Amplification and overexpression of the PSMB5 gene contributes to bortezomib resistance in retreatment of patients with multiple myeloma.

Background: The proteasome inhibitor Bortezomib is a novel anticancer drug that targets primarily the beta5 subunit (PSMB5) of the 26 S proteasome which has also demonstrated efficacy in re-treatment of almost half of relapsed Multiple Myeloma (MM) pts. Recent studies have identified qualitative and quantitative alterations at the level of PSMB5 subunit, which is located at 14q11, and cells that carry these alterations displayed a marked resistance to proteasome inhibition. We investigated the relevance of amplification and PSMB5 overexpression in the clinical outcome of pts with MM during retreatment with bortezomib. Methods: Between January and June 2008 pts with secretory MM on relapse were elegible for bortezomib re-treatment (1.3 or 1.0 mg/mq on days 1,4,8 and 11 of a 21 day cycle) if they had at least a partial remission to a bortezomib based on most recent treatment and a free interval of at least 6 months since the last dose. Bone marrow samples for morphologic analysis, mRNA expression levels of PSMB5, classical cytogenetics , FISH and in situ hybridization using a fluorescein-labeled probe to detect the amplification of PSMB5 gene, were obtained from 26 pts (16 male, 10 female mean age 64 years) before and during re-treatment with Bortezomib. Results: At the time of analyses all pts who received at least two cycles were evaluable. We identified 12 pts refractory to retreatment and five of these pts (3 males, 2 females, mean age 65 years) had a detectable amplification and overexpression of PSMB5 which interestingly appears rapidly following exposure to bortezomib and wanes with time off-therapy, even if it curiously reappeared rapidly after re-exposure to bortezomib. Conclusions: Amplification and overexpression of PSMB5 contributes to bortezomib resistance in clinical practice. These findings do highlight the susceptibility of proteasome units to genetic modifications under constant selective pressure which occur with continued treatment, furthermore, the drug resistance remains dormant but it rapidly revives upon re-exposure to bortezomib.