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Multiple myeloma gammopathies

Salvage autologous transplant and lenalidomide maintenance vs. lenalidomide/dexamethasone for relapsed multiple myeloma: the randomized GMMG phase III trial ReLApsE

Leukemia volume 35, pages 1134–1144 (2021)Cite this article

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Abstract

The role of salvage high-dose chemotherapy and autologous stem cell transplantation (sHDCT/ASCT) for relapsed and/or refractory multiple myeloma (RRMM) in the era of continuous novel agent treatment has not been defined. This randomized, open-label, phase III, multicenter trial randomized patients with 1st–3rd relapse of multiple myeloma (MM) to a transplant arm (n = 139) consisting of 3 Rd (lenalidomide 25 mg, day 1–21; dexamethasone 40 mg, day 1, 8, 15, and 22; 4-week cycles) reinduction cycles, sHDCT (melphalan 200 mg/m2), ASCT, and lenalidomide maintenance (10 mg/day) or to a control arm (n = 138) of continuous Rd. Median PFS was 20.7 months in the transplant and 18.8 months in the control arm (HR 0.87; 95% CI 0.65–1.16; p = 0.34). Median OS was not reached in the transplant and 62.7 months in the control arm (HR 0.81; 95% CI 0.52–1.28; p = 0.37). Forty-one patients (29%) did not receive the assigned sHDCT/ASCT mainly due to early disease progression, adverse events, and withdrawal of consent. Multivariate landmark analyses from the time of sHDCT showed superior PFS and OS (p = 0.0087/0.0057) in patients who received sHDCT/ASCT. Incorporation of sHDCT/ASCT into relapse treatment with Rd was feasible in 71% of patients and did not significantly prolong PFS and OS on ITT analysis while patients who received sHDCT/ASCT may have benefitted.

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Fig. 1: CONSORT diagram.
Fig. 2: Progression-free survival (PFS) and overall survival (OS) in the intention-to-treat population.
Fig. 3: Progression-free (PFS) and overall survival (OS) landmark analysis from high-dose chemotherapy (HDCT; transplant arm) and Rd cycle 5 (control arm).

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Acknowledgements

The trial was designed and conducted by the German Myeloma Multicenter Group (GMMG). We thank all investigators, study nurses, research staff, the coordination centers for clinical trials (KKS) in Heidelberg and Leipzig, and—most importantly—the participating patients and their families. Furthermore we thank the Dietmar Hopp-Stiftung, Celgene, Chugai, and Amgen for their support of the trial.

Author information

Author notes

  1. These authors contributed equally: Hartmut Goldschmidt, Marc-Andrea Baertsch

Authors and Affiliations

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

    Hartmut Goldschmidt, Marc-Andrea Baertsch, Jana Schlenzka, Marc-Steffen Raab, Jens Hillengass, Sandra Sauer, Carsten Müller-Tidow, Dirk Hose & Anja Seckinger

  2. National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany

    Hartmut Goldschmidt & Carsten Müller-Tidow

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

    Natalia Becker, Christina Habermehl & Thomas Hielscher

  4. Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center, Heidelberg, Germany

    Marc-Steffen Raab

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

    Jens Hillengass

  6. Coordination Centre for Clinical Trials (KKS), University Hospital Heidelberg, Heidelberg, Germany

    Steffen Luntz

  7. Institute for Human Genetics, University of Heidelberg, Heidelberg, Germany

    Anna Jauch

  8. Department of Oncology, Hematology, Immuno-Oncology and Rheumatology, Med. Klinik und Poliklinik III, University Hospital Bonn, Bonn, Germany

    Peter Brossart

  9. Department of Hematology, Oncology and Palliative Care, Community Hospital Bielefeld, Bielefeld, Germany

    Martin Goerner

  10. Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany

    Stefan Klein

  11. Clinic for Hematology and Stem Cell Transplantation, Helios-Hospital Berlin Buch, Berlin, Germany

    Martin Schmidt-Hieber

  12. Clinic for Hematology and Oncology, Carl-Thiem Klinikum Cottbus, Cottbus, Germany

    Martin Schmidt-Hieber

  13. Department of Hematology, Oncology and Stem Cell Transplantation, Evangelisches Krankenhaus Essen-Werden gGmbH, Essen, Germany

