Xpovio - Drug Monograph

Introduction

Xpovio (selinexor) is an oral, first-in-class selective inhibitor of nuclear export (SINE) compound approved by the FDA in 2019. It represents a novel mechanism of action in hematologic malignancies by targeting exportin 1 (XPO1), a key nuclear export protein. Xpovio is manufactured by Karyopharm Therapeutics and has revolutionized treatment approaches for patients with heavily pretreated multiple myeloma and diffuse large B-cell lymphoma.

Mechanism of Action

Xpovio functions as a selective inhibitor of nuclear export (SINE) by covalently binding to and inhibiting exportin 1 (XPO1), also known as chromosome region maintenance 1 (CRM1). XPO1 is responsible for transporting over 220 proteins from the nucleus to the cytoplasm, including tumor suppressor proteins (TSPs), growth regulators, and mRNA of oncogenic proteins.

By inhibiting XPO1, selinexor causes:

• Accumulation of TSPs (p53, p21, p73, FOXO, and Rb) in the nucleus
• Nuclear retention of oncoprotein mRNAs
• Downregulation of oncoprotein translation
• Cell cycle arrest and apoptosis of malignant cells
• Sensitization of cancer cells to other anticancer agents

Indications

Xpovio is FDA-approved for: 1. Multiple myeloma (in combination with dexamethasone) in adults who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody 2. Relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two systemic therapies

Dosage and Administration

• Multiple myeloma: 80 mg orally once weekly on days 1 and 3 of each week (in combination with 20 mg dexamethasone twice weekly)
• DLBCL: 60 mg orally once weekly on days 1 and 3 of each week

• Take with water
• Administer at approximately the same time of day
• Can be taken with or without food
• Tablets should be swallowed whole

• Recommended starting dose reduction for hematologic toxicity: 60 mg weekly
• Further reduction: 40 mg weekly
• Discontinue if toxicity persists at 40 mg weekly

• Renal impairment: No dosage adjustment needed for mild to moderate impairment; use with caution in severe impairment
• Hepatic impairment: No dosage adjustment needed for mild impairment; reduce dose in moderate to severe impairment
• Elderly: No dosage adjustment required based on age alone

Pharmacokinetics

• Median Tmax: 4 hours
• High-fat meal decreases AUC by 22% and Cmax by 42%

• Mean volume of distribution: 126 L
• Protein binding: 95%
• Blood-to-plasma ratio: 0.61

• Primarily metabolized by CYP3A4, UGT1A4, UGT1A3, and UGT1A9
• Forms inactive metabolites

• Mean elimination half-life: 6-8 hours
• Total clearance: 9.3 L/h
• Excretion: 50% feces (unchanged drug <10%), 30% urine (unchanged drug <10%)

Contraindications

Xpovio is contraindicated in patients with:

• Hypersensitivity to selinexor or any component of the formulation
• Pregnancy (based on mechanism of action and animal data)

Warnings and Precautions

• Reported in 74% of patients
• Monitor platelet counts at baseline, during treatment, and as clinically indicated
• May require dose interruptions, reductions, or platelet transfusions

• Reported in 34% of patients
• Monitor neutrophil counts at baseline and during treatment
• May require dose modifications or growth factor support

• Nausea/vomiting (72%), diarrhea (44%), anorexia (53%), weight loss (47%)
• Provide prophylactic antiemetics
• Monitor weight, nutritional status, and hydration

• Dizziness (30%), confusion (15%), delirium (5%)
• Advise patients to avoid driving or operating machinery

• New or exacerbation of cataracts reported
• Ophthalmologic evaluation recommended

• Can cause fetal harm based on mechanism of action
• Verify pregnancy status prior to initiation
• Advise effective contraception during treatment and for 1 week after last dose

Drug Interactions

• Avoid concomitant use with strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin)
• If unavoidable, monitor for increased selinexor toxicity

• Avoid concomitant use with strong CYP3A inducers (e.g., rifampin, carbamazepine, St. John's wort)
• May decrease selinexor efficacy

• Increased risk of bleeding with concomitant use
• Monitor coagulation parameters

• May potentiate neurological effects
• Use with caution with benzodiazepines, opioids, and other sedatives

Adverse Effects

• Fatigue (73%)
• Nausea (72%)
• Anorexia (53%)
• Diarrhea (44%)
• Vomiting (41%)
• Weight loss (38%)
• Constipation (31%)
• Dyspnea (25%)

• Thrombocytopenia (46%)
• Neutropenia (21%)
• Anemia (17%)
• Hyponatremia (13%)
• Infection (13%)
• Fatigue (10%)

Monitoring Parameters

• Complete blood count with differential
• Comprehensive metabolic panel (including sodium, potassium, creatinine, liver enzymes)
• Pregnancy test in women of reproductive potential
• Nutritional status and weight
• Performance status

• CBC weekly for first two months, then monthly
• Electrolytes (especially sodium) weekly for first month, then monthly
• Liver function tests monthly
• Weight at every visit
• Signs/symptoms of infection, bleeding, or neurological changes
• Hydration and nutritional status

• Ophthalmologic examinations
• Continued monitoring of blood counts and chemistry

Patient Education

• Take exactly as prescribed at scheduled times
• Do not crush or break tablets
• Report missed doses to healthcare provider

• Take anti-nausea medications as prescribed before doses
• Maintain adequate hydration (2-3 liters daily unless contraindicated)
• Eat small, frequent meals
• Report signs of infection (fever, chills), bleeding, or severe nausea/vomiting

• Avoid driving or operating machinery if experiencing dizziness or fatigue
• Use effective contraception during treatment and for 1 week after last dose
• Maintain regular follow-up appointments
• Inform all healthcare providers about Xpovio use

• Seek immediate medical attention for fever ≥100.4°F, unusual bleeding, severe dizziness, or confusion
• Carry patient wallet card provided by manufacturer

References

1. FDA Prescribing Information: Xpovio (selinexor). Revised 2023. 2. Chari A, Vogl DT, Gavriatopoulou M, et al. Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma. N Engl J Med. 2019;381(8):727-738. 3. Kalakonda N, Maerevoet M, Cavallo F, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 2020;7(7):e511-e522. 4. National Comprehensive Cancer Network. Multiple Myeloma Guidelines Version 3.2023. 5. Gasparetto C, Lentzsch S, Schiller G, et al. Selinexor in relapsed or refractory multiple myeloma after prior therapy with proteasome inhibitors and immunomodulatory agents: A retrospective study of the Mayo Clinic myeloma database. Am J Hematol. 2021;96(5):548-557. 6. Chen CI, Gutierrez M, de Larrea CF, et al. Clinical experience with selinexor in multiple myeloma patients refractory to previous therapies: a case series. Ther Adv Hematol. 2021;12:20406207211010832.