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Multiple myeloma long-term survivors exhibit sustained immune alterations decades after first-line therapy

Author

Listed:
  • Raphael Lutz

    (Heidelberg University Hospital
    Oncology Center Speyer
    Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
    German Cancer Research Center (DKFZ) and DKFZ–ZMBH Alliance)

  • Florian Grünschläger

    (Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
    German Cancer Research Center (DKFZ) and DKFZ–ZMBH Alliance
    Heidelberg University)

  • Malte Simon

    (Heidelberg University
    German Cancer Research Center (DKFZ)
    Leibniz Institute for Immunotherapy (LIT))

  • Mohamed H. S. Awwad

    (Heidelberg University Hospital)

  • Marcus Bauer

    (Martin Luther University Halle-)

  • Schayan Yousefian

    (Berlin Institute of Health (BIH) at Charité Universitätsmedizin
    Max Delbrück Center for Molecular Medicine in the Helmholtz Association
    Charité Universitätsmedizin)

  • Niklas Beumer

    (Heidelberg University
    German Cancer Research Center (DKFZ)
    DKFZ-Hector Cancer Institute at the University Medical Center Mannheim
    University of Heidelberg)

  • Lea Jopp-Saile

    (Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
    German Cancer Research Center (DKFZ) and DKFZ–ZMBH Alliance
    Heidelberg University
    Max Delbrück Center for Molecular Medicine in the Helmholtz Association)

  • Anastasia Sedlmeier

    (National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ))

  • Llorenç Solé-Boldo

    (Berlin Institute of Health (BIH) at Charité Universitätsmedizin
    Max Delbrück Center for Molecular Medicine in the Helmholtz Association
    Charité Universitätsmedizin)

  • Bogdan Avanesyan

    (Berlin Institute of Health (BIH) at Charité Universitätsmedizin
    Max Delbrück Center for Molecular Medicine in the Helmholtz Association
    Charité Universitätsmedizin)

  • Dominik Vonficht

    (Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
    German Cancer Research Center (DKFZ) and DKFZ–ZMBH Alliance
    Heidelberg University)

  • Patrick Stelmach

    (Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
    German Cancer Research Center (DKFZ) and DKFZ–ZMBH Alliance)

  • Georg Steinbuss

    (Heidelberg University Hospital)

  • Tobias Boch

    (Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
    German Cancer Research Center (DKFZ) and DKFZ–ZMBH Alliance
    University Hospital Mannheim)

  • Simon Steiger

    (German Cancer Research Center (DKFZ) and BioQuant)

  • Marc-Andrea Baertsch

    (Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • Nina Prokoph

    (Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • Karsten Rippe

    (German Cancer Research Center (DKFZ) and BioQuant)

  • Brian G. M. Durie

    (Cedars-Sinai Medical Center)

  • Claudia Wickenhauser

    (Martin Luther University Halle-)

  • Andreas Trumpp

    (Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
    German Cancer Research Center (DKFZ) and DKFZ–ZMBH Alliance)

  • Carsten Müller-Tidow

    (Heidelberg University Hospital
    Molecular Medicine Partnership Unit EMBL and University Hospital Heidelberg)

  • Daniel Hübschmann

    (Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
    National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ)
    German Cancer Research Center (DKFZ))

  • Niels Weinhold

    (Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • Marc S. Raab

    (Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • Benedikt Brors

    (German Cancer Research Center (DKFZ)
    Heidelberg University
    National Center for Tumor Diseases (NCT)
    Core Center Heidelberg)

  • Hartmut Goldschmidt

    (Heidelberg University Hospital)

  • Charles D. Imbusch

    (German Cancer Research Center (DKFZ)
    University Medical Center Mainz
    University Medical Center Mainz
    Partner Site Frankfurt/Mainz)

  • Michael Hundemer

    (Heidelberg University Hospital)

  • Simon Haas

    (Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
    German Cancer Research Center (DKFZ) and DKFZ–ZMBH Alliance
    Berlin Institute of Health (BIH) at Charité Universitätsmedizin
    Max Delbrück Center for Molecular Medicine in the Helmholtz Association)

Abstract

The long-term consequences of cancer and its therapy on the patients’ immune system years after cancer-free survival remain poorly understood. Here, we present an in-depth characterization of the bone marrow immune ecosystem of multiple myeloma long-term survivors, from initial diagnosis up to 17 years following a single therapy line and cancer-free survival. Using comparative single-cell analyses combined with molecular, genomic, and functional approaches, we demonstrate that multiple myeloma long-term survivors exhibit pronounced alterations in their bone marrow microenvironment associated with impaired immunity. These immunological alterations were frequently linked to an inflammatory immune circuit fueled by the long-term persistence or resurgence of residual myeloma cells. Notably, even in the complete absence of any detectable residual disease for decades, sustained changes in the immune system were observed, suggesting an irreversible ‘immunological scarring’ caused by the initial exposure to the cancer and therapy. Collectively, our study provides key insights into the molecular and cellular bone marrow ecosystem of long-term survivors of multiple myeloma, revealing both reversible and irreversible alterations in the immune compartment.

Suggested Citation

  • Raphael Lutz & Florian Grünschläger & Malte Simon & Mohamed H. S. Awwad & Marcus Bauer & Schayan Yousefian & Niklas Beumer & Lea Jopp-Saile & Anastasia Sedlmeier & Llorenç Solé-Boldo & Bogdan Avanesya, 2024. "Multiple myeloma long-term survivors exhibit sustained immune alterations decades after first-line therapy," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54543-0
    DOI: 10.1038/s41467-024-54543-0
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    References listed on IDEAS

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