Summary of medicine characteristics - Nexpovio
1. NAME OF THE MEDICINAL PRODUCT
NEXPOVIO 20 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 20 mg of selinexor.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Film-coated tablet
Blue, round, bi-convex, film-coated tablet (4 mm thick and 7 mm in diameter) with “K20” debossed on one side.
4. CLINICAL PARTICULARS4.1 Therapeutic indication
NEXPOVIO is indicated in combination with dexamethasone for the treatment of multiple myeloma in adult 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, and who have demonstrated disease progression on the last therapy.
4.2 Posology and method of administration
Treatment must be initiated and monitored under supervision of physicians experienced in the management of multiple myeloma.
Posology
The recommended starting dose is 80 mg of selinexor on Days 1 and 3 of each week.
The recommended starting dose of dexamethasone is 20 mg taken orally on Days 1 and 3 of each week with selinexor. For additional information regarding the administration of dexamethasone, refer to its Summary of Product Characteristics (SmPC).
Treatment should be continued until disease progression or unacceptable toxicity.
If a selinexor dose is missed or delayed or a patient vomits after a dose of selinexor, the patient should not repeat the dose. Patients should take the next dose on the next regularly scheduled day.
Dose modifications
Recommended NEXPOVIO dose modifications for adverse reactions are presented in Table 1 and Table 2.
Table 1: Prespecified dose modification steps for adverse reactions
| Recommended starting dose | First reduction | Second reduction | Third reduction | Discontinue* |
| 80 mg Days 1 and 3 of each week (160 mg total per week) | 100 mg once weekly | 80 mg once weekly | 60 mg once weekly |
* If symptoms do not resolve, treatment should be discontinued
Table 2: Dose modification guidelines for adverse reactions
| Adverse reaction3 | Occurrence | Action |
| Haematologic adverse reactions | ||
| Thrombocytopenia | ||
| Platelet count 25,000 to less than 75,000/mcL | Any |
Table 1 ). |
| Platelet count 25,000 to less than 75,000/mcL with concurrent bleeding | Any |
Table 1 ), after bleeding has resolved. |
| Platelet count less than 25,000/mcL | Any |
least 50,000/mcL.
Table 1 ). |
| Neutropenia | ||
| Absolute neutrophil count of 0.5 to 1.0 × 109/L without fever | Any |
Table 1 ). |
| Absolute neutrophil count less than 0.5 × 109/L OR Febrile neutropenia | Any |
to 1.0 × 109/L or higher.
Table 1 ). |
| Anaemia | ||
| Haemoglobin less than 8.0 g/dL | Any |
treatments per clinical guidelines. |
| Life-threatening consequences (urgent intervention indicated) | Any |
to 8 g/dL or higher.
treatments per clinical guidelines. |
| Adverse reaction3 | Occurrence | Action |
| Non-haematologic adverse reactions | ||
| Hyponatraemia | ||
| Sodium level 130 mmol/L or less | Any |
supportive care.
to 130 mmol/L or higher.
Table 1 ). |
| Fatigue | ||
| Grade 2 lasting greater than 7 days OR Grade 3 | Any |
baseline.
Table 1 ). |
| 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 |
anti-nausea medicinal products. |
| Grade 3 nausea (inadequate oral caloric or fluid intake) OR Grade 3 or higher vomiting (6 or more episodes per day) | Any |
Grade 2 or lower or baseline.
products.
Table 1 ). |
| Diarrhoea | ||
| Grade 2 (increase of 4 to 6 stools per day over baseline) | 1st |
|
| 2nd and subsequent |
| |
| Grade 3 or higher (increase of 7 stools or more per day over baseline; hospitalization indicated) | Any |
lower.
Table 1 ). |
| Weight loss and anorexia | ||
| Weight loss of 10% to less than 20% OR anorexia associated with significant weight loss or malnutrition | Any |
of baseline weight.
