Xpovio Adverse Reactions

Summary of the safety profile: The safety of selinexor in combination with bortezomib and dexamethasone has been evaluated in 195 patients with multiple myeloma. The most frequent adverse reactions (≥30%) were thrombocytopenia (62%), nausea (50%), fatigue (42%), anaemia (37%), decreased appetite (35%), diarrhoea (33%), and peripheral neuropathy (33%).
The most commonly reported serious adverse reactions (≥3%) were pneumonia (14.9%), cataract (4.6%), sepsis (4.1%), diarrhoea (3.6%), vomiting (3.6%) and anaemia (3.1%).
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 bortezomib and dexamethasone (SVd) are summarised in Table 7.
Adverse reactions reported in clinical trials with selinexor in combination with dexamethasone (Sd) are summarised in Table 8.
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. (See Tables 7 and 8.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Description of selected adverse reactions: Infections: Infection was the most common non-haematological toxicity.
In patients who received SVd, infections were reported in 70% of patients and 28% of patients had Grade 3 or 4 infections. Serious infections were reported in 28% of patients with fatal infections occurring in 4% of treated patients. Upper respiratory tract infection and pneumonia were the most commonly reported infections in 21% and 15% of patients, respectively. Infection led to dose discontinuation in 1% of patients, treatment interruption in 48% patients, and a dose reduction in 10% of patients.
In patients who received Sd, infections were reported 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: In patients who received SVd, thrombocytopenia occurred in 62% of patients and 41% of patients had Grade 3 or 4 thrombocytopenia. Thrombocytopenia was serious in 2% of patients. Of the 41% patients with Grade 3 or 4 thrombocytopenia, Grade 3 or higher concurrent bleeding events (concurrency defined as ±5 days) were reported in 5% of patients. Fatal haemorrhage occurred in 2% of patients with thrombocytopenia. Thrombocytopenia led to dose discontinuation in 2% of patients, treatment interruption in 35% of patients, and a dose reduction in 33% of patients.
In patients who received Sd, 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 Dosage & Administration), supportive care and platelet transfusions. Patients should be monitored for signs and symptoms of bleeding and evaluated promptly (see Precautions).
Neutropenia: In patients who received SVd, neutropenia occurred in 16% of patients and 10% of patients had Grade 3 or 4 events of neutropenia. 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 9% of patients, and a dose reduction in 5% of patients.
Febrile neutropenia, reported as serious, occurred in one patient (<1%) who received SVd; and was Grade 4. Febrile neutropenia led to treatment interruption and dose reduction; no dose discontinuation occurred due to febrile neutropenia. Of the 19 patients with Grade 3 or higher neutropenia, serious Grade 3 or higher concurrent infections (concurrency defined as ±5 days) were reported in 3 (16%) patients. Concurrent Grade 3 or higher infections included lower respiratory tract infection, bronchitis and ear infection (1 patient each).
In patients who received Sd, 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 who received Sd; 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: In patients who received SVd, anaemia occurred in 37% of patients and 16% of patients had Grade 3 anaemia, no patients had Grade 4 or 5 anaemia. Anaemia was serious in 3% of patients. Anaemia led to dose discontinuation in 1% of patients, treatment interruption in 6% of patients, and a dose reduction in 3% of patients.
In patients who received Sd, 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 Dosage & Administration) and with blood transfusions and/or erythropoietin administration as per medical guidelines. For dose modification guidelines refer to Table 6 of Dosage & Administration.
Gastrointestinal toxicity: In patients who received SVd, nausea occurred in 50% of patients and 8% of patients had Grade 3 or 4 nausea. Nausea was serious in 2% of patients. When anti-nausea treatment was administered, the median duration of nausea improved by 10 days. Nausea led to dose discontinuation in 3% of patients, treatment interruption in 7% of patients, and a dose reduction in 7% of patients.
Vomiting occurred in 21% of patients who received SVd, and 4% of patients had Grade 3 vomiting. No patients had Grade 4 vomiting. Vomiting was serious in 4% of patients. Vomiting led to dose discontinuation in 2% of patients, treatment interruption in 3% of patients, and a dose reduction in 3% of patients.
Diarrhoea occurred in 33% of patients who received SVd and 7% of patients had Grade 3 or 4 diarrhoea. Diarrhoea was serious in 4% of patients. Diarrhoea led to dose discontinuation in 1% of patients, treatment interruption in 8% of patients, and a dose reduction in 2% of patients.
In patients who received Sd, 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 who received Sd 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: In patients who received SVd, hyponatraemia occurred in 8% of patients and 5% of patients had Grade 3 or 4 hyponatremia. Hyponatraemia was serious in <1% 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 <1% of patients, and a dose reduction in 1% of patients.
In patients who received Sd, 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.
Cataract: In patients receiving SVd, the incidence of new onset or worsening cataracts requiring clinical intervention was reported in 24% of patients. The median time to new onset of cataract was 233 days. The median time for worsening of cataract in patients presenting with cataract at start of selinexor therapy was 261 days (SVd). Cataract did not lead to treatment discontinuation, it led to treatment interruption in 4% of patients and a dose reduction in 3% of patients. Cataract should be treated as per medical guidelines, including surgery if warranted (see Precautions and Dosage & Administration).
Tumour lysis syndrome: Tumour lysis syndrome (TLS) occurred in one (<1%) patient (who received Sd) 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 Precautions).
Elderly population: Among patients with multiple myeloma who received SVd, 56% were 65 years of age and over, while 17% were 75 years of age and over. When comparing patients 65 years of age and older to younger patients, older patients had a higher incidence of discontinuation due to an adverse reaction (28% vs 13%) and higher incidence of serious adverse reactions (57% vs 51%).
Among patients with multiple myeloma who received Sd, 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%).