What is selinexor?
Selinexor is an oral selective nuclear export of exportin 1 (XPO1). XPO1 is the nuclear exporter of several proteins important for cell growth, including tumor suppressor proteins (TSPs) and oncoprotein messenger RNA (mRNA). Selinexor reversibly binds to XPO1, consequently accumulating TSPs, and reductions in oncoproteins such as c-myc and cyclin D1 occur, resulting in cell cycle arrest and apoptosis of malignant cells.
Selinexor is approved in combination with dexamethasone for adult patients with relapsed or refractory multiple myeloma (MM) who have received at least four prior therapies. Patients must have refractory disease to at least two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 monoclonal antibody.
What is the basis for this approval?
Selinexor received accelerated FDA approval based the results of a phase IIb, multicenter, open-label study entitled STORM (N Engl J Med 2019;381:727-738). STORM included 122 relapsed/refractory MM patients. Subjects were treated with oral selinexor 80 mg and dexamethasone 20 mg on twice weekly (Days 1 and 3 of each week). The primary endpoint was overall response rate (partial response or better) based on the International Myeloma Working Group (IMWG) uniform response criteria for multiple myeloma.
The median age of participants was 65 years and median number of prior myeloma therapies was seven. More than 50 percent of subjects had high-risk cytogenetics. A partial response or better was achieved in 26 percent with a 4-week median time to response. The response duration lasted 4.4 months with a median progression-free and overall survival of 3.7 and 8.6 months, respectively. Thrombocytopenia (73%), fatigue (73%), nausea (72%), and anemia (67%) were the most common recorded toxicities. Adverse events leading to dose modification or interruption included thrombocytopenia (43%), fatigue (16%), and neutropenia (11%).
How do you administer this drug?
Selinexor is administered by mouth at a dose of 80 mg twice weekly at approximately the same time of day with or without food. Dose reductions include 100 mg weekly, 80 mg weekly, and 60 mg weekly. Selinexor is available in 20 mg tablet blister packs based on dosage.
Are there any pre-medications needed?
Selinexor has moderate emetic potential, thus an oral 5-HT3 receptor antagonist should be given prior to selinexor. Rescue antiemetics may also be needed.
What are common side effects (> or =10%)?
* Central nervous system: fatigue, neurologic toxicity, mental status changes, dizziness, insomnia, headache
* Endocrine & metabolic: weight loss, hyponatremia, hyperglycemia, dehydration, hypokalemia
* Gastrointestinal: nausea, vomiting, diarrhea, decreased appetite, constipation, dysgeusia
* Hematologic & oncologic: thrombocytopenia, anemia, neutropenia, leukopenia, lymphocytopenia
* Renal: increased serum creatinine
* Respiratory: dyspnea, upper respiratory tract infection, cough, pneumonia, epistaxis
* Miscellaneous: fever, infection, blurred vision
What are uncommon side effects (< 10%)?
Infection: sepsis (6%) (Leukemia 2020; doi: 10.1038/s41375-020-0756-6)
Are there any important drug interactions?
Selinexor is metabolized by cytochrome P450 CYP3A4, multiple UDP-glycuronosyltransferases, and glutathione S-transferases. Selinexor does not appear to inhibit or induce major CYP-P450 enzyme pathways based on in vitro studies. Selinexor does inhibit OATP1B3, but not other transporters.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
No alterations of selinexor dose are required in the setting of mild to severe renal impairment (e.g., CrCl 15-89 mL/min) or mild hepatic impairment. Selinexor has not been studied in end-stage renal disease or moderate to severe hepatic impairment (Clin Lymphoma Myeloma Leuk 2019;19(10):e118-e119).
What should my patients know about selinexor?
Selinexor and prophylactic antiemetics should be taken as prescribed. Patients will require blood tests to monitor complete blood counts and serum chemistries at baseline and throughout treatment. Toxicities are common within the first 2 months of treatment, thus blood tests may be needed weekly to biweekly during that time.
What else should I know about selinexor?
* Thrombocytopenia was reported in 74 percent (~60% grade 3/4). Median onset was day 22. Patients should be educated to immediately report any signs or symptoms of bleeding.
* Neutropenia occurred in 34 percent with onset at day 25. Patients should promptly report any signs and symptoms of concomitant infection or fever. Supportive care with white blood cell colony stimulating factors or antimicrobials may commence.
* Diarrhea occurred in 44 percent. Patients should be counseled to obtain over-the-counter anti-diarrheal agents. Oral fluid intake should be maintained.
* Hyponatremia occurred in 39 percent. Presentation was most commonly within the first 2 weeks of therapy. Intravenous saline or salt tablets may be needed to correct hyponatremia.
* Neurologic toxicities including dizziness, syncope, and mental status changes were reported in 30 percent of patients, usually within 2 weeks of starting selinexor. Counsel patients to avoid medications that may cause overlap of toxicities and to avoid driving heavy machinery after taking selinexor.
What online resources are available?
* Prescribing Information: https://bit.ly/2XOvdu1
* FDA Accelerated Approval: https://bit.ly/2BhFs2g
Are there clinical trials for selinexor?
Selinexor is being trialed with concurrent chemotherapy in non-Hodgkin lymphoma and in combination with other therapies such as carfilzomib ixazomib in multiple myeloma. Selinexor trials are currently accruing solid tumor malignancies. Interestingly, selinexor has also been found to interfere with the SARS-CoV-2 virus replication and is being studied in patients with severe COVID-19. More information is available at https://clinicaltrials.gov.
HEIDI D. FINNES, PharmD, BCOP, is Senior Manager of Pharmacy Cancer Research and Assistant Professor of Pharmacy in the College of Medicine at Mayo Clinic, Rochester, Minn. JANELLE E. MANN, PHARMD, BCOP, is Clinical Oncology Pharmacist/ Manager, Clinical Pharmacy Services at Washington University School of Medicine, Saint Louis, Mo. She serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.