Table 1 ). |
| Adverse reaction3 | Occurrence | Action |
| Other non-haematologic adverse reactions | ||
| Grade 3 or 4 (life threatening) | Any |
Table 1 ). |
a. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
Special populations
Elderly population
No dose adjustment of selinexor is required for patients over 65 years of age (see sections 4.8, 5.1 and 5.2).
Renal impairment
No dose adjustment of selinexor is required for patients with mild, moderate, or severe renal impairment (see section 5.2). There are no data in patients with end-stage renal disease or haemodialysis to support a dose recommendation.
Hepatic impairment
No dose adjustment of selinexor is required for patients with mild hepatic impairment (see section 5.2). There are insufficient data in patients with moderate or severe hepatic impairment to support a dose recommendation.
Paediatric population
The safety and efficacy of NEXPOVIO in children below the age of 18 years of age have not been established. No data are available (see section 5.1 and 5.2).
There is no relevant use of NEXPOVIO in children less than 18 years of age in the treatment of multiple myeloma.
Method of administration
NEXPOVIO is for oral use.
NEXPOVIO should be taken at approximately the same time on Days 1 and 3 of each week. The tablet should be swallowed whole with water. It should not be crushed, chewed, broken, or divided in order to prevent risk of skin irritation from the active substance. It can be taken with or without food.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Recommended concomitant treatments
Patients should be advised to maintain adequate fluid and caloric intake throughout treatment. Intravenous hydration should be considered for patients at risk of dehydration.
Prophylactic concomitant treatment with a 5-HT3 antagonist and/or other anti-nausea agents should be provided prior to and during treatment with NEXPOVIO (see section 4.8).
Haematology
Patients should have their complete blood counts (CBC) assessed at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment.
Thrombocytopenia
Thrombocytopenic events (thrombocytopenia and platelet count decreased) were frequently reported in patients receiving selinexor which can be severe (Grade 3/4). Grade 3/4 thrombocytopenia can sometimes lead to clinically significant bleeding and in rare cases may lead to potentially fatal haemorrhage (see section 4.8).
Thrombocytopenia can be managed with dose interruptions, modifications, platelet transfusions, and/or other treatments as clinically indicated. Patients should be monitored for signs and symptoms of bleeding and evaluated promptly. For dose modification guidelines refer to Table 1 and Table 2 in section 4.2.
Neutropenia
Neutropenia including severe neutropenia (Grade 3/4) has been reported with selinexor. In a few cases concurrent infections occurred in patients with Grade 3/4 neutropenia (see section 4.8).
Patients with neutropenia should be monitored for signs of infection and evaluated promptly. Neutropenia can be managed with dose interruptions, modifications, and colony-stimulating factors as per medical guidelines. For dose modification guidelines refer to Table 1 and Table 2 in section 4.2.
Gastrointestinal toxicity
Nausea, vomiting, diarrhoea, which sometimes can be severe and require the use of anti-emetic and anti-diarrhoeal medicinal products (see section 4.8).
Prophylaxis with 5HT3 antagonists and/or other anti-nausea agents should be provided prior to and during treatment with selinexor. Fluids with electrolytes should be administered to prevent dehydration in patients at risk.
Nausea/vomiting can be managed by dose interruption, reduction and/or discontinuation, and/or initiation of other antiemetics medicinal products as clinically indicated. Diarrhoea can be managed with dose modification or administration of anti-diarrhoea medicinal products. For dose modification guidelines refer to Table 2 of section 4.2.
Weight loss and anorexia
Selinexor can cause weight loss and anorexia. Patients should have their body weight, nutritional status and volume checked at baseline, during treatment, and as clinically indicated. Monitoring should be more frequent during the first two months of treatment. Patients experiencing new or worsening decreased appetite and weight may require dose modification, appetite stimulants, and nutritional consultations. For dose modification guidelines refer to Table 1 and Table 2 in section 4.2.
