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Multiple myeloma, gammopathies

Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial

Leukemia volume 32, pages 383–390 (2018)Cite this article

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Abstract

The Dutch-Belgian Cooperative Trial Group for Hematology Oncology Group-65/German-speaking Myeloma Multicenter Group-HD4 (HOVON-65/GMMG-HD4) phase III trial compared bortezomib (BTZ) before and after high-dose melphalan and autologous stem cell transplantation (HDM, PAD arm) compared with classical cytotoxic agents prior and thalidomide after HDM (VAD arm) in multiple myeloma (MM) patients aged 18–65 years. Here, the long-term follow-up and data on second primary malignancies (SPM) are presented. After a median follow-up of 96 months, progression-free survival (censored at allogeneic transplantation, PFS) remained significantly prolonged in the PAD versus VAD arm (hazard ratio (HR)=0.76, 95% confidence interval (95% CI) of 0.65–0.89, P=0.001). Overall survival (OS) was similar in the PAD versus VAD arm (HR=0.89, 95% CI: 0.74–1.08, P=0.24). The incidence of SPM were similar between the two arms (7% each, P=0.73). The negative prognostic effects of the cytogenetic aberration deletion 17p13 (clone size ⩾10%) and renal impairment at baseline (serum creatinine >2 mg dl−1) on PFS and OS remained abrogated in the PAD but not VAD arm. OS from first relapse/progression was similar between the study arms (HR=1.02, P=0.85). In conclusion, the survival benefit with BTZ induction/maintenance compared with classical cytotoxic agents and thalidomide maintenance is maintained without an increased risk of SPM.

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Acknowledgements

The investigators thank all participating patients and their families. Further the authors thank the ‘Zentrum zur Koordination klinischer Studien (KKS)’ Heidelberg, Germany and all participating study sites. Supported by the Dutch Cancer Foundation, the German Federal Ministry of Education and Research, and unrestricted Grant No. MMY3003 from Janssen-Cilag-Ortho Biotech. The German-speaking Myeloma Multicenter Group was supported by grants from Novartis, Amgen (No. P2004-0060), Chugai, and Roche.

Author contributions

Conception and design: PS, PB, SZ, EV, GMJB, DH, MvM-K, PWW, HML and HG. Financial support: AP. Administrative support: BvdH, LeJ, UB, HML and HG. Provision of study materials or patients: PS, IGHS-W, HS, SZ, EV, IWB, KCW, SC, GMJB, MS-K, CS, MP, DH, JH, MSR, RR, RMS, M-JK, MvM-K, UD, WL, PWW, HML and HG. Collection and assembly of data: PS, PB, LeJ, UB, HS, SZ, EV, AB, IWB, KCW, JH, MSR, EKM, SC, GMJB, MS-K, CS, MP, AJ, TH, RR, RMS, M-JK, MvM-K, UD, HWL, PY, HML and HG. Data analysis and interpretation: PS, BvdH, LeJ, SZ, MS-K, CS, PY, HML, TH, EKM and HG. Writing of the first manuscript draft: EKM and BvdH. Manuscript editing and writing: all authors. Final approval of manuscript: all authors.

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Authors and Affiliations

  1. Department of Internal Medicine V, University Clinic Heidelberg, Heidelberg, Germany

    H Goldschmidt, E K Mai, D Hose, J Hillengass, M S Raab & U Bertsch

  2. National Center for Tumor Diseases (NCT), University Clinic Heidelberg, Heidelberg, Germany

    H Goldschmidt

  3. Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands,

    H M Lokhorst

  4. Department of Hematology, HOVON Data Center, Erasmus MC Cancer Center, Rotterdam, The Netherlands

    B van der Holt

  5. Internal Medicine, Charité University Medicine Berlin, Berlin, Germany

    I W Blau

  6. Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands

    S Zweegman

  7. Department of Hematology, Oncology, Immunology, Rheumatology and Pulmonology, University Hospital of Tuebingen, Tuebingen, Germany

