Clustering analysis of iMCD serum proteomes demonstrates 6 distinct clusters with differential response to siltuximab. (A) Subtyping of iMCD patients into 6 clusters by elastic net clustering of iMCD samples using serum analyte levels, as measured by SOMAscan. Siltuximab responders (partial response or complete response, per durable clinical and tumor (radiologic lymph node) response criteria as determined in NCT01024036) are indicated with open triangles, nonresponders with closed triangles, and patients for which siltuximab was not given as a monotherapy or response was not assessed by independent clinical trial review are represented by closed circles. Lines are drawn around clusters as determined by elastic net with fivefold cross-validation. (B) Top 40 serum analytes that best distinguish between clusters 1 to 6, as selected by elastic net with fivefold cross-validation, across iMCD samples. (C) Proportion of patients within each cluster that demonstrated a partial or complete response to anti–IL-6 therapy when administered during active disease (as determined in NCT01024036). Cluster 1 patients demonstrated significantly higher response to siltuximab than the other patients (P = 8.94 × 10⁻⁴).