medwireNews: The antibody–drug conjugate (ADC) belantamab mafodotin used for the treatment of relapsed or refractory multiple myeloma appears to reach the epithelium of the cornea primarily via limbal vessels, where it contributes directly to epithelial changes, including eosinophilic intracytoplasmic inclusions, shows a case series study published in JAMA Ophthalmology.
The epithelial changes were evaluated in six corneal samples from nine adults who were diagnosed with symptomatic or asymptomatic pseudomicrocysts in at least one eye while receiving belantamab mafodotin, which comprises a monoclonal antibody conjugated to the microtubule inhibitor monomethyl auristatin-F (MMAF).
The corneal samples were obtained by impression cytology (n=4) or superficial keratectomy (n=2), and all of them showed epithelial cells with eosinophilic intracytoplasmic inclusions, basophilic granular cytoplasm, or both.
Additionally, apoptosis was noted in five of the corneal samples and corneal epithelial inflammation in three, while pharmacokinetic analyses conducted 6 to 112 days after the last belantamab mafodotin dose revealed the ADC in five of seven tear fluid samples and cysteine-maleimidocaproyl (cys-mcMMAF) in two tear samples. Among four patients who provided blood samples, plasma ADC was quantifiable in three.
“Corneal events, particularly microcyst-like epithelial changes (pseudomicrocysts) are a well-described class effect of MMAF-containing ADCs,” explain researchers Vivian Lee (University of Pennsylvania Perelman School of Medicine, Philadelphia, USA) and colleagues. The team says their results “suggest that belantamab mafodotin reaches corneal epithelial cells and is associated with pseudomicrocyst formation.”
Lee et al propose that the pattern of observed corneal changes implicate “the limbal vessels as a primary pathway for ADC to enter the cornea.” Additionally, the presence of ADCs and cys-mcMMAF in some of the human tear samples, which has also been noted in some animal models, means belantamab mafodotin and cys-mcMMAF “could potentially contribute to or correlate with corneal toxicity.” However, further study is required to confirm how belantamab mafodotin reaches the ocular surface, they note.
The nine patients included in the study had a median age of 67 to 68 years, and 67% were women. The duration of exposure to belantamab mafodotin ranged from 3.1 to 135.1 weeks.
The investigators acknowledge that their study was limited by the small clinical population, owing partly to the market withdrawal of belantamab mafodotin, and that the clinical response for each patient could not be correlated with the drug.
In an accompanying editorial on the study, Lauren Dalvin, from the Mayo Clinic in Rochester, Minnesota, USA, and colleagues say that corneal pseudomicrocysts may impact more than half of patients exposed to ADCs with a microtubule-inhibitor payload, highlighting that “these AEs [adverse events] are especially relevant due to their potential to necessitate ADC treatment disruptions, including dose reductions, dose delays, or discontinuations of life-saving anticancer therapy.”
The findings from Lee et al “shed important light on the mechanism of corneal changes associated with belantamab mafodotin,” they add, and call for further studies into strategies to prevent pseudomicrocyst formation.
“Expert leaders with a vested interest in ophthalmic AEs from anticancer drugs must educate both the ophthalmology and oncology communities to minimize treatment disruptions where possible and effectively maintain vision-related quality of life,” the editorialists conclude.
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JAMA Ophthalmol 2025; doi:10.1001/jamaophthalmol.2025.1008
JAMA Ophthalmol 2025; doi:10.1001/jamaophthalmol.2025.1135
