Overview
Selinexor belongs to a class of medications called selective inhibitors of nuclear export (SINE). It is indicated along with Dexamethasone to treat relapsed refractory multiple myeloma (RRMM) in adult patients treated with at least one or other medication or in patients who have received at least four prior therapies, but the disease has worsened since the last treatment. It was approved by the United States Food and Drug Administration (USFDA) in 2019 and received conditional marketing authorization from the European Medicines Agency (EMA) on 28th January 2021.
How Does Selinexor Work?
A protein called exportin one (XPO1), a major mediator of nuclear export of many cargo proteins such as tumor suppressor proteins, growth regulators, etc., is found at high levels in cancer cells, which prevents certain other proteins from stopping cancer growth. Selinexor acts by blocking exportin one and enhances the action of these proteins, thus destroying the cancer cells and slowing the progression of the disease.
Indications of Selinexor
Selinexor is indicated along with Dexamethasone for treating relapsed cases of multiple myeloma in adult patients who have undergone prior therapies at least four times or in cases where the disease is refractory to two proteasome inhibitors, immunomodulatory agents, and anti-CD 38 monoclonal antibodies and there has been demonstrated progression of the disease.
What Is the Dosage of Selinexor?
Selinexor is recommended at a starting dose of 80 milligrams (four 20 mg tablets) to be taken orally on day one and day three of each week until unacceptable toxicity or until disease progression. A starting dose of Dexamethasone 20 mg is recommended to be taken orally with each dose of Selinexor on days one and three of each week. Each tablet must be swallowed as a whole with water and must be taken approximately at the same time. If a dose is missed, the next dose must be taken at the next regularly scheduled time; and if the patient vomits a dose, it must not be repeated, but the next dose must be taken at regularly scheduled intervals.
What Are the Warnings and Precautions of Selinexor?
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Thrombocytopenia: Selinexor may cause thrombocytopenia, leading to fatal hemorrhage. 74 percent of patients reported adverse reactions, 61 percent showed grade 3 or grade 4 thrombocytopenia, bleeding occurred in around five percent, and fatal hemorrhage was seen in less than one percent of patients. Therefore, platelet counts and any signs and symptoms of bleeding must be frequently monitored during the treatment, especially during the first two months. A prompt evaluation must be done, and the drug must be interrupted or permanently discontinued based on the severity of the condition if serious adverse reactions are suspected. Platelet transfusion may be indicated in severe cases of thrombocytopenia.
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Neutropenia: Patients undergoing treatment with Selinexor are at an increased risk of infections; neutropenia was reported in 34 percent of patients, severe neutropenia (21 percent), and febrile neutropenia (three percent) of patients, with a median time to onset being 25 days. Therefore the patients must be monitored frequently for any signs and symptoms of infection. Supportive treatment with antimicrobial drugs and growth factors can be considered based on the severity of the adverse reaction.
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Hyponatremia: Treatment with Selinexor can cause hyponatremia; it was reported in 39 percent of patients, and grade III or IV hyponatremia was seen in 22 percent of patients. Frequent monitoring of sodium levels must be done during the treatment, along with a review of the patient’s diet. Hyponatremia can be treated with intravenous saline or tablets, and the treatment with Selinexor can be interrupted, reduced, or discontinued based on the severity of the reaction.
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Infections: Patients under treatment with Selinexor are at an increased risk of infections caused by non-opportunistic organisms, such as upper respiratory tract infections, sepsis, and pneumonia.
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Gastrointestinal Toxicity: Nausea and vomiting were reported with a median time to onset of three and five days, respectively. Medications such as anti-nausea agents and prophylactic 5-HT3 antagonists can be advised before or during the treatment, along with administering intravenous (IV) fluids or electrolyte replacement therapy to prevent dehydration in patients. Selinexor may also cause diarrhea, which can be managed by anti-diarrheal agents, along with IV fluids, to prevent dehydration. Weight loss was reported in some patients with a median time of onset of 15 days. The patient must be monitored during the first two months of treatment, and loss of appetite and anorexia can be managed by dose modifications, appetite stimulants, and good nutritional support.
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Neurological Toxicity: Dizziness, syncope, delirium, and depressed level of consciousness were observed in 30 percent of patients, and severe events in around nine percent of patients, with a median time of 15 days. These can be managed by optimization of hydration, monitoring hemoglobin levels, and avoiding concomitant medications which aggravate the symptoms.
