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

David I. Lichter, Hadi Danaee, Michael D. Pickard, Olga Tayber, Michael Sintchak, Hongliang Shi, Paul G. Richardson, Jamie Cavenagh, Joan Bladé, Thierry Façon, Ruben Niesvizky, Melissa Alsina, William Dalton, Pieter Sonneveld, Sagar Lonial, Helgi van de Velde, Deborah Ricci, Dixie-Lee Esseltine, William L. Trepicchio, George Mulligan and Kenneth C. Anderson


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.