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

Ann Hematol. 2014 Aug;93(8):1371-80. doi: 10.1007/s00277-014-2063-7. Epub 2014 Apr 1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Aged
  • Angiogenesis Inhibitors / administration & dosage
  • Angiogenesis Inhibitors / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bone Marrow Examination / methods
  • Boronic Acids / administration & dosage
  • Bortezomib
  • Dexamethasone / administration & dosage
  • Female
  • Follow-Up Studies
  • Gene Expression Profiling
  • Humans
  • Lenalidomide
  • Male
  • Melphalan / administration & dosage
  • Middle Aged
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / metabolism
  • Neoplasm Proteins / analysis*
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology
  • Neoplastic Stem Cells / chemistry
  • Paraffin Embedding
  • Peptide Hydrolases / analysis*
  • Peptide Hydrolases / biosynthesis
  • Peptide Hydrolases / genetics
  • Peptide Hydrolases / physiology
  • Prednisolone / administration & dosage
  • Pyrazines / administration & dosage
  • Salvage Therapy
  • Survival Analysis
  • Syndecan-1 / analysis
  • Thalidomide / administration & dosage
  • Thalidomide / analogs & derivatives*
  • Thalidomide / therapeutic use
  • Treatment Outcome
  • Ubiquitin-Protein Ligases

Substances

  • Adaptor Proteins, Signal Transducing
  • Angiogenesis Inhibitors
  • Boronic Acids
  • CRBN protein, human
  • Neoplasm Proteins
  • Pyrazines
  • SDC1 protein, human
  • Syndecan-1
  • Thalidomide
  • Bortezomib
  • Dexamethasone
  • Prednisolone
  • Ubiquitin-Protein Ligases
  • Peptide Hydrolases
  • Lenalidomide
  • Melphalan