Introduction: Therapeutic plasma exchange (TPE) is traditionally performed for hyperviscosity, neuropathy and to mitigate renal injury in the setting of high clonal free light chain burden in patients with multiple myeloma (MM) with unknown clinical benefit. Materials and Methods: Retrospective study of adults ≥18 years with MM who received TPE in the in-patient setting in the United States from 1993 to 2015. We examined the temporal trends of TPE utilization in MM hospitalizations, hospital charges, in-hospital mortality, and length of hospitalization and the predictors of in-hospital mortality and length of hospitalizations. Results: The number of MM-hospitalizations for TPE in adults increased significantly from 1993 to 2015 (1% in 1993-1999 to 2.1% in 2008-2015 of all MM discharges, P for trend <.0001). About 70% of TPE recipients had acute kidney injury (AKI). The median hospital charges increased 5-fold during the time period ($ 24 407 to $ 113 496; P for trend <.0001). In-hospital mortality decreased (17.5% (SE 2.66) in 1993-1997 to 8.7% (1.39) in 2007 to 2013) P for trend <.005) while the length of stay remained unchanged (11.2 days vs 11.9 days, P for trend 0.17). On adjusted analysis, significant predictors of in-hospital mortality among MM TPE recipients include, Charlson Comorbidity Index (CCI) (3 vs 2 adjusted odds ratio, aOR 2.16, 95% CI 1.26-3.71; P =.005), year (continuous) (aOR 0.93, 95% CI 0.90-0.96; P <.001) and race (other vs white; aOR 0.44, 95% CI 0.25-0.78; P = 0.004). Conclusions: There has been a substantial increase in the use and associated cost of TPE in hospitalized MM patients.