Selinexor is a nuclear export inhibitor. Selinexor is (2 Z )-3-{3-[3,5-bis(trifluoromethyl)phenyl]-1 H -1,2,4-triazol-1-yl}- N '-(pyrazin-2-yl)prop-2-enehydrazide. It is a white to off-white powder and has the molecular formula C 17 H 11 F 6 N 7 O and a molecular mass of 443.31 g/mol. The molecular structure is shown below: XPOVIO tablets for oral dosing are supplied in six strengths, with each tablet containing 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, or 80 mg of selinexor as the active ingredient. The inactive ingredients are colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, Opadry 200 clear, Opadry II blue, povidone K30, and sodium lauryl sulfate. Molecular Structure

XPOVIO is a nuclear export inhibitor indicated: In combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. In combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma 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

Multiple Myeloma XPOVIO in combination with bortezomib and dexamethasone is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. XPOVIO in combination with dexamethasone is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma 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.

Tablets: 10 mg, blue, round, bi-convex, film-coated tablets with “X10” debossed on one side and nothing on the other side. 20 mg, blue, round, bi-convex, film-coated tablets with “K20” debossed on one side and nothing on the other side. 40 mg tablets, blue, oval, film-coated, debossed on both sides with “X40”. 50 mg tablets, blue, oval, film-coated, debossed on both sides with “X50”. 60 mg tablets, blue, oval, film-coated, debossed on both sides with “X60”. 80 mg tablets, blue, oval, film-coated, debossed on both sides with “X80”. Tablets:10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg.

Multiple Myeloma in Combination with Bortezomib and Dexamethasone (XVd) : Recommended dosage of XPOVIO is 100 mg taken orally once weekly in combination with bortezomib and dexamethasone. Multiple Myeloma in Combination with Dexamethasone (Xd) : Recommended dosage of XPOVIO is 80 mg taken orally on Days 1 and 3 of each week in combination with dexamethasone. See Full Prescribing Information for dosage in patients with severe hepatic impairment

Recommended Dosage for Multiple Myeloma In Combination with Bortezomib and Dexamethasone (XVd) The recommended dosage of XPOVIO is 100 mg taken orally once weekly on Day 1 of each week until disease progression or unacceptable toxicity in combination with: Bortezomib 1.3 mg/m 2 administered subcutaneously once weekly on Day 1 of each week for 4 weeks followed by 1 week off. Dexamethasone 20 mg taken orally twice weekly on Days 1 and 2 of each week. Refer to Clinical Studies and the prescribing information of bortezomib and dexamethasone for additional dosing information. In Combination with Dexamethasone (Xd) The recommended dosage of XPOVIO is 80 mg taken orally on Days 1 and 3 of each week until disease progression or unacceptable toxicity in combination with dexamethasone 20 mg taken orally with each dose of XPOVIO on Days 1 and 3 of each week. For additional information regarding the administration of dexamethasone, refer to its prescribing information

Recommended Monitoring for Safety Monitor complete blood count (CBC) with differential, standard blood chemistries, body weight, nutritional status, and volume status at baseline and during treatment as clinically indicated. Monitor more frequently during the first three months of treatment . Assess the need for dosage modifications of XPOVIO for adverse reactions

Recommended Concomitant Treatments Advise patients to maintain adequate fluid and caloric intake throughout treatment. Consider intravenous hydration for patients at risk of dehydration . Provide prophylactic antiemetics. Administer a 5-HT3 receptor antagonist and other anti-nausea agents prior to and during treatment with XPOVIO

