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.

  • Brief Communication
  • Published:

Multiple myeloma gammopathies

Bortezomib-based induction therapy with high or low-dose dexamethasone in newly diagnosed, transplant-eligible multiple myeloma

Leukemia volume 33, pages 258–261 (2019)Cite this article

Subjects

The advent of novel agents in the treatment of multiple myeloma (MM) improved disease control, survival and reduced toxicities. However, as demonstrated by the study from Rajkumar et al. [1], accompanying steroid therapy is also of critical importance in newly diagnosed MM (NDMM). In their phase III trial, Rajkumar et al. Compared lenalidomide (LEN) with either high (40 mg on days 1–4, 9–12, 17–20; 480 mg per cycle) or low (40 mg on days 1, 8, 15, 22; 160 mg per cycle) dose dexamethasone (DEX) in both transplant-eligible and -ineligible NDMM. The trial was stopped prematurely after one year due to a significant difference in overall survival (OS), favoring the low-dose DEX arm (96 vs. 87%, p < 0.001). This difference was caused by an increased rate in early mortality and toxicities grade ≥ 3 (mainly infections, deep vein thrombosis, and fatigue) within the first four months in the high-dose DEX arm (early deaths: 12 vs. 1, p = 0.003; grade ≥ 3 toxicity: 52 vs. 35%, p < 0.001) [1]. To date, no comparison of high vs. low DEX doses has been performed in transplant-eligible NDMM receiving the proteasome inhibitor (PI) bortezomib (BTZ), which is widely applied during induction therapy (IT) prior to stem cell collection and high-dose therapy (HDT).

Therefore, our present analysis retrospectively compared IT regimens from two subsequently conducted multicenter phase III trials applying BTZ (1.3 mg/m2 on days 1, 4, 8, 11) and doxorubicine (DOXO, 9 mg/m2 on days 1–4) with either high-dose DEX (hd-PAD, 40 mg on days 1–4, 9–12, 17–20; 480 mg per cycle) as applied in the German-speaking Myeloma Multicenter Group (GMMG) HD4 trial (05/2005-05/2008, n = 192, EudraCT No. 2004-000944-26) vs. low-dose DEX (ld-PAD, 20 mg on days 1–4, 9–12, 17–20; 240 mg per cycle, EudraCT No. 2010-019173-16) as applied in the subsequent GMMG MM5 trial (07/2010-11/2013, n = 111). Primary endpoints for these trials have been published previously [2, 3]. The trials were conducted in accordance with the European Clinical Trial Directive, the Declaration of Helsinki and local ethics committees. The maximum age for inclusion was different between the trials (HD4: 65 years vs. MM5: 70 years). Therefore, we included only patients up to 65 years in the MM5 ld-PAD group. BTZ was administered intravenously (IV) in the HD4 trial. In the MM5 trial, the route of administration of BTZ was changed from IV to subcutaneous (SC) in 02/2012. Since SC BTZ resulted in lower overall adverse events (AE), peripheral neuropathy (PN), gastrointestinal and metabolic/nutritional AE compared to IV BTZ [4], only patients receiving IV BTZ were included in the ld-PAD group (MM5) for the current analysis.

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

References

  1. Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11:29–37.

    Article  CAS  Google Scholar 

  2. Goldschmidt H, Lokhorst HM, Mai EK, van der Holt B, Blau IW, Zweegman S, et al. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2017. https://doi.org/10.1038/leu.2017.211.

  3. 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. https://doi.org/10.1038/leu.2015.80.

  4. 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 

  5. Neben K, Lokhorst HM, Jauch A, Bertsch U, Hielscher T, van der Holt B, et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012;119:940–8.

    Article  CAS  Google Scholar 

  6. Vesole D, Oken M, Heckler C, Greipp P, Katz M, Jacobus S, et al. Oral antibiotic prophylaxis of early infection in multiple myeloma: a URCC/ECOG randomized phase III study. Leukemia. 2012;26:2517–20.

    Article  CAS  Google Scholar 

  7. Drayson MT, Bowcock S, Planche T, Iqbal G, Wood J, Raynes K, et al. Tackling early morbidity and mortality in myeloma (TEAMM): assessing the benefit of antibiotic prophylaxis and its effect on healthcare associated infections in 977 patients. Blood. 2017;130:903.

    Article  Google Scholar 

Download references

Acknowledgements

The GMMG-HD4 trial was supported by the German Federal Ministry of Education and Research (BMBF), Janssen-Cilag-Ortho Biotech, Novartis, Amgen, Chugai, and Roche. The GMMG-MM5 trial was supported by Celgene, Janssen-Cilag, Chugai and The Binding Site.

