Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma

Ajai Chari; Dan T Vogl; Maria Gavriatopoulou; Ajay K Nooka; Andrew J Yee; Carol A Huff; Philippe Moreau; David Dingli; Craig Cole; Sagar Lonial; Meletios Dimopoulos; A Keith Stewart; Joshua Richter; Ravi Vij; Sascha Tuchman; Marc S Raab; Katja C Weisel; Michel Delforge; Robert F Cornell; David Kaminetzky; James E Hoffman; Luciano J Costa; Terri L Parker; Moshe Levy; Martin Schreder; Nathalie Meuleman; Laurent Frenzel; Mohamad Mohty; Sylvain Choquet; Gary Schiller; Raymond L Comenzo; Monika Engelhardt; Thomas Illmer; Philip Vlummens; Chantal Doyen; Thierry Facon; Lionel Karlin; Aurore Perrot; Klaus Podar; Michael G Kauffman; Sharon Shacham; Lingling Li; Shijie Tang; Carla Picklesimer; Jean-Richard Saint-Martin; Marsha Crochiere; Hua Chang; Samir Parekh; Yosef Landesman; Jatin Shah; Paul G Richardson; Sundar Jagannath

doi:10.1056/NEJMoa1903455

Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma

Ajai Chari, Dan T Vogl, Maria Gavriatopoulou, Ajay K Nooka, Andrew J Yee, Carol A Huff, Philippe Moreau, David Dingli, Craig Cole, Sagar Lonial, Meletios Dimopoulos, A Keith Stewart, Joshua Richter, Ravi Vij, Sascha Tuchman, Marc S Raab, Katja C Weisel, Michel Delforge, Robert F Cornell, David KaminetzkyJames E Hoffman, Luciano J Costa, Terri L Parker, Moshe Levy, Martin Schreder, Nathalie Meuleman, Laurent Frenzel, Mohamad Mohty, Sylvain Choquet, Gary Schiller, Raymond L Comenzo, Monika Engelhardt, Thomas Illmer, Philip Vlummens, Chantal Doyen, Thierry Facon, Lionel Karlin, Aurore Perrot, Klaus Podar, Michael G Kauffman, Sharon Shacham, Lingling Li, Shijie Tang, Carla Picklesimer, Jean-Richard Saint-Martin, Marsha Crochiere, Hua Chang, Samir Parekh, Yosef Landesman, Jatin Shah, Paul G Richardson, Sundar Jagannath

Division of Internal Medicine 2 (University Hospital Krems)

Research output: Journal article (peer-reviewed) › Journal article

485 Citations (Scopus)

Abstract

BACKGROUND: Selinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options.

METHODS: We administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point.

RESULTS: A total of 122 patients in the United States and Europe were included in the modified intention-to-treat population (primary analysis), and 123 were included in the safety population. The median age was 65 years, and the median number of previous regimens was 7; a total of 53% of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in 6 patients.

CONCLUSIONS: Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM ClinicalTrials.gov number, NCT02336815.).

Original language	English
Pages (from-to)	727-738
Number of pages	12
Journal	New England Journal of Medicine
Volume	381
Issue number	8
DOIs	https://doi.org/10.1056/NEJMoa1903455
Publication status	Published - 22 Aug 2019

Keywords

Administration, Oral
Adult
Aged
Antineoplastic Combined Chemotherapy Protocols/adverse effects
Biomarkers, Tumor/blood
Dexamethasone/administration & dosage
Drug Administration Schedule
Drug Resistance, Neoplasm
Female
Humans
Hydrazines/administration & dosage
Intention to Treat Analysis
Karyopherins/antagonists & inhibitors
Male
Middle Aged
Multiple Myeloma/drug therapy
Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors
Survival Analysis
Thrombocytopenia/chemically induced
Triazoles/administration & dosage
Young Adult