Dosage Modifications for Adverse Reactions Recommended XPOVIO dosage reduction steps are presented in Table 1 . Table 1: XPOVIO Dosage Reduction Steps for Adverse Reactions Recommended Starting Dosage Multiple Myeloma In Combination with Bortezomib and Dexamethasone (XVd) Multiple Myeloma In Combination with Dexamethasone (Xd) 100 mg once weekly 80 mg Days 1 and 3 of each week (160 mg total per week) First Reduction 80 mg once weekly 100 mg once weekly Second Reduction 60 mg once weekly 80 mg once weekly Third Reduction 40 mg once weekly 60 mg once weekly Fourth Reduction Permanently discontinue Permanently discontinue Recommended dosage modifications for hematologic adverse reactions in patients with multiple myeloma are presented in Table 2 . Recommended dosage modifications for non-hematologic adverse reactions are presented in Table 3 . Table 2: XPOVIO Dosage Modification Guidelines for Hematologic Adverse Reactions in Patients with Multiple Myeloma Adverse Reaction Occurrence Action Thrombocytopenia Platelet count 25,000 to less than 75,000/mcL Any Reduce XPOVIO by 1 dose level . Platelet count 25,000 to less than 75,000/mcL with concurrent bleeding Any Interrupt XPOVIO. Restart XPOVIO at 1 dose level lower after bleeding has resolved. Administer platelet transfusions per clinical guidelines. Platelet count less than 25,000/mcL Any Interrupt XPOVIO. Monitor until platelet count returns to at least 50,000/mcL. Restart XPOVIO at 1 dose level lower . Neutropenia Absolute neutrophil count of 0.5 to 1 x 10 9 /L without fever Any Reduce XPOVIO by 1 dose level . Absolute neutrophil count less than 0.5 x 10 9 /L OR febrile neutropenia Any Interrupt XPOVIO. Monitor until neutrophil counts return to 1 x 10 9 /L or higher. Restart XPOVIO at 1 dose level lower . Anemia Hemoglobin less than 8 g/dL Any Reduce XPOVIO by 1 dose level . Administer blood transfusions per clinical guidelines. Life-threatening consequences Any Interrupt XPOVIO. Monitor hemoglobin until levels return to 8 g/dL or higher. Restart XPOVIO at 1 dose level lower . Administer blood transfusions per clinical guidelines. Table 3: XPOVIO Dosage Modification Guidelines for Non-Hematologic Adverse Reactions Adverse Reaction Occurrence Action Nausea and Vomiting Grade 1 or 2 nausea (oral intake decreased without significant weight loss, dehydration or malnutrition) OR Grade 1 or 2 vomiting (5 or fewer episodes per day) Any Maintain XPOVIO and initiate additional anti-nausea medications. Grade 3 nausea (inadequate oral caloric or fluid intake) OR Grade 3 or higher vomiting (6 or more episodes per day) Any Interrupt XPOVIO. Monitor until nausea or vomiting has resolved to Grade 2 or lower or baseline. Initiate additional anti-nausea medications. Restart XPOVIO at 1 dose level lower . Diarrhea Grade 2 (increase of 4 to 6 stools per day over baseline) 1 st Maintain XPOVIO and institute supportive care. 2 nd and subsequent Reduce XPOVIO by 1 dose level . Institute supportive care. Grade 3 or higher (increase of 7 stools or more per day over baseline; hospitalization indicated) Any Interrupt XPOVIO and institute supportive care. Monitor until diarrhea resolves to Grade 2 or lower. Restart XPOVIO at 1 dose level lower . Weight Loss and Anorexia Weight loss of 10% to less than 20% OR Anorexia associated with significant weight loss or malnutrition Any Interrupt XPOVIO and institute supportive care. Monitor until weight returns to more than 90% of baseline weight. Restart XPOVIO at 1 dose level lower . Hyponatremia Sodium level 130 mmol/L or less Any Interrupt XPOVIO, evaluate, and provide supportive care. Monitor until sodium levels return to greater than 130 mmol/L. Restart XPOVIO at 1 dose level lower . Fatigue Grade 2 lasting greater than 7 days OR Grade 3 Any Interrupt XPOVIO. Monitor until fatigue resolves to Grade 1 or baseline. Restart XPOVIO at 1 dose level lower . Ocular Toxicity Grade 2, excluding cataract Any Perform ophthalmologic evaluation. Interrupt XPOVIO and provide supportive care. Monitor until ocular symptoms resolve to Grade 1 or baseline. Restart XPOVIO at 1 dose level lower . Grade ≥3, excluding cataract Any Permanently discontinue XPOVIO. Perform ophthalmologic evaluation. Other Non-Hematologic Adverse Reactions Grade 3 or 4 Any Interrupt XPOVIO. Monitor until resolved to Grade 2 or lower; restart XPOVIO at 1 dose level lower

