Complement as the enabler of carfilzomib‐induced thrombotic microangiopathy

Abstract

Summary 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.

Thrombotic microangiopathy in untreated myeloma patients receiving carfilzomib, cyclophosphamide and dexamethasone on the CARDAMON study

“…Since atypical HUS (aHUS) is characterised by the same triad of intravascular haemolysis, thrombocytopenia and AKI, this has led to several published reports of carfilzomib-induced aHUS. [22][23][24] Complement levels, including C3 and C4, were generally normal. However, some patients were found to be heterozygous for CFHR3-CFHR1 deletions on genetic testing 21 and one had an elevated Bb fragment level with elevation in the soluble membrane attack complex (C5b-9) on a TMA functional panel, reflecting alternate pathway complement activation.…”

“…Drug induced (DI)-TMA secondary to carfilzomib is a recently recognised complication, with 30 cases identified in the literature, 11,[13][14][15][16][17][18][19][20][21][22][23][24] six published as stand-alone case reports [14][15][16][17]18,20,23 and the rest described within six case series 11,13,19,21,22,24 (Table I). Most patients (28/30) were treated for RRMM having previously received 1-5 lines of therapy.…”

“…However, evidence of therapeutic benefit shown by normalisation of haematological parameters, improvement in renal function and reduced hospital stays remains limited to anecdotal reports. 24 PI-induced vascular endothelial growth factor (VEGF) inhibition 16 was also frequently suggested, whereby PIs downregulate key angiogenic factors including VEGF, either via p53 accumulation (VEGF mRNA expression depends on cellular levels of p53), 18 or through the inactivation of NF-kB. 16 This is consistent with carfilzomib's well-known cardiorenal effects causing HT, reversible rise in creatinine and common acute rise in N-terminal pro-brain natriuretic peptide (NT-proBNP) in the absence of structural cardiomyopathy.…”

“…This correlates well with other reported cases, whereby the cornerstone of clinical management was stopping carfilzomib together with supportive care, which often involved renal replacement therapy. TPE was employed in eight case series, 13,14,16,18,19,21,22,24 at times with high-dose prednisolone (Table I) and this was, similarly, the mainstay therapeutic strategy in our patient population where empirical TPE was given in 7/8. As with other types of secondary TMA, the role of TPE in the treatment of DI-TMA with ADAMTS13 activity levels >50% is unclear, with no strong evidence of faster resolution or improved treatment outcomes.…”

Weekly carfilzomib plus cyclophosphamide and dexamethasone in the treatment of relapsed/refractory multiple myeloma: Final results from the MCRN‐003/MYX.1 single arm phase II trial

“…This feature has been reported in other studies with carfilzomib although the true incidence is not known. The etiology remains unknown although may be related to complement activation with a possible genetic predisposition 39,40 . Further study is required to mitigate this risk and, similar to the cardio‐toxicity, is necessary to ensure optimal use of the drug going forward.…”