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

DI Lichter; H Danaee; MD Pickard; O Tayber; M Sintchak; HL Shi; PG Richardson; J Cavenagh; J Blade; T Facon; R Niesvizky; M Alsina; W Dalton; Pieter Sonneveld; S Lonial; H te Velde; D Ricci; DL Esseltine; WL Trepicchio; G Mulligan; KC Anderson

doi:10.1182/blood-2012-05-426924

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

DI Lichter, H Danaee, MD Pickard, O Tayber, M Sintchak, HL Shi, PG Richardson, J Cavenagh, J Blade, T Facon, R Niesvizky, M Alsina, W Dalton, Pieter Sonneveld, S Lonial, H te Velde, D Ricci, DL Esseltine, WL Trepicchio, G MulliganKC Anderson

Hematology

Research output: Contribution to journal › Article › Academic › peer-review

56 Citations (Scopus)

Abstract

Variations within proteasome beta (PSMB) genes, which encode the beta subunits of the 20S proteasome, may affect 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, in the present study, PSMB gene sequence variation was characterized in tumor DNA samples from patients who participated in the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study of bortezomib versus high-dose dexamethasone for treatment of relapsed multiple myeloma. Twelve new PSMB variants were identified. No associations were found between PSMB single nucleotide polymorphism genotype frequency and clinical response to bortezomib or dexamethasone treatment or between PSMB single nucleotide polymorphism allelic frequency and pooled overall survival or time to progression. Although specific PSMB5 variants have been identified previously in preclinical models of bortezomib resistance, these variants were not detected in patient tumor samples collected after clinical relapse from bortezomib, which suggests that alternative mechanisms underlie bortezomib insensitivity. This study is registered at www.clinicaltrials.gov as NCT00048230. (Blood. 2012;120(23):4513-4516)

Original language	Undefined/Unknown
Pages (from-to)	4513-4516
Number of pages	4
Journal	Blood
Volume	120
Issue number	23
DOIs	https://doi.org/10.1182/blood-2012-05-426924
Publication status	Published - 2012

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EMC MM-02-41-03

Access to Document

10.1182/blood-2012-05-426924

http://hdl.handle.net/1765/66860

Cite this

Lichter, DI., Danaee, H., Pickard, MD., Tayber, O., Sintchak, M., Shi, HL., Richardson, PG., Cavenagh, J., Blade, J., Facon, T., Niesvizky, R., Alsina, M., Dalton, W., Sonneveld, P., Lonial, S., te Velde, H., Ricci, D., Esseltine, DL., Trepicchio, WL., ... Anderson, KC. (2012). Sequence analysis of beta-subunit genes of the 20S proteasome in patients with relapsed multiple myeloma treated with bortezomib or dexamethasone. Blood, 120(23), 4513-4516. https://doi.org/10.1182/blood-2012-05-426924

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title = "Sequence analysis of beta-subunit genes of the 20S proteasome in patients with relapsed multiple myeloma treated with bortezomib or dexamethasone",

abstract = "Variations within proteasome beta (PSMB) genes, which encode the beta subunits of the 20S proteasome, may affect 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, in the present study, PSMB gene sequence variation was characterized in tumor DNA samples from patients who participated in the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study of bortezomib versus high-dose dexamethasone for treatment of relapsed multiple myeloma. Twelve new PSMB variants were identified. No associations were found between PSMB single nucleotide polymorphism genotype frequency and clinical response to bortezomib or dexamethasone treatment or between PSMB single nucleotide polymorphism allelic frequency and pooled overall survival or time to progression. Although specific PSMB5 variants have been identified previously in preclinical models of bortezomib resistance, these variants were not detected in patient tumor samples collected after clinical relapse from bortezomib, which suggests that alternative mechanisms underlie bortezomib insensitivity. This study is registered at www.clinicaltrials.gov as NCT00048230. (Blood. 2012;120(23):4513-4516)",