Starting Dosage and Dosage Modifications for Adverse Reactions in Patients with Severe Hepatic Impairment For patients with severe hepatic impairment, defined by NCI-ODWG (National Cancer Institute Organ Dysfunction Working Group) criteria as total bilirubin >3x upper limit of normal with any level of AST, use the starting dosage of XPOVIO as shown in Table 4 . See Table 5 for dosage modifications for adverse reactions in patients with severe hepatic impairment. Table 4: XPOVIO Starting Dosage in Patients with Severe Hepatic Impairment AST = aspartate aminotransferase; ULN = upper limit of normal Total Bilirubin Levels XPOVIO Dosage Multiple Myeloma in Combination with Bortezomib and Dexamethasone (XVd) Multiple Myeloma in Combination with Dexamethasone (Xd) >3x ULN (and any AST) 80 mg once weekly 100 mg once weekly Table 5: XPOVIO Dosage Modifications for Adverse Reactions for Patients with Severe Hepatic Impairment Multiple Myeloma In Combination with Bortezomib and Dexamethasone (XVd) Multiple Myeloma In Combination with Dexamethasone (Xd) Recommended Starting Dosage 80 mg once weekly 100 mg once weekly First Reduction 60 mg once weekly 80 mg once weekly Second Reduction 40 mg once weekly 60 mg once weekly Third Reduction Permanently discontinue Permanently discontinue 2.6 Administration Each XPOVIO dose should be taken at approximately the same time of day and each tablet should be swallowed whole with water. Do not break, chew, crush, or divide the tablets. If a dose of XPOVIO is missed or delayed, instruct patients to take their next dose at the next regularly scheduled time. If a patient vomits a dose of XPOVIO, the patient should not repeat the dose and the patient should take the next dose on the next regularly scheduled day.

Thrombocytopenia : Monitor platelet counts throughout treatment. Manage with dose interruption and/or reduction and supportive care. Neutropenia : Monitor neutrophil counts throughout treatment. Manage with dose interruption and/or reduction and granulocyte colony-stimulating factors. Gastrointestinal Toxicity : Nausea, vomiting, diarrhea, anorexia, and weight loss may occur. Provide antiemetic prophylaxis. Manage with dose interruption and/or reduction, antiemetics, and supportive care. Hyponatremia : Monitor serum sodium levels throughout treatment. Correct for concurrent hyperglycemia and high serum paraprotein levels. Manage with dose interruption, reduction, or discontinuation, and supportive care. Serious Infection : Monitor for infection and treat promptly. Neurological Toxicity : Advise patients to refrain from driving and engaging in hazardous occupations or activities until neurological toxicity resolves. Optimize hydration status and concomitant medications to avoid dizziness or mental status changes. Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential and males with a female partner of reproductive potential, of the potential risk to a fetus and use of effective contraception ( 5.7 , 8.1 , 8.3 ). Cataract : Cataracts may develop or progress. Treatment of cataracts usually requires surgical removal of the cataract

Thrombocytopenia XPOVIO can cause life-threatening thrombocytopenia, potentially leading to hemorrhage. Thrombocytopenia is the leading cause of dosage modifications . In patients with multiple myeloma who received XPOVIO 100 mg once weekly (BOSTON, n=195), thrombocytopenia was reported in 92% of patients and severe (Grade 3-4) thrombocytopenia was reported in 43% of patients. The median time to first onset was 22 days for any grade thrombocytopenia and 43 days for Grade 3 or 4 thrombocytopenia. Bleeding occurred in 16% of patients with thrombocytopenia, clinically significant bleeding (Grade ≥3 bleeding) occurred in 4% of patients with thrombocytopenia, and fatal hemorrhage occurred in 2% of patients with thrombocytopenia. Permanent discontinuations of XPOVIO due to thrombocytopenia occurred in 2% of patients. In patients with multiple myeloma who received XPOVIO 80 mg twice weekly (STORM, n=202), thrombocytopenia was reported as an adverse reaction in 74% of patients and severe (Grade 3-4) thrombocytopenia was reported in 61% of patients. The median time to onset of the first event was 22 days. Bleeding occurred in 23% of patients with thrombocytopenia, clinically significant bleeding occurred in 5% of patients with thrombocytopenia, and fatal hemorrhage occurred in <1% of patients. Monitor platelet counts at baseline and throughout treatment. Monitor more frequently during the first three months of treatment. Institute platelet transfusion and/or other treatments as clinically indicated. Monitor patients for signs and symptoms of bleeding and evaluate promptly. Interrupt, reduce dose, or permanently discontinue based on severity of adverse reaction

