Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma

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

N1 - Copyright © 2019 Massachusetts Medical Society.

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.).

U2 - 10.1056/NEJMoa1903455

DO - 10.1056/NEJMoa1903455

M3 - SCORING: Journal article

C2 - 31433920

VL - 381

SP - 727

EP - 738

JO - NEW ENGL J MED

JF - NEW ENGL J MED

SN - 0028-4793

IS - 8

ER -