title: Expression of cereblon protein assessed by immunohistochemicalstaining in myeloma cells is associated with superior response of thalidomide- and lenalidomide-based treatment, but not bortezomib-based treatment, in patients with multiple myeloma.
abstract: Cereblon (CRBN) is essential for the anti-myeloma (MM) activity of immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide. However, the clinical implications of CRBN in MM patients are unclear. Using immunohistochemical (IHC) staining on paraffin-embedded bone marrow sections, the expression of CRBN protein in myeloma cells (MCs) was assessed in 40 relapsed/refractory MM (RRMM) patients who received lenalidomide/dexamethasone (LD) and 45 and 22 newly diagnosed MM (NDMM) patients who received thalidomide/dexamethasone (TD) and melphalan/bortezomib/prednisolone (MVP), respectively. IHC staining were scored on a scale representing the diffuseness and intensity of positive-staining MCs (range, 0-8) and a score ≥4.5 was used for CRBN positivity (CRBN(+)) on a cut-point analysis of all possible scores and response of TD and LD. Compared to CRBN(+) NDMM patients, CRBN(-) NDMM patients had more international staging system (ISS) III (26 vs. 61 %, respectively; P = 0.006). In the LD and TD cohorts, the response rate (RR) was higher in CRBN(+) patients than CRBN(-) patients (LD 79 vs. 33 %, respectively; P = 0.005) (TD 75 vs. 29 %, respectively; P = 0.005); however, this trend was not observed in the MVP cohort. In the LD and TD cohorts, the positive and negative prediction value of CRBN(+) for treatment response was 79 and 67 % and 75 and 71 %, respectively. Multivariate analysis showed that CRBN(+) was a significant factor associated with superior RR for LD and TD. The data suggest that expression of CRBN protein in MCs assessed using the IHC is a feasible approach to predict the response of IMiDs in MM patients.
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, B4:0509, No.7, Chung-Shan South Road, 10002, Taipei, R.O.C, Taiwan, syhuang55@ntuh.gov.tw.
authors.forename: Shang-Yi
authors.initials: SY
authors.lastname: Huang
authors.forename: Chung-Wu
authors.initials: CW
authors.lastname: Lin
authors.forename: Hsiu-Hsia
authors.initials: HH
authors.lastname: Lin
authors.forename: Ming
authors.initials: M
authors.lastname: Yao
authors.forename: Jih-Luh
authors.initials: JL
authors.lastname: Tang
authors.forename: Shang-Ju
authors.initials: SJ
authors.lastname: Wu
authors.forename: Yao-Chang
authors.initials: YC
authors.lastname: Chen
authors.forename: Hsiao-Yun
authors.initials: HY
authors.lastname: Lu
authors.forename: Hsin-An
authors.initials: HA
authors.lastname: Hou
authors.forename: Chien-Yuan
authors.initials: CY
authors.lastname: Chen
authors.forename: Wen-Chien
authors.initials: WC
authors.lastname: Chou
authors.forename: Woei
authors.initials: W
authors.lastname: Tsay
authors.forename: Sheng-Je
authors.initials: SJ
authors.lastname: Chou
authors.forename: Hwei-Fang
authors.initials: HF
authors.lastname: Tien
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001856:Bone Marrow Examination / Q000379:methods; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D003907:Dexamethasone / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008558:Melphalan / Q000008:administration & dosage; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000737:chemistry; D016612:Paraffin Embedding; D010447:Peptide Hydrolases / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D011239:Prednisolone / Q000008:administration & dosage; D011719:Pyrazines / Q000008:administration & dosage; D016879:Salvage Therapy; D016019:Survival Analysis; D053668:Syndecan-1 / Q000032:analysis; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome; D044767:Ubiquitin-Protein Ligases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors; D001897:Boronic Acids; C502543:CRBN protein, human; D009363:Neoplasm Proteins; D011719:Pyrazines; C508241:SDC1 protein, human; D053668:Syndecan-1; D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone; D011239:Prednisolone; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; D000077269:Lenalidomide; D008558:Melphalan