Selective inhibition of nuclear export with oral selinexor for treatment of relapsed or refractory multiple myeloma

Dan T. Vogl, David M Dingli, Robert Frank Cornell, Carol Ann Huff, Sundar Jagannath, Divaya Bhutani, Jeffrey Zonder, Rachid Baz, Ajay Nooka, Joshua Richter, Craig Cole, Ravi Vij, Andrzej Jakubowiak, Rafat Abonour, Gary Schiller, Terri L. Parker, Luciano J. Costa, David Kaminetzky, James E. Hoffman, Andrew J. YeeAjai Chari, David Siegel, Rafael Fonseca, Scott Van Wier, Gregory Ahmann, Ilsel Lopez, Michael Kauffman, Sharon Shacham, Jean Richard Saint-Martin, Carla D. Picklesimer, Cassandra Choe-Juliak, Alexander Keith Stewart

Research output: Contribution to journalArticle

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Abstract

Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease). The primary end point was overall response rate (ORR). Results Of 79 patients, 48 had quad-refractory and 31 had penta-refractory myeloma. Patients had received a median of seven prior regimens. The ORR was 21% and was similar for patients with quad-refractory (21%) and penta-refractory (20%) disease. Among patients with high-risk cytogenetics, including t(4;14), t(14;16), and del(17p), the ORR was 35% (six of 17 patients). The median duration of response was 5 months, and 65% of responding patients were alive at 12 months. The most common grade Ö 3 adverse events were thrombocytopenia (59%), anemia (28%), neutropenia (23%), hyponatremia (22%), leukopenia (15%), and fatigue (15%). Dose interruptions for adverse events occurred in 41 patients (52%), dose reductions occurred in 29 patients (37%), and treatment discontinuation occurred in 14 patients (18%). Conclusion The combination of selinexor and dexamethasone has an ORR of 21% in patients with heavily pretreated, refractory myeloma with limited therapeutic options.

Original languageEnglish (US)
Pages (from-to)859-866
Number of pages8
JournalJournal of Clinical Oncology
Volume36
Issue number9
DOIs
StatePublished - Jan 1 2018

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Cell Nucleus Active Transport
Multiple Myeloma
Rubiaceae
Therapeutics
Dexamethasone
KPT-330
Tumor Suppressor Proteins
Hyponatremia
Oncogene Proteins
Glucocorticoid Receptors
Leukopenia
Protein Biosynthesis
Neutropenia
Cytogenetics
Thrombocytopenia
Fatigue
Anemia
Anti-Idiotypic Antibodies

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Selective inhibition of nuclear export with oral selinexor for treatment of relapsed or refractory multiple myeloma. / Vogl, Dan T.; Dingli, David M; Cornell, Robert Frank; Huff, Carol Ann; Jagannath, Sundar; Bhutani, Divaya; Zonder, Jeffrey; Baz, Rachid; Nooka, Ajay; Richter, Joshua; Cole, Craig; Vij, Ravi; Jakubowiak, Andrzej; Abonour, Rafat; Schiller, Gary; Parker, Terri L.; Costa, Luciano J.; Kaminetzky, David; Hoffman, James E.; Yee, Andrew J.; Chari, Ajai; Siegel, David; Fonseca, Rafael; Van Wier, Scott; Ahmann, Gregory; Lopez, Ilsel; Kauffman, Michael; Shacham, Sharon; Saint-Martin, Jean Richard; Picklesimer, Carla D.; Choe-Juliak, Cassandra; Stewart, Alexander Keith.

In: Journal of Clinical Oncology, Vol. 36, No. 9, 01.01.2018, p. 859-866.

