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 multidrug refractory multiple myeloma (rMM) patients was performed by using the Multiple Myeloma Mutation Panel. Patients were pretreated with both immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), and 88%, 78%, and 68% were refractory to an IMiD, a PI, or both, respectively. The majority of patients had progressive (82%) or refractory (78%) disease immediately before sampling, with 43% being IMiD refractory and 46% being PI refractory in the most recent line of therapy.Comparedwith newly diagnosedMM,an increased prevalence ofmutations in theRas pathway genesKRAS,NRAS, and/orBRAF(72%), as well as TP53 (26%),CRBN(12%), andCRBNpathwaygenes (10%)wasobserved.Longitudinalanalysesperformed in3 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 mutationsinMMcellsconferredlenalidomideresistanceinvitro.Thesedataindicateadifferential genetic landscape in rMM associated with drug response. [ABSTRACT FROM AUTHOR]