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10.1056/NEJMoa1903455

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Chari, A., Vogl, D. T., Gavriatopoulou, M., Nooka, A. K., Yee, A. J., Huff, C. A., Moreau, P., Dingli, D., Cole, C., Lonial, S., Dimopoulos, M., Stewart, A. K., Richter, J., Vij, R., Tuchman, S., Raab, M. S., Weisel, K. C., Delforge, M., Cornell, R. F., ... Jagannath, S. (2019). Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma. New England Journal of Medicine, 381(8), 727-738. https://doi.org/10.1056/NEJMoa1903455

@article{c5ec9c075d8446feab3a7e31c49ac6c7,

title = "Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma",

abstract = "BACKGROUND: Selinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options.METHODS: We administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point.RESULTS: A total of 122 patients in the United States and Europe were included in the modified intention-to-treat population (primary analysis), and 123 were included in the safety population. The median age was 65 years, and the median number of previous regimens was 7; a total of 53% of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in 6 patients.CONCLUSIONS: Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM ClinicalTrials.gov number, NCT02336815.).",

keywords = "Administration, Oral, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols/adverse effects, Biomarkers, Tumor/blood, Dexamethasone/administration & dosage, Drug Administration Schedule, Drug Resistance, Neoplasm, Female, Humans, Hydrazines/administration & dosage, Intention to Treat Analysis, Karyopherins/antagonists & inhibitors, Male, Middle Aged, Multiple Myeloma/drug therapy, Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors, Survival Analysis, Thrombocytopenia/chemically induced, Triazoles/administration & dosage, Young Adult",

author = "Ajai Chari and Vogl, {Dan T} and Maria Gavriatopoulou and Nooka, {Ajay K} and Yee, {Andrew J} and Huff, {Carol A} and Philippe Moreau and David Dingli and Craig Cole and Sagar Lonial and Meletios Dimopoulos and Stewart, {A Keith} and Joshua Richter and Ravi Vij and Sascha Tuchman and Raab, {Marc S} and Weisel, {Katja C} and Michel Delforge and Cornell, {Robert F} and David Kaminetzky and Hoffman, {James E} and Costa, {Luciano J} and Parker, {Terri L} and Moshe Levy and Martin Schreder and Nathalie Meuleman and Laurent Frenzel and Mohamad Mohty and Sylvain Choquet and Gary Schiller and Comenzo, {Raymond L} and Monika Engelhardt and Thomas Illmer and Philip Vlummens and Chantal Doyen and Thierry Facon and Lionel Karlin and Aurore Perrot and Klaus Podar and Kauffman, {Michael G} and Sharon Shacham and Lingling Li and Shijie Tang and Carla Picklesimer and Jean-Richard Saint-Martin and Marsha Crochiere and Hua Chang and Samir Parekh and Yosef Landesman and Jatin Shah and Richardson, {Paul G} and Sundar Jagannath",

note = "Publisher Copyright: {\textcopyright} 2019 Massachusetts Medical Society.",

year = "2019",

month = aug,

day = "22",

doi = "10.1056/NEJMoa1903455",

language = "English",

volume = "381",

pages = "727--738",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "8",

}

Chari, A, Vogl, DT, Gavriatopoulou, M, Nooka, AK, Yee, AJ, Huff, CA, Moreau, P, Dingli, D, Cole, C, Lonial, S, Dimopoulos, M, Stewart, AK, Richter, J, Vij, R, Tuchman, S, Raab, MS, Weisel, KC, Delforge, M, Cornell, RF, Kaminetzky, D, Hoffman, JE, Costa, LJ, Parker, TL, Levy, M, Schreder, M, Meuleman, N, Frenzel, L, Mohty, M, Choquet, S, Schiller, G, Comenzo, RL, Engelhardt, M, Illmer, T, Vlummens, P, Doyen, C, Facon, T, Karlin, L, Perrot, A, Podar, K, Kauffman, MG, Shacham, S, Li, L, Tang, S, Picklesimer, C, Saint-Martin, J-R, Crochiere, M, Chang, H, Parekh, S, Landesman, Y, Shah, J, Richardson, PG & Jagannath, S 2019, 'Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma', New England Journal of Medicine, vol. 381, no. 8, pp. 727-738. https://doi.org/10.1056/NEJMoa1903455

