Oral selinexor-dexamethasone for triple-class refractory multiple myeloma

A. Chari, D. T. Vogl, M. Gavriatopoulou, A. K. Nooka, A. J. Yee, C. A. Huff, P. Moreau, D. Dingli, C. Cole, S. Lonial, M. Dimopoulos, A. K. Stewart, J. Richter, R. Vij, S. Tuchman, M. S. Raab, K. C. Weisel, M. Delforge, R. F. Cornell, D. KaminetzkyJ. E. Hoffman, L. J. Costa, T. L. Parker, M. Levy, M. Schreder, N. Meuleman, L. Frenzel, M. Mohty, S. Choquet, G. Schiller, R. L. Comenzo, M. Engelhardt, T. Illmer, P. Vlummens, C. Doyen, T. Facon, L. Karlin, A. Perrot, K. Podar, M. G. Kauffman, S. Shacham, L. Li, S. Tang, C. Picklesimer, J. R. Saint-Martin, M. Crochiere, H. Chang, S. Parekh, Y. Landesman, J. Shah, P. G. Richardson, S. Jagannath

Research output: Contribution to journalArticle

5 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 languageEnglish (US)
Pages (from-to)727-738
Number of pages12
JournalNew England Journal of Medicine
Volume381
Issue number8
DOIs
StatePublished - Aug 22 2019

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Multiple Myeloma
Dexamethasone
Thrombocytopenia
Tumor Suppressor Proteins
Therapeutics
KPT-330
Proteasome Inhibitors
Cell Nucleus Active Transport
Alkylating Agents
Oncogene Proteins
Appetite
Advisory Committees
Chromosome Aberrations
Nausea
Population
Disease-Free Survival
Fatigue
Confidence Intervals
Hemorrhage
Safety

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Chari, A., Vogl, D. T., Gavriatopoulou, M., Nooka, A. K., Yee, A. J., Huff, C. A., ... 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

Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. / 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.; Kaminetzky, D.; Hoffman, J. E.; Costa, L. J.; Parker, T. L.; Levy, M.; Schreder, M.; Meuleman, N.; Frenzel, L.; Mohty, M.; Choquet, S.; Schiller, G.; Comenzo, R. L.; Engelhardt, M.; Illmer, T.; Vlummens, P.; Doyen, C.; Facon, T.; Karlin, L.; Perrot, A.; Podar, K.; Kauffman, M. G.; Shacham, S.; Li, L.; Tang, S.; Picklesimer, C.; Saint-Martin, J. R.; Crochiere, M.; Chang, H.; Parekh, S.; Landesman, Y.; Shah, J.; Richardson, P. G.; Jagannath, S.

In: New England Journal of Medicine, Vol. 381, No. 8, 22.08.2019, p. 727-738.

Research output: Contribution to journalArticle

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, JR, 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
Chari A, Vogl DT, Gavriatopoulou M, Nooka AK, Yee AJ, Huff CA et al. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. New England Journal of Medicine. 2019 Aug 22;381(8):727-738. https://doi.org/10.1056/NEJMoa1903455
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. ; Kaminetzky, D. ; Hoffman, J. E. ; Costa, L. J. ; Parker, T. L. ; Levy, M. ; Schreder, M. ; Meuleman, N. ; Frenzel, L. ; Mohty, M. ; Choquet, S. ; Schiller, G. ; Comenzo, R. L. ; Engelhardt, M. ; Illmer, T. ; Vlummens, P. ; Doyen, C. ; Facon, T. ; Karlin, L. ; Perrot, A. ; Podar, K. ; Kauffman, M. G. ; Shacham, S. ; Li, L. ; Tang, S. ; Picklesimer, C. ; Saint-Martin, J. R. ; Crochiere, M. ; Chang, H. ; Parekh, S. ; Landesman, Y. ; Shah, J. ; Richardson, P. G. ; Jagannath, S. / Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. In: New England Journal of Medicine. 2019 ; Vol. 381, No. 8. pp. 727-738.
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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.",
author = "A. Chari and Vogl, {D. T.} and M. Gavriatopoulou and Nooka, {A. K.} and Yee, {A. J.} and Huff, {C. A.} and P. Moreau and D. Dingli and C. Cole and S. Lonial and M. Dimopoulos and Stewart, {A. K.} and J. Richter and R. Vij and S. Tuchman and Raab, {M. S.} and Weisel, {K. C.} and M. Delforge and Cornell, {R. F.} and D. Kaminetzky and Hoffman, {J. E.} and Costa, {L. J.} and Parker, {T. L.} and M. Levy and M. Schreder and N. Meuleman and L. Frenzel and M. Mohty and S. Choquet and G. Schiller and Comenzo, {R. L.} and M. Engelhardt and T. Illmer and P. Vlummens and C. Doyen and T. Facon and L. Karlin and A. Perrot and K. Podar and Kauffman, {M. G.} and S. Shacham and L. Li and S. Tang and C. Picklesimer and Saint-Martin, {J. R.} and M. Crochiere and H. Chang and S. Parekh and Y. Landesman and J. Shah and Richardson, {P. G.} and S. Jagannath",
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month = "8",
day = "22",
doi = "10.1056/NEJMoa1903455",
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TY - JOUR

T1 - Oral selinexor-dexamethasone for triple-class refractory multiple myeloma

AU - Chari, A.

AU - Vogl, D. T.

AU - Gavriatopoulou, M.

AU - Nooka, A. K.

AU - Yee, A. J.

AU - Huff, C. A.

AU - Moreau, P.

AU - Dingli, D.

AU - Cole, C.

AU - Lonial, S.

AU - Dimopoulos, M.

AU - Stewart, A. K.

AU - Richter, J.

AU - Vij, R.

AU - Tuchman, S.

AU - Raab, M. S.

AU - Weisel, K. C.

AU - Delforge, M.

AU - Cornell, R. F.

AU - Kaminetzky, D.

AU - Hoffman, J. E.

AU - Costa, L. J.

AU - Parker, T. L.

AU - Levy, M.

AU - Schreder, M.

AU - Meuleman, N.

AU - Frenzel, L.

AU - Mohty, M.

AU - Choquet, S.

AU - Schiller, G.

AU - Comenzo, R. L.

AU - Engelhardt, M.

AU - Illmer, T.

AU - Vlummens, P.

AU - Doyen, C.

AU - Facon, T.

AU - Karlin, L.

AU - Perrot, A.

AU - Podar, K.

AU - Kauffman, M. G.

AU - Shacham, S.

AU - Li, L.

AU - Tang, S.

AU - Picklesimer, C.

AU - Saint-Martin, J. R.

AU - Crochiere, M.

AU - Chang, H.

AU - Parekh, S.

AU - Landesman, Y.

AU - Shah, J.

AU - Richardson, P. G.

AU - Jagannath, S.

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.

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