Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes

In this study, targeted sequencing to screen 50 multi-drug refractory MM (rMM) patients was performed employing the Multiple Myeloma Mutation-Panel (M 3 P). All patients included were pretreated with both immunomodulatory agents (IMiD) and proteasome inhibitors (PI), and 88%, 78% and 68% were refractory to an IMiD, a PI, or both, respectively. The majority of patients had progressive and refractory disease immediately prior to sampling (82% and 78%), with 43% IMiD-refractory and 46% PI-refractory in the most recent line of therapy. Compared with newly diagnosed MM, an increased prevalence of mutations in the Ras pathway genes KRAS , NRAS and/or BRAF (72%), as well as TP53 (26%), CRBN (12%) and CRBN-pathway genes (10%) was observed. Longitudinal analyses performed in three patients with CRBN mutations at time of IMiD resistance confirmed that these mutations were undetectable at earlier, IMiD-sensitive time points. Furthermore, the functional introduction of these mutations in MM cells conferred lenalidomide resistance in vitro. These data indicate a differential genetic landscape in rMM associated with drug response.