TY - JOUR

T1 - Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma

AU - Chari, Ajai

AU - Vogl, Dan T

AU - Gavriatopoulou, Maria

AU - Nooka, Ajay K

AU - Yee, Andrew J

AU - Huff, Carol A

AU - Moreau, Philippe

AU - Dingli, David

AU - Cole, Craig

AU - Lonial, Sagar

AU - Dimopoulos, Meletios

AU - Stewart, A Keith

AU - Richter, Joshua

AU - Vij, Ravi

AU - Tuchman, Sascha

AU - Raab, Marc S

AU - Weisel, Katja C

AU - Delforge, Michel

AU - Cornell, Robert F

AU - Kaminetzky, David

AU - Hoffman, James E

AU - Costa, Luciano J

AU - Parker, Terri L

AU - Levy, Moshe

AU - Schreder, Martin

AU - Meuleman, Nathalie

AU - Frenzel, Laurent

AU - Mohty, Mohamad

AU - Choquet, Sylvain

AU - Schiller, Gary

AU - Comenzo, Raymond L

AU - Engelhardt, Monika

AU - Illmer, Thomas

AU - Vlummens, Philip

AU - Doyen, Chantal

AU - Facon, Thierry

AU - Karlin, Lionel

AU - Perrot, Aurore

AU - Podar, Klaus

AU - Kauffman, Michael G

AU - Shacham, Sharon

AU - Li, Lingling

AU - Tang, Shijie

AU - Picklesimer, Carla

AU - Saint-Martin, Jean-Richard

AU - Crochiere, Marsha

AU - Chang, Hua

AU - Parekh, Samir

AU - Landesman, Yosef

AU - Shah, Jatin

AU - Richardson, Paul G

AU - Jagannath, Sundar

PY - 2019/8/22

Y1 - 2019/8/22

N2 - BACKGROUND: Selinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options.METHODS: We administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point.RESULTS: A total of 122 patients in the United States and Europe were included in the modified intention-to-treat population (primary analysis), and 123 were included in the safety population. The median age was 65 years, and the median number of previous regimens was 7; a total of 53% of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in 6 patients.CONCLUSIONS: Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM ClinicalTrials.gov number, NCT02336815.).

AB - BACKGROUND: Selinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options.METHODS: We administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point.RESULTS: A total of 122 patients in the United States and Europe were included in the modified intention-to-treat population (primary analysis), and 123 were included in the safety population. The median age was 65 years, and the median number of previous regimens was 7; a total of 53% of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in 6 patients.CONCLUSIONS: Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM ClinicalTrials.gov number, NCT02336815.).

KW - Administration, Oral

KW - Adult

KW - Aged

KW - Antineoplastic Combined Chemotherapy Protocols/adverse effects

KW - Biomarkers, Tumor/blood

KW - Dexamethasone/administration & dosage

KW - Drug Administration Schedule

KW - Drug Resistance, Neoplasm

KW - Female

KW - Humans

KW - Hydrazines/administration & dosage

KW - Intention to Treat Analysis

KW - Karyopherins/antagonists & inhibitors

KW - Male

KW - Middle Aged

KW - Multiple Myeloma/drug therapy

KW - Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors

KW - Survival Analysis

KW - Thrombocytopenia/chemically induced

KW - Triazoles/administration & dosage

KW - Young Adult

UR - http://www.scopus.com/inward/record.url?scp=85071342977&partnerID=8YFLogxK

U2 - 10.1056/NEJMoa1903455

DO - 10.1056/NEJMoa1903455

M3 - Journal article

C2 - 31433920

SN - 0028-4793

VL - 381

SP - 727

EP - 738

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 8

ER -

Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma

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