Abstract
Purpose
To describe structural changes in corneal epithelium using anterior segment optical coherence tomography (AS-OCT) in two relapsed and refractory multiple myeloma (RRMM) patients with bilateral belantamab-associated superficial keratopathy (BASK).
Observations: case 1
A 56-year-old male who was diagnosed with RRMM and initiated on belantamab mafodotin, presented on day 42 (three weeks after the second infusion) with decreased pinhole visual acuity from 20/20 and 20/25 to 20/70 and 20/50 in the right eye and left eye, respectively. Slit-lamp examination revealed moderate superficial keratopathy with microcystic-like epithelial changes (MECs) in the paracentral cornea in both eyes. AS-OCT demonstrated increased bilateral heterogeneous signal intensity and hyperreflective lesions as well as increased thickness in the paracentral corneal epithelium with uninvolved central cornea. Given bilateral MECs, the third infusion was withheld, and then given on day 62 after five weeks of drug-free interval. Although MECs had improved on day 82, pinhole visual acuity remained at 20/50 and 20/40 in the right eye and the left eye. AS-OCT showed that hyperreflective lesions mostly resolved and corneal epithelial thickness returned to baseline, despite a slightly increased persisting heterogeneous signal intensity in the peripheral corneal epithelium in both eyes.
Case 2
A 77-year-old male with RRMM was started on belantamab mafodotin infusions. His pinhole visual acuity decreased from 20/40 and 20/30 at baseline to 20/60 and 20/40 on day 41 (three weeks after the second infusion) in the right eye and left eye, respectively. Slit-lamp examination showed diffuse, moderate MECs in both eyes, which was more severe in the peripheral cornea. AS-OCT demonstrated increased bilateral heterogeneous signal intensity and hyperreflective lesions in the corneal epithelium, which are more severe in the right eye along with increased corneal epithelial thickness. Therefore, belantamab mafodotin was withheld.
Conclusions and Impotance
AS-OCT objectively demonstrated structural changes such as signal intensity and thickness alterations with hyperreflective lesions in the corneal epithelium related to BASK. AS-OCT might be useful for clinicians to monitor ocular surface adverse events in RRMM patients receiving belantamab mafodotin and to adjust therapeutic plans for the patients.
1
Introduction
Multiple myeloma (MM) is a malignancy of the hematopoietic system characterized by abnormal proliferation of plasma cells in the bone marrow. MM constitutes 1–2% of all malignancies, with the median age at diagnosis of 69 years. Although MM is relatively rare, a significant number of patients suffer from relapsed or refractory MM (RRMM), management of which is still quite challenging. RRMM displays an extremely poor prognosis (median overall survival of 9.3 months) and is resistant to current treatment plans, demonstrating unmet needs for novel therapeutics. ,
Recently, belantamab mafodotin, an antibody-drug conjugate (ADC) against B-cell maturation antigen (BCMA), has shown promise with fast and favorable responses in RRMM. However, it has been shown to cause significant ocular surface adverse events (AEs) in the form of “superficial keratopathy” involving multiple, bilateral, microcystic-like epithelial changes (MECs) that might necessitate temporary cessation or discontinuation of treatment. , Belantamab-associated superficial keratopathy (BASK) is currently assessed according to the DREAMM-2 study protocol-specified criteria, called “keratopathy and visual acuity (KVA) scale”. Aside from changes in best-corrected visual acuity (BCVA), KVA scale is based on corneal changes on slit-lamp examination (SLE) which is partially subjective and requires special consideration. In the DREAMM-2 study, 69% of patients receiving belantamab (2.5mg/kg) developed BASK by the fourth infusion. Among patients with MECs, over 70% had <SPAN role=presentation tabIndex=0 id=MathJax-Element-1-Frame class=MathJax style="POSITION: relative" data-mathml='≥’>≥≥
≥
2 lines BCVA decline, and/or symptoms of blurred vision or subjective dry eye. However, the majority (80%) of patients with MECs spontaneously recovered at follow-up visits, which was mainly approximately 2–6 months post-treatment. Despite BASK being well described using in vivo confocal microscopy (IVCM), its pathogenesis has not been completely elucidated.
