Belantamab Mafodotin

Belantamab mafodotin is an antibody–drug conjugate. Its antibody part is an afucosylated, humanised IgG1 kappa monoclonal antibody specific for B-cell maturation antigen (BCMA), made in Chinese hamster ovary cells by recombinant DNA technology. It is linked to the cytotoxic agent maleimidocaproyl monomethyl auristatin F (mcMMAF). BCMA is found on the surface of myeloma cells, so the conjugate carries the cytotoxic agent to the tumour cells.

Mechanism of Action

• Binding and uptake: the conjugate binds to BCMA on the cell surface and is rapidly taken up into the tumour cell.
• Cytotoxic payload: inside the cell the cytotoxic agent (cys-mcMMAF) is released. It disrupts the microtubule network, which leads to cell-cycle arrest and apoptosis (programmed cell death).
• Immune effects: the antibody also enhances the recruitment and activation of immune effector cells, which kill tumour cells by antibody-dependent cellular cytotoxicity and phagocytosis.
• Immunogenic cell death: apoptosis induced by the conjugate is accompanied by markers of immunogenic cell death, which may contribute to an adaptive immune response against the tumour cells.
• Cardiac electrophysiology: no meaningful QTc prolongation (more than 10 ms) was seen at doses up to 3.4 mg/kg every 3 weeks.
• Immunogenicity: anti-drug antibodies were rarely detected, with no evidence of an effect on pharmacokinetics, efficacy or safety.

Pharmacokinetics

• Absorption: given by intravenous infusion. The peak level of the conjugate occurs at or shortly after the end of the infusion, while the released payload (cys-mcMMAF) peaks about 24 hours after dosing. After the first 3-week interval at 2.5 mg/kg, the geometric mean peak concentration (Cmax) of the conjugate was 43.7 µg/mL. With dosing every 3 weeks, accumulation of the conjugate is minimal to moderate (cycle 3 to cycle 1 ratio 1.13 for Cmax and 1.58 for AUC) and accumulation of the payload is negligible.
• Distribution: the steady-state volume of distribution of the conjugate is about 10.8 L. In vitro, the payload has low plasma-protein binding (70% unbound at 5 ng/mL).
• Metabolism: the antibody part is expected to be broken down by ubiquitous proteolytic enzymes into small peptides and amino acids. The payload showed limited metabolic clearance in human liver S9 fraction studies. In vitro it neither inhibits nor induces cytochrome P450 enzymes and is not a sensitive substrate of them, but it is a substrate of the transporters OATP1B1, OATP1B3, MRP1, MRP2, MRP3 and BSEP, and possibly of P-glycoprotein.
• Elimination: as with other monoclonal antibodies, the conjugate is expected to be cleared by breakdown into peptides and amino acids rather than excreted unchanged. Its terminal half-life is about 12 days after the first dose and about 14 days at steady state.
• Special populations: dosing is by body weight, and the medicine has been studied in patients weighing 37 to 170 kg. No dose adjustment is recommended in older patients or in renal impairment; data are limited in moderate and severe hepatic impairment (see Administration and Dosage).

Blenrep is used in adults with relapsed or refractory multiple myeloma, always in combination with other medicines.

• With bortezomib and dexamethasone: patients who have received at least one prior therapy.
• With pomalidomide and dexamethasone: patients who have received at least one prior therapy including lenalidomide.

• Hypersensitivity to belantamab mafodotin or to any of the excipients (sodium citrate dihydrate, citric acid monohydrate, trehalose dihydrate, disodium edetate, polysorbate 80).

Eye reactions dominate the safety profile. The most common reactions (any grade) were corneal examination findings including keratopathy (84%), reduced visual acuity (81%), thrombocytopenia (62%), blurred vision (52%), dry eye (36%), foreign body sensation in the eyes (32%), photophobia (30%), eye irritation (28%), neutropenia (27%), anaemia (23%), diarrhoea (23%), neuropathies (23%) and eye pain (21%). The most common serious reactions were pneumonia (9%), pyrexia (4%), COVID-19 (3%), COVID-19 pneumonia (3%) and thrombocytopenia (2%). Side effects led to treatment discontinuation in 24% of patients (most often ocular events, 7%), to dose reduction in 63% (ocular events, 39%) and to dose delay in 83% (ocular events, 67%). The profile is based on more than 7,500 patients with multiple myeloma, including 516 who received belantamab mafodotin in triplet combinations.

