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

K. Martin Kortüm, Elias K. Mai, Nur H. Hanafiah, Chang Xi Shi, Yuan Xiao Zhu, Laura Bruins, Santiago Barrio, Patrick Jedlowski, Maximilian Merz, Jing Xu, Robert A. Stewart, Mindaugas Andrulis, Anna Jauch, Jens Hillengass, Hartmut Goldschmidt, P. Leif Bergsagel, Esteban Braggio, A. Keith Stewart, Marc S. Raab

Research output: Contribution to journalArticlepeer-review

94 Scopus citations


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. 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 3 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.

Original languageEnglish (US)
Pages (from-to)1226-1233
Number of pages8
Issue number9
StatePublished - Sep 1 2016

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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