Selinexor
Selinexor, marketed under the brand name Xpovio, is an oral first-in-class selective inhibitor of nuclear export (SINE) approved for the treatment of adults with relapsed or refractory multiple myeloma (MM) and diffuse large B-cell lymphoma (DLBCL).[1][2] Developed by Karyopharm Therapeutics, it targets exportin-1 (XPO1), a key protein responsible for shuttling tumor suppressor proteins, growth regulators, and oncoproteins out of the cell nucleus, thereby forcing their accumulation in the nucleus to induce cancer cell apoptosis and inhibit proliferation.[3][4] The U.S. Food and Drug Administration (FDA) first granted accelerated approval to selinexor in July 2019 in combination with dexamethasone for adult patients with relapsed or refractory MM 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.[1] This approval was based on the phase IIb STORM trial, which demonstrated an overall response rate of 25.3% in heavily pretreated patients.[5] In December 2020, the FDA converted this to regular approval and expanded the indication to include patients with MM after at least one prior line of therapy, supported by the phase III BOSTON trial showing improved progression-free survival when combined with bortezomib and dexamethasone compared to standard therapy.[1] Additionally, in June 2020, selinexor received accelerated approval as a monotherapy for adults with relapsed or refractory DLBCL after at least two prior systemic therapies, based on the phase IIb SADAL trial with an overall response rate of 28%.[2][5] Selinexor's mechanism of action represents a novel therapeutic approach in oncology by disrupting nuclear-cytoplasmic transport, a process often dysregulated in cancers, leading to the reactivation of tumor suppressor functions and downregulation of oncogenic pathways without directly targeting DNA.[3][4] It is administered orally, with recommended dosing of 80 mg on Days 1 and 3 weekly with dexamethasone for heavily pretreated MM, 100 mg once weekly with bortezomib and dexamethasone for MM after one prior therapy, or 60 mg on Days 1 and 3 weekly as monotherapy for DLBCL, alongside supportive care for common adverse effects such as nausea, fatigue, and thrombocytopenia.[6] It has also received approvals in various countries, including China in July 2025 for MM combination therapy.[7] As of 2025, ongoing clinical trials are investigating its potential in other malignancies, including endometrial cancer (SIENDO trial) and myelofibrosis (SENTRY trial, enrollment completed September 2025).[8][9]Clinical Aspects
Medical Uses
Selinexor is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of relapsed or refractory multiple myeloma (RRMM) in adults. The FDA indication includes use in combination with dexamethasone for patients who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 monoclonal antibody.[1] It is also approved in combination with bortezomib and dexamethasone for adults who have received at least one prior line of therapy.[1] The EMA authorizes selinexor in combination with dexamethasone for adults with RRMM who have received at least four prior therapies meeting similar refractoriness criteria, and in combination with bortezomib and dexamethasone for those with at least one prior therapy.[10] As the first-in-class selective inhibitor of nuclear export (SINE) compound, selinexor addresses an unmet need in quadruple- or penta-refractory multiple myeloma patients, where standard therapies have failed.[11] In the pivotal phase 2b STORM trial evaluating selinexor plus dexamethasone in penta-refractory RRMM patients, the overall response rate (ORR) was 25.3%, with a median duration of response of 3.8 months among responders. This regimen provides a mechanism of action that promotes nuclear retention of tumor suppressor proteins, offering clinical benefit in heavily pretreated multiple myeloma cases despite common adverse effects such as thrombocytopenia that may require monitoring in eligible patients. Selinexor is also approved by the FDA as monotherapy for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified—including DLBCL arising from follicular lymphoma—after at least two prior lines of systemic therapy.[2] Patient eligibility typically requires ineligibility for or failure of hematopoietic stem cell transplantation and prior therapies including anti-CD20 monoclonal antibodies, but excludes those with high-grade lymphomas other than DLBCL.[2] In the phase 2b SADAL trial of monotherapy selinexor in relapsed or refractory DLBCL after two to five prior therapies, the ORR was 28.3%, including a 12.1% complete response rate, with responses observed across germinal center B-cell and non-germinal center B-cell subtypes.[12]Adverse Effects
