Background: ICIs have transformed MM mortality. Pts receiving ICIs may experience high-grade irAEs that limit continuation of treatment per current guidelines. We aimed to evaluate the safety and response rate of ICI rechallenge. Methods: 551 MM pts treated with ICI were retrospectively reviewed from Jan 2014 to Jan 2020 after IRB approval. The incidence of a recurrent irAE in pts with ICI rechallenge within the same drug class after an initial high-grade (Grade III/IV) irAE was evaluated. Age, gender, irAEs, and outcomes were descriptively analyzed within the rechallenged cohort. Results: 32.7% of pts (180/551) experienced a high-grade irAE. 60.0% of these (108/180) pts were on combination therapy with at least one ICI. 50.6% (91/180) of pts were rechallenged with ICI within the same drug class. The rechallenged cohort had a median age of 63.8 [range: 28-86] years and 48.4% was female. The cohort’s initial irAE occurred at a median of 7.6 weeks from treatment onset with Grade 3/4 severity of 60.0% /40.0% (91). Toxicities included colitis 27.5% (25/91), hepatitis 23.1% (21/91), skin toxicity 22.0% (20/91), adrenal insufficiency 5.5% (5/91) hypophysitis 5.5% (5/91), neurological abnormality 4.4% (4/91), pancreatitis 3.3% (3/91), hematological abnormality 3.3% (3/91), arthralgia 3.3% (3/91), myalgia 3.3% (3/91), pneumonitis 2.2% (2/91), insulin dependent diabetes 1.1% (1/91), fatigue 1.1% (1/91), vasculitis 1.1% (1/91), and hyponatremia 1.1% (1/91). ICI rechallenge occurred at a median of 9.7 weeks from the first Grade 3/4 irAE. 51.8% (29/56) pts initially treated with combo were rechallenged with combo, while 48.2% (27/56) were rechallenged with single agent ICI. Of pts initially treated with single ICI, 60% (21/35) were rechallenged with single agent ICI and 40% (14/35) with combo. With a median follow-up of 21.1 months after rechallenge, irAEs occurred in 75.8% (69/91), with 44.9% of irAEs (31/69) presenting as a different type from the initial event and 31.9% (22/69) as high-grade events. There were no rechallenge irAE-related deaths. Within the rechallenge cohort, 39.6% (36/91) of pts had disease progression. Clinical benefit was achieved in 60.4% (55/91) of pts: 40.7% (37/91) complete response, 11.0% (10/91) partial response and 8.8% (8/91) stable disease. Conclusions: ICI rechallenge can be safely administered in pts with MM after recovery from an initial high-grade irAE. Rechallenge irAE’s did not always reflect initial irAE’s. Close monitoring for any type or grade of IRAE is recommended.