttgart, Germany

    Heinrich Fiechtner

  8. Private Practice for Hematology/Oncology, Darmstadt, Germany

    Georgi Kojouharoff

  9. Center for Oncology, Lebach, Germany

    Stephan Kremers

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  1. Martin Kropff
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Correspondence to Martin Kropff.

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Funding

This study was supported by research funding from Janssen Research & Development and Millennium Pharmaceuticals, Inc.

Conflict of interest

MK received honoraria, consultancy fees, and speaker’s bureau/advisory committee from Janssen, Celgene, and Mundipharma. WK received honoraria, consultancy fees, and speaker’s bureau/advisory committee from Janssen, Celgene, Mundipharma, and Roche. MV is an employee of Janssen; WEB received an honorarium from Janssen-Cilag. All other authors report no conflicts of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Kropff, M., Vogel, M., Bisping, G. et al. Bortezomib and low-dose dexamethasone with or without continuous low-dose oral cyclophosphamide for primary refractory or relapsed multiple myeloma: a randomized phase III study. Ann Hematol 96, 1857–1866 (2017). https://doi.org/10.1007/s00277-017-3065-z

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