Neutropenia XPOVIO can cause life-threatening neutropenia, potentially increasing the risk of infection . In patients with multiple myeloma who received XPOVIO 100 mg once weekly (BOSTON, n=195), neutropenia was reported in 48% of patients and severe neutropenia (Grade 3-4) was reported in 12% of patients. The median time to onset of the first event was 23 days for any grade neutropenia and 40 days for Grade 3-4 neutropenia. Febrile neutropenia was reported in <1% of patients. In patients with multiple myeloma who received XPOVIO 80 mg twice weekly (STORM, n=202), neutropenia was reported as an adverse reaction in 34% of patients and severe (Grade 3-4) neutropenia was reported in 21% of patients. The median time to onset of the first event was 25 days. Febrile neutropenia was reported in 3% of patients. Obtain white blood cell counts with differential at baseline and throughout treatment. Monitor more frequently during the first three months of treatment. Monitor patients for signs and symptoms of concomitant infection and evaluate promptly. Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF). Interrupt, reduce dose or permanently discontinue based on severity of adverse reaction

Gastrointestinal Toxicity XPOVIO can cause severe gastrointestinal toxicities . Nausea/Vomiting In patients with multiple myeloma who received XPOVIO once weekly (BOSTON, n=195) with use of antiemetic prophylaxis (88% of patients), nausea was reported in 50% of patients and Grade 3 nausea was reported in 8% of patients. The median time to onset of the first event was 6 days. Vomiting was reported in 21% of patients and Grade 3 vomiting was reported in 4.1% of patients. The median time to onset of the first event was 8 days. Permanent discontinuation due to nausea occurred in 3.1% of patients and due to vomiting occurred in 2.1% of patients. In patients with multiple myeloma receiving XPOVIO 80 mg twice weekly (STORM, n=202) with use of antiemetic prophylaxis, nausea was reported as an adverse reaction in 72% of patients and Grade 3 nausea occurred in 9%. The median time to first onset of nausea was 3 days. Vomiting was reported in 41% of patients and Grade 3 vomiting occurred in 4% of patients. The median time to first onset of vomiting was 5 days. Provide prophylactic antiemetics. Administer 5-HT3 receptor antagonists and other anti-nausea agents prior to and during treatment with XPOVIO. Interrupt, reduce dose or permanently discontinue based on severity of adverse reaction . Administer intravenous fluids to prevent dehydration and replace electrolytes as clinically indicated. Diarrhea In patients with multiple myeloma who received XPOVIO once weekly (BOSTON, n=195), diarrhea was reported in 32% of patients and Grade 3 diarrhea was reported in 6% of patients. The median time to onset of the first event was 50 days. Permanent discontinuation due to diarrhea occurred in 1% of patients. In patients with multiple myeloma who received XPOVIO 80 mg twice weekly (STORM, n=202), diarrhea was reported as an adverse reaction in 44% of patients and Grade 3 diarrhea occurred in 6% of patients. The median time to onset of diarrhea was 15 days. Interrupt, reduce dose or permanently discontinue based on severity of adverse reaction . Provide standard anti-diarrheal agents, administer intravenous fluids to prevent dehydration and replace electrolytes as clinically indicated. Anorexia/Weight Loss In patients with multiple myeloma who received XPOVIO 100 mg once weekly (BOSTON, n=195), anorexia was reported in 35% of patients and Grade 3 anorexia was reported in 3.6% of patients. The median time to onset of the first event was 35 days. Permanent discontinuations due to anorexia occurred in 2.1% of patients. Weight loss was reported in 26% of patients and Grade 3 weight loss was reported in 2.1% of patients. The median time to onset of the first event was 58 days. Permanent discontinuation due to weight loss occurred in 1% of patients. In patients with multiple myeloma who received XPOVIO 80 mg twice weekly (STORM n=202), anorexia was reported as an adverse reaction in 53% of patients and Grade 3 anorexia occurred in 5% of patients. The median time to onset of anorexia was 8 days. Weight loss was reported as an adverse reaction in 47% of patients and Grade 3 weight loss occurred in 1% of patients treated with XPOVIO. The median time to onset of weight loss was 15 days. Monitor weight, nutritional status, and volume status at baseline and throughout treatment. Monitor more frequently during the first three months of treatment. Interrupt, reduce dose or permanently discontinue based on severity of adverse reaction . Provide nutritional support, fluids, and electrolyte repletion as clinically indicated

