Blood Journal
Leading the way in experimental and clinical research in hematology

Sequence analysis of β-subunit genes of the 20S proteasome in patients with relapsed multiple myeloma treated with bortezomib or dexamethasone

  1. David I. Lichter1,*,
  2. Hadi Danaee1,
  3. Michael D. Pickard1,
  4. Olga Tayber1,
  5. Michael Sintchak1,
  6. Hongliang Shi1,
  7. Paul G. Richardson2,
  8. Jamie Cavenagh3,
  9. Joan Bladé4,
  10. Thierry Façon5,
  11. Ruben Niesvizky6,
  12. Melissa Alsina7,
  13. William Dalton7,
  14. Pieter Sonneveld8,
  15. Sagar Lonial9,
  16. Helgi van de Velde10,
  17. Deborah Ricci11,
  18. Dixie-Lee Esseltine1,
  19. William L. Trepicchio1,
  20. George Mulligan1, and
  21. Kenneth C. Anderson2
  1. 1 Millennium Pharmaceuticals, Inc., Cambridge, MA, United States;
  2. 2 Dana-Farber Cancer Institute, Boston, MA, United States;
  3. 3 Department of Haematology, St. Bartholomew's Hospital, London, United Kingdom;
  4. 4 Hematology Department, Hospital Clinic, University of Barcelona, Spain;
  5. 5 Claude Huriez Hospital, Lille, France;
  6. 6 Center of Excellence for Lymphoma and Myeloma, Weill Medical College of Cornell University, New York Presbyterian Hospital, NY, United States;
  7. 7 H. Lee Moffitt Cancer Center, Tampa, FL, United States;
  8. 8 University Hospital Rotterdam, Netherlands;
  9. 9 Emory University, Atltanta, GA, United States;
  10. 10 Janssen Research & Development, Beerse, Belgium;
  11. 11 Janssen Research & Development, Raritan, NJ, United States
  1. * Corresponding author; email: david.lichter{at}


Variation within proteasome β (PSMB) genes, which encode the β subunits of the 20S proteasome, may impact proteasome function, assembly, and/or binding of proteasome inhibitors. To investigate the potential association between PSMB gene variants and treatment-emergent resistance to bortezomib, and/or long-term outcomes, PSMB gene sequence variation was characterized in tumor DNA samples from patients who participated in the phase 3 APEX study (bortezomib vs. high-dose dexamethasone for treatment of relapsed multiple myeloma [MM]). Twelve new PSMB variants were identified. No associations were found between PSMB single nucleotide polymorphism (SNP) genotype frequency and clinical response to bortezomib or dexamethasone treatment, or between PSMB SNP allelic frequency and pooled overall survival or time to progression. While specific PSMB5 variants have been previously identified in preclinical models of bortezomib resistance, these variants were not detected in patient tumor samples collected after clinical relapse from bortezomib. This suggests that alternative mechanisms underlie bortezomib insensitivity. This study is registered at (NCT00048230).

  • Submitted May 1, 2012.
  • Accepted September 16, 2012.