ConfUsional state and dizziness
Selinexor can cause confusional state and dizziness. Patients should be instructed to avoid situations where dizziness or confusional state may be a problem and to not take other medicinal products that may cause dizziness or confusional state without adequate medical advice. Patients should be advised not to drive or operate heavy machinery until symptoms resolve (see section 4.7).
Hyponatraemia
Selinexor can cause hyponatraemia. Patients should have their sodium levels checked at baseline, during treatment, and as clinically indicated. Monitoring should be more frequent during the first two months of treatment. Correct sodium levels for concurrent hyperglycaemia (serum glucose >150 mg/dL) and high serum paraprotein levels. Hyponatraemia should be treated as per medical guidelines (intravenous sodium chloride solution and/or salt tablets), including dietary review.
Patients may require selinexor dose interruption and/or modification. For dose modification guidelines refer to Table 1 and Table 2 in section 4.2.
Tumour lysis syndrome
Tumour lysis syndrome (TLS) has been reported in patients receiving therapy with selinexor. Patients at a high risk for TLS should be monitored closely. Treat TLS promptly in accordance with institutional guidelines.
Women of childbearing potential/contraception in males and females
Women of childbearing potential should be advised to avoid becoming pregnant or abstain from sexual intercourse while being treated with selinexor and for at least 1 week following the last dose of selinexor.
Women of childbearing potential and male patients of reproductive potential should be advised to use effective contraceptive measures or abstain from sexual activity to prevent pregnancy during treatment with selinexor and for at least 1 week following the last dose of selinexor (see section 4.6).
Excipients
This medicinal product contains less than 1 mmol sodium (23 mg) per 20 mg tablet, that is to say essentially ‘sodium-free’.
4.5 Interaction with other medicinal products and other forms of interaction
No dedicated clinical drug interaction studies have been conducted.
Concomitant use of strong CYP3A4 inducer might lead to lower exposure of selinexor.
4.6 Fertility, pregnancy and lactation
Women of childbearing potential/Contraception in males and females
Women of childbearing potential should be advised to avoid becoming pregnant or abstain from sexual intercourse while being treated with selinexor and for at least 1 week following the last dose of selinexor. A pregnancy test is recommended for women of childbearing potential prior to initiating selinexor treatment.
Women of childbearing potential and male patients of reproductive potential should be advised to use effective contraceptive measures or abstain from sexual activity to prevent pregnancy during treatment with selinexor and for at least 1 week following the last dose of selinexor.
Pregnancy
There are no data from the use of selinexor in pregnant women. Studies in animals have shown selinexor can cause foetal harm (see section 5.3). Selinexor is not recommended during pregnancy and in women of childbearing potential not using contraception.
If the patient becomes pregnant while taking selinexor, selinexor should be immediately discontinued, and the patient should be apprised of the potential hazard to the foetus.
Breast-feeding
It is unknown whether selinexor or its metabolites are excreted in human milk. A risk to breast-fed children cannot be excluded. Breast-feeding should be discontinued during treatment with selinexor and for 1 week after the last dose.
Fertility
Based on findings in animals, selinexor may impair fertility in females and males (see section 5.3).
4.7 Effects on ability to drive and use machines
Selinexor may have major influence on the ability to drive and use machines. Selinexor can cause fatigue, confusional state and dizziness. Patients should be instructed to avoid situations where dizziness or confusional state may be a problem and to not take other medicinal products that may cause dizziness or confusional state without adequate medical advice. Patients should be advised not to drive or operate machines if they experience any of these symptoms.
4.8 Undesirable effects
Summary of the safety profile
The safety of selinexor in combination with dexamethasone has been evaluated in 214 patients with multiple myeloma, including 83 patients with penta-refractory disease. The most frequent adverse reactions (>30%) were nausea (75%), thrombocytopenia (75%), fatigue (66%), anaemia (60%), decreased appetite (56%), decreased weight (49%), diarrhoea (47%), vomiting (43%), hyponatraemia (40%), neutropenia (36%) and leukopenia (30%).
The most commonly reported serious adverse reactions (>3%) were pneumonia (7.5%), sepsis (6.1%) thrombocytopenia (4.7%), acute kidney injury (3.7%), and anaemia (3.3%).
Tabulated list of adverse reactions
Adverse reactions reported in clinical trials with selinexor in combination with dexamethasone are summarised in Table 3.
These reactions are presented by system organ class (SOC) and by frequency. Frequency categories are defined as: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 3: Adverse drug reactions (ADRs) observed in patients treated with selinexor in combination with dexamethasone
| System organ class/ preferred term | All ADRs/frequency | Grade 3–4 ADRs/frequency |
| Infections and infestations | Very common Pneumonia, upper respiratory tract infection Common Sepsis, bacteraemia | Common Pneumonia, sepsis, bacteraemia Uncommon Upper respiratory tract infection |
| Blood and lymphatic system disorders | Very common Thrombocytopenia, anaemia, neutropenia, leukopenia, lymphopenia Common Febrile neutropenia | Very common Thrombocytopenia, anaemia, neutropenia, leukopenia, lymphopenia Common Febrile neutropenia |
| Metabolism and nutrition disorders | Very common Hyponatraemia, dehydration, decreased appetite, hyperglycaemia, hypokalaemia Common Hypocalcaemia, hypophosphataemi a, hyperkalaemia, | Very common Hyponatraemia Common Dehydration, decreased appetite, hypokalaemia, hyperglycaemia, hypocalcaemia, hyperkalaemia, hyperamylasaemia, hypophosphataemia |
| System organ class/ preferred term | All ADRs/frequency | Grade 3–4 ADRs/frequency |
| hypomagnesaemia, hyperamylasaemia, hyperuricaemia, hyperlipasaemia Uncommon Tumour lysis syndrome | hyperuricaemia, hyperlipasaemia Uncommon Tumour lysis syndrome | |
| Psychiatric disorders | Very common Confusional state, insomnia Common Delirium, hallucination | Common Confusional state, insomnia Uncommon Delirium, hallucination |
| Nervous system disorders | Very common Dizziness, dysgeusia, headache Common Peripheral neuropathy, syncope, ageusia, taste disorder, balance disorder, cognitive disorder, disturbance in attention, memory impairment Uncommon Encephalopathy | Common Syncope, cognitive disorder Uncommon Peripheral neuropathy, encephalopathy |
| Eye disorders | Very common Vision blurred Common Cataract, visual impairment | Common Cataract Uncommon Vision blurred, visual impairment |
| Cardiac disorders | Common Tachycardia | None |
| Vascular disorders | Common Hypotension | Uncommon Hypotension |
| Respiratory, thoracic and mediastinal disorders | Very common Dyspnoea, epistaxis, cough | Common Dyspnoea Uncommon Epistaxis |
| Gastrointestinal disorders | Very common Nausea, diarrhoea, vomiting, abdominal pain, constipation Common Dyspepsia, dry mouth, abdominal discomfort, flatulence | Common Nausea, diarrhoea, vomiting, constipation Uncommon Abdominal pain |
| Skin and subcutaneous tissue disorders | Common Alopecia, night sweats, pruritus | None |
| System organ class/ preferred term | All ADRs/frequency | Grade 3–4 ADRs/frequency |
| Musculoskeletal and connective tissue disorders | Common Muscle spasms, hypercreatinaemia | Uncommon Muscle spasms hypercreatinaemia |
| Renal and urinary disorders | Common Acute kidney injury | Common Acute kidney injury |
| General disorders and administration site conditions | Very common Fatigue, pyrexia, asthenia Common General physical health deterioration, malaise, gait disturbance, chills | Very common Fatigue Common Asthenia, general physical health deterioration, pain Uncommon Pyrexia |
| Investigations | Very common Weight decreased Common Aspartate aminotransferase increased, alanine aminotransferase increased, blood alkaline phosphatase increased | Common Alanine aminotransferase increased Uncommon Weight decreased, aspartate aminotransferase increased |
| Injury, poisoning and procedural complications | Common Fall | Common Fall |
Description of selected adverse reactions
Infections
Infection was the most common non-haematological toxicity; occurring in 53% of patients. Of these, 22% were Grade 3 or 4. Upper respiratory tract infection and pneumonia were the most commonly reported infections (in 15% and 13% of patients, respectively) with 25% of reported infections being serious and fatal infections occurring in 3% of treated patients. Infection led to dose discontinuation in 7% of patients, treatment interruption in 19% patients, and a dose reduction in 1% of patients.
Thrombocytopenia
Thrombocytopenia occurred in 75% of patients and 65% of these ADRs were Grade 3 or 4.
Thrombocytopenia was serious in 5% of patients. Of the 65% patients with
Grade 3 or 4 thrombocytopenia, serious/grade 3 or higher concurrent bleeding events (concurrency defined as ±5 days) were reported in 5% of patients. Thrombocytopenia led to dose discontinuation in 3% of patients, treatment interruption in 22% of patients, and a dose reduction in 32% of patients.
Thrombocytopenia can be managed with dose modifications (see section 4.2), supportive care and platelet transfusions. Patients should be monitored for signs and symptoms of bleeding and evaluated promptly (see section 4.4).
Neutropenia
Neutropenia occurred in 36% of patients and 25% of these were Grade 3 or 4. Neutropenia was serious in 1% of patients. None of the patients had a dose discontinuation due to neutropenia, and neutropenia led to treatment interruption in 2% of patients, and a dose reduction in 6% of patients.
Febrile neutropenia occurred in 3% of patients; all were Grade 3 or 4. Febrile neutropenia was reported to be serious in 2% of patients and led to a dose discontinuation, treatment interruption, or a dose reduction in less than 1% of patients (each). Of the 53 patients with Grade 3 or higher neutropenia, serious/Grade 3 or higher concurrent infections (concurrency defined as ±5 days) were reported in 6 (11%) patients. Most commonly reported Grade 3 or higher concurrent infection included urinary tract infection (3 patients), and sepsis (2 patients).
Anaemia
Anaemia occurred in 61% of patients and 44% of these were Grade 3 or 4. Anaemia was serious in 3% of patients. Anaemia led to dose discontinuation in <1% of patients, treatment interruption in 4% of patients, and a dose reduction in 1% of patients.
Anaemia can be managed with dose modifications (see section 4.2) and with blood transfusions and/or erythropoietin administration as per medical guidelines. For dose modification guidelines refer to Table 2 of section 4.2.
Gastrointestinal toxicity
Nausea/vomiting occurred in 79% of patients and 10% of these were Grade 3 or 4 and was serious in 3% of patients. When anti-nausea treatment was administered, the median duration of nausea or vomiting improved by 3 days. Nausea/vomiting led to dose discontinuation in 5% of patients, treatment interruption in 8% of patients, and a dose reduction in 5% of patients.
Diarrhoea occurred in 47% of patients and 7% were Grade 3 or 4 and diarrhoea was serious in 2% of patients. Diarrhoea led to dose discontinuation in 1% of patients, treatment interruption in 2% of patients, and a dose reduction in 1% of patients.
Hyponatraemia
Hyponatraemia occurred in 40% of patients and 24% were Grade 3 or 4. Hyponatraemia was serious in 3% of patients. Most cases of hyponatraemia were not associated with any symptoms. There were no reports of concurrent seizures. Hyponatraemia did not lead to any dose discontinuation, and it led to treatment interruption in 6% of patients, and a dose reduction in 1% of patients.
Tumour lysis syndrome
Tumour lysis syndrome (TLS) occurred in one (<1%) patient which was considered Grade 3 and serious. Patients at a high risk for TLS should be monitored closely. Treat TLS promptly in accordance with institutional guidelines (see section 4.4).
Elderly population
Among patients with multiple myeloma who received NEXPOVIO, 47% were 65 years of age and over, while 11% were 75 years of age and over. When comparing patients 75 years of age and older to younger patients, older patients had a higher incidence of discontinuation due to an adverse reaction (52% vs 25%), higher incidence of serious adverse reactions (74% vs 59%), and higher incidence of fatal adverse reactions (22% vs 8%).
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in
4.9 Overdose
In general, overdoses have been associated with similar side effects to those reported for standard dosing and have generally been reversible within 1 week.
Symptoms
Potential acute symptoms include nausea, vomiting, diarrhoea, dehydration and confusion. Potential signs include low sodium levels, elevated liver enzymes, and low blood counts. Patients should be monitored closely and provided supportive care as appropriate. No fatalities due to overdose have been reported to date.
Management
In the event of an overdose, monitor the patient for any adverse reactions and appropriate symptomatic treatment should be provided immediately.
5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XX66
Mechanism of action
Selinexor is a reversible covalent selective inhibitor of nuclear export (SINE) compound that specifically blocks exportin 1 (XPO1). XPO1 is the major mediator of the nuclear export of many cargo proteins including tumour suppressor proteins (TSPs), growth regulators and mRNAs of growth promoting (oncogenic) proteins. XPO1 inhibition by selinexor leads to marked accumulation of TSPs in the nucleus, cell cycle arrest, reductions in several oncoproteins such as c-Myc and cyclin D1, and apoptosis of cancer cells.
Cardiac electrophysiology
The effect of multiple doses of selinexor up to 175 mg twice weekly on the QTc interval was evaluated in patients with heavily pre-treated haematologic malignancies. Selinexor had no large effect (i.e. no greater than 20 ms) on QTc interval at the therapeutic dose level.
Clinical efficacy and safety
Relapsed/refractory multiple myeloma
Study KPC-330–012 (STORM), a phase 2, multi-centre, single-arm, open-label, study, enrolled patients with relapsed and/or refractory multiple myeloma (RRMM). STORM Part 2 required patients to have measurable disease per International Myeloma Working Group (IMWG) criteria, have previously received three or more antimyeloma treatment regimens including an alkylating agent, glucocorticoids, bortezomib, carfilzomib, lenalidomide, pomalidomide, and an anti-CD38 monoclonal antibody; and whose myeloma was documented to be refractory to glucocorticoids, a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 monoclonal antibody, and to the last line of therapy. Patients had to have an ECOG performance status score <2, adequate hepatic, renal and haematopoietic function. Systemic light chain amyloidosis, active central nervous system myeloma, peripheral neuropathy of grade 3 or higher, or painful neuropathy of grade 2 or higher were exclusion criteria.
Patients were treated with 80 mg selinexor in combination with 20 mg dexamethasone on Days 1 and 3 of every week. Treatment continued until disease progression, death or unacceptable toxicity.
Among patients enrolled in STORM Part 2 (n=123), eighty-three (83) patients had RRMM that was refractory to two proteasome inhibitors (bortezomib, carfilzomib), two immunomodulators (lenalidomide, pomalidomide) and an anti-CD38 monoclonal antibody (daratumumab). The median duration of selinexor treatment in these 83 patients was 9 weeks (range: 1 to 61 weeks). The median total dose of selinexor received was 880 mg (range 160 to 6,220 mg), with a median dose of 105 mg (range: 22 to 180 mg) received per week.
The data presented below is from the 83 patients whose disease was refractory to bortezomib (B), carfilzomib ©, lenalidomide (L), pomalidomide (P), and daratumumab (D) (penta-refractory).
-
Table 4 provides patients disease and prior treatment characteristics.
