Camilleri Marquita, Cuadrado Maria, Phillips Elizabeth, Wilson William, Jenner Richard, Pang Gavin, Kamora Sumaiya, Streetly Matthew, Popat Rakesh, Bygrave Ceri, Owen Roger, Cavenagh James, Chapman Mike, Sive Jonathan, Eccersley Lydia, Sheaff Michael, Benjamin Reuben, Ramasamy Karthik, Cook Gordon, Virchis Andres, Chavda Selina J, Clifton-Hadley Laura, Scully Marie Anne, Yong Kwee
Haematology Department, University College Hospitals, London, UK.
Cancer Institute, University College London, London, UK.
Br J Haematol. 2021 May;193(4):750-760. doi: 10.1111/bjh.17377. Epub 2021 Mar 1.
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/m on day 1) at start of maintenance before dose escalation to 56 mg/m 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.
蛋白酶体抑制剂与血栓性微血管病（TMA）相关，TMA是一组以闭塞性微血管血栓形成为特征的疾病，可导致微血管病性溶血性贫血、血小板减少和终末器官损害。迄今为止，卡非佐米相关的TMA主要在复发/难治性骨髓瘤患者中被描述。我们报告了8例新诊断的骨髓瘤患者，他们在II期CARDAMON试验中接受卡非佐米治疗时发生了TMA事件。前3例发生在维持单药卡非佐米治疗期间，2例发生在诱导期，使用卡非佐米联合环磷酰胺和地塞米松（KCd），3例发生在KCd巩固期。TMA出现时，8例中有6例高血压；8例中有7例发生急性肾损伤，3例在TMA其他方面缓解后肾功能损害仍持续存在。卡非佐米相关TMA的机制尚不清楚，尽管已知高血压患者似乎特别易感。鉴于前3例发生在超过5周的治疗中断后的维持期，因此制定了一项方案修订：积极管理高血压，在维持期开始时卡非佐米逐步给药（第天20mg/m），然后再将剂量逐步增加至最大56mg/m，并在维持期卡非佐米输注前添加10mg地塞米松作为预处理。修订后维持期未再发生TMA事件，TMA发生率从每1000个患者周期4.2例降至1.6例。