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Embryo-fetal Toxicity: Selinexor has the potential to cause fetal harm when administered to a pregnant woman. According to animal studies, structural abnormalities and growth alterations occurred in pregnant animals; when Selinexor was administered below the recommended doses during the organogenesis stage. Females of reproductive potential must be advised to use effective contraception during the treatment with Selinexor, and for one week, after the last dose.
What Are the Adverse Effects of Selinexor?
Significant adverse reactions are known to be associated with Selinexor:
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Gastrointestinal toxicity symptoms include nausea, vomiting, diarrhea, loss of appetite, and weight loss.
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Treatment with Selinexor may be associated with a reduction in the platelet count (thrombocytopenia), bleeding, and in some rare cases, fatal hemorrhage.
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A reduction in neutrophil count (neutropenia) can occur, leading to an increased risk of infections such as respiratory tract infections.
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The low sodium concentration in the blood (hyponatremia) was observed during the treatment with Selinexor.
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Selinexor may cause syncope, dizziness, delirium or confusion, and a depressed level of consciousness.
For Patients
What Is Multiple Myeloma?
Multiple myeloma is a form of cancer of the plasma cells (a type of white blood cell mainly found in the bone marrow). When B lymphocytes respond to an infection, they mature and form plasma cells. Plasma cells become cancerous and increase abnormally, crowding normal blood cells and resulting in multiple myeloma. Multiple myeloma is characterized by reduced red blood cells, white blood cells, and platelets. It increases the risk of infections, bone weakness, fractures, bleeding, anemia, and fatigue. It may also cause severe back pain, muscle weakness, numbness, dizziness, and confusion.
What Is Selinexor?
Selinexor is a prescription medicine used along with Dexamethasone and Bortezomib for the treatment of multiple myeloma in adult patients who did not respond to at least four prior therapies and whose disease has worsened since the last treatment. The drug works by destroying cancer cells, thus slowing the disease's progression. The treatment must be started under the supervision of a doctor experienced in treating the disease and must be continued as long as it is beneficial to the patient.
How Should It Be Stored?
Selinexor is available in child-resistant blister packs and must be stored at room temperature or below 30 degrees Celsius. All medicines must be kept out of reach of children.
Instructions To Be Followed Before Taking Selinexor
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Patients must take Selinexor exactly as prescribed by the doctor; the dose must not be modified, and the tablet must not be crushed, broken, chewed, or divided. It must be swallowed as a whole with water. Dexamethasone and medications to prevent nausea and vomiting must also be taken as prescribed.
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If a dose is missed, or if the patient vomits a dose, the next dose must be taken on the next regularly scheduled day.
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Blood tests are frequently advised, and body weight is regularly monitored, especially during the first two months of treatment.
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Patients must adequately consume fluids to prevent dehydration and a healthy diet to prevent weight loss throughout the treatment with Selinexor.
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Driving or operating machines must be avoided, as Selinexor can cause dizziness and confusion.
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Selinexor must not be used for reasons other than prescribed or by other people, even if they have the same symptoms, as it might harm them.
What Should the Patients Inform the Doctor About Before Taking Selinexor?
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Patients must inform the doctor if they have bleeding problems or a recent active infection.
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Female patients must inform the doctor if they are pregnant or planning to get pregnant, as Selinexor may harm the fetus. Female patients of reproductive age must use effective birth control measures during the treatment and for one week after the last dose of Selinexor.
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Females who are breastfeeding or planning to breastfeed must inform the doctor as many drugs can pass into the breast milk, and it is not known whether Selinexor can pass into the breast milk. Therefore, nursing mothers must not breastfeed during the treatment and for one week after the last dose of Selinexor.
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Patients must inform the doctor if they are taking any other medications, over-the-counter drugs, and vitamin or herbal supplements before starting the treatment with Selinexor.
What Are the Side Effects of Selinexor?
Treatment with Selinexor has been associated with some serious and common side effects. Patients must inform the doctor immediately in the case of serious adverse effects.
Serious side effects of Selinexor include:
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Severe nausea and vomiting.
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Loss of appetite and weight loss.
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Low sodium levels in the blood.
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Increased risk for infections.
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Dizziness, fainting, confusion, decreased alertness, etc.
Common side effects include:
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Decreased red blood cell count (anemia).
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Constipation.
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Tiredness.
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Fertility problems.