    K C Weisel

  8. Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands

    E Vellenga

  9. Department of Hematology and Oncology, University Clinic of Saarland, Homburg, Germany

    M Pfreundschuh

  10. Hematology, Academic Medical Center, Amsterdam, The Netherlands

    M J Kersten

  11. Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University of Cologne, Cologne, Germany

    C Scheid

  12. Deptartment of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands

    S Croockewit

  13. Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands

    R Raymakers

  14. EMEA Medical, Janssen, Athens, Greece

    A Potamianou

  15. Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany

    A Jauch

  16. Laboratorium Tumor Genetica, Radboud University Medical Centre, Nijmegen, The Netherlands

    M Stevens-Kroef

  17. Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, T, he Netherlands

    A Broijl & P Sonneveld

  18. Klinik für Hämatologie/Onkologie, Kath. Krankenhaus Hagen gem. GmbH - St-Marien-Hospital, Hagen, Germany

    H W Lindemann

  19. Deptartment of Internal Medicine, University Hospital Maastricht, Maastricht, The Netherlands

    G M J Bos

  20. Internal Medicine III, Oncology, Hematology and Rheumatology, University Clinic Bonn, Bonn, Germany

    P Brossart

  21. Department of Hematology, Isala Clinics, Zwolle, The Netherlands

    M van Marwijk Kooy

  22. Department of Hematology, Haga Hospital, The Hague, The Netherlands

    P Ypma

  23. Department of Hematology, University Hospital Essen, Essen, Germany

    U Duehrsen

  24. Department of Hematology, Medisch Spectrum Twente, Enschede, The Netherlands

    R M Schaafsma

  25. Division of Biostatistics, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany

    T Hielscher

  26. HOVON Datacenter, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

    Le Jarari

  27. Department of Hematology and Oncology, Asklepios Hospital Hamburg Altona, Hamburg, Germany

    H J Salwender

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Correspondence to H Goldschmidt.

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Competing interests

EKM: Honoraria: Janssen-Cilag, Takeda; Advisory boards: Takeda; Other support (travel grants): Janssen-Cilag, Takeda, Celgene, Onyx and Mundipharma; PS: Research support from Janssen, Celgene, Amgen, Takeda, Karyopharm Honoraria and advisory boards: Janssen, Celgene, Amgen, Takeda, Karyopharm; MSR: Research Support from Novartis, Amgen, Morphosys; Consulting for Novartis, Amgen, Celgene, Janssen; JH: Advisory boards: Celgene, Janssen, Novartis; Speakers honoraria: Celgene, Janssen, BMS, Amgen; Consultancy: Amgen; Travel support: Amgen, BMS, Takeda; Research Support: Novartis, Sanofi; HJS: Honoraria: Janssen, Celgene; Travel support: Janssen, Celgene; KCW: Consultancy: Amgen, Bristol Myers Squibb, Celgene, Novartis, Janssen, Takeda; Honoraria: Amgen, Bristol Myers Squibb, Celgene, Novartis, Janssen, Takeda; Research funding: Celgene, Janssen; IWB: Research grant: Celgene and Janssen; Advisory boards: Janssen, Celgene, Amgen, Takeda, Novartis, BMS; PS: SkylineDx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; SZ: Celgene: Honoraria, Research Funding; Takeda Millennium: Honoraria, Research Funding; Onyx: Honoraria; Annemiek Broijl: Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Christ of Scheid: Janssen: Honoraria; Celgene: Honoraria; AP: Janssen: Employment; Dirk Hose: Takeda: Other: Travel grant; EngMab AG: Research Funding; M-JK: Takeda Millennium: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; UD: Alexion: Honoraria; Janssen: Honoraria; HML: Janssen: Honoraria, Research Funding; Genmab: Honoraria, Research Funding; Amgen: Honoraria; Goldschmidt: Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; BMS: Honoraria, Research Funding. The remaining authors declare no conflict of interest.

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Parts of this manuscript have been presented at the 2015 ASH Annual Meeting, Orlando, Florida, Abstract #27.

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Goldschmidt, H., Lokhorst, H., Mai, E. et al. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia 32, 383–390 (2018). https://doi.org/10.1038/leu.2017.211

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