Ajai Chari1, Dan T Vogl1, Maria Gavriatopoulou1, Ajay K Nooka1, Andrew J Yee1, Carol A Huff1, Philippe Moreau1, David Dingli1, Craig Cole1, Sagar Lonial1, Meletios Dimopoulos1, A Keith Stewart1, Joshua Richter1, Ravi Vij1, Sascha Tuchman1, Marc S Raab1, Katja C Weisel1, Michel Delforge1, Robert F Cornell1, David Kaminetzky1, James E Hoffman1, Luciano J Costa1, Terri L Parker1, Moshe Levy1, Martin Schreder1, Nathalie Meuleman1, Laurent Frenzel1, Mohamad Mohty1, Sylvain Choquet1, Gary Schiller1, Raymond L Comenzo1, Monika Engelhardt1, Thomas Illmer1, Philip Vlummens1, Chantal Doyen1, Thierry Facon1, Lionel Karlin1, Aurore Perrot1, Klaus Podar1, Michael G Kauffman1, Sharon Shacham1, Lingling Li1, Shijie Tang1, Carla Picklesimer1, Jean-Richard Saint-Martin1, Marsha Crochiere1, Hua Chang1, Samir Parekh1, Yosef Landesman1, Jatin Shah1, Paul G Richardson1, Sundar Jagannath1. 1. From the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai (A.C., S.P., S.J.), and New York University Langone Medical Center (D.K.) - both in New York; the Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.T.V.); the School of Medicine, National and Kapodistrian University of Athens, Athens (M.G., M. Dimopoulos); the Winship Cancer Institute, Emory University, Atlanta (A.K.N., S.L.); Massachusetts General Hospital Cancer Center (A.J.Y.), Tufts Medical Center (R.L.C.), and the Dana-Farber Cancer Institute (P.G.R.), Boston, and Karyopharm Therapeutics, Newton (M.G.K., S.S., L.L., S. Tang, C.P., J.-R.S.-M., M.C., H.C., Y.L., J.S.) - all in Massachusetts; Johns Hopkins University, Baltimore (C.A.H.); the University of Nantes, Nantes (P.M.), Hôpital Necker (L.F.), Hôpital Saint-Antoine (M.M.), and La Pitié-Salpêtrière Hospital (S.C.), Paris, University Hospital, Lille (T.F.), Centre Hospitalier Lyon Sud, Pierre-Benite (L.K.), and Centre Hospitalo-Universitaire Vandoeuvre-lès-Nancy, Nancy (A.P.) - all in France; the Mayo Clinic, Rochester, MN (D.D.); the University of Michigan, Ann Arbor (C.C.); the Mayo Clinic of Arizona, Phoenix (A.K.S.); Hackensack University Medical Center, Hackensack, NJ (J.R.); Washington University School of Medicine, St. Louis (R.V.); Lineberger Comprehensive Cancer Center at University of North Carolina-Chapel Hill, Chapel Hill (S. Tuchman); the University of Heidelberg, Heidelberg (M.S.R.), University Medical Center Hamburg-Eppendorf, Hamburg (K.C.W.), the University of Tübingen, Tübingen (K.C.W.), University Hospital Würzburg, Würzburg (M.S.), the University of Freiburg, Freiburg (M.E.), and Gemeinschaftspraxis Hämatologie-Onkologie, Dresden (T.I.) - all in Germany; the University of Leuven, Leuven (M. Delforge), Institut Jules Bordet, Université Libre de Bruxelles, Brussels (N.M.), University Hospital Ghent, Ghent (P.V.), and Centre Hospitalier Universitaire Université Catholique de Louvain Namur, Yvoir (C.D.) - all in Belgium; Vanderbilt University Medical Center, Nashville (R.F.C.); Sylvester Cancer Center, University of Miami, Miami (J.E.H.); the University of Alabama at Birmingham, Birmingham (L.J.C.); Yale School of Medicine, New Haven, CT (T.L.P.); Baylor University Medical Center, Dallas (M.L.); the David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles (G.S.); and University Hospital Krems, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria (K.P.).
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.).
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.).
Authors: Christie P M Verkleij; Marloes E C Broekmans; Mark van Duin; Kristine A Frerichs; Rowan Kuiper; A Vera de Jonge; Martin Kaiser; Gareth Morgan; Amy Axel; Rengasamy Boominathan; Jocelyn Sendecki; Amy Wong; Raluca I Verona; Pieter Sonneveld; Sonja Zweegman; Homer C Adams; Tuna Mutis; Niels W C J van de Donk Journal: Blood Adv Date: 2021-04-27
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Authors: William C Hahn; Joel S Bader; Theodore P Braun; Andrea Califano; Paul A Clemons; Brian J Druker; Andrew J Ewald; Haian Fu; Subhashini Jagu; Christopher J Kemp; William Kim; Calvin J Kuo; Michael McManus; Gordon B Mills; Xiulei Mo; Nidhi Sahni; Stuart L Schreiber; Jessica A Talamas; Pablo Tamayo; Jeffrey W Tyner; Bridget K Wagner; William A Weiss; Daniela S Gerhard Journal: Cell Date: 2021-03-04 Impact factor: 41.582
Authors: Yvette L Kasamon; Lauren S L Price; Olanrewaju O Okusanya; Nicholas C Richardson; Ruo-Jing Li; Lian Ma; Yu-Te Wu; Marc Theoret; Richard Pazdur; Nicole J Gormley Journal: Oncologist Date: 2021-07-01