Patients exposed to, and putatively resistant to, lenalidomide had lower CRBN levels in paired samples before and after therapy. In summary, CRBN is an essential requirement for IMiD activity and a possible biomarker for the clinical assessment of antimyeloma efficacy....CRBN is required for lenalidomide and pomalidomide response,...further investigated the CRBN expression level in 9 MM patients with physician-reported lenalidomide resistance. In 8 of 9 MM patients, with pre- and post-lenalidomide therapy samples analyzed by quantitative PCR, the CRBN expression level showed a significant reduction (20%-90% reduction) at the time of drug resistance (Figure 5A).

...37-year-old IgG-kappa MM patient presenting with progressive, multi-drug refractory EMD….Initial myeloma treatment for the patient occurred over multiple years and included the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, the proteasome inhibitor bortezomib, cortiosteroids, radiation, one autologous and two allogeneic transplantations. She experienced extramedullary relapse...a Q99* truncating mutation as well as a R283K point mutation were observed in CRBN, that we recently demonstrated as essential for the anti-MM action of IMiDs...this is the first description of CRBN mutations in a primary myeloma sample and furthermore of a “triple negative” MM patient possessing mutations probably contributing to resistance to all three major drug classes utilized in MM therapy....The presence of mutations of interest was evaluated by capillary sequencing in an expanded cohort of 25 CD138+ MM samples with low CRBN expression... Therapy subsequent to biopsy for genome sequencing was with pomalidomide and dexamethasone without response. Unfortunately, the patient succumbed to her disease in less than the 12 weeks required at the time for sequencing and data analysis.