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 thrombocytopaenia (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%), thrombocytopaenia (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%), thrombocytopaenia (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 10.
Adverse reactions reported in clinical trials with selinexor in combination with dexamethasone (Sd) are summarised in Table 11.
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 10 and 11.)

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Diffuse Large B-Cell Lymphoma: The safety of XPOVIO was evaluated in SADAL. Patients received XPOVIO 60 mg orally on Days 1 and 3 of every week (n=134). The study required an absolute neutrophil count ≥1000/μL, platelet count ≥75,000/μL, hepatic transaminases ≤2.5 times upper limit of normal (ULN) unless abnormal from lymphoma, and bilirubin ≤2 times ULN. The study permitted a maximum of 5 prior systemic regimens for DLBCL. Antiemetic prophylaxis with a 5HT-3 receptor antagonist was required. The median duration of XPOVIO treatment was 2.1 months (range: 1 week to 3.7 years) with 38% receiving at least 3 months and 22% receiving at least 6 months of treatment. The median exposure was 100 mg per week.
Fatal adverse reactions occurred in 3.7% of patients within 30 days and 5% of patients within 60 days of last treatment; the most frequent fatal adverse reaction was infection (4.5% of patients). Serious adverse reactions occurred in 46% of patients who received XPOVIO; the most frequent serious adverse reaction was infection (21% of patients).
Discontinuation due to adverse reactions occurred in 17% of patients who received XPOVIO. Adverse reactions which results in discontinuation in ≥2% of patients included: infection, fatigue, thrombocytopaenia, and nausea.
Adverse reactions led to XPOVIO dose interruption in 61% of patients and dose reduction in 49%, with 17% of all patients having 2 or more dose reductions. The median time to first dose modification (reduction or interruption) was 4 weeks, with the leading causes being thrombocytopaenia (40% of all patients), neutropenia (16%), fatigue (16%), nausea (10%), and anaemia (10%). The median time to first dose reduction was 6 weeks, with 83% of first dose reductions occurring within the first 3 months.
The most common adverse reactions, excluding laboratory abnormalities, in ≥20% of patients were fatigue, nausea, diarrhea, decreased appetite, weight decreased, constipation, vomiting, and pyrexia. Table 12 summarizes selected adverse reactions in SADAL. (See Table 12.)

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Clinically relevant adverse reactions in <10% of patients who received XPOVIO included: Injury: fall (8%); Metabolic and nutrition disorders: dehydration (7%); Neurologic disorders: headache (4.5%), syncope (2.2%); Infection: sepsis (6%), herpes virus infection (3%); Eye disorders: cataract (3.7%); Blood and lymphatic disorders: febrile neutropenia (3%); Cardiac disorders: cardiac failure (3%).
Table 13 summarizes selected new or worsening laboratory abnormalities in SADAL. Grade 3-4 laboratory abnormalities in ≥15% included thrombocytopaenia, lymphopenia, neutropenia, anaemia, and hyponatremia. Grade 4 laboratory abnormalities in ≥5% were thrombocytopaenia (18%), lymphopenia (5%), and neutropenia (9%). (See Table 13.)

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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.
Thrombocytopaenia: In patients who received SVd, thrombocytopaenia occurred in 62% of patients and 41% of patients had Grade 3 or 4 thrombocytopaenia. Thrombocytopaenia was serious in 2% of patients. Of the 41% patients with Grade 3 or 4 thrombocytopaenia, 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 thrombocytopaenia. Thrombocytopaenia 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, thrombocytopaenia occurred in 75% of patients and 65% of these ADRs were Grade 3 or 4. Thrombocytopaenia was serious in 5% of patients. Of the 65% patients with Grade 3 or 4 thrombocytopaenia, serious/Grade 3 or higher concurrent bleeding events (concurrency defined as ±5 days) were reported in 5% of patients. Thrombocytopaenia led to dose discontinuation in 3% of patients, treatment interruption in 22% of patients, and a dose reduction in 32% of patients.
In patients with DLBCL who received XPOVIO 60 mg twice weekly, thrombocytopaenia developed or worsened in 86% of patients, including Grade 3-4 thrombocytopaenia in 49% of patients (Grade 4, 18%). The median time to first onset was 28 days for any grade thrombocytopaenia and 33 days for Grade 3 or 4 thrombocytopaenia.
Thrombocytopaenia 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).
In patients with DLBCL, Grade 3 neutropenia developed in 21% of patients and Grade 4 neutropenia developed in 9% of patients. The median time to first onset of Grade 3 or 4 neutropenia was 32 days. Febrile neutropenia was reported in 3% of 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 7 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.
In patients with DLBCL (SADAL, n=134), gastrointestinal toxicity occurred in 80% of patients with Grade 3 or 4 in 13%.
In patients with DLBCL (SADAL. n=134), with use of antiemetic prophylaxis, nausea occurred in 57% of patients and Grade 3 nausea occurred in 6% of patients. Vomiting occurred in 28% of patients and Grade 3 vomiting occurred in 1.5% of patients. The median time to first onset was 3 days for nausea and 7 days for vomiting.
In patients with DLBCL, diarrhea occurred in 37% of patients and Grade 3 diarrhea occurred in 3% of patients treated with XPOVIO. The median time to onset of the first event was 12 days.
In patients with DLBCL, anorexia was reported as an adverse reaction in 37% of patients and Grade 3 anorexia occurred in 3.7% of patients treated with XPOVIO. Weight loss (Grade 1-2) was reported as an adverse reaction in 30% 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.
In patients with DLBCL, hyponatremia developed in 62% of patients and Grade 3 hyponatremia developed in 16% of patients treated with XPOVIO. In approximately 63% of cases, hyponatremia occurred in the context of gastrointestinal toxicity such as nausea, vomiting, diarrhea, dehydration, and anorexia.
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%).
Among 134 patients with DLBCL who received XPOVIO in SADAL, 61% were 65 years of age and older, while 25% were 75 years of age and older. Clinical studies of XPOVIO in patients with relapsed or refractory DLBCL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.