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

Abstract

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.

Keywords: Carfilzomib; Case report; Eculizumab; Multiple myeloma (MM); Thombotic microangiopathy (TMA).

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1

Course of CFZ-TMA in the two patients. a Case #1: This patient developed acute kidney injury, fever and pulmonary hemorrhage during the first consolidation with carfilzomib, lenalidomide and dexamethasone (KRd) after ASCT. Laboratory findings (thrombocytopenia) and schistocytosis of 11‰ were consistent with thrombotic microangiopathy (TMA). Therapeutic plasma exchange (TPE) was immediately initiated, but shortly after dialysis was necessary. As blood values did not improve, we finally administered eculizumab for a total of seven doses and saw a rapid response in LDH, platelet number and kidney function with our patient being still in PR. b Case #2: This patient, who is treated in the DSMM XVII study (Arm A: Elotuzumab-KRd) developed head ache, malignant hypertension and laboratory distortions (thrombocytopenia, increase of LDH and acute kidney injury) consistent with TMA. After a short period of TPE, eculizumab was infused (total of six infusions). Blood values improved but kidney function remains decreased

Fig. 2

a Chest-CT in patient case 1, d1 of CFZ-TMA onset: Bipulmonary extensive ground-glass opacities in all lung fields, mostly omitting the periphery and predominantly occurring in the right lung. b Mechanism of CFZ-TMA: Within the proximal complement activation C3 is cleaved by the C3 convertase to anaphylactic 3a and C3b. C3b then cleaves C5 to C5a and C5b, the latter together with C6-C9 forming the membrane attack complex (MAC) within the terminal pathway. Activity of the C3 convertase is regulated by complement factor H and regulated proteins. Proteasome inhibition blocks CFH [11]. The monoclonal antibody eculizumab counteracts the resulting overactivation of C3b by binding C5

Fig. 3

Guideline for diagnostic and therapeutic approach for TMA in MM: Whenever clinical and laboratory findings are consistent with TMA, one should rapidly terminate possible causative drugs, initiate therapeutic plasma exchange (TPE) and apply a first dose of eculizumab. As soon as ADAMTS13 activity is determined further therapeutic decisions can be drawn