Table 4: Demographics and disease characteristics of patients with relapsed refractory multiple myeloma treated with 80 mg selinexor and 20 mg dexamethasone (N=83)
| Characteristics | |
| Median from diagnosis to start of study treatment , years (range) | 7 years (1, 23) |
| Number of prior treatment regimens , median (range) | 8 (4, 18) |
| Age, median (range) | 65 years (40, 86) |
| Patients < 65 years of age, n (%) | 40 (48) |
| Patients 65–74 years of age, n (%) | 31 (37) |
| Patients > 75 years of age, n (%) | 12 (15) |
| Males: Females, n (%) | 51 M (61): 32 F (39) |
| Refractory status to specific treatment combinations, n (%) | |
| Penta refractory (BCLPD) | 83(100) |
| Daratumumab in any combination | 57 (69) |
| Daratumumab as single agent | 26 (31) |
| Previous stem cell transplant1, n (%) >2 transplants | 67 (81) 23(28) |
| Previous CAR-T Cell Therapy, n (%) | 2 (2.4) |
| Revised Integrated Staging System at baseline, n (%) | |
| I | 10 (12) |
| II | 56 (68) |
| III | 17 (21) |
| High-risk cytogenetics, n (%) (includes any of del(17p)/p53, t(14; 16), t(4; 14), or 1q21) | 47 (57) |
| ECOG performance status: 0 to 1, n (%) | 74 (89) |
1 One patient had an allogeneic stem cell transplant.
The primary efficacy endpoint was overall response rate (ORR) as assessed by an Independent Review Committee based on the International Myeloma Working Group (IMWG) uniform response criteria for multiple myeloma. Responses were assessed monthly and as per IMWG guidelines.
-
Table 5 provides an overview of the efficacy results.
Table 5: Efficacy results: assessed by Independent Review Committee
| Efficacy endpoint | NEXPOVIO 80 mg + dexamethasone 20 mg N=83 |
| Overall response rate (ORR) , n (%) (includes sCR + VGPR + PR)1 | 21 (25.3) |
| 95% confidence interval | 16.4, 36 |
| sCR, MRD negative, n (%) | 1 (1.2) |
| CR, n (%) | 0 (0) |
| VGPR, n (%) | 4 (4.8) |
| PR, n (%) | 16 (19.3) |
| Efficacy endpoint | NEXPOVIO 80 mg + dexamethasone 20 mg N=83 |
| Minimal response (MR), n (%) | 10 (12.0) |
| Stable disease (SD), n (%) | 32 (38.6) |
| Progressive disease (PD) /not evaluable (NE), n (%) | 20 (24.1) |
| Median time to first response (weeks) (range: 1 to 10 weeks) | 3.9 |
| Median duration of response (DOR) months (95% confidence interval) | 3.8 (2.3, 10.8) |
1sCR= stringent complete response, CR= complete response, VGPR= very good partial response, PR= partial response
Paediatric population
The European Medicines Agency (EMA) has waived the obligation to submit the results of studies with selinexor in all subsets of the paediatric population in the treatment of RRMM (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited.
The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
5.2 Pharmacokinetic properties
Absorption
Following oral administration of selinexor peak plasma concentration, Cmax is reached within 4 hours. Concomitant administration of a high fat meal (800–1,000 calories with approximately 50% of total caloric content of the meal from fat) did not have a clinically significant effect on the pharmacokinetics of selinexor.
Distribution
Selinexor is 95.0% bound to human plasma proteins. In a population pharmacokinetic (PK) analysis, the apparent volume of distribution (Vd/F) of selinexor was 133 L in cancer patients.
Biotransformation
Selinexor is metabolised by CYP3A4, multiple UDP-glucuronosyltransferases (UGTs) and glutathione S- transferases (GSTs).
Elimination
Following a single dose of 80 mg selinexor the mean half-life (t1/2) is 6 to 8 hours. In a population PK analysis, the apparent total clearance (CL/F) of selinexor was 18.6 L/h in cancer patients.
Specific populations
Age, sex and race
Age (18 to 94 years of age), sex, or race had no clinically significant effect on the pharmacokinetics of selinexor.
In the population PK dataset, age and race were not identified as a significant covariate, gender was identified as a significant covariate.
