Belantamab mafodotin–induced corneal changes in patients with multiple myeloma

(Image credit: © chokniti / Adobe Stock)

Investigators from across the US and UK reported that histopathologic study of the corneal epithelium of patients with multiple myeloma who had been treated with belantamab mafodotin (Blenrep, GlaxoSmithKline), an antibody-drug conjugate (ADC), detected changes in the corneal epithelium. Specifically, the study showed ADCs in the corneas of these patients.¹ The study was led by Vivian Lee, MD, who is from the Department of Ophthalmology and Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia.

Belantamab mafodotin, a maleimidocaproyl monomethyl auristatin-F (MMAF)–containing ADC, is an investigational drug that targets B-cell maturation antigen on malignant multiple myeloma plasma cells.^2,3 

“Corneal events, particularly microcyst-like epithelial changes (pseudomicrocysts) are a well-described class effect of MMAF-containing ADCs.^4-9 ADCs are thought to reach the cornea via vascularized limbus10or tear film, where antigen-negative corneal epithelial cell death may occur through MMAF toxicity.^11-14 Although pseudomicrocyst development has not been replicated in belantamab mafodotin–treated preclinical models and confirmatory histology in patients is lacking, evidence has suggested that belantamab mafodotin–driven pseudomicrocysts are partly due to ADC macropinocytosis by corneal epithelial cells,"^10,15,16 the investigators explained.

When MMAF enters the cells, the microtubule-dependent processes underlying migration, cell cycle progression, and differentiation of limbal cells are disrupted.^16,17 Affected cells migrate toward the central cornea in various stages of apoptosis, and cells completing apoptosis slough off from the surface.9,16,18 

The results is that the development of the pseudomicrocyst-associated changes may affect the cornea’s refractive power by, for example, causing an initial hyperopic shift and then a myopic shift with development of substantial astigmatism.^19,20 ADCs also can worsen dry eye diseases, with changes in tear film parameters occurring early after exposure tobelantamab mafodotin,^21-23 although this mechanism is not completely understood, the authors explained.

Study objective

The investigators set out to characterize the corneal epithelial changes in patients with relapsed or refractory multiple myeloma that had been treated with belantamab mafodotin. They conducted a multicenter, phase 3b case series study in the US from March 26, 2020, to November 21, 2022, among adults with relapsed or refractory multiple myeloma.

The primary end point included the pathologic characteristics and composition of the corneal epithelial changes obtained by impression cytology (IC) or superficial keratectomy (SK). Tear film and blood were collected to determine the drug concentrations at the time the samples were obtained.

Findings

The investigators screened 16 patients, of whom nine (median age, 67 years; range, 57.0-81.0) were included in the study. Of the corneal samples obtained, six samples from six patients could be evaluated, ie, four by IC and two by SK.

Of the nine patients (6 women) included, the median patient age was 67.0 years (range, 57.0-81.0) for those with samples obtained by IC and 68.0 (65.0-81.0) years for those with samples obtained by SK.

“All samples demonstrated epithelial cells with eosinophilic intracytoplasmic inclusions [defined as small particles that are freely suspended in the cytoplasmic matrix], basophilic granular cytoplasm, or both, among the corneal epithelial cells. Five samples were positive for apoptosis, and three samples showed evidence of inflammation. All patients experienced complete IC or SK wound healing. ADC was detected in the tear fluid of five of seven patients with tear fluid sampling, while ADC was quantifiable in three of four patients with blood samples,” Dr. Lee and colleagues reported.

They concluded, “In this case series study, intracytoplasmic inclusions were observed among the corneal epithelial cells of patients with relapsed or refractory multiple myeloma treated with belantamab mafodotin who developed pseudomicrocysts. The pattern of corneal changes suggested that the limbal vessels were the primary pathway for ADC to enter the cornea, but ADC was also detected in the tear fluid. This study improves the understanding of potential mechanisms behind pseudomicrocyst development with ADC treatment.”

References

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9. Schloesser L, Loeffler KU, Heine A, Holz FG, Herwig-Carl MC. Dynamics of microcyst-like epithelial changes associated with belantamabmafodotin therapy in a patient with multiple myeloma-a case report.Blood Cancer J. 2024;14:133. doi:10.1038/s41408-024-01110-x

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12. Okeley NM, Miyamoto JB, Zhang X, et al. Intracellular activation of SGN-35, a potent anti-CD30 antibody-drug conjugate.Clin Cancer Res. 2010;16:888-897. doi:10.1158/1078-0432.CCR-09-2069

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14. Aschauer J, Donner R, Lammer J, et al. Corneal toxicity associated with belantamabmafodotin is not restricted to the epithelium: neuropathy studied with confocal microscopy.Am J Ophthalmol. 2022;242:116-124. doi:10.1016/j.ajo.2022.06.009

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16. Farooq AV, Degli Esposti S, Popat R, et al. Corneal epithelial findings in patients with multiple myeloma treated with antibody-drug conjugate belantamabmafodotin in the pivotal, randomized, DREAMM-2 study.Ophthalmol Ther. 2020;9:889-911. doi:10.1007/s40123-020-00280-8

17. Donaghy H. Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates.MAbs. 2016;8:659-671. doi:10.1080/19420862.2016.1156829

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