Author information

Authors and Affiliations

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

    Elias K. Mai, Uta Bertsch, Jana Schlenzka, Jens Hillengass, Marc S. Raab, Maximilian Merz, Marc-Andrea Baertsch, Dirk Hose & Hartmut Goldschmidt

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

    Thomas Hielscher

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

    Hans J. Salwender

  4. Department of Internal Medicine III, University Medical Center Mainz, Mainz, Germany

    Markus Munder

  5. Department of Hematology and Oncology, Helios Hospital Berlin Buch, Berlin, Germany

    Christian Gerecke

  6. Department of Hematology, University Clinic Essen, Essen, Germany

    Ulrich Dührsen

  7. University Hospital Bonn, Bonn, Germany

    Peter Brossart

  8. Department of Hematology and Oncology, Klinikum Baden Baden, Baden Baden, Germany

    Kai Neben

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

    Anna Jauch

  10. Department of Medicine, Hematology/Oncology, Goethe-University of Frankfurt, Frankfurt, Germany

    Hans Martin

  11. Department of Hematology and Oncology, Katholisches Krankenhaus Hagen, Hagen, Germany

    Hans-Walter Lindemann

  12. Medical Clinic, Charité University Medicine Berlin, Berlin, Germany

    Igor W. Blau

  13. Department of Internal Medicine I, University Hospital Köln, Köln, Germany

    Christof Scheid

  14. Department of Hematology, Oncology and Immunology, University Hospital Tübingen, Tübingen, Germany

    Katja C. Weisel

  15. Nationales Centrum für Tumorerkrankungen (NCT) Heidelberg, Heidelberg, Germany

    Hartmut Goldschmidt

Authors
  1. Elias K. Mai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas Hielscher
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Uta Bertsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jana Schlenzka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hans J. Salwender
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Markus Munder
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christian Gerecke
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ulrich Dührsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Peter Brossart
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kai Neben
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jens Hillengass
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Marc S. Raab
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Maximilian Merz
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Marc-Andrea Baertsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Anna Jauch
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Dirk Hose
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Hans Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Hans-Walter Lindemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Igor W. Blau
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Christof Scheid
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Katja C. Weisel
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Hartmut Goldschmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

for the German-speaking Myeloma Multicenter Group (GMMG)

Corresponding author

Correspondence to Elias K. Mai.

Ethics declarations

Conflict of interest

EKM: Janssen: honoraria, travel grant; Takeda: honoraria, travel grant, advisory board; Celgene: travel grant; Onyx: travel grant; Munidpharma: travel grant. TH: nothing to disclose. UB: Novartis: travel grant. JS: nothing to disclose. HJS: Janssen-Cilag: research funding, honraria, travel grant; Celgene: research funding, honraria, travel grant. MMu: Janssen: advisory board, travel grant; BMS: advisory board, travel grant; Celgene: advisory board; Takeda: advisory board, travel grant; Amgen: advisory board, travel grant. CG: nothing to disclose. UD: nothing to disclose. PB: nothing to disclose. KN: Janssen: advisory board, travel grant; Takeda: advisory board; Celgene: advisory board, travel grant; Boehringer Ingelheim: advisory board; Roche: advisory board; BMS: advisory board; TEVA: advisory board. JH: Amgen: consultancy, honoraria, advisory board, travel grant; Celgene: consultancy, honoraria, advisory board, travel grant; Janssen: honoraria, advisory board, travel grant; Sanofi: research funding; Novartis: honoraria, advisory board, travel grant; BMS: honoraria, travel grant; Takeda: honoraria, travel grant. MSR: Amgen: honoraria, advisory board, research funding, travel grant; Novartis: honoraria, advisory board, research funding, travel grant; Celgene: honoraria, advisory board, travel grant; Janssen: honoraria, advisory board, travel grant; BMS: honoraria, advisory board, travel grant. MMe: Takeda: research funding; Janssen: travel grant; Celgene: travel grant. M-AB: Amgen: travel grant; BMS: travel grant; Janssen: travel grant; Novartis: travel grant, honoraria, research support; Takeda: honoraria. AJ: nothing to disclose. DH: Celgene: advisory board, research funding; Engmab: advisory board, research funding; Takeda: advisory board, travel grant. HM: nothing to disclose. H-WL: nothing to disclose. SC: nothing to disclose. IWB: nothing to disclose. CS: Amgen: honoraria, advisory board, travel grant; BMS: honoraria, advisory board, travel grant; Celgene: honoraria, advisory board, travel grant; Janssen: honoraria, advisory board, travel grant; Novartis: honoraria, advisory board, travel grant; Takeda: honoraria, advisory board, travel grant. KCW: Amgen: honoraria, advisory board, research funding; BMS: honoraria, advisory board; Celgene: honoraria, advisory board, research funding; Janssen: honoraria, advisory board, research funding; Novartis: honoraria, advisory board; Takeda: honoraria, advisory board; Sanofi: research funding. HG: BMS: honoraria, advisory board, research funding, travel grant; Celgene: honoraria, advisory board, research funding, travel grant; Janssen-Cilag: honoraria, advisory board, research funding, travel grant; Novartis: honoraria, advisory board, research funding; Amgen: honoraria, advisory board, travel grant; Takeda: advisory board, travel grant; Chugai: advisory board, research funding.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mai, E.K., Hielscher, T., Bertsch, U. et al. Bortezomib-based induction therapy with high or low-dose dexamethasone in newly diagnosed, transplant-eligible multiple myeloma. Leukemia 33, 258–261 (2019). https://doi.org/10.1038/s41375-018-0195-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-018-0195-9

This article is cited by

Search

Advanced search

Quick links