Background: PROCLAIM^SM (www.proclaimregistry.com) is an IL-2 observational registry with over 40 participating sites consisting of a retrospective (n = 170, locked) and prospective cohort (n > 343 on-going). Previously, we reported a median overall survival (mOS) of 20 months (mo) with a median follow-up of 37 mo in mM patients treated with HD IL-2 between 2007 and 2012 from a retrospective cohort (ASCO 2014). We report for the first time, analysis of 240 prospective patients. Methods: Patients must have received at least one dose of HD IL-2 prior to 2014 for this analysis. Response rates are reported per standard RECIST criteria and mOS by the method of Kaplan-Meier. All patients provided informed consent. Survival is current to January 2015. Results: For the 240 prospective patients, the mOS is 17.9 mo and the ORR is 15.2% at a median follow-up of 20.1 mo. The 1 year survival rate of patients receiving aPD1 or IPI after HD IL-2 is 100% and 68% respectively, compared to 58% in the IL-2 only group. The mOS for these patients is 25.1 (n = 20), 18.4 (n = 75), and 14 mo (n = 112), and the median follow-up is 24.2, 20.6, and 17.4 mo, respectively. Of the 20 aPD1 patients, 12 received IPI first, 4 aPD1 first, and 4 aPD1 only. The median time between the last IL-2 dose and start of IPI/aPD1 is 3.8 mo. There were no differences in IL-2 treatment intensity between these 3 groups. Ten of 73 IPI patients suffered treatment-related autoimmune disease (2/10 high grade) in post treatment follow-up, compared to 0 in the 20 aPD1 patients. There were no treatment-related deaths in the combined retrospective and prospective cohorts (n = 578). Conclusions: The mOS for mM patients receiving aPD1 after HD IL-2 is significantly prolonged over either treatment with IL-2 only, or IPI therapy following IL-2. The small ‘n’ for the aPD1 group and intrinsic shortcomings of registries limits a definitive conclusion about the optimal sequencing of immunotherapies. Checkpoint therapy after IL-2 appears to be well tolerated, does not impact therapeutic activity and provides a path forward for trials designed to enhance durable, unmaintained IL-2 responses. Clinical trial information: NCT00686959