Endothelial injury and dysfunction with emerging immunotherapies in multiple myeloma, the impact of COVID-19, and endothelial protection with a focus on the evolving role of defibrotide.

Patients with multiple myeloma (MM) were among the groups impacted more severely by the COVID-19 pandemic, with higher rates of severe disease and COVID-19-related mortality. MM and COVID-19, plus post-acute sequelae of SARS-CoV-2 infection, are associated with endothelial dysfunction and injury, with overlapping inflammatory pathways and coagulopathies. Existing treatment options for MM, notably high-dose therapy with autologous stem cell transplantation and novel chimeric antigen receptor (CAR) T-cell therapies and bispecific T-cell engaging antibodies, are also associated with endothelial cell injury and mechanism-related toxicities. These pathologies include cytokine release syndrome (CRS) and neurotoxicity that may be exacerbated by underlying endotheliopathies. In the context of these overlapping risks, prophylaxis and treatment approaches mitigating the inflammatory and pro-coagulant effects of endothelial injury are important considerations for patient management, including cytokine receptor antagonists, thromboprophylaxis with low-molecular-weight heparin and direct oral anticoagulants, and direct endothelial protection with defibrotide in the appropriate clinical settings.
Competing Interests: Declaration of competing interest C.C.M.: Advisory boards for AbbVie, Bristol Myers Squibb, GSK, Janssen, Karyopharm, Sanofi, and Takeda; consultancy for AbbVie, Janssen, Karyopharm, and Sanofi. E.R.: None. E.C.: None. F.C.: None. M.H.K.: Grants to institution for clinical trials from Bristol Myers Squibb/Celgene, Janssen, AbbVie, Arcellx/Kite, Roche and Poseida Therapeutics. R.M.B.: None. J.M.C.: Consulting and scientific advisory boards for Abbott, Anthos, Bristol Myers Squibb, Roche, Sanofi, and Werfen; research funding to the institution from CSL Behring. M.I.: None. L.-J.W.: None. A.P.R.: None. M.D.-R.: Speaker fees from Jazz Pharmaceuticals and research funding to institution from Novartis Spain, CSL Behring, and Sysmex Europe GmbH. J.M.M.: Research support from Pfizer, Gilead, Novartis, Bristol Myers Squibb, Amgen, and Roche, and advisory committees for Rocket Pharma, Jazz Pharma, Novartis, Gilead, and Sandoz. C.C.-S.: Consultancy with Sanofi, membership of the board of directors, speakers bureau, or advisory committee for ADC Therapeutics SA, Bristol Myers Squibb, Celgene, Karyopharm, Roche, and Sanofi; research funding from ADC Therapeutics SA, Roche, and Sanofi; honoraria from ADC Therapeutics SA, AstraZeneca, Bristol Myers Squibb, Incyte, Janssen Oncology, and Takeda. P.G.R.: Grants to institution for clinical trials from Bristol Myers Squibb / Celgene, Karyopharm, and Oncopeptides; advisory committees for Bristol Myers Squibb / Celgene, GSK, Karyopharm, Oncopeptides, Adaptive Biotechnologies, and Sanofi.
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