Selinexor treatment is commonly associated with hematologic and gastrointestinal adverse effects. The most frequent adverse events reported in clinical trials include thrombocytopenia (73% all grades, 58% Grade 3/4), nausea (72% all grades, 9% Grade 3/4), fatigue (73% all grades, 25% Grade 3/4), anemia (52% all grades, 44% Grade 3/4), and hyponatremia (40% all grades, 24% Grade 3/4).[6] These effects are observed across indications such as multiple myeloma and diffuse large B-cell lymphoma (DLBCL), where selinexor is frequently used in relapsed or refractory settings.[6] Serious adverse risks encompass gastrointestinal toxicity, including vomiting and diarrhea, neurological effects such as dizziness and delirium, and infections secondary to neutropenia (20% Grade 3/4).[6] The FDA prescribing information highlights boxed warnings for fatal infections, thrombocytopenia, and hyponatremia, emphasizing the need for vigilant monitoring to mitigate these potentially life-threatening complications.[13] Adverse effects are managed through dose interruptions or reductions—for instance, reducing from 80 mg to 60 mg weekly—as well as supportive measures like antiemetics for nausea and thrombopoietin mimetics for thrombocytopenia.[6][14] In pivotal trials, approximately 19% of patients discontinued selinexor due to adverse events, underscoring the importance of proactive tolerability strategies.[6]Dosage and Administration
Selinexor is administered orally in tablet form for the treatment of relapsed or refractory multiple myeloma (RRMM) and diffuse large B-cell lymphoma (DLBCL).[6] For RRMM in combination with dexamethasone (Xd regimen), the recommended dosage is 80 mg taken orally on Days 1 and 3 of each week until disease progression or unacceptable toxicity.[6] In combination with bortezomib and dexamethasone (XVd regimen) for RRMM after at least one prior line of therapy, the dosage is 100 mg taken orally once weekly on Day 1 of each week until disease progression or unacceptable toxicity.[6] For adult patients with relapsed or refractory DLBCL after at least two prior systemic therapies, the recommended dosage is 60 mg taken orally on Days 1 and 3 of each week until disease progression or unacceptable toxicity.[6] Tablets should be swallowed whole with water, with or without food, at approximately the same time each day; they must not be broken, chewed, crushed, or divided.[6] If a dose is missed or vomited, the next dose should be taken at the regularly scheduled time without doubling the dose.[6] Prophylactic antiemetics, such as a 5-HT3 receptor antagonist and an antihistamine, are recommended prior to each dose to manage nausea and vomiting.[6] Patients should maintain adequate fluid and caloric intake throughout treatment.[6] Monitoring of complete blood counts (CBC), blood chemistries including electrolytes, and weight is required at baseline and regularly during treatment, with increased frequency during the first three months to detect hematologic toxicities early.[6] Dose interruptions and reductions are recommended for adverse reactions, with stepwise reductions available: for the 80 mg or 60 mg twice-weekly regimens, reduce to 60 mg or 40 mg, respectively, on Days 1 and 3; for the 100 mg once-weekly regimen, reduce to 80 mg, then 60 mg weekly.[6]| Adverse Reaction | Dosage Modification Guidelines |
|---|---|
| Hematologic Toxicities (e.g., Thrombocytopenia, Neutropenia, Anemia) | Grade 3/4: Interrupt until recovery to Grade 2 or less, then resume at reduced dose. Platelets <25,000/mcL: Interrupt and transfuse if needed; resume at reduced dose.[6] |
| Non-Hematologic Toxicities (e.g., Nausea ≥Grade 3, Diarrhea ≥Grade 3, Hyponatremia) | Grade 3/4: Interrupt until recovery to Grade 2 or less, then resume at reduced dose with supportive care. For persistent Grade 2 non-hematologic toxicity: Consider dose reduction.[6] |