Renal impairment
The degree of renal impairment was determined by creatinine clearance as estimated by the Cockcroft-Gault equation. Results from population PK analyses of patients with normal (n=283, CLcr: >=90 mL/min), mild (n=309, CLcr: 60 to 89 mL/min), moderate (n=185, CLcr: 30 to 59 mL/min) or severe (n=13, CLcr: 15 to 29 mL/min) renal dysfunction indicated that creatinine clearance had no impact on the PK of NEXPOVIO. Therefore, mild, moderate, or severe renal impairment is not expected to alter selinexor PK, and no adjustments in the dose of selinexor are required in patients with renal dysfunction.
Hepatic impairment
Population PK analysis indicated that mild hepatic impairment (bilirubin >1–1.5 x ULN or AST > ULN, but bilirubin < ULN, n=119) had no clinically significant effect on the PK of selinexor. Similar finding was observed in a small number of patients with moderate (bilirubin >1.5–3 x ULN; any AST, n=10) and severe hepatic impairment (bilirubin >3 x ULN; any AST, n=3).
5.3 Preclinical safety data
Repeated-dose Toxicity
Findings in the repeat dose 13-week rat study were decrements in body weight gain and food consumption, and haematopoietic/lymphoid hypoplasia, and male/female reproductive organ effects. In the 13-week monkey study, the treatment-related effects observed included body weight loss, gastrointestinal effects, and lymphoid/haematologic depletion. Gastrointestinal toxicities, including anorexia, decrements in body weight gain and reduced food consumption were noted to be CNS-mediated. No safety margin for these toxicities could be established.
Genotoxicity
Selinexor was not mutagenic in a bacterial reverse mutation assay. Selinexor was not clastogenic in either the in vitro cytogenetic assay in human lymphocytes or in the in vivo rat micronucleus assay.
Carcinogenicity
Carcinogenicity studies have not been conducted with selinexor.
Toxicity to Reproduction and Development
Fertility studies in animals have not been conducted with selinexor. In repeat-dose oral toxicity studies, selinexor was administered for up to 13 weeks in rats and monkeys. Reduced sperm, spermatids, and germ cells in epididymides and testes were observed in rats, decreased ovarian follicles were also observed in rats, and single cell necrosis of testes was observed in monkeys. These findings were observed at systemic exposures approximately 0.11, 0.28, and 0.53 times, respectively, the exposure (AUClast) in humans at the recommended human dose of 80 mg. Developmental effects were seen with daily exposure in pregnant rats at systemic exposures below the exposure (AUClast) in humans at the recommended human dose of 80 mg.
Other Toxicities
A guinea pig sensitisation assay showed that selinexor at 25% induced a mild grade II dermal contact hypersensitivity response at 24 and 48 hours.
6. PHARMACEUTICAL PARTICULARS6.1 List of excipients
Tablet core
Microcrystalline cellulose (pH-101) (E460i)
Croscarmellose sodium (E468)
Povidone K30 (E1201)
Colloidal silicon dioxide (E551)
Magnesium stearate (E470b)
Microcrystalline cellulose (pH-102) (E460i)
Sodium lauryl sulphate (E514i)
Tablet coating
Talc (E553b)
Poly(vinyl alcohol) partially hydrolysed (E1203)
Glyceryl monostearate (E471)
Polysorbate 80 (E433)
Titanium dioxide (E171)
Macrogol (E1521)
Indigo carmine aluminium lake (E132)
Brilliant blue FCF aluminium lake (E133)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
4 years.
6.4 Special precautions for storage
The medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PVC/PCTFE/PVC-aluminium blisters containing 3, 4, 5 or 8 film-coated tablets.
One outer carton contains four child resistant inner cartons, each with one blister. Cartons contain a total of 12, 16, 20 or 32 film-coated tablets. Not all pack-sizes may be marketed.
6.6 Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
Karyopharm Europe GmbH
Franziska-Bilek-Weg 9
D-80339 München
Germany
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/21/1537/001
EU/1/21/1537/002
EU/1/21/1537/003
EU/1/21/1537/004