Validation of a novel proteomically definable iMCD subgroup that has superior response to siltuximab, increased disease activity, and elevated IL-6 levels. (A) A heat map of the 7 serum analytes that best distinguish cluster 1 vs other clusters, as selected by elastic net with fivefold cross-validation in the discovery dataset. (B) Correlation analysis between cluster 1 score and response, disease activity, and IL-6 levels in the discovery cohort (2-sided P values). (C) A heat map of the 7 serum analytes tested in an independent validation dataset. (D) Correlation analysis between cluster 1 score and response, disease activity, and IL-6 levels in the validation cohort (1-sided P values). Box plots show center median, first and third quartile, and whiskers extend to 1.5 × interquartile range. Cluster 1 scores are scaled from 0 to 1 for each cohort.