Very common (≥1/10): COVID-19, upper respiratory tract infection, pneumonia; thrombocytopenia, neutropenia, anaemia, lymphopenia; insomnia; neuropathies (a grouped term); corneal examination findings (including keratopathy), reduced visual acuity, blurred vision, dry eye, foreign body sensation in the eyes, photophobia, eye irritation, eye pain, cataract; cough; diarrhoea, nausea, constipation; increased aspartate aminotransferase, alanine aminotransferase and gamma-glutamyltransferase; arthralgia, back pain; fatigue, pyrexia; infusion-related reactions.

Common (≥1/100 to <1/10): urinary tract infection, bronchitis, COVID-19 pneumonia; leukopenia, febrile neutropenia; hypogammaglobulinaemia; decreased appetite; visual impairment, increased lacrimation, diplopia, eye pruritus, eye discomfort, corneal ulcer; dyspnoea; vomiting; rash; increased blood creatine phosphokinase; albuminuria; asthenia.

Uncommon (≥1/1,000 to <1/100): hepatitis B reactivation, pneumonitis, portosinusoidal vascular disease.

Not known: corneal hypoaesthesia (reduced sensation of the cornea).

Serious reactions to watch for are corneal ulcers (ulcerative and infective keratitis), changes in the corneal nerve plexus with reduced corneal sensation, severe thrombocytopenia with gastrointestinal or intracranial bleeding, infusion-related reactions, pneumonitis (including fatal cases) and hepatitis B reactivation, which can lead to fulminant hepatitis, hepatic failure and death. Dose modification is needed in nearly all patients.

No interaction studies have been performed. From the in vitro and clinical data available, the risk of pharmacokinetic or pharmacodynamic interactions is low.

• Combination partners: clinical assessments of belantamab mafodotin given with bortezomib, lenalidomide, pomalidomide and/or dexamethasone showed no clinically relevant interaction with these small-molecule medicines.
• Enzymes and transporters: the payload (cys-mcMMAF) does not inhibit or induce CYP enzymes and is not a sensitive substrate of them. It is a substrate of several transporters (OATP1B1, OATP1B3, MRP1, MRP2, MRP3, BSEP and possibly P-glycoprotein), but clinically relevant interactions with inhibitors or inducers of these are not expected.
• Anticoagulants: because thrombocytopenia can cause serious bleeding, patients taking anticoagulants may need more frequent blood-count monitoring.

Treatment is started and monitored by physicians experienced in treating multiple myeloma. Blenrep is for intravenous infusion only. It must be diluted before use and is given with an infusion pump through an infusion set made of polyvinyl chloride or polyolefin, over about 30 minutes. It must not be given as an intravenous push or bolus injection. If an infusion-related reaction occurs, the infusion may take longer than 30 minutes, provided that the total in-use time (preparation and administration) does not exceed 6 hours. Filtering the diluted solution is not required; if it is filtered, a 0.2 µm or 0.22 µm polyethersulfone filter is recommended. Instructions for dilution, handling and disposal are in section 6.6 of the SmPC.

Recommended Dose

Doses are based on the baseline actual body weight, and treatment continues according to the schedule until disease progression or unacceptable toxicity.

• With bortezomib and dexamethasone (3-week cycles): 2.5 mg/kg once every 3 weeks. Bortezomib and dexamethasone are given for the first 8 cycles.
• With pomalidomide and dexamethasone (4-week cycles): 2.5 mg/kg once in cycle 1; from cycle 2 onwards, 1.9 mg/kg once every 4 weeks.

Dose Reduction Levels

Dose modifications are needed for nearly all patients to manage safety and tolerability.

• With bortezomib and dexamethasone: reduced level 1 is 1.9 mg/kg every 3 weeks. There is no second reduced level.
• With pomalidomide and dexamethasone: reduced level 1 is 1.9 mg/kg every 8 weeks; reduced level 2 is 1.4 mg/kg every 8 weeks.
• After a dose reduction for an ocular reaction the dose is not increased again. After a reduction for other reactions, re-escalation is a matter of clinical judgement.

Dose Modifications for Side Effects

The SmPC tables give the full grading criteria; the main rules are as follows.

