title: Bortezomib mitigates adverse prognosis conferred by Bcl-2 overexpression in patients with relapsed/refractory multiple myeloma.
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 response 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.
authors: Division of Hematology, University of Southern California, Los Angeles, CA, USA.
authors: Sikander
authors: S
authors: Ailawadhi
authors: Jeff
authors: J
authors: Miecznikowski
authors: Dan P
authors: DP
authors: Gaile
authors: Dongliang
authors: D
authors: Wang
authors: Taimur
authors: T
authors: Sher
authors: George
authors: G
authors: Mulligan
authors: Barb
authors: B
authors: Bryant
authors: Gregory E
authors: GE
authors: Wilding
authors: Terry
authors: T
authors: Mashtare
authors: Leighton
authors: L
authors: Stein
authors: Aisha
authors: A
authors: Masood
authors: Rachel
authors: R
authors: Neuwirth
authors: Kelvin P
authors: KP
authors: Lee
authors: Asher
authors: A
authors: Chanan-Khan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019254:Genes, bcl-2 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D046228:Microarray Analysis; D015337:Multicenter Studies as Topic / Q000706:statistics & numerical data; D009101:Multiple Myeloma / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D012008:Recurrence; D017211:Treatment Failure; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib