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J Clin Oncol. 2018 Mar 20;36(9):859-866. doi: 10.1200/JCO.2017.75.5207. Epub 2018 Jan 30.

Selective Inhibition of Nuclear Export With Oral Selinexor for Treatment of Relapsed or Refractory Multiple Myeloma.

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Dan T. Vogl, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; David Dingli, Mayo Clinic, Rochester, MN; Robert Frank Cornell, Vanderbilt University Medical Center, Nashville, TN; Carol Ann Huff, Johns Hopkins University, Baltimore, MD; Sundar Jagannath, Tisch Cancer Institute, Mount Sinai School of Medicine; David Kaminetzky, New York University Langone Medical Center; Ajai Chari, Icahn School of Medicine at Mount Sanai, New York, NY; Divaya Bhutani and Jeffrey Zonder, Karmanos Cancer Institute, Wayne State University, Detroit; Craig Cole, University of Michigan, Ann Arbor, MI; Rachid Baz, H. Lee Moffitt Cancer Center and Research Institute, Tampa; James E. Hoffman, Sylvester Cancer Center, University of Miami, Miami, FL; Ajay Nooka, Winship Cancer Institute, Emory University, Atlanta, GA; Joshua Richter and David Siegel, John Theurer Cancer Center at the Hackensack University Medical Center, Hackensack, NJ; Ravi Vij, Washington University School of Medicine, St Louis, MO; Andrzej Jakubowiak, University of Chicago Medical Center, Chicago, IL; Rafat Abonour, Indiana University Cancer Center, Indianapolis, IN; Gary Schiller, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA; Terri L. Parker, Yale School of Medicine, New Haven, CT; Luciano J. Costa, University of Alabama at Birmingham, Birmingham, AL; Andrew J. Yee, Massachusetts General Hospital Cancer Center, Boston; Michael Kauffman, Sharon Shacham, Jean-Richard Saint-Martin, Carla D. Picklesimer, and Cassandra Choe-Juliak, Karyopharm Therapeutics, Newton, MA; Rafael Fonseca, Scott Van Wier, Gregory Ahmann, Ilsel Lopez, and A. Keith Stewart, Mayo Clinic of Arizona, Phoenix, AZ.


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 ≥ 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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