Research output: Contribution to journalArticle

Vogl, DT, Dingli, DM, Cornell, RF, Huff, CA, Jagannath, S, Bhutani, D, Zonder, J, Baz, R, Nooka, A, Richter, J, Cole, C, Vij, R, Jakubowiak, A, Abonour, R, Schiller, G, Parker, TL, Costa, LJ, Kaminetzky, D, Hoffman, JE, Yee, AJ, Chari, A, Siegel, D, Fonseca, R, Van Wier, S, Ahmann, G, Lopez, I, Kauffman, M, Shacham, S, Saint-Martin, JR, Picklesimer, CD, Choe-Juliak, C & Stewart, AK 2018, 'Selective inhibition of nuclear export with oral selinexor for treatment of relapsed or refractory multiple myeloma', Journal of Clinical Oncology, vol. 36, no. 9, pp. 859-866. https://doi.org/10.1200/JCO.2017.75.5207
Vogl, Dan T. ; Dingli, David M ; Cornell, Robert Frank ; Huff, Carol Ann ; Jagannath, Sundar ; Bhutani, Divaya ; Zonder, Jeffrey ; Baz, Rachid ; Nooka, Ajay ; Richter, Joshua ; Cole, Craig ; Vij, Ravi ; Jakubowiak, Andrzej ; Abonour, Rafat ; Schiller, Gary ; Parker, Terri L. ; Costa, Luciano J. ; Kaminetzky, David ; Hoffman, James E. ; Yee, Andrew J. ; Chari, Ajai ; Siegel, David ; Fonseca, Rafael ; Van Wier, Scott ; Ahmann, Gregory ; Lopez, Ilsel ; Kauffman, Michael ; Shacham, Sharon ; Saint-Martin, Jean Richard ; Picklesimer, Carla D. ; Choe-Juliak, Cassandra ; Stewart, Alexander Keith. / Selective inhibition of nuclear export with oral selinexor for treatment of relapsed or refractory multiple myeloma. In: Journal of Clinical Oncology. 2018 ; Vol. 36, No. 9. pp. 859-866.
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abstract = "Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease). The primary end point was overall response rate (ORR). Results Of 79 patients, 48 had quad-refractory and 31 had penta-refractory myeloma. Patients had received a median of seven prior regimens. The ORR was 21{\%} and was similar for patients with quad-refractory (21{\%}) and penta-refractory (20{\%}) disease. Among patients with high-risk cytogenetics, including t(4;14), t(14;16), and del(17p), the ORR was 35{\%} (six of 17 patients). The median duration of response was 5 months, and 65{\%} of responding patients were alive at 12 months. The most common grade {\"O} 3 adverse events were thrombocytopenia (59{\%}), anemia (28{\%}), neutropenia (23{\%}), hyponatremia (22{\%}), leukopenia (15{\%}), and fatigue (15{\%}). Dose interruptions for adverse events occurred in 41 patients (52{\%}), dose reductions occurred in 29 patients (37{\%}), and treatment discontinuation occurred in 14 patients (18{\%}). Conclusion The combination of selinexor and dexamethasone has an ORR of 21{\%} in patients with heavily pretreated, refractory myeloma with limited therapeutic options.",
author = "Vogl, {Dan T.} and Dingli, {David M} and Cornell, {Robert Frank} and Huff, {Carol Ann} and Sundar Jagannath and Divaya Bhutani and Jeffrey Zonder and Rachid Baz and Ajay Nooka and Joshua Richter and Craig Cole and Ravi Vij and Andrzej Jakubowiak and Rafat Abonour and Gary Schiller and Parker, {Terri L.} and Costa, {Luciano J.} and David Kaminetzky and Hoffman, {James E.} and Yee, {Andrew J.} and Ajai Chari and David Siegel and Rafael Fonseca and {Van Wier}, Scott and Gregory Ahmann and Ilsel Lopez and Michael Kauffman and Sharon Shacham and Saint-Martin, {Jean Richard} and Picklesimer, {Carla D.} and Cassandra Choe-Juliak and Stewart, {Alexander Keith}",
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TY - JOUR

T1 - Selective inhibition of nuclear export with oral selinexor for treatment of relapsed or refractory multiple myeloma

AU - Vogl, Dan T.

AU - Dingli, David M

AU - Cornell, Robert Frank

AU - Huff, Carol Ann

AU - Jagannath, Sundar

AU - Bhutani, Divaya

AU - Zonder, Jeffrey

AU - Baz, Rachid

AU - Nooka, Ajay

AU - Richter, Joshua

AU - Cole, Craig

AU - Vij, Ravi

AU - Jakubowiak, Andrzej

AU - Abonour, Rafat

AU - Schiller, Gary

AU - Parker, Terri L.

AU - Costa, Luciano J.

AU - Kaminetzky, David

AU - Hoffman, James E.

AU - Yee, Andrew J.

AU - Chari, Ajai

AU - Siegel, David

AU - Fonseca, Rafael

AU - Van Wier, Scott

AU - Ahmann, Gregory

AU - Lopez, Ilsel

AU - Kauffman, Michael

AU - Shacham, Sharon

AU - Saint-Martin, Jean Richard

AU - Picklesimer, Carla D.

AU - Choe-Juliak, Cassandra

AU - Stewart, Alexander Keith

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease). The primary end point was overall response rate (ORR). Results Of 79 patients, 48 had quad-refractory and 31 had penta-refractory myeloma. Patients had received a median of seven prior regimens. The ORR was 21% and was similar for patients with quad-refractory (21%) and penta-refractory (20%) disease. Among patients with high-risk cytogenetics, including t(4;14), t(14;16), and del(17p), the ORR was 35% (six of 17 patients). The median duration of response was 5 months, and 65% of responding patients were alive at 12 months. The most common grade Ö 3 adverse events were thrombocytopenia (59%), anemia (28%), neutropenia (23%), hyponatremia (22%), leukopenia (15%), and fatigue (15%). Dose interruptions for adverse events occurred in 41 patients (52%), dose reductions occurred in 29 patients (37%), and treatment discontinuation occurred in 14 patients (18%). Conclusion The combination of selinexor and dexamethasone has an ORR of 21% in patients with heavily pretreated, refractory myeloma with limited therapeutic options.

AB - Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease). The primary end point was overall response rate (ORR). Results Of 79 patients, 48 had quad-refractory and 31 had penta-refractory myeloma. Patients had received a median of seven prior regimens. The ORR was 21% and was similar for patients with quad-refractory (21%) and penta-refractory (20%) disease. Among patients with high-risk cytogenetics, including t(4;14), t(14;16), and del(17p), the ORR was 35% (six of 17 patients). The median duration of response was 5 months, and 65% of responding patients were alive at 12 months. The most common grade Ö 3 adverse events were thrombocytopenia (59%), anemia (28%), neutropenia (23%), hyponatremia (22%), leukopenia (15%), and fatigue (15%). Dose interruptions for adverse events occurred in 41 patients (52%), dose reductions occurred in 29 patients (37%), and treatment discontinuation occurred in 14 patients (18%). Conclusion The combination of selinexor and dexamethasone has an ORR of 21% in patients with heavily pretreated, refractory myeloma with limited therapeutic options.

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DO - 10.1200/JCO.2017.75.5207

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