Belantamab mafodotin (Blenrep) is an antibody-drug conjugate (ADC) used to treat adults with relapsed or refractory multiple myeloma. This treatment targets B-cell maturation antigen (BCMA), a protein highly expressed on myeloma cells. Ocular toxicity is the most significant safety concern and a dose-limiting factor associated with Blenrep. This risk has led to a mandatory Risk Evaluation and Mitigation Strategy (REMS) program to ensure patient safety.
Manifestations of Ocular Toxicity
The drug primarily causes keratopathy, which is damage to the corneal epithelium, the outermost layer of the eye’s surface. This corneal change is frequently observed in patients receiving Blenrep and is often described as microcyst-like epithelial changes (MECs) upon examination.
Patients may experience symptoms such as blurred vision, dry eyes, foreign body sensation, photophobia, eye irritation, and eye pain. Decreased visual acuity, or a reduction in the sharpness of vision, is also a common manifestation.
In clinical trials, nearly 90% of patients experienced a reduction in visual acuity, and over 85% had corneal exam findings. These adverse events often occur early, with the median time to onset for moderate to severe findings being about 36 days after starting therapy. Ocular toxicity can sometimes be detected by an eye exam before a patient notices symptoms, emphasizing the need for routine monitoring.
Underlying Cause of Corneal Damage
Blenrep is an Antibody-Drug Conjugate (ADC) where the antibody targets BCMA on myeloma cells. However, the toxic payload is responsible for off-target damage in the eye. The cytotoxic component is monomethyl auristatin F (MMAF), which disrupts microtubules within the cell.
Corneal epithelial cells are susceptible to MMAF because they are constantly turning over. The drug enters these cells through a non-specific process, such as macropinocytosis, causing the toxic payload to accumulate. This off-target absorption disrupts the cell’s internal structure, leading to epithelial cell death and the characteristic keratopathy. Similar ocular side effects have been observed with other ADCs that use the MMAF payload.
Mandatory Ophthalmic Monitoring and Management
Due to the high risk of ocular toxicity, treatment requires a strict, mandatory monitoring program under the Risk Evaluation and Mitigation Strategy (REMS). This mandates close collaboration between the oncologist and an eye care professional (ophthalmologist or optometrist). Patients must undergo comprehensive ophthalmic examinations, including visual acuity testing and a slit lamp examination, at baseline before the first dose.
These eye exams must be repeated prior to every subsequent dose of Blenrep and promptly if the patient reports new or worsening eye symptoms. Examination results, particularly the worst finding from the most affected eye, are used to grade toxicity severity based on the Keratopathy and Visual Acuity (KVA) scale. The KVA grade dictates the management strategy.
Management primarily involves modifying the Blenrep dosing schedule. Keratopathy is the most frequent reason for dose interruptions and reductions in clinical trials.
Dose Modification Guidelines
- For grade 2 or higher toxicity, treatment is typically withheld until the condition improves to grade 1 or better.
- Once the condition improves, the drug may be resumed at the same or a reduced dose.
- If the ocular toxicity is severe or persistent, permanent discontinuation of Blenrep may be necessary.
In addition to dose modifications, patients should use preservative-free lubricant eye drops at least four times daily to manage symptoms like dry eyes. Patients must also avoid wearing contact lenses until the end of treatment, though bandage contact lenses may be used under specialist supervision.
Reversibility and Long-Term Visual Outcomes
The corneal changes caused by Blenrep are generally reversible upon dose interruption or discontinuation. The damaged corneal epithelial cells are typically replaced by new, healthy cells, allowing the microcyst-like changes and associated symptoms to resolve. However, recovery time varies significantly among patients.
The median time for resolution of moderate to severe corneal findings is around 91 days, though recovery can take several months. While decreased visual acuity is common, most patients who experience a reduction in vision to 20/50 or worse see a return to their baseline visual acuity or better. Severe, permanent vision loss is uncommon, provided monitoring and dose modification protocols are strictly followed.