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Multiple myeloma gammopathies

Response-adapted lenalidomide maintenance in newly diagnosed myeloma: results from the phase III GMMG-MM5 trial

Leukemia volume 34, pages 1853–1865 (2020)Cite this article

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Abstract

The MM5 trial aimed at demonstrating a progression-free survival (PFS) difference in continued vs. response-adapted (in case of complete response, CR) lenalidomide (LEN) maintenance therapy (MT) in newly diagnosed, transplant-eligible multiple myeloma (MM). Patients were equally randomized to receive induction therapy with PAd (bortezomib/doxorubicin/dexamethasone) or VCD (bortezomib/cyclophosphamide/dexamethasone), high-dose melphalan and autologous blood stem cell transplantation, and LEN consolidation, followed by either LEN MT for a fixed duration of 2 years (LEN-2Y) or until achievement of CR (LEN-CR, intention-to-treat population n = 502): arms A1:PAd + LEN-2Y (n = 125), B1:PAd + LEN-CR (n = 126), A2:VCD + LEN-2Y (n = 126), B2:VCD + LEN-CR (n = 125). In the LEN-CR group (B1 + B2), n = 88/17.5% patients did not start or discontinued LEN MT due to CR. There was no PFS (p = 0.60, primary endpoint) nor overall survival (OS) (p = 0.15) difference between the four study arms. On pooled LEN MT strategies, OS (hazard ratio, hazard ratio [HR] = 1.42, p = 0.03) but not PFS (HR = 1.15, p = 0.20) was shorter in LEN-CR (B1 + B2) vs. LEN-2Y (A1 + A2) groups. PFS was shortened on landmark analyses from the start of LEN MT in patients being in CR in the LEN-CR group (LEN-CR vs. LEN-2Y, HR = 1.84, p = 0.02). OS from first progression was shortened in the LEN-CR vs. LEN-2Y group (HR = 1.60, p = 0.01). LEN MT should be applied beyond CR for at least 2 years.

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Fig. 1: Consort diagram of the GMMG-MM5 trial.
Fig. 2: PFS and OS from randomization.
Fig. 3: PFS and OS from the start of maintenance therapy in patients achieving CR/non-CR.
Fig. 4: PFS and OS from randomization in patients with adverse cytogenetics.
Fig. 5: Overall survival from first disease progression.

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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 (Supplementary Material 3).

Author information

Author notes

  1. These authors contributed equally: Hartmut Goldschmidt, Elias K. Mai

  2. Members of the German-speaking Myeloma Multicenter Group (GMMG) are listed at the end of the paper.

Authors and Affiliations

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

    Hartmut Goldschmidt, Elias K. Mai, Uta Bertsch, Maximilian Merz, Barbara Hügle-Dörr, Nicola Giesen, Dirk Hose, Anja Seckinger, Stefanie Huhn, Jens Hillengass & Marc S. Raab

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

    Hartmut Goldschmidt & Uta Bertsch

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

    Jan Dürig

  4. Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany

    Christof Scheid

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

    Katja C. Weisel

  6. Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Katja C. Weisel

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

    Christina Kunz, Thomas Hielscher & Diana Tichy

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

    Markus Munder

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

    Hans-Walter Lindemann

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

    Steffen Luntz & Bernhard Rabold

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

    Anna Jauch

  12. Department of Hematology and Oncology, Asklepios Hospital Hamburg St. Georg, Hamburg, Germany

    Ahmet Elmaagacli

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

    Stephan Fuhrmann

  14. University Hospital Bonn, Bonn, Germany

    Peter Brossart

  15. Department of Hematology, Oncology and Palliative Care, Klinikum Bielefeld, Bielefeld, Germany

    Martin Goerner

  16. Internal Medicine V, Klinikum Darmstadt, Darmstadt, Germany

    Helga Bernhard

  17. Medical Clinic A, Klinikum Ludwigshafen, Ludwigshafen, Germany

    Martin Hoffmann

  18. Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

    Jens Hillengass

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

    Igor W. Blau

  20. Department of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany

    Mathias Hänel

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

    Hans J. Salwender

Authors
  1. Hartmut Goldschmidt
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  2. Elias K. Mai
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Consortia

for the German-speaking Myeloma Multicenter Group (GMMG)

Contributions

Conception and design: HG, UB, CK and TH. Responsible statisticians: CK, TH and DT. Administrative support: HG, UB and SL. Provision of study materials or patients and/or collection, assembly and review of data: all authors. Data analysis and interpretation: HG, EKM, UB, MSR, TH, TD and CK. Writing of the first manuscript draft: EKM, HG, UB, CK and TH. Manuscript editing, discussion of trial data/results, and final writing: all authors. Final approval of manuscript: all authors.

