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

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 CAR-DAMON 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 stepup dosing (20 mg/m 2 on day 1) at start of maintenance before dose escalation to 56 mg/m 2 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 4Á2 to 1Á6 per 1 000 patient cycles.

Carfilzomib-Induced Thrombotic Microangiopathy: Focus on Pathogenesis

“…The CARDAMON study, a phase II trial of carfilzomib, cyclophosphamide, and dexamethasone in untreated myeloma patients, reported TMA in eight out of 281 patients. ADAMTS13 activity was checked in seven of these eight patients, and all had normal activity [ 19 ]. Lastly, Fotiou et al reported TMA in six out of 114 patients (5%) with relapsed and refractory myeloma multiple myeloma who received carfilzomib.…”

“…Carfilzomib-induced TMA has been reported as early as 24 h and as late as 24 months after therapy [ 19 ]. In this report, our patient presented on cycle 1, day 6.…”

“…Taken together, these data suggest a multi-factorial mechanism for the pathogenesis of carfilzomib-induced TMA. The first risk factor is the multiple myeloma diagnosis, as multiple myeloma is an independent risk factor for TMA [ 19 ]. Therefore, we must consider the underlying malignancy in these patients as a contributing factor.…”

“…Carfilzomib is a second-generation proteasome inhibitor approved by the US Food and Drug Administration (FDA) in 2012 as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy [7]. Since that time, increasing reports of TMA secondary to carfilzomib have been published [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. The most important step in the management of carfilzomibinduced TMA is stopping the drug.…”

Simultaneous Cases of Carfilzomib-Induced Thrombotic Microangiopathy in 2 Patients With Multiple Myeloma

“…Although the incidence of TMA disorders is low, reaching up to 2.8% in patients receiving carfilzomib plus cyclophosphamide and dexamethasone in the phase 2 CARDAMON trial, our experience suggests that a high index of suspicion for carfilzomib-induced TMA is warranted in the real-world setting. 8 TMA syndromes, including TTP, HUS, and DITMA, are characterized by microvascular endothelial injury and thrombosis leading to thrombocytopenia and microangiopathic hemolytic anemia. 5,9 Several drug culprits of DITMA are recognized, including quinine, gemcitabine, tacrolimus, and proteasome inhibitors (bortezomib, carfilzomib, ixazomib).…”