    Peter Reimer

  14. Department of Hematology, Oncology and Gastroenterology, Kliniken Maria Hilf GmbH, Mönchengladbach, Germany

    Ullrich Graeven

  15. Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Duesseldorf, Germany

    Roland Fenk

  16. Department of Hematology, Oncology and Stem Cell Transplantation, Klinikum Chemnitz GmbH, Chemnitz, Germany

    Mathias Haenel

  17. Department of Hematology and Oncology, Goethe University, Frankfurt, Germany

    Hans Martin

  18. Department of Hematology and Oncology, Kath. Krankenhaus Hagen gem. GmbH, Hagen, Germany

    Hans W. Lindemann

  19. Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany

    Christoph Scheid

  20. Internal Medicine III, Charité Campus Benjamin Franklin, Berlin, Germany

    Axel Nogai

  21. Asklepios Tumorzentrum Hamburg, AK Altona and AK St. Georg, Hamburg, Germany

    Hans Salwender

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

    Richard Noppeney

  23. Department of Hematology, Oncology and Immunology, University of Tuebingen, Tuebingen, Germany

    Britta Besemer

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

    Katja Weisel

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  1. Hartmut Goldschmidt
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Consortia

for the German Myeloma Multicenter Group (GMMG)

Contributions

HG designed the trial and HG, MAB, JS, NB, CH and TH analyzed the data. HG, MAB, JS, MSR, JH, AJ, PB, MG, SK, MS-H, PR, UG, RF, MH, HM, HWL, CS, AN, HS, RN, and KW collected data. MAB wrote and all co-authors revised and approved the article.

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Correspondence to Hartmut Goldschmidt.

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Conflict of interest

HG—Amgen: consultancy, research funding; Novartis: honoraria, research funding; ArtTempi: honoraria; Janssen: consultancy, honoraria, research funding; Sanofi: consultancy, research funding; Mundipharma: research funding; Takeda: consultancy, research funding; Celgene: consultancy, honoraria, research funding; Bristol-Myers Squibb: consultancy, honoraria, research funding; Adaptive Biotechnology: consultancy; Chugai: honoraria, research funding. MAB—Takeda: consultancy, honoraria; Novartis: consultancy, research funding. Travel support: Celgene, Amgen, and Janssen. M-SB: Celgene: consultancy, honoraria; Novartis: consultancy, honoraria, research funding; BMS: consultancy, honoraria, research funding; Amgen: consultancy, honoraria, research funding. JH—Janssen: honoraria, advisory board; Amgen: advisory board; BMS: honoraria, advisory board, research funding; Oncotracker: advisory board; Adaptive Biotech: advisory board; GSK: advisory board. Celgene: consultancy, honoraria, Other: advisory board, research funding. CM-T—research funding: Pfizer, Daiichi Sankyo, BiolineRx, Bayer; advisory boards: Pfizer, Janssen. MS-H—consultancy: Celgene; financial support of educational meetings: Janssen, Takeda, Novartis, Pfizer, Roche, Vifor, Celgene. PR—Honoraria: Takeda, BMS, Roche, Celgene, Sanofi-Aventis; travel support: Celgene, Takeda, Abbvie. UG—honoraria: Sirtex, Daiichi Sankyo, Boehringer Ingelheim, Amgen, Servier, AstraZeneca; consultancy, advisory boards: Merck, BMS, Hexal, Amgen, Celgene, Johnson & Johnson, MSD; travel support: Merck, Amgen, Boehringer Ingelheim. RF—Takeda: honoraria; Bristol-Meyers Squibb: honoraria, Other: travel grant; Celgene: honoraria, Other: travel grant, research funding; Janssen: honoraria; Amgen: honoraria. MH—Novartis: honoraria; Roche: honoraria; Amgen: honoraria; Takeda: honoraria. CS—Novartis: honoraria, research funding; Takeda: honoraria, research funding; Janssen: honoraria, research funding; Celgene: honoraria; BMS: honoraria; Amgen: honoraria; GSK: honoraria. AN—honoraria: Celgene, Takeda, Amgen, Alexion, Sanofi, Janssen, BMS. Research funding: Celgene, Janssen, Takeda. Travel support: Celgene, Takeda, Alexion. HS—Celgene: honoraria, Other: travel suppport, research funding; Janssen: honoraria, Other: travel support, research funding; Novartis: honoraria, Other: travel suppport, research funding; Takeda: honoraria; Amgen: honoraria, Other: travel suppport, research funding; Bristol-Myers Squibb: honoraria, Other: travel suppport, research funding. BB—Janssen: honoraria. KW—Amgen, Celgene, Janssen, and Sanofi: research funding; Amgen, BMS, Celgene, Janssen, Takeda, Adaptive Biotech: honoraria; Amgen, Adaptive Biotech, BMS, Celgene, Janssen, Juno, Sanofi, GSK, Karyopharm and Takeda: consultancy, membership on an entity’s Board of Directors or advisory committees.

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Goldschmidt, H., Baertsch, MA., Schlenzka, J. et al. Salvage autologous transplant and lenalidomide maintenance vs. lenalidomide/dexamethasone for relapsed multiple myeloma: the randomized GMMG phase III trial ReLApsE. Leukemia 35, 1134–1144 (2021). https://doi.org/10.1038/s41375-020-0948-0

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