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

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 Avanesyan, Dominik Vonficht, Patrick Stelmach, Georg Steinbuss, Tobias Boch, Simon Steiger, Marc-Andrea Baertsch, Nina Prokoph, Karsten Rippe, Brian G. M. Durie, Claudia Wickenhauser, Andreas Trumpp, Carsten Müller-Tidow, Daniel Hübschmann, Niels Weinhold, Marc S. Raab, Benedikt Brors (), Hartmut Goldschmidt (), Charles D. Imbusch (), Michael Hundemer () and Simon Haas ()
Additional contact information
Raphael Lutz: Heidelberg University Hospital
Florian Grünschläger: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Malte Simon: Heidelberg University
Mohamed H. S. Awwad: Heidelberg University Hospital
Marcus Bauer: Martin Luther University Halle-
Schayan Yousefian: Berlin Institute of Health (BIH) at Charité Universitätsmedizin
Niklas Beumer: Heidelberg University
Lea Jopp-Saile: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
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
Bogdan Avanesyan: Berlin Institute of Health (BIH) at Charité Universitätsmedizin
Dominik Vonficht: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Patrick Stelmach: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Georg Steinbuss: Heidelberg University Hospital
Tobias Boch: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Simon Steiger: German Cancer Research Center (DKFZ) and BioQuant
Marc-Andrea Baertsch: Heidelberg University Hospital
Nina Prokoph: Heidelberg University Hospital
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)
Carsten Müller-Tidow: Heidelberg University Hospital
Daniel Hübschmann: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Niels Weinhold: Heidelberg University Hospital
Marc S. Raab: Heidelberg University Hospital
Benedikt Brors: German Cancer Research Center (DKFZ)
Hartmut Goldschmidt: Heidelberg University Hospital
Charles D. Imbusch: German Cancer Research Center (DKFZ)
Michael Hundemer: Heidelberg University Hospital
Simon Haas: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54543-0

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