• Ocular reactions: graded from the corneal examination findings together with visual acuity, using the more severely affected eye. The treating physician reviews the eye examination findings before choosing the dose. Mild (Grade 1): continue at the current dose. Moderate (Grade 2) or severe (Grade 3): withhold until corneal findings and visual acuity have improved to mild severity or better, then resume at reduced dose level 1. A corneal epithelial defect such as a corneal ulcer, or visual acuity worse than 20/200 (Grade 4): withhold until improved to mild severity or better, then resume at reduced level 1 (with bortezomib) or reduced level 2 (with pomalidomide); consider permanent discontinuation if worsening symptoms do not respond to appropriate management.
• Thrombocytopenia: Grade 3 without bleeding: patients on 2.5 mg/kg are reduced to 1.9 mg/kg, and patients already on 1.9 mg/kg or lower continue at the same dose. Grade 3 with bleeding: withhold until Grade 2 or better, then resume at 1.9 mg/kg (if previously on 2.5 mg/kg) or at the same dose. Grade 4: withhold; consider restarting once recovered to Grade 3 or better, and only if there is no active bleeding.
• Infusion-related reactions: Grade 2: interrupt the infusion and give supportive treatment; once symptoms are Grade 1 or better, resume at an infusion rate reduced by at least 50% and consider premedication. Grade 3: interrupt, treat, and resume at a slower rate once resolved; consider premedication for later infusions. Grade 4: permanently discontinue (if the reaction is anaphylactic or life-threatening, stop the infusion permanently and give emergency care).
• Pneumonitis: Grade 3 or higher: permanently discontinue.
• Other reactions: Grade 3: withhold until Grade 1 or better, then resume at 1.9 mg/kg (if previously on 2.5 mg/kg) or at the same dose. Grade 4: consider permanent discontinuation; if treatment continues, withhold until Grade 1 or better and resume on the same rule.

Special Populations

• Elderly (65 years and over): no dose adjustment.
• Renal impairment: no dose adjustment in mild (eGFR 60–89 mL/min), moderate (30–59 mL/min) or severe impairment not requiring dialysis (below 30 mL/min), or in end-stage renal disease requiring dialysis.
• Hepatic impairment: no dose adjustment in mild impairment. Data in moderate and severe impairment are limited; Blenrep should be used in these patients only if the potential benefits outweigh the risks.
• Body weight: studied in patients weighing 37 to 170 kg. If body weight changes by more than 10% during treatment, the dose is recalculated from the actual weight at the time of dosing.
• Children and adolescents: there is no relevant use in the paediatric population for relapsed or refractory multiple myeloma.

Missed Dose

• If a planned dose is missed for a reason other than an adverse reaction, treatment resumes at the start of the next planned cycle.
• If it is missed because of an adverse reaction, treatment resumes at the start of the next planned cycle after the reaction has recovered, following the dose-modification rules above.

Eye Examinations Are Required

The SmPC requires an ophthalmic examination, including visual acuity and slit-lamp examination, performed by an eye care professional before each of the first 4 doses of Blenrep, and as clinically indicated after that. Regular eye monitoring is recommended throughout treatment, and the treating physician reviews the eye findings before deciding each dose. Corneal events are very common: corneal examination findings (such as superficial punctate keratopathy, microcyst-like epithelial changes and haze) occurred in 84% of patients and reduced visual acuity in 81%.

• Lubricating drops: patients should use preservative-free artificial tears at least 4 times a day during treatment.
• Contact lenses: patients should avoid contact lenses until the end of treatment. Bandage contact lenses may be used under the direction of an ophthalmologist.
• Symptoms: patients should report any change in vision promptly and temporarily avoid driving or operating machinery if visual symptoms occur.
• Corneal ulcers and nerve changes: corneal ulcers (ulcerative and infective keratitis) and changes in the subbasal nerve plexus of the cornea with reduced corneal sensation have been reported. They need prompt management by an eye care professional, and Blenrep is interrupted until a corneal ulcer has healed.
• Dose changes: corneal findings, with or without a change in visual acuity, may require a dose delay or reduction, or discontinuation (see Administration and Dosage).

