Hepatitis E virus infections in people with multiple myeloma: an emerging challenge in the era of immunotherapeutic approaches

Hepatitis E virus (HEV) is an under-recognized cause of viral hepatitis, with rising incidence in high-income countries largely driven by zoonotic transmission. Patients with multiple myeloma (MM) are especially vulnerable to HEV, yet there have been no recommendations for antiviral treatment or on its impact on the management of myeloma treatment. Here, we describe 7 patients (5 males, 2 females) with MM who were diagnosed with HEV infection at a tertiary care center in Western Europe within less than one year. All cases were confirmed by positive HEV RNA PCR in peripheral blood. Although no instances of fulminant hepatitis were observed, HEV prompted clinically relevant interruptions: autologous stem cell transplantation was postponed, lymphocyte apheresis for CAR T-cell manufacturing was delayed, and bispecific antibody regimens were suspended for up to five months. Ribavirin was initiated in 4 cases. The 3 patients undergoing T-cell-redirecting therapies, including one with prior ciltacabtagene autoleucel and 2 on bispecific antibodies, progressed to chronic infection despite ribavirin treatment. One patient, despite clearing HEV from peripheral blood, developed persistent vertigo and tested positive for HEV RNA in cerebrospinal fluid, indicating neuroinvasion. As the largest reported cohort of MM patients with HEV infections and the first to document chronic infection during treatment with T-cell-redirecting therapies, this study emphasizes the urgent need to increase awareness of HEV as an emerging threat, refine screening protocols at baseline or during unexplained aminotransferase flares, and to establish standardized therapeutic strategies in the era of novel immunotherapeutic approaches.