Belantamab mafodotin interacts in the following cases:
There are limited data in patients with moderate hepatic impairment (total bilirubin greater than 1.5 × ULN to ≤ 3.0 × ULN and any AST level), or in patients with severe hepatic impairment (total bilirubin greater than > 3.0 × ULN and any AST level) to support a dose recommendation; belantamab mafodotin should only be used in these patients if the potential benefits outweigh any potential risks.
Based on findings in animals and the mechanism of action, belantamab mafodotin may impair fertility in females and males of reproductive potential.
Therefore, physicians may counsel women of childbearing potential and men being treated with belantamab mafodotin who desire children in the future regarding fertility preservation.
There are no data from the use of belantamab mafodotin in pregnant women. Based on the mechanism of action of the cytotoxic component monomethyl auristatin F (MMAF), belantamab mafodotin can cause embryo-foetal harm when administered to a pregnant woman. Human immunoglobulins (IgG) are known to cross the placental barrier, and therefore, being an IgG, belantamab mafodotin has the potential to be transmitted from the mother to the developing foetus.
Belantamab mafodotin is not recommended during pregnancy unless the benefit to the mother outweighs the potential risks to the foetus. If a pregnant woman needs to be treated she must be clearly advised on the potential risk to the foetus.
It is unknown whether belantamab mafodotin is excreted in human milk. Immunoglobulin G (IgG) is present in human milk in small amounts. Since belantamab mafodotin is a humanised IgG monoclonal antibody, and based on the mechanism of action, it may potentially cause serious adverse reactions in breastfed newborns or infants of treated mothers. Belantamab mafodotin is not to be used during breast-feeding and breast-feeding is to be avoided for at least 3 months after the last dose of belantamab mafodotin.
The pregnancy status of women of child-bearing potential must be verified prior to initiating therapy with belantamab mafodotin. Women of child-bearing potential have to use effective contraception during treatment with belantamab mafodotin and for at least 4 months after the last dose.
Men with female partners of child-bearing potential have to use effective contraception during treatment with belantamab mafodotin and for at least 6 months after the last dose.
Based on findings in animals and the mechanism of action, belantamab mafodotin may impair fertility in females and males of reproductive potential.
Therefore, physicians may counsel women of childbearing potential and men being treated with belantamab mafodotin who desire children in the future regarding fertility preservation.
Belantamab mafodotin has a moderate influence on the ability to drive and use machines. Patients must be advised to use caution when driving or operating machines while on belantamab mafodotin as it may affect patients' vision and influence their ability to drive or use machines due to impact on visual acuity and other ocular adverse reactions.
The most common adverse reactions (any grade) were corneal examination findings (including keratopathy) (84%), visual acuity reduced (81%), thrombocytopenia (62%), vision blurred (52%), dry eye (36%), foreign body sensation in eyes (32%), photophobia (30%), eye irritation (28%), neutropenia (27%), anaemia (23%), diarrhoea (23%), neuropathies (23%), and eye pain (21%).
The most common serious adverse reactions (any grade) were pneumonia (9%), pyrexia (4%), COVID-19 (3%), COVID-19 pneumonia (3%), and thrombocytopenia (2%).
The proportion of subjects with treatment discontinuation due to adverse reactions was 24%. The most common adverse reaction leading to treatment discontinuation was ocular events (7%).
The frequency of dose reduction due to adverse reactions was 63%. The most common adverse reactions leading to dose reduction were ocular events (39%), thrombocytopenia (12%), platelet count decreased (6%), insomnia (5%), peripheral sensory neuropathy (5%), neuropathy peripheral (5%), neutropenia (4%), fatigue (3%), and neutrophil count decreased (2%).
The frequency of dose delay due to adverse reactions was 83%. The most common adverse reactions leading to dose delay were ocular events (67%), thrombocytopenia (16%), COVID-19 (11%), platelet count decreased (8%), neutropenia (8%), upper respiratory tract infection (7%), pneumonia (7%), diarrhoea (4%), pyrexia (4%), neutrophil count decreased (4%), peripheral sensory neuropathy (4%), bronchitis (3%), COVID-19 pneumonia (3%), cataract (3%), neuropathy peripheral (3%), and alanine aminotransferase increased (3%).