For Doctors
Description
Selinexor is a first-class nuclear export inhibitor with Selinexor as the active ingredient, along with other inactive ingredients such as magnesium stearate, microcrystalline cellulose, colloidal silicon dioxide, sodium lauryl sulfate, croscarmellose sodium, etc. It is available as 20 mg film-coated tablets in blister packs to be taken orally in combination with Dexamethasone, for the treatment of multiple myeloma in adult patients.
Mechanism of Action
Selinexor is a reversible covalent compound, a selective inhibitor of nuclear export (SINE), which inhibits the major mediator of the nuclear export of many proteins, exportin 1 (XPO1). This results in a marked accumulation of tumor suppressor proteins (TSPs), a reduction in oncogenic proteins, cell cycle arrest, and apoptosis of malignant cells. The combination of Selinexor with Dexamethasone and/or Bortezomib indicated cytotoxic effects in multiple myeloma and increased anti-tumor activity, including in those resistant to proteasome inhibitors.
Pharmacodynamics
The relationship between Selinexor exposure and response with the time course of pharmacodynamic response is not known. Multiple doses of Selinexor of up to 175 mg (2.2 times the recommended dose), administered twice weekly, were evaluated in patients with pretreated hematologic malignancies; however, no significant effects were observed with Selinexor on the QTc interval at the therapeutic dose level.
Pharmacokinetics
After a single dose of 80 mg of Selinexor, the mean plasma concentration was 680, and the mean area under the curve (AUC) was 5386 ng h/mL. It increased proportionally over the increase in doses, and no clinically relevant accumulation was noted at a steady state.
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Absorption: After an oral administration of Selinexor, maximum serum concentration is reached within four hours on concomitant administration with a high-fat meal; no significant changes were observed concerning the pharmacokinetics of the drug.
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Distribution: Selinexor demonstrated an apparent volume of distribution of 125 L in patients with malignancy, with a protein binding of 95 percent.
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Metabolism: Selinexor is metabolized by the enzymes UDP - glucuronosyltransferases (UGTs) and glutathione S-transferases (GSTs), and CYP3A4.
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Elimination: After a single dose administration of 80 mg Selinexor, the mean half-life was around six to eight hours, and the apparent total clearance was 17.9 L/h in cancer patients.
Drug Interactions
No drug interaction studies have been conducted with Selinexor. In vitro studies demonstrated Selinexor as a substrate of CYP3A4, UGTs, and GSTs and an inhibitor of OATP1B3 enzyme activity, but it does not inhibit any other solute carrier (SLC) transporters.
Clinical Studies
The STORM study was conducted to determine the efficacy of Selinexor with Dexamethasone. It was a multicenter, open-label, single-arm study conducted in adult patients with relapsed refractory multiple myeloma (RRMM). In the STORM Part two study, 122 patients were included who had previously undergone anti-myeloma treatment regimens with various medications such as glucocorticoids, an alkylating agent, Carfilzomib, Lenalidomide, etc. However, myeloma was refractory until the last line of therapy.
When patients were treated with 80 mg of Selinexor in combination with Dexamethasone, on days one and three of every week, treatment continued until disease progression or unacceptable toxicity. Among the patients involved in the study, 83 patients had RRMM, which was refractory to two proteasome inhibitors, two immunomodulators, and an antiCD monoclonal antibody, with a median duration of nine weeks, the median dose of 105 mg and a total dose of Selinexor received was 880 mg.
Non-clinical Toxicology
Selinexor was not mutagenic in a bacterial reverse mutation or Ames assay; carcinogenicity and fertility studies have not been conducted with Selinexor. However, on repeat dose toxicity studies, reduced sperm, spermatids, and germ cells decreased ovarian follicles were observed in rats, and single-cell necrosis of testes was observed in monkeys.
Use of Selinexor in Specific Populations
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Pregnancy: No data is available regarding the drug-associated risk in pregnant women. However, according to animal studies, Selinexor can harm the fetus when administered to pregnant women. Structural abnormalities and growth alterations were observed in pregnant rats on administering Selinexor during the organogenesis stage. Females are advised about the risk of pregnancy and must use effective contraception during the treatment with Selinexor and for one week after the last dose.
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Nursing Mothers: No data is available regarding the presence of Selinexor or its metabolites in human milk, its effects on the breastfed infant, or milk production. However, it is not advisable for women to breastfeed during the treatment with Selinexor and one week after the last dose.
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Pediatric Use: The safety and effectiveness of Selinexor in pediatric patients have not been established.
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Geriatric Use: No significant differences were observed in patients above 65 years of age compared to younger patients. However, a higher incidence of discontinuation of the drug due to adverse reactions was observed in older patients.
