A 62-year-old woman experienced severe renal insufficiency and significant thrombocytopenia during the 7th cycle of carfilzomib and dexamethasone therapy for relapsed multiple myeloma. She was diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from a routine check upon admission. She was subsequently diagnosed with thrombotic microangiopathy (TMA) as well, and platelet fragments were detected in her blood. Treatment with plasma exchange, hemodialysis, and antiviral medications was successful. Although coronavirus disease 2019 (COVID-19) was identified as the primary trigger of TMA, carfilzomib was probably a predisposing factor that contributed to endothelial damage. Even though severe cases of COVID-19 have been less frequent since the Omicron variant became dominant, patients with MM, especially those under treatment with carfilzomib, should be given repeated booster vaccinations. Antiviral medication should also be considered in patients infected with COVID-19, even if symptoms are mild.