Hyponatremia XPOVIO can cause severe or life-threatening hyponatremia . In patients with multiple myeloma who received XPOVIO 100 mg once weekly (BOSTON, n=195), hyponatremia was reported in 58% of patients and Grade 3-4 hyponatremia was reported in 14% of patients. The median time to first onset was 21 days for any grade hyponatremia and the median time to first onset for Grade 3 or 4 hyponatremia was 22 days. In patients with multiple myeloma who received XPOVIO 80 mg twice weekly (STORM, n=202), hyponatremia was reported as an adverse reaction in 39% of patients and Grade 3 or 4 hyponatremia was reported in 22% of patients. The median time to onset of the first event was 8 days. Monitor sodium level at baseline and throughout treatment. Monitor more frequently during the first two months of treatment. Correct sodium levels for concurrent hyperglycemia (serum glucose >150 mg/dL) and high serum paraprotein levels. Assess hydration status and manage hyponatremia per clinical guidelines, including intravenous saline and/or salt tablets as appropriate and dietary review. Interrupt, reduce dose or permanently discontinue based on severity of the adverse reaction

Serious Infection XPOVIO can cause serious and fatal infections. Most of these infections were not associated with Grade 3 or higher neutropenia . In patients with multiple myeloma who received XPOVIO 100 mg once weekly (BOSTON, n=195), 69% of patients experienced any grade of infection. Grade ≥3 infections were reported in 32% of patients, and deaths from infections occurred in 3.1% of patients. The most frequently reported Grade ≥3 infection was pneumonia in 14% of patients, followed by sepsis in 4.1% and upper respiratory tract infection in 3.6% of patients. In patients with multiple myeloma who received XPOVIO 80 mg twice weekly (STORM, n=202), 52% of patients experienced any grade of infection. Grade ≥3 infections were reported in 25% of patients, and deaths from infections occurred in 4% of patients within 30 days of last treatment. Upper respiratory tract infection of any grade occurred in 21%, pneumonia in 13%, and sepsis in 6% of patients. The most frequently reported Grade ≥3 infections were pneumonia in 9% of patients, followed by sepsis in 6%. The median time to onset was 54 days for pneumonia and 42 days for sepsis. Atypical infections reported after XPOVIO include, but are not limited to, fungal pneumonia and herpes virus infection. Monitor for signs and symptoms of infection, evaluate and treat promptly

Neurological Toxicity XPOVIO can cause life-threatening neurological toxicities . In patients with multiple myeloma who received XPOVIO 100 mg once weekly (BOSTON, n=195), neurological adverse reactions (excluding peripheral neuropathy) including dizziness, syncope, depressed level of consciousness, vertigo, amnesia, and mental status changes (including delirium and confusional state) occurred in 26% of patients and severe events (Grade 3-4) occurred in 3.6% of patients. The median time to the first event was 29 days. Permanent discontinuation due to neurological adverse reactions occurred in 2.1% of patients. In patients with multiple myeloma who received XPOVIO 80 mg twice weekly (STORM, n=202), neurological adverse reactions, including dizziness, syncope, depressed level of consciousness, and mental status changes (including delirium and confusional state) occurred in 30% of patients and severe events (Grade 3-4) occurred in 9% of patients. The median time to the first event was 15 days. Coadministration of XPOVIO with other products that cause dizziness or mental status changes may increase the risk of neurological toxicity. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, until the neurological toxicity fully resolves. Optimize hydration status, hemoglobin level, and concomitant medications to avoid exacerbating dizziness or mental status changes. Institute fall precautions as appropriate

Embryo-Fetal Toxicity Based on data from animal studies and its mechanism of action, XPOVIO can cause fetal harm when administered to a pregnant woman. Selinexor administration to pregnant animals during organogenesis resulted in structural abnormalities and alterations to growth at exposures below those occurring clinically at the recommended dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with a female partner of reproductive potential to use effective contraception during treatment with XPOVIO and for 1 week after the last dose

Cataract New onset or exacerbation of cataract has occurred during treatment with XPOVIO . In patients with multiple myeloma who received XPOVIO 100 mg once weekly (BOSTON, n=195), the incidence of new onset or worsening cataracts requiring clinical intervention was reported in 22% of patients. The median time to new onset of cataract was 228 days and was 237 days for worsening of cataract in patients presenting with cataract at start of XPOVIO therapy. Treatment of cataracts usually requires surgical removal of the cataract.