Thrombocytopenia and Bleeding

Thrombocytopenia (including decreased platelet count) is very common and may lead to serious bleeding, including gastrointestinal and intracranial bleeding. Complete blood counts with differential and platelet counts should be monitored frequently throughout treatment. Patients with Grade 3 or 4 thrombocytopenia, or taking anticoagulants, may need more frequent monitoring and a dose delay or reduction. Supportive therapy such as platelet transfusion is given according to standard medical practice.

Infusion-Related Reactions

Most infusion-related reactions were Grade 1 or 2 and resolved within the same day. If a Grade 2 or higher reaction occurs during administration, the infusion rate is reduced or the infusion is stopped, depending on severity; appropriate treatment is given, and the infusion is restarted at a slower rate once the patient is stable. Premedication should be considered for later infusions after a Grade 2 or higher reaction.

Pneumonitis

Pneumonitis, including fatal cases, has been observed. Patients with new or worsening unexplained lung symptoms such as cough or breathlessness must be evaluated to exclude pneumonitis. In suspected or confirmed Grade 3 or higher pneumonitis, Blenrep is discontinued and appropriate treatment started.

Hepatitis B Reactivation

Hepatitis B virus can reactivate in patients given medicines directed against B cells, including Blenrep, and in some cases this may lead to fulminant hepatitis, hepatic failure and death. Patients with positive hepatitis B serology must be monitored for clinical and laboratory signs of reactivation, as set out in clinical guidelines. If reactivation occurs, Blenrep must be withheld and the patient treated according to clinical guidelines.

Traceability

Blenrep is a biological medicinal product, so the name and batch number of the administered product should be clearly recorded.

Pregnancy, Contraception and Breastfeeding

• Pregnancy test: the pregnancy status of women of childbearing potential must be verified before treatment starts.
• Contraception in women: women of childbearing potential must use effective contraception during treatment and for at least 4 months after the last dose.
• Contraception in men: men with female partners of childbearing potential must use effective contraception during treatment and for at least 6 months after the last dose.
• Pregnancy: there are no data from pregnant women. Because of the mechanism of its cytotoxic component (MMAF), belantamab mafodotin can cause embryo-foetal harm, and as an IgG antibody it may cross the placenta. It is not recommended in pregnancy unless the benefit to the mother outweighs the risk to the foetus; a pregnant woman who needs treatment must be clearly advised of the potential risk to the foetus.
• Breastfeeding: it is not known whether belantamab mafodotin passes into human milk. Because of the potential for serious reactions in breastfed infants, Blenrep must not be used during breastfeeding, and breastfeeding is to be avoided for at least 3 months after the last dose.

Excipients

Blenrep contains polysorbate 80 (E433), which may cause allergic reactions: 0.28 mg per 70 mg vial and 0.4 mg per 100 mg vial after reconstitution. It contains less than 1 mmol (23 mg) of sodium per dose, that is, it is essentially sodium-free.

Effect on Driving

Blenrep has a moderate influence on the ability to drive and use machines, because of its effects on visual acuity and other ocular reactions. Patients should take care when driving or operating machines and avoid doing so temporarily if visual symptoms occur.

Blenrep vials must be stored in a refrigerator at 2–8 °C. This is a cold-chain product: it stays refrigerated during transport and storage until it is reconstituted. For storage after reconstitution and dilution, see Shelf Life below. Each pack holds one 6 mL type 1 glass vial (70 mg or 100 mg of powder) sealed with a bromobutyl rubber stopper and an aluminium overseal.

• Unopened vial: 4 years.
• Reconstituted solution: up to 4 hours at room temperature (20–25 °C) or up to 4 hours in a refrigerator (2–8 °C). Do not freeze.
• Diluted solution: should be used immediately. If it is not, it can be kept in a refrigerator (2–8 °C) for up to 24 hours before administration; do not freeze. A refrigerated solution is allowed to reach room temperature before administration, and it may then be kept at room temperature (20–25 °C) for a maximum of 6 hours, including the infusion time.

Prescription only (Rx), subject to restricted medical prescription (Annex II B of the marketing authorisation). Treatment is started and monitored by physicians experienced in treating multiple myeloma. Blenrep is given as an intravenous infusion, so it is supplied to the hospital or clinic that administers it, by cold-chain delivery at 2–8 °C, one vial per pack. The SmPC requires an ophthalmic examination (visual acuity and slit-lamp examination) by an eye care professional before each of the first 4 doses and as clinically indicated afterwards, so the eye examinations must be arranged together with the infusion schedule.