Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Multiple myeloma, gammopathies

Long-term follow-up of subcutaneous versus intravenous bortezomib during induction therapy for newly diagnosed multiple myeloma treated within the GMMG-MM5 Phase III Trial

Leukemia volume 35, pages 3007–3011 (2021)Cite this article

Subjects

Response rates after induction therapy, first ASCT and best response during study were analyzed according to route of administration of bortezomib and summarized in Supplementary Table 2. There were no significant differences between IV and SC bortezomib administration with respect to overall response rates (ORR, defined as partial response or better) after induction therapy (IV: 226/74.4%; SC: 209/75.4%), after first ASCT (IV: 238/88.1%; SC: 226/90.4%) or during the entire study (IV: 278/91.5%; SC: 256/91.4%; p = 1.00). There were also no significant differences found for CR rates after induction therapy (IV: 20/6.6%; SC: 10/3.6%). Significantly more patients treated with IV bortezomib achieved a CR after first ASCT compared to SC-treated patients (IV: 63/ 23.3%; SC: 40/15.9%; p = 0.04). Analysis of CR rates during the entire study revealed that 124 patients (40.8%) treated with IV bortezomib and 93 patients (33.2%) treated with SC bortezomib achieved a CR during the study (p = 0.06).

Median follow-up in this safety subpopulation cohort of 584 patients was 57.6 months (IV: 65.4 months; SC: 51.1 months). The SC application of bortezomib during induction therapy had no significant univariable effect on PFS compared to the IV application (hazard ratio/HR: 1.00, 95% CI: 0.80–1.24; p = 0.973, Fig. 1B). The same observation was made when investigating the two subgroups of different induction regimes (PAd and VCD) separately (Supplementary Fig. 2A, B). Overall, 171 deaths occurred during the observation period (IV: 104; SC 67). No significant univariable effect of SC bortezomib on OS was observed (HR: 0.94, 0.68–1.29; p = 0.686, Fig. 1C). Also, subgroup analyses of PAd and VCD revealed no significant differences in OS between IV- and SC-treated patients (Supplementary Fig. 2C, D). Multivariable analyses adjusting for possible confounders due to the non-randomized comparison confirmed that the route of administration of bortezomib during induction therapy had no impact on PFS and OS (Supplementary Table 3).

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Flow chart and survival analyses of the GMMG MM5 trial.

References

  1. Röllig C, Knop S, Bornhäuser M. Multiple myeloma. Lancet. 2015;385:2197–208.

    Article  Google Scholar 

  2. Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431–40.

    Article  Google Scholar 

  3. Arnulf B, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, van de Velde H, et al. Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma. Haematologica. 2012;97:1925–8.

    Article  Google Scholar 

  4. Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, et al. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015;29:1721–9.

    Article  CAS  Google Scholar 

  5. Goldschmidt H, Mai EK, Dürig J, Scheid C, Weisel KC, Kunz C, et al. Response-adapted lenalidomide maintenance in newly diagnosed myeloma: results from the phase III GMMG-MM5 trial. Leukemia. 2020;34:1853–65.

    Article  CAS  Google Scholar 

  6. Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376:1311–20.

    Article  CAS  Google Scholar 

  7. Moreau P, Attal M, Hulin C, Arnulf B, Belhadj K, Benboubker L, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394:29–38.

    Article  CAS  Google Scholar 

  8. Voorhees PM, Kaufman JL, Laubach J, Sborov DW, Reeves B, Rodriguez C, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136:936–45.

    Article  CAS  Google Scholar 

  9. Salwender H, Bertsch U, Weisel K, Duerig J, Kunz C, Benner A, et al. Rationale and design of the German-speaking myeloma multicenter group (GMMG) trial HD6: a randomized phase III trial on the effect of elotuzumab in VRD induction/consolidation and lenalidomide maintenance in patients with newly diagnosed myeloma. BMC Cancer. 2019;19:504.

    Article  Google Scholar 

  10. Merz M, Salwender H, Haenel M, Mai EK, Bertsch U, Kunz C, et al. Subcutaneous versus intravenous bortezomib in two different induction therapies for newly diagnosed multiple myeloma: an interim analysis from the prospective GMMG-MM5 trial. Haematologica. 2015;100:964–9.

    Article  CAS  Google Scholar 

  11. Merz M, Salwender H, Haenel M, Mai EK, Bertsch U, Kunz C, et al. Peripheral neuropathy associated with subcutaneous or intravenous bortezomib in patients with newly diagnosed myeloma treated within the GMMG MM5 phase III trial. Haematologica. 2016;101:e485–87.

