Complement as the enabler of carfilzomib-induced thrombotic microangiopathy

Br J Haematol. 2021 Apr;193(1):181-187. doi: 10.1111/bjh.16796. Epub 2020 May 29.

Abstract

Carfilzomib has been associated with the development of thrombotic microangiopathy (TMA) in relapsed/refractory multiple myeloma patients, a severe disease with no currently available aetiological treatment. We evaluated the potential role of terminal complement pathway in four patients with carfilzomib-induced TMA. Membrane attack complex (C5b-9) deposition on endothelial cells in culture exposed to plasma from patients during the acute phase of the disease suggests complement overactivation as a mechanism of potential endothelial damage in three out of four patients. If confirmed in larger cohorts, C5b-9 evaluation will allow early identification of patients who could benefit from complement blockade and treatment monitoring.

Keywords: C5b-9 deposits; carfilzomib; drug-induced thrombotic microangiopathy; eculizumab; endothelial cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Complement Membrane Attack Complex / adverse effects
  • Complement Membrane Attack Complex / metabolism
  • Complement System Proteins / drug effects*
  • Complement System Proteins / metabolism
  • Endothelial Cells / immunology
  • Endothelial Cells / metabolism
  • Female
  • Humans
  • Male
  • Middle Aged
  • Multiple Myeloma / complications
  • Multiple Myeloma / drug therapy*
  • Oligopeptides / adverse effects*
  • Oligopeptides / therapeutic use
  • Prospective Studies
  • Proteasome Inhibitors / adverse effects
  • Proteasome Inhibitors / therapeutic use
  • Thrombotic Microangiopathies / chemically induced*
  • Thrombotic Microangiopathies / drug therapy
  • Thrombotic Microangiopathies / etiology
  • Thrombotic Microangiopathies / metabolism
  • Ubiquitin / antagonists & inhibitors*
  • Ubiquitin / metabolism

Substances

  • Antibodies, Monoclonal, Humanized
  • Complement Membrane Attack Complex
  • Oligopeptides
  • Proteasome Inhibitors
  • Ubiquitin
  • carfilzomib
  • Complement System Proteins
  • eculizumab