Corneal Epithelial Findings in Patients with Multiple Myeloma Treated with Antibody–Drug Conjugate Belantamab Mafodotin in the Pivotal, Randomized, DREAMM-2 Study

Abstract

Introduction: Patients with relapsed or refractory multiple myeloma (RRMM) represent an unmet clinical need. Belantamab mafodotin (belamaf; GSK2857916) is a first-in-class antibody-drug conjugate (ADC; or immunoconjugate) that delivers a cytotoxic payload, monomethyl auristatin F (MMAF), to myeloma cells. In the phase II DREAMM-2 study (NCT03525678), single-agent belamaf (2.5 mg/kg) demonstrated clinically meaningful anti-myeloma activity (overall response rate 32%) in patients with heavily pretreated disease. Microcyst-like epithelial changes (MECs) were common, consistent with reports from other MMAFcontaining ADCs. Methods: Corneal examination findings from patients in DREAMM-2 were reviewed, and the clinical descriptions and accompanying images (slit lamp microscopy and in vivo confocal microscopy [IVCM]) of representative events were selected. A literature review on corneal

The role of belantamab mafodotin for patients with relapsed and/or refractory multiple myeloma

“…The precise mechanism of corneal damage has not been fully elucidated, but result in microcystic epithelial damage (microcyst-like epithelial changes or MECs) likely due to non-specific ADC uptake into the actively dividing epithelial cells in the basal layer of the cornea. 17,[20][21][22] Both on-target and off-target corneal toxicities have been described with ADCs, although given that BCMA is not expressed in the cornea, MECs from belamaf are likely due to offtarget effects of belamaf.…”

“…This highlights that ocular exam findings of MECs or changes in BCVA are often not associated with patient-reported ocular symptoms. 17,21 The median time to the onset and duration of ocular AEs at the 2.5 mg/kg dose were as follows: 37 days and 87 days for MECs, 64 days and 33 days for BCVA changes, 52 days and 43 days for blurred vision, and 42 days and 39 days for dry eyes. At the time of last follow-up at the time of data cut-off, recovery was noted in 48% patients for MECs, 59% for BCVAs, 63% for blurred vision, and 79% for dry eyes.…”

“…At the time of last follow-up at the time of data cut-off, recovery was noted in 48% patients for MECs, 59% for BCVAs, 63% for blurred vision, and 79% for dry eyes. 17,21 Farooq et al reviewed the corneal findings in the DREAMM-2 study and hypothesized that following systemic administration of belamaf, it enters the cornea via tears and/or via the vasculature of the limbus. This then leads to internalization of belamaf by the basal corneal epithelium through macropinocytosis.…”

“…Interestingly, macropinocytosis is also thought to be the etiology responsible for belamaf-induced thrombocytopenia through apoptosis of megakaryocyte progenitors. 20,21 Agents that inhibit macropinocytosis, such as imipramine, phenoxybenzamine, and vinblastine may be an option to mitigate these effects, but these agents have yet to be tested for this indication in clinical trials. 23 Prophylactic corticosteroid eye drops were found to be of limited benefit in trials of other ADCs, but as noted in the DREAMM-2 ocular substudy, this strategy was deemed to be of no benefit in preventing belamafassociated keratopathy.…”

“…This highlights that ocular exam findings of MECs or changes in BCVA are often not associated with patient-reported ocular symptoms. 17,21…”