Carfilzomib is a proteasome inhibitor (PI) used in multiple myeloma (MM) that is resistant to other therapies. Despite its efficacy and potency, carfilzomib has been associated with kidney injuries, cardiovascular toxic effects, and hematological adverse events. Tumor lysis syndrome (TLS) following the use of PIs in MM, a malignancy not known to cause TLS, has seldom been reported. We present a case of a patient with a known diagnosis of MM who received prior therapy including bortezomib, a first-generation PI, developing worsening heart failure and new onset TLS days after the administration of carfilzomib.