Objectives The treatment of choice for extramedullary plasmacytoma (EMP) is radiotherapy (RT). It is under discussion whether the management of an anaplastic form of EMP requires the addition of systemic therapy. Case presentation We present a case of a 66-year-old male who was diagnosed with anaplastic plasmacytoma of the maxillary sinus. After the exclusion of multiple myeloma, Dara-VMP (daratumumab, bortezomib, melphalan, and prednisolone) regimen was initiated. During the third cycle of Dara-VMP, a progression of the tumor was observed. RT and BRd (bendamustine, dexamethasone, and lenalidomide) regimen were initiated. After 4 cycles of BRd, disease progression was established. KRd (carfilzomib, lenalidomide, and dexamethasone) regimen was initiated. The first cycle of KRd was not completed, as the patient was diagnosed with COVID-19. After the infection, the progression of EMP was observed. Conclusions In this case, the anaplastic EMP was resistant to RT and chemotherapy regimens with novel agents, including a monoclonal antibody, an immunomodulatory drug, and proteasome inhibitors.