Monitoring the Sign & Symptoms of Variant Creutzfeldt-Jakob Disease Among Patients with Multiple Myeloma Treated with Ixazomib Capsules in China: A Real-World Pharmacovigilance Survey

Introduction: Variant Creutzfeldt-Jakob disease (vCJD) is a fatal and transmittable neurodegenerative disorder in humans, associated with ingestion of products from Bovine spongiform encephalopathy (BSE) affected cattle. ¹ Since April 2018, Ixazomib is approved by National Medical Products Administration (NMPA) for the treatment of multiple myeloma (MM), in China. Before March 2019, the gelatin used for encapsulating ixazomibcapsules was sourced from countries with BSE outbreaks, although all the sources were fully complaint with regulations MM patients were still at risk for BSE, particularly vCJD. Definitive diagnosis of vCJD requires brain biopsy, which is a complex procedure with many complications. World Health Organization (WHO) has indicated a combination of signs and symptoms to assist in defining possible, probable, and definite vCJD cases. ^2,3 Here we present phase-2 results from a retrospective analysis, conducted to describe physician-observed signs and symptoms, which may be related to vCJD in MM patients, treated with ixazomibbefore December 2019 in China.

Methods: This multi-centre, cross-sectional, web-based survey was conducted in China. Licensed physicians who have prescribed ixazomibcapsules for MM patients before December 2019 and participated in the Phase 1 survey, titled attending or above, specialized in haematology or other related departments and practised in outpatient clinics once a week in the past six months were included. The primary objective was to describe physicians' observed signs and symptoms and the secondary objective was to describe physicians' concerns and awareness of signs and symptoms, which may be related to vCJD in MM patients treated with ixazomib. Eligible physicians completed an online questionnaire with closed-ended multiple-choice questions related to patients' clinical characteristics, responder characteristics, awareness on vCJD-related signs and symptoms, concern on vCJD risk, willingness to prescribe ixazomib in future. Physicians' concern about MM patients who have consumed contaminated ixazomibto get vCJD was measured on a 10-point scale, in which 0 stands for no concern while 10 stands for extremely concerned. Statistical analysis was performed using R, version 3.2

Results: A total of 311 valid questionnaires were received from 318 physicians. The baseline characteristics of respondents are depicted in Table 1. The mean (standard deviation) time of awareness on potential contamination was 19.1 (4.69) months. The average degree of concern decreased from 4.6 in phase 1 to 4.2 in phase 2, as measured on a 10-point scale and willingness to prescribe ixazomibhad increased from 70.1% to 87.8% , after knowing NINLARO ® capsule was sourced (produced before December 2019) from regions with BSE outbreak. A total of 288 respondents reported 1,485 deceased MM patients, who also received ixazomib before 2020. During phase 1, 7 respondents reported 17 patients, who were presented with at least 4 out of 5 prespecified symptoms for potential vCJD. Of which, 2 respondents reported that presented symptoms of 2 patients were caused by vCJD. However, in phase 2, all the 7 respondents have changed their opinion and reported no patient with at least 4 out of 5 prespecified symptoms for potential vCJD, this indicates the possibility of respondents developing better understanding of cVJD after phase 1. Further during phase 2, one respondent reported 2 new living patients presented with at least four of five pre-specified symptoms for potential vCJD and/or ixazomib. On further investigation, the respondent reported the symptoms were not related to vCJD and no tests were performed further to confirm a vCJD diagnosis, possibility of occurrence of these symptoms after phase 1 cannot be ruled out. Additionally, another respondent reported death of a patient that died due to severe diarrhea before reaching hospital. As per respondent, the death may be associated with NINLARO ® and not related to vCJD as the patient was prescribed with ixazomib before December 2019.

Conclusion: This study indicates that the risk of vCJD was no longer a concerning factor for physicians and would no longer influence their willingness to prescribe ixazomib.