Selinexor Trials Move Nuclear Suppressor Protein-Export Inhibition Closer to the Clinic for Multiple Myeloma
Adverse events tied to selinexor appear to be common, however, requiring vigilant supportive care, dose delays, and modifications.
Exportin 1 (XPO1; also called chromosomal maintenance 1 or CRM1) orchestrates the export of nuclear proteins and RNA into surrounding cellular cytoplasm, via modulation of hundreds of “cargo proteins” that shuttle these products — including most tumor-suppressor proteins — through pores in the nuclear envelope. XPO1 is commonly overexpressed in multiple myeloma cells and other tumor cells, allowing them to clear p53, p73, FOXO, BRCA1, and other tumor-suppressor proteins that would normally counteract oncogene transcription.
“The central scientific insight that led to the development of XPO1 inhibitors was the understanding that most tumor-suppressor proteins, the glucocorticoid receptor, and many oncoprotein mRNAs are shuttled from the nucleus to the cytoplasm by a single transport protein: XPO1,” said Dan Vogl, MD, the Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Blocking XPO1-mediated nuclear export of tumor-suppressor proteins leads to their retention and accumulation in the nucleus, allowing them to block oncoprotein mRNA translation, he explained.1,2
Karyopharm Therapeutics' Selinexor (KPT-33) is a first-in-class, investigational XPO1 inhibitor. On November 7, 2018, the US Food and Drug Administration granted selinexor fast-track designation for patients with refractory diffuse large B-cell lymphoma (DLBCL) who cannot undergo high-dose chemotherapy with stem-cell rescue or chimeric antigen receptor T-cell (CAR-T) immunotherapy. Updated clinical trial findings from the phase 2 STORM study were presented at the American Society of Hematology (ASH) 2018 Annual Meeting in San Diego, California.
“Prior to conducting the trial [that was] presented this year at the ASH annual meeting, we conducted a preliminary phase 2 trial of selinexor and dexamethasone in 79 patients with quad- or penta-refractory myeloma using 2 different dosing schedules, demonstrating a promising response rate and acceptable toxicity that could be managed with appropriate supportive care,” Dr Vogl said.2
The findings included an “impressive response rate in patients who have myeloma that is refractory to all of the important classes of medications and who have essentially no other treatment options,” he added.
The overall response rate (ORR) was 21% overall and in patients with quad-refractory myeloma, and 20% among patients with penta-refractory disease.2 Patients with high-risk t(4;14), t(14;16) and del(17p) cytogenetic signatures had a higher response rate (6/17 patients; ORR 35%).2 The median response duration was 5 months, with 65% of responders alive at 12 months.2