The adverse reaction frequencies are based on all-cause adverse event frequencies, from patients with multiple myeloma exposed to belantamab mafodotin, for which, after thorough assessment, a causal relationship between the medicinal product and the adverse event is at least a reasonable possibility.
The safety of belantamab mafodotin has been evaluated in more than 7500 patients with multiple myeloma, including 516 patients who received belantamab mafodotin in triplet combinations as part of the DREAMM-6 (a Phase 1/2, open-label dose exploration study), DREAMM-7, and DREAMM-8 studies, 312 patients who received belantamab mafodotin as monotherapy in the DREAMM-2 and DREAMM-3 studies, and including patients from the post-marketing setting.
Adverse reactions are listed in Table 1 by system organ class and by frequency.
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Frequencies 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: frequency cannot be estimated from the available data
Table 1. Adverse reactions in multiple myeloma patients treated with belantamab mafodotin in clinical trials and post-marketing:
| System organ class (SOC) | Adverse reaction | Frequency | Incidence (%) | |
|---|---|---|---|---|
| Any grade | Grade 3-4 | |||
| Infections and infestations | COVID-19 | Very common | 18 | 3 |
| Upper respiratory tract infection | Very common | 15 | <1 | |
| Pneumonia | Very common | 13 | 7 | |
| Urinary tract infection | Common | 9 | 2 | |
| Bronchitis | Common | 5 | ˂1 | |
| COVID-19 pneumonia | Common | 3 | 2 | |
| Hepatitis B reactivation | Uncommon | <1 | <1 | |
| Blood and lymphatic system disorders | Thrombocytopeniaa | Very common | 62 | 47 |
| Neutropeniab | Very common | 27 | 22 | |
| Anaemia | Very common | 23 | 12 | |
| Lymphopeniac | Very common | 10 | 7 | |
| Leukopeniad | Common | 9 | 4 | |
| Febrile neutropenia | Common | 1 | 1 | |
| Immune system disorders | Hypogammaglobulinemia | Common | 2 | ˂1 |
| Metabolism and nutrition disorders | Decreased appetite | Common | 8 | <1 |
| Psychiatric disorders | Insomnia | Very Common | 13 | 1 |
| Nervous system disorders | Neuropathiese | Very common | 23 | 2 |
| Eye disorders | Corneal examination findings (including keratopathy)f,g | Very common | 84 | 62 |
| Visual acuity reducedf | Very common | 81 | 50 | |
| Vision blurred | Very common | 52 | 13 | |
| Dry eye | Very common | 36 | 5 | |
| Foreign body sensation in eyes | Very common | 32 | 2 | |
| Photophobia | Very common | 30 | 1 | |
| Eye irritation | Very common | 28 | 3 | |
| Eye pain | Very common | 21 | <1 | |
| Cataract | Very common | 13 | 4 | |
| Visual impairment | Common | 8 | 5 | |
| Lacrimation increased | Common | 5 | <1 | |
| Diplopia | Common | 3 | <1 | |
| Eye pruritus | Common | 2 | <1 | |
| Ocular discomfort | Common | 1 | <1 | |
| Corneal ulcerh | Common | 1 | <1 | |
| Corneal hypoesthesia | Not known | - | - | |
| Respiratory, thoracic and mediastinal disorders | Cough | Very common | 11 | ˂1 |
| Dyspnoea | Common | 9 | 1 | |
| Pneumonitis | Uncommon | <1 | <1 | |
| Gastrointestinal disorders | Diarrhoea | Very common | 23 | 2 |
| Nausea | Very common | 17 | <1 | |
| Constipation | Very common | 15 | <1 | |
| Vomiting | Common | 7 | <1 | |
| Hepatobiliary Disorders | Increased aspartate aminotransferase | Very common | 15 | 2 |
| Increased alanine aminotransferase | Very common | 13 | 3 | |
| Increased gamma glutamyltransferase | Very common | 11 | 5 | |
| Porto-sinusoidal vascular disorderi | Uncommon | <1 | <1 | |
| Skin and subcutaneous tissue disorders | Rash | Common | 4 | <1 |
| Musculoskeletal and connective tissue disorders | Arthralgia | Very common | 11 | <1 |
| Back pain | Very common | 11 | 1 | |
| Increased creatine phosphokinase | Common | 3 | 1 | |
| Renal and urinary disorders | Albuminuriaj | Common | 3 | <1 |
| General disorders and administration site conditions | Fatigue | Very common | 19 | 3 |
| Pyrexia | Very common | 18 | <1 | |
| Asthenia | Common | 6 | 1 | |
| Injury, poisoning and procedural complications | Infusion-related reactionsk | Very common | 11 | <1 |
a Includes thrombocytopenia and platelet count decreased.
