Carfilzomib-Induced Thrombotic Microangiopathy: Focus on Pathogenesis

Abstract

Drug-induced thrombotic microangiopathies present in similar fashion but have varied pathogenic mechanisms. Carfilzomib is an irreversible proteasome inhibitor. Since its initial approval as a single agent for the treatment of relapsed or refractory multiple myeloma in 2012, there have been increasing reports of carfilzomib-induced thrombotic microangiopathy. However, the mechanism of this disease process is not fully understood. Without treatment, there is a high likelihood of end-organ damage, especially in the kidneys, and death. In recent reports, the lifesaving role of eculizumab, a terminal complement inhibitor, in managing and further preventing end-stage renal disease has been described. In this article, we present a case of carfilzomib-induced thrombotic microangiopathy in a patient with multiple myeloma and discuss the pathogenesis of thrombotic microangiopathy in this setting.

Carfilzomib, thalidomide, and dexamethasone is safe and effective in relapsed and/or refractory multiple myeloma: final report of the single arm, multicenter phase II ALLG MM018/AMN002 study.

“… 10 , 14 , 30 Another adverse event of special interest, carfilzomib-induced thrombotic thrombocytopenic purpura, while rare has been reported in association with carfilzomib previously. 31 Both of our patients who developed this adverse event were Asian and developed a non-immune thrombocytopenia with a nadir platelet count of <30x10 9 /L, blood film features of microangiopathic hemolysis with red cell fragmentation, and ADAMTS-13 levels >10%, thus excluding a diagnosis of de novo thrombotic thrombocytopenic purpura. Both were on the 56 mg/m 2 dose, developed features early in treatment (first and third cycle) and responded to immunosuppression and plasma exchange.…”

Rediscovering hemostasis abnormalities in multiple myeloma: The new era

“…It can also be caused by proteasome inhibitors (PIs) [ 46 , 83 ]. A complex process contributing to the development of TMA caused by carfilzomib has been reported [ 115 ]. Diagnosing multiple myeloma stands as the initial risk element [ 115 ].…”

“…A complex process contributing to the development of TMA caused by carfilzomib has been reported [ 115 ]. Diagnosing multiple myeloma stands as the initial risk element [ 115 ]. Mutations in the alternate complement pathway constitute the second risk element [ 115 ].…”

“…Diagnosing multiple myeloma stands as the initial risk element [ 115 ]. Mutations in the alternate complement pathway constitute the second risk element [ 115 ]. Studies have shown that mutations in genes of the alternative complement pathway could contribute to TMA caused by carfilzomib [ 115 ].…”

Complement biology for hematologists

“…HELLP syndrome AP, TP AP activation may be involved 113 No association with genetic variant in complement AP genes 114,115 "serum levels C5a and/or sC5b-9 at diagnosis. 116 Placental deposition of C5b-9 117 Ex vivo model with " C5b-9 deposits on endothelial cells in activated plasma from HELLP patients [118][119][120][121] Eculizumab (anti-C5) (phase 1) (NCT04103489) Cases reports 122 and cases series 123…”