Proteasome inhibitor‐associated thrombotic microangiopathy: A review of cases reported to the <scp>FDA</scp> adverse event reporting system and published in the literature
Authors: Michelle Nadeau Nguyen, Afrouz Nayernama, S. Christopher Jones, Bindu Kanapuru, Nicole Gormley, Peter E. Waldron
Journal: American Journal of Hematology (2020)

Proteasome inhibitors (PIs) have emerged as an important treatment strategy for multiple myeloma (MM). Currently, there are three FDA-approved PIs including bortezomib, carfilzomib, and ixazomib.1-3 Bortezomib, the first PI that was approved, is currently indicated for the treatment of patients with multiple myeloma and mantle cell lymphoma.1 Carfilzomib and ixazomib are indicated for the treatment of relapsed/refractory myeloma.2, 3 Although PIs are generally well tolerated, common toxicities specific to the class include thrombocytopenia, hepatotoxicity, and other toxicities as described in the US prescribing information.1-3 Recently, several published case reports have described thrombotic microangiopathy (TMA) among patients receiving bortezomib and ixazomib (Table 1). Thrombotic microangiopathy represents a clinical spectrum of diseases related to microvascular thrombi, including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), characterized by systemic or intra-renal thrombi, hematologic abnormalities, and related organ dysfunction.4 Many causes of TMA have been described including A Disintegrin and Metalloprotease with a Thrombospondin type 1 motif member 13 (ADAMTS13) deficiency, Shiga toxin producing bacterial infections, complement-mediated (also known as atypical HUS), and drug-induced TMA.4, 5 Drug- induced TMA is a rare but serious outcome that we estimate to occur at a rate of approximately one case per million population per year.5, 6 Notably, TMA is an identified risk with carfilzomib, and this safety finding was added to carfilzomib's prescribing information in 2015.3 We evaluated postmarketing adverse event reports from the FDA Adverse Event Reporting System (FAERS) and published in the literature. This was to investigate a potential association between PI exposure, specifically bortezomib and ixazomib, and TMA to determine if the prescribing information should be updated similar to carfilzomib, as a therapeutic class effect. We report our findings for bortezomib-associated and ixazomib-associated TMA as well as the regulatory actions taken by the FDA. We identified 27 unique cases of TMA from FAERS (n = 24) and the literature (n = 3) associated with bortezomib (n = 21) and ixazomib (n = 6) use (Table 1). A case with histologic findings of TMA or laboratory evidence of TMA (eg, thrombocytopenia and evidence of schistocytes on blood smear) was considered a confirmed case of TMA (Table S1). We applied the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) causality assessment to our cases and determined causality as certain in one case, probable in four cases, and possible in the remaining 22 cases. The median time to event onset of TMA from the first dose of bortezomib or ixazomib was 34 and 78 days, respectively, among the cases that reported this information. Notably, this is consistent with the time to onset for TMA observed with carfilzomib.7 As is expected for non-immune mediated, drug-induced TMA, 10 cases reported normal ADAMTS-13 levels.5 Twenty three of the cases reported use of the PI for the treatment of multiple myeloma. The median case age was 57 years and the cases were evenly distributed among males and females. Although TMA is rare, it has a risk for fatality often manifesting clinically as end-organ damage involving the kidney, related to endothelial injury.4 Most patients with TMA require hospitalization and many require long-term treatment with renal replacement therapy. All cases in our case series reported serious outcomes including hospitalization (n = 18) and death (n = 2). Both fatal cases occurred in the setting of TMA among the ixazomib cases. Renal injury was the most common serious clinical manifestation of TMA (n = 23) and led to renal replacement therapy in 10 cases, including two cases that required long-term dialysis. We assessed the cases for the presence of concomitant medications and comorbidities as potential confounding factors. Overall, we determined the drug-event causality as certain in one case and as probable in four cases without apparent contributory factors. The remaining 22 cases were confounded by relevant comorbidities, concomitant medications, or did not report this information. Underlying malignancy is considered a risk factor for TMA. However, MM is a rare underlying cause of TMA and usually occurs at the initial presentation, prior to treatment, or at disease recurrence.8 Other suggested mechanisms for TMA in MM include systemic chemotherapy and hematopoietic stem cell transplantation (HSCT)-induced endothelial injury.4, 8 Although MM was reported as the underlying malignancy for our certain and probable cases, all patients improved clinically with PI therapy discontinuation and other supportive interventions. This is not the expected outcome for TMA due to uncontrolled malignancy, and favors drug-induced TMA. A causal association is further supported by a positive rechallenge with respect to bortezomib re-initiation in one of the cases. The most frequently reported confounding factors among the remaining possible cases included prior HSCT (n = 7), possible infection (n = 4), and underlying hypertension (n = 3). Although the mechanism by which PI-induced TMA could occur is unknown, dysregulation of the vascular endothelial growth factor (VEGF) signal pathway is a proposed mechanism.9, 10 The PIs affect VEGF signaling through the NF-κB pathway; blocking the ubiquitination of IκB leads to decreased NF-κB activity and reduced VEGF production. Vascular endothelial growth factor is produced by podocytes within the kidney, and maintains microvasculature integrity via paracrine signaling through VEGF receptors found on glomerular capillary endothelial cells.9, 10 In animal models, antagonism of VEGF receptor signaling by genetic or pharmacologic manipulation is associated with TMA, including impaired endothelial cell proliferation and capillary formation with subsequent loss of glomerular and mesangial cells.9, 10 To our knowledge, this is the largest published case series describing TMA with bortezomib and ixazomib. These cases are characterized by serious clinical outcomes including death in some instances. Although our analysis is limited by the quality of spontaneous adverse event reporting and other limitations inherent to spontaneous reporting systems (eg, under-reporting, reporting biases), the strong temporal association and biologic plausibility provide evidence supportive of a drug-event causal association between the drugs, bortezomib and ixazomib, and the event, TMA. Additionally, the known association of TMA with carfilzomib suggests this may be a class effect related to proteasome inhibition.3 The US prescribing information for bortezomib and ixazomib was recently updated to include the risk of TMA under warnings and precautions, with recommendations to discontinue PI therapy for suspected TMA.1, 2 This revision of the prescribing information is intended to increase clinicians' awareness of the risk for TMA with bortezomib and ixazomib, and to mitigate the risk for serious outcomes by improving the likelihood of early therapeutic interventions. The authors report no conflict of interest. Table S1 Case Definition for Thrombotic Microangiopathy (TMA) Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.