b Includes neutropenia and neutrophil count decreased.
c Includes lymphopenia and lymphocyte count decreased.
d Includes leukopenia and white blood cell count decreased.
e Includes peripheral sensory neuropathy, neuropathy peripheral, neuralgia, polyneuropathy, peripheral motor neuropathy, sensory loss, peripheral sensorimotor neuropathy.
f Based on ophthalmic examination findings.
g Includes superficial punctate keratopathy, microcyst-like epithelial changes, stippled vortex staining pattern, sub-epithelial haze, corneal epithelial defects, and stromal opacity with or without changes in visual acuity.
h Includes infective keratitis and ulcerative keratitis.
i Signs or symptoms may include abnormal liver function tests, portal hypertension, varices, and ascites.
j Includes albuminuria, albumin urine present, urine albumin/creatinine ratio increased, and microalbuminuria.
k Includes adverse reactions determined to be related to infusion. Infusion reactions may include, but are not limited to, pyrexia, chills, diarrhoea, nausea, asthenia, hypertension, lethargy, and tachycardia.
Across pooled datasets from 3 trials of belantamab mafodotin in combination with other therapies (n=516), DREAMM-6 (a Phase 1/2, open-label dose exploration study), DREAMM-7 and DREAMM-8, ocular events were reported and included ophthalmic examination findings and ocular adverse reactions. The most common (> 25%) were reduced visual acuity (90%), corneal examination findings based on the ophthalmic examination findings (89%), blurred vision (62%), dry eye (44%), foreign body sensation in eyes (40%), photophobia (37%), eye irritation (35%), and eye pain (27%).
Corneal examination findings (keratopathies such as superficial punctate keratopathy and microcyst- like deposits) were reported based on the ophthalmic examination findings as Grade 1 in 5% of patients, Grade 2 in 14%, Grade 3 in 59% and Grade 4 in 12%. Cases of corneal ulcer (ulcerative and infective keratitis) were reported in < 1% of patients (n=5). At least 1 corneal examination finding or BCVA-related event (Grade ≥ 2) was reported by 86% of patients.
Table 2 includes a summary of decreased vision in patients with normal baseline (snellen equivalent visual acuity 20/25 or better in at least one eye) and corneal examination findings from pooled data of belantamab mafodotin in combination with other therapies.
Table 2. Median duration and resolution of the first ocular events in clinical trials (DREAMM-6, DREAMM-7, DREAMM-8; n=516):
| Bilateral reduction in BCVA | Corneal examination findings (Grade 2+ events) | ||
|---|---|---|---|
| 20/50 or worse | 20/200 or worse | ||
| Patients with event, n (%) | 161 (31) | 8 (2) | 423 (82) |
| Median time to first onset (days) | 85 | 99 | 43 |
| Improvement of first eventa, n (%) | 155 (96) | 8 (100) | NA |
| Resolution of first eventb, n (%) | 145 (90)c | 6 (75)c | 355 (84)d |
| Median time to resolution of first event, days (range) | 57 (8, 908) | 86.5 (22, 194) | 106 (8, 802) |
| Ongoing first eventb, n (%) | 16 (10) | 2 (25) | 68 (16) |
| On treatment and follow-up ongoing, n (%) | 3 (2) | - | 4 (< 1) |
| Discontinued treatment and follow-up ongoing, n (%) | 2 (1) | - | 8 (2) |
| Discontinued treatment and follow-up ended, n (%) | 11 (7) | 2 (25) | 56 (13) |
NA = Not applicable.