    Article  CAS  Google Scholar 

  12. Richardson PG, Sonneveld P, Schuster MW, Stadtmauer EA, Facon T, Harousseau JL, et al. Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose-modification guideline. Br J Haematol. 2009;144:895–903.

    Article  CAS  Google Scholar 

  13. Merz M, Dechow T, Scheytt M, Schmidt C, Hackanson B, Knop S. The clinical management of lenalidomide-based therapy in patients with newly diagnosed multiple myeloma. Ann Hematol. 2020;99:1709–25.

    Article  CAS  Google Scholar 

  14. Pawlyn C, Khan MS, Muls A, Sriskandarajah P, Kaiser MF, Davies FE, et al. Lenalidomide-induced diarrhea in patients with myeloma is caused by bile acid malabsorption that responds to treatment. Blood. 2014;124:2467–8.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The GMMG-MM5 trial was supported by Celgene, Janssen-Cilag, Chugai, and The Binding Site. The GMMG thanks the Koordinierungszentrum für Klinische Studien (KKS) Heidelberg for the support of the trial and data monitoring. The GMMG thanks all participating investigators and centers.

Author information

Authors and Affiliations

  1. Asklepios Tumorzentrum Hamburg, AK Altona, Hamburg, Germany

    Hans Salwender

  2. Department of Hematology/Oncology and Stem Cell Transplantation, AK St. Georg, Hamburg, Germany

    Ahmet Elmaagacli & Christian Jehn

  3. Department of Hematology, Celltherapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany

    Maximilian Merz

  4. Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany

    Kaya Miah & Axel Benner

  5. Klinikum Chemnitz, Chemnitz, Germany

    Mathias Haenel

  6. Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany

    Elias K. Mai, Uta Bertsch, Marc S. Raab & Hartmut Goldschmidt

  7. National Center for Tumor Diseases (NCT), Heidelberg, Germany

    Uta Bertsch & Hartmut Goldschmidt

  8. Charité Universitätsmedizin, Berlin, Germany

    Igor W. Blau

  9. University Hospital Cologne, Cologne, Germany

    Christof Scheid

  10. Vrije Universiteit Brussel (VUB), Laboratory of Hematology and Immunology & Labor für Myelomforschung, Jette, Belgium

    Dirk Hose & Anja Seckinger

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

    Anna Jauch

  12. Coordination Centre for Clinical Trials (KKS), Heidelberg, Germany

    Steffen P. Luntz

  13. University Hospital Tubingen, Tubingen, Germany

    Britta Besemer

  14. University Medical Center Mainz, Mainz, Germany

    Markus Munder

  15. University Hospital Bonn, Bonn, Germany

    Peter Brossart

  16. Helios Hospital Berlin Buch, Buch, Germany

    Stephan Fuhrmann

  17. Kath. Krankenhaus Hagen, Hagen, Germany

    Hans-Walter Lindemann

  18. University Hospital Hamburg, Hamburg, Germany

    Katja Weisel

  19. University Hospital Essen, Essen, Germany

    Jan Duerig

Authors
  1. Hans Salwender
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ahmet Elmaagacli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maximilian Merz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kaya Miah
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Axel Benner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mathias Haenel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christian Jehn
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Elias K. Mai
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Uta Bertsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Igor W. Blau
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Christof Scheid
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Dirk Hose
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Anja Seckinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Anna Jauch
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Marc S. Raab
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Steffen P. Luntz
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Britta Besemer
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Markus Munder
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Peter Brossart
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Stephan Fuhrmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Hans-Walter Lindemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Katja Weisel
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Jan Duerig
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Hartmut Goldschmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception and design: HS, MMe, HG, UB, KM, and AB. Responsible statisticians: KM and AB. Administrative support: HG, UB, and SPL. Provision of study materials or patients and/or collection, assembly and review of data: all authors. Data analysis and interpretation: HS, AE, MMe, HG, EKM, KM, and AB. Writing of the first manuscript draft: HS, AE, MMe, and HG. Manuscript editing, discussion of trial data/results, and final writing: all authors. Final approval of manuscript: all authors.

Corresponding author

Correspondence to Hans Salwender.

