Recent development of new therapies with immune checkpoint inhibitors (ICIs) and MAPK-inhibitors (MAPKis) have significantly improved the outcome in metastatic cutaneous melanoma (CM). However, therapy response is limited to subgroups of patients and clinically useful predictive biomarkers for treatment outcome are lacking. To discover treatment-related systemic changes in plasma and potential biomarkers associated with treatment outcomes, we analysed 45 plasma samples with HiRIEF LC-MS/MS, collected before (pre-trm) and during treatment (trm). Of these, 27 samples were taken from 15 metastatic CM patients treated with ICIs (13 pre-trm and 14 trm samples; 12 matched) and 9 patients treated with MAPKis (9 matched). Matched samples were trm and pre-trm samples taken from the same individual before treatment and after the first cycle of treatment (before the second cycle), with a median of 20 days between samples (range: 7-57, SD: 10.26). We have analysed the change in the plasma protein levels during treatment, by comparing the plasma levels in the trm samples to the pre-trm samples, to detect treatment-induced alterations in the plasma proteome. We have analysed the patients treated with ICIs separately from the patients with MAPKis, to detect treatment-specific changes for both.