a Improvement was defined as no longer 20/50, or 20/200, or worse in at least one eye.
b At time of data cut-off (DREAMM-6: 28 FEB 2023; DREAMM-7: 02 OCT 2023; DREAMM-8: 29 JAN 2024).
c Resolution of BCVA was defined as 20/25 or better in at least one eye.
d Resolution of corneal examination findings was defined as Grade 1 or better based on the ophthalmic examination findings.
Across DREAMM-6, DREAMM-7, and DREAMM-8 (n=516), the incidence of IRRs was 6%. Nearly all IRRs were reported as Grade 1 (2%) and Grade 2 (4%), while < 1% experienced Grade 3 IRRs. One patient discontinued treatment due to IRRs. The incidence of IRRs was 4% during the first infusion, < 1% during the second infusion, and 2% during the subsequent infusions. IRRs were managed in 3% of patients with an event by dose reductions and 41% by dose delays, while 50% required additional premedication.
Across DREAMM-6, DREAMM-7, and DREAMM-8 (n=516), thrombocytopenic events (thrombocytopenia and platelet count decreased) occurred in 74% of patients. Grade 2 thrombocytopenic events occurred in 10% of patients, Grade 3 in 26%, and Grade 4 in 33%. Clinically significant bleeding (≥ Grade 2) occurred in 5% of patients with concomitant low platelet levels (Grades 3 to 4). These clinically significant bleeding events included: thrombocytopenia, platelet count decreased, epistaxis, urinary tract haemorrhage, haemorrhoidal haemorrhage, gastrointestinal haemorrhage, mouth haemorrhage, cerebral haemorrhage, and haematuria, and were Grade 2 in < 1%, Grade 3 in 2%, Grade 4 in 3%, and Grade 5 in < 1% of patients. The median time to onset for the first occurrence of thrombocytopenia was 8 days (range: 1, 659). The median duration of the first occurrence of thrombocytopenia was 15 days (range: 1, 361). Thrombocytopenia was managed in 35% of patients with an event by dose reduction and 44% by dose delay, while 2% required permanent discontinuation.
Across DREAMM-6, DREAMM-7, and DREAMM-8 (n=516), COVID-19 was reported in 23% of patients with 4% in Grade 3 and ˂ 1% in Grade 4. A fatal outcome occurred in ˂ 1% of patients, 16% had an event that led to dose delay, while ˂ 1% required permanent discontinuation.
Across DREAMM-6, DREAMM-7, and DREAMM-8 (n=516), pneumonia was reported in 18% of patients with 9% in Grade 3 and < 1% in Grade 4. Of pneumonia events occurring, 2% had a fatal outcome, < 1% led to dose reduction, 11% led to dose delay, while 2% required permanent discontinuation.
Across DREAMM-6, DREAMM-7, and DREAMM-8 (n=516), COVID-19 pneumonia was reported in 5% of patients with 3% in Grade 3 and ˂ 1% in Grade 4. A fatal outcome occurred in 1% of patients, 4% had an event that led to dose delay, while ˂ 1% required permanent discontinuation.
Across DREAMM-6, DREAMM-7, and DREAMM-8 (n=516), 226 patients were less than 65 years of age, 211 patients were 65 to less than 75 years of age, and 79 patients were 75 years of age or older. Serious adverse events occurred in 45% of patients less than 65 years of age, compared with 60% in those aged 65 to less than 75 years of age and 56% in those 75 years of age or older. The most common serious adverse reaction was pneumonia in 9% of patients less than 65 years of age, 17% in the 65 to less than 75 years of age group, and 9% in the 75 years of age or older group.
Ocular events (Grade 3 or 4) occurred in 76% of patients under 65 years of age, compared with 79% in those aged 65 to less than 75 years of age, and 71% in those 75 years of age or older.
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