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

Camilleri, M; Cuadrado, M; Phillips, E; Wilson, W; Jenner, R; Pang, G; Kamora, S; ... Yong, K; + view all (2021) Thrombotic microangiopathy in untreated myeloma patients receiving carfilzomib, cyclophosphamide and dexamethasone on the CARDAMON study. British Journal of Haematology 10.1111/bjh.17377. (In press). Green open access

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Abstract

Proteasome inhibitors have been associated with thrombotic microangiopathy (TMA) — a group of disorders characterised by occlusive microvascular thrombosis causing microangiopathic haemolytic anaemia, thrombocytopenia and end‐organ damage. To date, carfilzomib‐associated TMA has predominantly been described in relapsed/refractory myeloma patients. We report eight patients with newly diagnosed myeloma who experienced TMA events while receiving carfilzomib on the phase II CARDAMON trial. The first three occurred during maintenance single‐agent carfilzomib, two occurred at induction with carfilzomib given with cyclophosphamide and dexamethasone (KCd) and three occurred during KCd consolidation. At TMA presentation 6/8 were hypertensive; 7/8 had acute kidney injury and in three, renal impairment persisted after resolution of TMA in other respects. The mechanism of carfilzomib‐associated TMA remains unclear, though patients with known hypertension seem particularly susceptible. Given the first three cases occurred during maintenance after a longer than five‐week treatment break, a protocol amendment was instituted with: aggressive hypertension management, carfilzomib step‐up dosing (20 mg/m2 on day 1) at start of maintenance before dose escalation to 56 mg/m2 maximum, and adding 10 mg dexamethasone as premedication to maintenance carfilzomib infusions. No further TMA events occurred during maintenance following this amendment and the TMA incidence reduced from 4·2 to 1·6 per 1 000 patient cycles.

Type: Article
Title: Thrombotic microangiopathy in untreated myeloma patients receiving carfilzomib, cyclophosphamide and dexamethasone on the CARDAMON study
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/bjh.17377
Publisher version: https://doi.org/10.1111/bjh.17377
Language: English
Additional information: Copyright © 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Keywords: carfilzomib, clinical trials, myeloma, thrombocytopenia, thrombotic haemolytic anaemias
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > CRUK Cancer Trials Centre
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: https://discovery.ucl.ac.uk/id/eprint/10123458
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