Ethics declarations

Conflict of interest

HS: honoraria: AbbVie, Amgen, BMS, Celgene, Chugai, GSK, Janssen, Oncopeptides, Sanofi, Sebia, Takeda; travel, accommodations, expenses: Amgen, BMS, Celgene, Janssen, Sanofi. AE: honoraria: Janssen, Celgene, Takeda; consulting or advisory role: Janssen, Amgen, Celgene, Takeda, Sanofi; travel, accommodations, expenses: Janssen, Takeda, Celgene, Amgen, Novartis. MMe: consulting or advisory role: BMS, Amgen, Takeda; research funding: Takeda; travel, accommodations, expenses: Celgen, AMGEN, Takeda, Abbvie, Janssen. KM: no COI AB: no COI MHä: honoraria: Novartis, Amgen, Roche, Takeda; consulting or advisory role: Celgene. CJ: honoraria: Janssen, Celgene, Takeda; consulting or advisory role: Janssen, Amgen, Celgene, Takeda, Sanofi; travel, accommodations, expenses: Janssen, Takeda, Celgene, Amgen, Novartis EKM: honoraria: Janssen, Celgene, Takeda, GSK; consulting or advisory role: Janssen, Celgene, Takeda, GSK; research funding: Takeda; travel, accomodations, expenses: Janssen, Takeda, Celgene, Onyx, BMS, Mundipharma. UB: no COI IWB: research funding: Celgene, BMS, Janssen. CS: honoraria: BMS, Janssen, Celgene, Novartis, Amgen, Takeda; consulting or advisory role: BMS, Janssen, Celgene, Novartis, Amgen, Takeda; speakers bureau: Takeda; research funding: Takeda, Novartis; travel, accommodations, expenses: BMS, Janssen, Celgene, Novartis, Amgen, Takeda. DH: consulting or advisory role: I. Lamkap Bio AG. Discoveric AG; research funding: Celgene AG. Sanofi. Engmab AG; travel, accommodations, expenses: Celgene. AS: consulting or advisory role: I. Lamkap Bio AG. Discoveric AG; research funding: Celgene AG. Sanofi. Engmab AG. AJ: no COI MSR: consulting or advisory role, travel support: BMS, Amgen, Incyte, Takeda, Novartis, Janssen, AbbVie, Sanofi, Roche; Research Funding: Amgen, Novartis, Sanofi SPL: no COI BB: honoraria: Janssen-Cilag, GSK, Takeda. MMu: honoraria: Janssen, BMS, Takeda, Celgene, Amgen, GSK, Sanofi-Genzyme; consulting or advisory role: Janssen, BMS, Takeda, Celgene, Amgen, GSK; research funding: BMS, Incyte; travel, accomodations, expenses: Janssen, BMS, Takeda, Amgen. PB: consulting or advisory role: BMS, AMGEN, Roche, MSD; research funding: BMS; travel, accommodations, expenses: BMS. SF: consulting or advisory role: Amgen, BMS, Celgene, Sanofi, Janssen. H-WL: no COI KW: Grants from Amgen, Celgene, Sanofi, Janssen (all to the institution), honoraria and advisory board from Amgen, BMS, Celgene, Adaptive Biotech, Janssen, GSK, Karyopharm, Roche, Sanofi, Takeda, Oncopeptides. JD: consulting or advisory role: Celgene; speakers bureau: Celgene; travel, accommodations, expenses: Celgene. HG: Grants and/or provision of Investigational Medicinal Product: Amgen, BMS, Celgene, Chugai, Dietmar-Hopp-Foundation, Janssen, Johns Hopkins University, Sanofi. Research Support: Amgen, BMS, Celgene, Chugai, Janssen, Incyte, Molecular Partners, Merck Sharp and Dohme (MSD), Sanofi, Mundipharma GmbH, Takeda, Novartis. Advisory Boards: Adaptive Biotechnology, Amgen, BMS, Celgene, Janssen, Sanofi, Takeda. Honoraria: Amgen, BMS, Celgene, Chugai, GlaxoSmithKline (GSK), Janssen, Novartis, Sanofi.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Salwender, H., Elmaagacli, A., Merz, M. et al. Long-term follow-up of subcutaneous versus intravenous bortezomib during induction therapy for newly diagnosed multiple myeloma treated within the GMMG-MM5 Phase III Trial. Leukemia 35, 3007–3011 (2021). https://doi.org/10.1038/s41375-021-01298-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-021-01298-y

This article is cited by

Search

Advanced search

Quick links