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

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

313 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
Pages (from-to)727-738
Number of pages12
JournalNew England Journal of Medicine
Volume381
Issue number8
DOIs
Publication statusPublished - 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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