The diagnosis of DITMA can be challenging given its nonspecific symptoms that overlap with other TMA syndromes. Previous studies have proposed that for a drug to be associated with DITMA, there should be: (1) evidence of clinical and/or pathologic findings of TMA; (2) exclusion of alternative causes of TMA; (3) no other new drug exposures other than the suspected culprit medication; and (4) a lack of recurrence of TMA in absence of the drug.10 In the case of patients with MM, other causes of TMA have also been described, including the underlying plasma cell disorder itself and stem cell transplantation.14 In the 2 cases we have described, these alternative causes were considered unlikely given that only 1 patient underwent transplantation remotely and neither had a previous history of TMA secondary to their disease. With respect to other TMA syndromes, ADAMTS13 levels > 10% and negative stool studies for E coli O157:H7 suggested against TTP or typical HUS, respectively. No other drug culprits were identified, and the close timing between the receipt of carfilzomib and symptom onset supported a causal relationship.
Because specific therapies are lacking, management of DITMA has traditionally included drug discontinuation and supportive care for end-organ injury.5 The terminal complement inhibitor, eculizumab, improves hematologic abnormalities and renal function in patients with atypical HUS but its use for treating patients with DITMA is not standard.15 Therefore, the decision to administer eculizumab to our 2 patients was driven by their severe renal insufficiency without improvement after plasma exchange, which suggested a phenotype similar to atypical HUS. After administration of eculizumab, renal function stabilized and then gradually improved over weeks to months, a time course similar to that described in cases of patients with DITMA secondary to other anticancer therapies treated with eculizumab.16 Although these results suggest a potential role for eculizumab in proteasome inhibitor–induced TMA, distinguishing the benefit of eculizumab over drug discontinuation alone remains challenging, and well-designed prospective investigations are needed.
The clustered occurrence of our 2 cases is unique from previous reports that describe carfilzomib-induced TMA as a sporadic event (Table 2).13,17-28 Both immune-mediated and direct toxic effects have been proposed as mechanisms of DITMA, and while our cases do not differentiate between these mechanisms, we considered whether a combined model of initiation, whereby patient or environmental risk factors modulate occurrence of the disease in conjunction with the inciting drug, could explain the clustered occurrence of cases. In this series, drug manufacturing was not a shared risk factor as each patient received carfilzomib from different lot numbers. Furthermore, other patients at our center received carfilzomib from the same batches without developing DITMA. We also considered the role of infection given that 1 patient was diagnosed with influenza A and both presented with nonspecific, viral-like symptoms during the winter season. Interestingly, concurrent viral infections have been reported in other cases of carfilzomib-induced DITMA as well and have also been discussed as a trigger of atypical HUS.20,29 Finally, genetic testing was negative for complement pathway mutations that might predispose to complement dysregulation.
The absence of complement mutations in our 2 patients differs from a recent series describing heterozygous CFHR3-CHFR1 deletions in association with carfilzomib-induced TMA.22 In that report, the authors hypothesized that carfilzomib decreases expression of complement factor H (CFH), a negative regulator of complement activation, thereby leading to complement dysregulation in patients who are genetically predisposed. In a second series, plasma from patients with DITMA secondary to carfilzomib induced the deposition of the complement complex, C5b-9, on endothelial cells in culture, suggesting activation of the complement pathway.30 The effective use of eculizumab would also point to a role for complement activation, and ongoing investigations should aim to identify the triggers and mechanisms of complement dysregulation in this setting, especially for patients like ours in whom genetic testing for complement pathway mutations is negative (Figure 2).
