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The induction strategies administered in the treatment of multiple myeloma exhibit a deleterious effect on the endothelium

Bone Marrow Transplantation volume 55, pages 2270–2278 (2020)Cite this article

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Abstract

Multiple myeloma induction treatment includes proteasome inhibitors (PI) and immunomodulatory agents at present. The incidence of engraftment syndrome, a transplant complication potentially related to endothelium, has increased in the last years. Our aim was to investigate whether bortezomib (Velcade, V), thalidomide (T), and dexamethasone (D) affect the endothelium, and explore defibrotide (DF) as protective agent. Endothelial cells (ECs) in culture were exposed to the compounds separately or in combination, without (VTD) and with DF (VTD + DF). Changes in markers of: (i) inflammation (ICAM-1 expression and leukocyte adhesion), (ii) VWF production, (iii) cell permeability (VE-cadherin expression and cell monolayer integrity), and (iv) oxidative stress (ROS production and eNOS expression) were measured. ICAM-1 and VWF expression increased significantly in VTD but were similar to controls in VTD + DF. Separately, bortezomib was the main deleterious agent whereas dexamethasone showed no harmful effect. Leukocyte adhesion showed similar trends. VE-cadherin expression was lower in VTD and normalized in VTD + DF. EC permeability increased only with bortezomib. No changes were observed in oxidative stress markers. Our results demonstrate that bortezomib damages the endothelium, and DF prevents this effect. A better knowledge of the induction drugs impact will allow the design of measures to protect the endothelium.

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Fig. 1: Expression of ICAM-1 on ECs exposed to the study compounds in combination, in the absence and presence of DF, and individually.
Fig. 2: Leukocyte attachment on EC monolayers exposed to the study compounds in combination, in the absence and presence of DF, and individually.
Fig. 3: Expression of VWF on ECs exposed to the study compounds in combination, in the absence and presence of DF, and individually.
Fig. 4: Expression of VE-cadherin on ECs exposed to the study compounds in combination, in the absence and presence of DF, and individually.
Fig. 5: Bar diagrams represent data corresponding to the oxidative stress experiments.

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Acknowledgements

We thank the Primary Hemostasis Laboratory staff (Hospital Clinic, Barcelona) for technical support, and Dr Urooj Zafar for his constructive comments.

Funding

Study partially supported by Jazz Pharmaceuticals (IST-16-10355); German José Carreras Leukaemia Foundation (Grant 03 R/2019); Instituto de Salud Carlos III, Spanish Government (PIE15/00027, DTS16/00133, and FIS PI19/00888), and Generalitat de Catalunya (2017-SGR675, CERCA).

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Authors and Affiliations

  1. Josep Carreras Leukaemia Research Institute, Hospital Clinic de Barcelona, Universitat de Barcelona, Barcelona, Spain

    Julia Martinez-Sanchez, Marta Palomo & Enric Carreras

  2. Hematopathology, Department of Pathology, Centre de Diagnostic Biomedic (CDB), Hospital Clinic de Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain

    Julia Martinez-Sanchez, Marta Palomo, Sergi Torramade-Moix, Ana Belen Moreno-Castaño, Gines Escolar & Maribel Diaz-Ricart

  3. Barcelona Endothelium Team, Barcelona, Spain

    Julia Martinez-Sanchez, Marta Palomo, Enric Carreras & Maribel Diaz-Ricart

  4. Stem Cell Transplantation Unit, IDIBAPS, Hospital Clinic de Barcelona, Universitat de Barcelona, Barcelona, Spain

    Montserrat Rovira, Gonzalo Gutiérrez-García, Francesc Fernández-Avilés & Laura Rosiñol

  5. Hematology, Oncology and Tumor Immunology Department, Charité Universitätsmedizin Berlin, Berlin, Germany

    Olaf Penack

  6. Berlin-Brandenburg Center for Regenerative Therapies, Berlin, Germany

    Olaf Penack

  7. Berlin Institute of Health, Berlin, Germany

    Olaf Penack

  8. Amyloidosis and Multiple Myeloma/AL Unit, Department of Hematology, Hospital Clinic de Barcelona, Universitat de Barcelona, Barcelona, Spain

    Laura Rosiñol

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Contributions

JM-S designed and conducted the experiments, analyzed the results, designed the images, and wrote the manuscript. MP contributed to the design and conducted the experiments, analyzed the results, and reviewed the manuscript. ST-M participated in the experiments, cell culture maintenance, and figures. ABM-C, MR, GG-G, FF-A, GE, OP, and LR reviewed results and manuscript. EC and MD-R designed, supervised, and reviewed the study, results, and manuscript.

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Correspondence to Maribel Diaz-Ricart.

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Conflict of interest

Research partially supported by Jazz Pharmaceuticals plc/Gentium Inc. MP received speaker’s fees from Jazz Pharmaceuticals. GG-G received a grant from Pfizer and Gilead. GE, OP, EC, and MD-R received research funding and speaker’s fees from Jazz Pharmaceuticals. LR received honoraria from Janssen, Celgene, Amgen, and Takeda. The other authors declare that they have no conflict of interest.

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Martinez-Sanchez, J., Palomo, M., Torramade-Moix, S. et al. The induction strategies administered in the treatment of multiple myeloma exhibit a deleterious effect on the endothelium. Bone Marrow Transplant 55, 2270–2278 (2020). https://doi.org/10.1038/s41409-020-0947-9

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