Case Report: A diagnostic chameleon of EBV-associated immune dysregulation: HLH unmasking multiple myeloma with subsequent emergence of aggressive B-cell lymphoma.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyper-inflammatory syndrome most commonly triggered by infection, autoimmune disease, or malignancy. Multiple myeloma (MM)-associated HLH is rare. We report a 70-year-old female who presented with HLH as the initial manifestation of MM. Following MM-directed therapy, both MM and HLH achieved remission; however, HLH relapsed with persistent Epstein-Barr virus (EBV) viremia despite continued MM control. Anti-PD-1 monoclonal antibody therapy transiently suppressed EBV viremia, but HLH subsequently recurred. Repeat bone marrow examination revealed an unclassifiable aggressive large B-cell lymphoma. Because tissue biopsy was not feasible, lymphoma classification relied primarily on bone marrow findings, representing an important diagnostic limitation. Although EBER positivity was detected, this finding alone was insufficient to establish a direct pathogenic role of EBV in lymphoma development. Subsequent R-CHOP chemotherapy achieved temporary HLH control; however, severe chemotherapy-related myelosuppression and sepsis developed, and the patient ultimately died of multi-organ failure. This case highlights the challenges of developing lymphoid neoplasms in the setting of EBV-associated immune dysregulation, the diagnostic limitations of bone marrow-based lymphoma classification, the transient and limited efficacy of PD-1 blockade for EBV reactivation control, and the therapeutic difficulties encountered in this highly complex clinical setting.