Late Presentation of Carfilzomib Associated Thrombotic Microangiopathy

Haddadin, Michael; Al-Sadawi, Mohammad; Madanat, Sally; Tam, Eric; Taiwo, Evelyn; Luhrs, Carol; McFarlane, Samy I.

doi:10.12691/ajmcr-7-10-5

Cited by 14 publications

(18 citation statements)

References 34 publications

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“…In the literature, the time interval between the first carfilzomib dose and TMA diagnosis varies widely, with the earliest presentation occurring within 24 h of the first single dose of carfilzomib at 20 mg/m 214 and the latest recorded at 24 months. 20 Similarly, in our patient group, two DI-TMA occurred within 14 days of drug initiation and six occurred afterwards with a median time of 8Á5 months (7-15 months). A new observation we make in our series is that 5/6 (83Á3%) of carfilzomib-induced TMA which did not occur at the first cycle of induction had a treatment-free period of more than five weeks.…”

Section: Discussionsupporting

confidence: 61%

“…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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…As reviewed recently [ 6 ], TMA in MM can be elicited by ASCT- or allogeneic-SCT, MM progression, or anti-myeloma therapy. Drug-induced TMA (DITMA) may occur in MM due to PIs bortezomib or CFZ [ 3 , 16 , 17 ]. CFZ-TMA can appear early after onset of the drug, but also as late as two years after first administration [ 1 , 2 ].…”

Section: Discussionmentioning

confidence: 99%

Two cases of carfilzomib‐induced thrombotic microangiopathy successfully treated with Eculizumab in multiple myeloma

et al. 2021

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Background Treatment with proteasome inhibitors like carfilzomib in patients with multiple myeloma (MM) can induce thrombotic microangiopathy (TMA) characterized by neurological symptoms, acute kidney injury, hemolysis and thrombocytopenia. Successful treatment with the monoclonal antibody eculizumab was described for these patients, but reports of ideal management and definitive treatment protocols are lacking. Case Presentation The first case describes a 43-years-old IgG-kappa-MM patient that developed TMA during the first course of carfilzomib-lenalidomide-dexamethasone (KRd) consolidation after autologous stem cell transplantation (ASCT). In the second case, a 59-years-old IgG-kappa-MM patient showed late-onset TMA during the fourth and last cycle of elotuzumab-KRd consolidation within the DSMM XVII study of the German study group MM (DSMM; clinicalTrials.gov Identifier: NCT03948035). Concurrently, he suffered from influenza A/B infection. Both patients had a high TMA-index for a poor prognosis of TMA. Therapeutically, in both patients plasma exchange (TPE) was initiated as soon as TMA was diagnosed. In patient #1, dialysis became necessary. For both patients, only when the complement inhibitor eculizumab was administered, kidney function and blood values impressively improved. Conclusion In this small case series, two patients with MM developed TMA due to carfilzomib treatment (CFZ-TMA), the second patient as a late-onset form. Even though TMA could have been elicited by influenza in the second patient and occurred after ASCT in both patients, with cases of TMA post-transplantation in MM being described, a relation of TMA and carfilzomib treatment was most likely. In both patients, treatment with eculizumab over two months efficiently treated TMA without recurrence and with both patients remaining responsive months after TMA onset. Taken together, we describe two cases of TMA in MM patients on carfilzomib-combination treatment, showing similar courses of this severe adverse reaction, with good responses to two months of eculizumab treatment.

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“…17 More frequently, Len causes DAT þ hemolysis by cold agglutinins or warm autoantibodies. 18,27,28 Proteasome inhibitor (bortezomib, carfilzomib, ixazomib)-induced TMA with hemolysis has also been described, 19,29,30 possibly with delayed occurrence weeks after proteasome inhibitor initiation. 29 Patients with drug-induced TMA are severely ill, with fever, kidney injury, and neurologic symptoms.…”

Section: Discussionmentioning

confidence: 99%

Dapsone-Induced Hemolytic Anemia in Multiple Myeloma: Case Report of Various Differential Diagnoses

Rassner

Jung

Schneider

et al. 2020

Clinical Lymphoma Myeloma and Leukemia

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Late Presentation of Carfilzomib Associated Thrombotic Microangiopathy

Cited by 14 publications

References 34 publications

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

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

Two cases of carfilzomib‐induced thrombotic microangiopathy successfully treated with Eculizumab in multiple myeloma

Dapsone-Induced Hemolytic Anemia in Multiple Myeloma: Case Report of Various Differential Diagnoses

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