Corresponding author

Correspondence to Hartmut Goldschmidt.

Ethics declarations

Conflict of interest

HG: honoraria: Amgen, BMS, Celgene, Chugai, Janssen, Novartis, Takeda; consulting or advisory role: Amgen, BMS, Celgene, Chugai, Janssen, Novartis, Takeda; speakers bureau: Amgen, BMS, Celgene, Janssen, Novartis, Takeda; research funding: Amgen, BMS, Celgene, Chugai, Janssen, Novartis, Takeda; travel, accomodations, expenses: BMS, Celgene, Janssen, Novartis, Takeda. EKM: honoraria: Janssen, Celgene, Takeda; consulting or advisory role: Janssen, Celgene, Takeda; research funding: Takeda; travel, accomodations, expenses: Janssen, Takeda, Celgene, Onyx, Mundipharma. JD: consulting or advisory role: Celgene; speakers bureau: Celgene; travel, accomodations, expenses: Celgene. 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, accomodations, expenses: BMS, Janssen, Celgene, Novartis, Amgen, Takeda. KCW: honoraria: AMGEN, BMS, Celgene, Novartis, Janssen, Takeda; consulting or advisory role: AMGEN, BMS, Celgene, Juno, Janssen, Adaptive, Sanofi, Takeda; research funding: AMGEN, Celgene, Sanofi, Janssen; CK: no COI. UB: travel, accomodations, expenses: Sanofi TH: no COI. MMe: consulting or advisory role: Amgen, Takeda; research funding: Takeda; travel, accomodations, expenses: Celgen, AMGEN, Takeda, Abbvie, Janssen. MMu: honoraria: Janssen, BMS, Takeda, Celgene, Amgen; consulting or advisory role: Janssen, BMS, Takeda, Celgene, Amgen; research funding: BMS; travel, accomodations, expenses: Janssen, BMS, Takeda, Amgen. HWL: no COI. BHD: no COI. DT: no COI. NG: consulting or advisory role: Pfizer; travel, accomodations, expenses: Celgene, BMS. DH: consulting or advisory role: I. Lamkap Bio AG. Discoveric AG; research funding: Celgene AG. Sanofi. Engmab AG; travel, accomodations, expenses: Celgene. AS: consulting or advisory role: I. Lamkap Bio AG. Discoveric AG; research funding: Celgene AG. Sanofi. Engmab AG. SH: honoraria: Janssen; travel, accomodations, expenses: Celgene. SL: no COI. AJ: no COI. AE: consulting or advisory role: Amgen; travel, accomodations, expenses: Janssen, Amgen. BR: no COI. SF: consulting or advisory role: Sanofi, BMS, Amgen. PB: consulting or advisory role: BMS, AMGEN,Roche, MSD; research funding: BMS; travel, accomodations, expenses: BMS. MG: no COI. HB: no COI. MH: honoraria: MSD. JH: honoraria: AMGEN, Janssen; research funding: Celgene; travel, accomodations, expenses: AMGEN, Janssen. MSR: honoraria: Celgene, BMS, Novartis, Janssen, Takeda; consulting or advisory role: Celgene, BMS, Novartis, Janssen, Takeda; research funding: Celgene, Novartis, AMGEN; travel, accomodations, expenses: Janssen, BMS, Takeda. IWB: research funding: Celgene, BMS, Janssen. MH: honoraria: Novartis, Amgen, Roche, Takeda; consulting or advisory role: Celgene. HJS: honoraria: Celgene, Janssen, Cilag; travel, accomodations, expenses: Celgene, Janssen, Cilag.

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Goldschmidt, H., Mai, E.K., Dürig, J. et al. Response-adapted lenalidomide maintenance in newly diagnosed myeloma: results from the phase III GMMG-MM5 trial. Leukemia 34, 1853–1865 (2020). https://doi.org/10.1038/s41375-020-0724-1

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