Clinical course and treatment history of 3 MM patients with acquired IMiD resistance. CD138-purified tumor samples were obtained after progression to an IMiD-based treatment and from earlier IMiD-responsive disease stages in each patient. A mutation in CRBN was identified at IMiD-resistant disease stage (black circles). This mutation, however, was undetectable at earlier IMiD-sensitive disease stages in all 3 patients (white circles), suggesting a correlation with the acquired IMiD resistance in these patients. Patient #12 (CRBN mutation Q327TER) was a 72-year-old female diagnosed with MM immunoglobulin G kappa (IgG κ). She was initially treated with bortezomib (BTZ), rapidly relapsed, and died as a result of PD during lenalidomide (LEN) treatment (detection of CRBN mutation). Patient #32 (CRBN mutation P411H) was a 44-year-old female diagnosed with MM IgG κ. She was treated with several chemotherapy agents, high-dose melphalan (HDM), and novel agents, including BTZ, carfilzomib (CFZ), LEN, and pomalidomide (POM), and she died during PD from POM-refractory disease (detection of CRBN mutation). Patient #24 (CRBN mutation F381C) was a 64-year-old male diagnosed with MM IgA λ. Initial treatments included tandem (tand.) HDM and interferon (IFN) maintenance. After a long disease course with several short retreatments including BTZ, LEN, and HDM, the disease became lenalidomide-refractory (detection of CRBN mutation) and conventional chemotherapy was begun. Black arrows indicate refractoriness to the indicated treatment. CTX, chemotherapy; mt., maintenance; RIC-allo, reduced-intensity conditioning allogeneic stem cell transplantation; Thal, thalidomide.