PROGENy reveals RAS mutations do not strongly increase MAPK activity in all RAS-mutant tumors, but patients with increased MAPK activity have decreased survival. (A) Violin plots showing the distribution of MAPK pathway activation for MM patient samples in CoMMpass based on PROGENy predictions reveals a surprisingly similar range of scores for WT RAS and RAS-mutated patients, though mean of distribution is significantly different. P values for all combinations using Welch’s 2-tailed t tests. (B) MM cell lines (data from www.keatslab.org) show more pronounced effects of RAS mutation driving MAPK activity than patient samples in panel A. (C) Activating mutations at the Q61 codon show the strongest effect in driving MAPK activity in NRAS mutants in CoMMpass samples, whereas KRAS mutations do not show similar codon-specific effects. P values by Welch’s 2-tailed t test. (D) Histogram of PROGENy-predicted MAPK activation colored by quartiles. Survival analyses demonstrate that high levels of MAPK activity are predictive of poorer outcomes. P values were calculated using Wald’s test. (E) Association between PROGENy-predicted MAPK scores and common genomic markers in MM.