Bortezomib mitigates adverse prognosis conferred by Bcl-2 overexpression in patients with relapsed/refractory multiple myeloma

• Published in: Leukemia & lymphoma 2012-06, Vol.53 (6), p.1174-1182
• Main Authors: Ailawadhi, Sikander, Miecznikowski, Jeff, Gaile, Dan P., Wang, Dongliang, Sher, Taimur, Mulligan, George, Bryant, Barb, Wilding, Gregory E., Mashtare, Terry, Stein, Leighton, Masood, Aisha, Neuwirth, Rachel, Lee, Kelvin P., Chanan-Khan, Asher
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Apoptosis - genetics; Bcl-2; Boronic Acids - pharmacology; Boronic Acids - therapeutic use; Bortezomib; Clinical Trials as Topic - statistics & numerical data; Cluster Analysis; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Genes, bcl-2 - drug effects; Genes, bcl-2 - genetics; Humans; Microarray Analysis; Multicenter Studies as Topic - statistics & numerical data; Multiple Myeloma - diagnosis; Multiple Myeloma - drug therapy; Multiple Myeloma - genetics; Multiple Myeloma - pathology; Myeloma; Prognosis; Pyrazines - pharmacology; Pyrazines - therapeutic use; Recurrence; Treatment Failure; Up-Regulation - drug effects; Up-Regulation - genetics
• ISSN: 1042-8194; 1029-2403
• DOI: 10.3109/10428194.2011.637212

Abstract Overexpression of the Bcl-2 family of genes results in increased transcription of anti-apoptotic proteins. In vitro data suggest that this may enhance acquired chemoresistance and correlate with extramedullary invasion. This has led to pursuing the Bcl-2 family of proteins as therapeutic targets in several malignant disorders, including multiple myeloma (MM). The impact of novel therapeutic agents such as bortezomib on these molecular markers is not known. We investigated the association between the expression of anti-apoptotic members of the Bcl-2 family and the efficacy of bortezomib in patients with relapsed/refractory MM. Gene expression data generated prospectively from large clinical trials were utilized. Hypothesis testing using a multisample test for equivalence was performed. The association between Bcl-2 expression levels and clinical reponse was negated in bortezomib-treated patients (p = 0.014), while not so in dexamethasone-treated patients (p = 0.92). Similar results were noted for variant 2 of the Mcl-1 gene (p = 0.003). Results for Bcl-xl did not meet the level of significance. Thus, the importance of the Bcl-2 family of proteins as prognostic markers in MM should be reassessed in the novel therapeutic agent era. Our data suggest that bortezomib may overcome the prognostic effect conferred by overexpression of some of the anti-apoptotic Bcl-2 family of genes in patients with relapsed/refractory MM.