AbstractImmunomodulatory drugs (IMiDs) are key components of treatment for hematologic malignancies, especially multiple myeloma (MM). Cereblon (CRBN) expression was described to be essential for the activity of thalidomide. Furthermore, IMiD binding to CRBN is cytotoxic to multiple myeloma cells and absence of CRBN confers IMiDs resistance. Interleukin‐6 (IL‐6) is a potent pleiotropic cytokine that regulates plasma cell (PC) growth via the IL‐6 receptor (IL‐6R). IL‐6/IL‐6R autocrine activity is implicated in the development and progression of cancers including cervical cancer, prostate cancer, and multiple myeloma. The aim of the study was to evaluate CRBN and IL‐6R expressions and their impact on clinical efficacy of dexamethasone–thalidomide therapy in multiple myeloma (MM) patients, in addition to their association with other clinical and prognostic parameters. Forty‐six newly diagnosed MM patients were enrolled in the study. We measured CRBN expression prior to therapy initiation by real‐time polymerase chain reaction in 46 bone marrow (BM) aspiration samples of patients and controls. In addition, IL‐6R expression was evaluated on BM biopsies of patients and controls by immunohistochemistry (IHC). Twenty‐eight males (60.9%) and 18 females (39.1%) were enrolled. The mean age was 65.11 ± 7.3 yr (range 39–77 yr). Median CRBN expression in 46 BM samples of MM patients was significantly higher than in controls (P < 0.001). Among established prognostic parameters, international staging system (ISS), serum beta‐2‐microglobulin (B2M), and serum albumin correlated reversely with CRBN expression. IL‐6R expression was significantly higher in patients than in controls. IL‐6R expression was significantly associated with response to treatment (P < 0.001), B2M (P = 0.032), and ISS (P = 0.028). Strong intensity expression was associated with low CRBN expression (P = 0.001).In conclusion, CRBN expression may provide a biomarker to predict response to IMiD in patients with MM and its high expression can serve as a marker of good prognosis. Strong IL‐6R expression is associated with poor response to therapy in multiple myeloma patients and may be used as a prognostic marker.