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

Sikander Ailawadhi, Jeff Miecznikowski, Dan P. Gaile, Dongliang Wang, Taimur Sher, George Mulligan, Barb Bryant, Gregory E. Wilding, Terry Mashtare, Leighton Stein, Aisha Masood, Rachel Neuwirth, Kelvin P. Lee, Asher A Chanan Khan

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1174-1182
Number of pages9
JournalLeukemia and Lymphoma
Volume53
Issue number6
DOIs
StatePublished - Jun 2012
Externally publishedYes

Fingerprint

Multiple Myeloma
bcl-2 Genes
Apoptosis Regulatory Proteins
Dexamethasone
Proteins
Therapeutics
Clinical Trials
Gene Expression
Bortezomib
Genes

Keywords

  • Bcl-2
  • Bortezomib
  • Myeloma

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

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

In: Leukemia and Lymphoma, Vol. 53, No. 6, 06.2012, p. 1174-1182.

Research output: Contribution to journalArticle

Ailawadhi, S, Miecznikowski, J, Gaile, DP, Wang, D, Sher, T, Mulligan, G, Bryant, B, Wilding, GE, Mashtare, T, Stein, L, Masood, A, Neuwirth, R, Lee, KP & Chanan Khan, AA 2012, 'Bortezomib mitigates adverse prognosis conferred by Bcl-2 overexpression in patients with relapsed/refractory multiple myeloma', Leukemia and Lymphoma, vol. 53, no. 6, pp. 1174-1182. https://doi.org/10.3109/10428194.2011.637212
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 A. / Bortezomib mitigates adverse prognosis conferred by Bcl-2 overexpression in patients with relapsed/refractory multiple myeloma. In: Leukemia and Lymphoma. 2012 ; Vol. 53, No. 6. pp. 1174-1182.
@article{1ee9d565aab646fcb44078e90fc7e4ae,
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 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.",
keywords = "Bcl-2, Bortezomib, Myeloma",
author = "Sikander Ailawadhi and Jeff Miecznikowski and Gaile, {Dan P.} and Dongliang Wang and Taimur Sher and George Mulligan and Barb Bryant and Wilding, {Gregory E.} and Terry Mashtare and Leighton Stein and Aisha Masood and Rachel Neuwirth and Lee, {Kelvin P.} and {Chanan Khan}, {Asher A}",
year = "2012",
month = "6",
doi = "10.3109/10428194.2011.637212",
language = "English (US)",
volume = "53",
pages = "1174--1182",
journal = "Leukemia and Lymphoma",
issn = "1042-8194",
publisher = "Informa Healthcare",
number = "6",

}

TY - JOUR

T1 - Bortezomib mitigates adverse prognosis conferred by Bcl-2 overexpression in patients with relapsed/refractory multiple myeloma

AU - Ailawadhi, Sikander

AU - Miecznikowski, Jeff

AU - Gaile, Dan P.

AU - Wang, Dongliang

AU - Sher, Taimur

AU - Mulligan, George

AU - Bryant, Barb

AU - Wilding, Gregory E.

AU - Mashtare, Terry

AU - Stein, Leighton

AU - Masood, Aisha

AU - Neuwirth, Rachel

AU - Lee, Kelvin P.

AU - Chanan Khan, Asher A

PY - 2012/6

Y1 - 2012/6

N2 - 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.

AB - 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.

KW - Bcl-2

KW - Bortezomib

KW - Myeloma

UR - http://www.scopus.com/inward/record.url?scp=84861381663&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861381663&partnerID=8YFLogxK

U2 - 10.3109/10428194.2011.637212

DO - 10.3109/10428194.2011.637212

M3 - Article

C2 - 22054286

AN - SCOPUS:84861381663

VL - 53

SP - 1174

EP - 1182

JO - Leukemia and Lymphoma

JF - Leukemia and Lymphoma

SN - 1042-8194

IS - 6

ER -