author = "DI Lichter and H Danaee and MD Pickard and O Tayber and M Sintchak and HL Shi and PG Richardson and J Cavenagh and J Blade and T Facon and R Niesvizky and M Alsina and W Dalton and Pieter Sonneveld and S Lonial and {te Velde}, H and D Ricci and DL Esseltine and WL Trepicchio and G Mulligan and KC Anderson",

year = "2012",

doi = "10.1182/blood-2012-05-426924",

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volume = "120",

pages = "4513--4516",

journal = "Blood",

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Lichter, DI, Danaee, H, Pickard, MD, Tayber, O, Sintchak, M, Shi, HL, Richardson, PG, Cavenagh, J, Blade, J, Facon, T, Niesvizky, R, Alsina, M, Dalton, W, Sonneveld, P, Lonial, S, te Velde, H, Ricci, D, Esseltine, DL, Trepicchio, WL, Mulligan, G & Anderson, KC 2012, 'Sequence analysis of beta-subunit genes of the 20S proteasome in patients with relapsed multiple myeloma treated with bortezomib or dexamethasone', Blood, vol. 120, no. 23, pp. 4513-4516. https://doi.org/10.1182/blood-2012-05-426924

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T1 - Sequence analysis of beta-subunit genes of the 20S proteasome in patients with relapsed multiple myeloma treated with bortezomib or dexamethasone

AU - Lichter, DI

AU - Danaee, H

AU - Pickard, MD

AU - Tayber, O

AU - Sintchak, M

AU - Shi, HL

AU - Richardson, PG

AU - Cavenagh, J

AU - Blade, J

AU - Facon, T

AU - Niesvizky, R

AU - Alsina, M

AU - Dalton, W

AU - Sonneveld, Pieter

AU - Lonial, S

AU - te Velde, H

AU - Ricci, D

AU - Esseltine, DL

AU - Trepicchio, WL

AU - Mulligan, G

AU - Anderson, KC

PY - 2012

Y1 - 2012

N2 - Variations within proteasome beta (PSMB) genes, which encode the beta subunits of the 20S proteasome, may affect 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, in the present study, PSMB gene sequence variation was characterized in tumor DNA samples from patients who participated in the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study of bortezomib versus high-dose dexamethasone for treatment of relapsed multiple myeloma. Twelve new PSMB variants were identified. No associations were found between PSMB single nucleotide polymorphism genotype frequency and clinical response to bortezomib or dexamethasone treatment or between PSMB single nucleotide polymorphism allelic frequency and pooled overall survival or time to progression. Although specific PSMB5 variants have been identified previously in preclinical models of bortezomib resistance, these variants were not detected in patient tumor samples collected after clinical relapse from bortezomib, which suggests that alternative mechanisms underlie bortezomib insensitivity. This study is registered at www.clinicaltrials.gov as NCT00048230. (Blood. 2012;120(23):4513-4516)

AB - Variations within proteasome beta (PSMB) genes, which encode the beta subunits of the 20S proteasome, may affect 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, in the present study, PSMB gene sequence variation was characterized in tumor DNA samples from patients who participated in the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study of bortezomib versus high-dose dexamethasone for treatment of relapsed multiple myeloma. Twelve new PSMB variants were identified. No associations were found between PSMB single nucleotide polymorphism genotype frequency and clinical response to bortezomib or dexamethasone treatment or between PSMB single nucleotide polymorphism allelic frequency and pooled overall survival or time to progression. Although specific PSMB5 variants have been identified previously in preclinical models of bortezomib resistance, these variants were not detected in patient tumor samples collected after clinical relapse from bortezomib, which suggests that alternative mechanisms underlie bortezomib insensitivity. This study is registered at www.clinicaltrials.gov as NCT00048230. (Blood. 2012;120(23):4513-4516)

U2 - 10.1182/blood-2012-05-426924

DO - 10.1182/blood-2012-05-426924

M3 - Article

C2 - 23018640

SN - 0006-4971

VL - 120

SP - 4513

EP - 4516

JO - Blood

JF - Blood

IS - 23

ER -