Carfilzomib-associated thrombotic microangiopathy: clinical features and outcomes

Abstract

Background: Carfilzomib, a new proteasome inhibitor indicated for patients with relapsed/refractory myeloma, has been associated with cases of thrombotic microangiopathy (CFZ-TMA). The role of variants in the complement alternative pathway and therapeutic potential of complement blockade with eculizumab remain to be determined.

Methods: We report 37 cases of CFZ-TMA recorded in the French reference center for TMA with their clinical characteristics, genetic analysis and outcome according to treatments.

Results: A trigger was identified in more than half of cases, including eight influenza and five severe acute respiratory syndrome coronavirus-2 cases. All patients presented with acute kidney injury (AKI) [KDIGO stage 3 in 31 (84%) patients] while neurological (n = 13, 36%) and cardiac (n = 7, 19%) damage were less frequent. ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I repeats-13) and complement activity were normal (n = 28 and 18 patients tested) and no pathogenic variant in the alternative complement pathway was found in 7 patients tested. TMA resolved in most (n = 34, 94%) patients but 12 (44%) still displayed stage 3 AKI at discharge. Nineteen (51%) patients were treated with therapeutic plasma exchange, 14 (38%) patients received corticosteroids and 18 (50%) were treated with eculizumab. However, none of these treatments demonstrated a significant impact on outcomes.

Conclusion: This study is the largest case series of CFZ-TMA since its approval in 2012. Patients present with severe AKI and experience frequent sequelae. Complement variants and blockade therapy do not seem to play a role in the pathophysiology and prognosis of the disease.

Keywords: carfilzomib; complement; eculizumab; myeloma; thrombotic microangiopathy.