Anterior segment optical coherence tomography (AS-OCT) is a non-invasive, objective tool which provides high-resolution details about corneal changes in ocular surface and corneal diseases. AS-OCT is widely used for diagnostic and follow-up purposes in clinical practice. It enables quantitative measurement of corneal epithelial, stromal, and endothelial thicknesses. , Given the fact that BASK was commonly observed in patients receiving belantamab mafodotin, it is important to evaluate this novel finding objectively. Herein, we present AS-OCT findings of two RRMM patients who developed BASK during their treatment course.
2
Case presentation
2.1
Case 1
A 56-year-old male with a history of hypertension and type 2 diabetes mellitus was diagnosed with RRMM as a result of unresponsiveness to multiple prior therapies three and a half years ago. Given previous multiple treatment failures ( <SPAN role=presentation tabIndex=0 id=MathJax-Element-2-Frame class=MathJax style="POSITION: relative" data-mathml='≥’>≥≥
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4), belantamab mafodotin was chosen as the next therapeutic agent. Following the protocol under a Risk Evaluation and Mitigation Strategy (REMS), the patient was referred to our clinic for baseline evaluation. At that time, his pinhole visual acuity (VA) was 20/20 and 20/25 in the right eye (OD) and left eye (OS), respectively. SLE was unremarkable with clear corneas and no abnormal findings in the anterior and posterior segments in OU. The patient denied any ocular symptoms, previous ocular disease or surgery. Belantamab mafodotin infusion (2.5 mg/kg) was initiated for him (day 0), and the second infusion was given on day 21. One week following the second infusion, the patient noticed visual loss in both eyes (OU). Additional symptoms of ocular discomfort such as blurriness and dryness were also experienced two weeks after the second infusion. At the follow-up visit on day 42, his pinhole VA had decreased to 20/70 in OD, and 20/50 in OS. In SLE, a ring-shaped, moderate amount of superficial keratopathy in the form of diffuse MECs in the paracentral cornea was observed in OU. The central portion of the cornea was clear in OU ( Fig. 1 ). At the same time, corneal topography revealed irregular astigmatism which was greater in OD than in OS. The horizontal B-scan image through central cornea on AS-OCT(OptoVue RTVue, Fremont, CA) revealed increased heterogeneous signal intensity and hyperreflective lesions in the paracentral corneal epithelium with uninvolved central cornea. Several disruptions in the line of the Bowman’s layer (BL) were observed in OD ( Fig. 1 ). In addition, the mean of the full corneal epithelial thickness (CET) increased from 49μm to 47μm at the baseline to 79μm and 73μm on day 42 in OD and OS, respectively. Although there was no change in CET at the central cornea, increased CET was demonstrated at the 1mm, 2mm, and 3mm nasally and temporally away from the central cornea in OU ( Fig. 3 ). The indicated bilateral corneal findings were recorded as grade 2 (moderate) superficial keratopathy (KVA scale); therefore, the third infusion was withheld based on regulations under REMS. The patient was placed on bilateral topical prednisolone acetate twice daily and preservative-free artificial tears eight times daily. Despite profound changes observed in OD compared to OS, MECs clinically improved based on the KVA scale on SLE in OU on day 59, and pinhole VA was 20/40 and 20/30 in OD and OS, respectively. After discussion with the Hematology team, the patient received the third dose of belantamab mafodotin (2.5 mg/kg) on day 62. At the most recent visit on day 82, his pinhole VA was 20/50 and 20/40 in OD and OS, respectively. There was residual mild superficial keratopathy in OU, which improved further with bilateral topical prednisolone acetate once daily. On AS-OCT, the hyperreflective lesions mostly resolved despite the slightly increased persistent heterogeneous signal intensity in the peripheral corneal epithelium in OU ( Fig. 1 ). The mean of full CET decreased to 51μm OD and 51μm in OS, which was similar to baseline measurements; no thickening of CET at any point on day 82 was detected on AS-OCT in OU compared to baseline measurements. Except for corneal epithelium and BL, no abnormality of the stromal layer or other components of the cornea in OU was observed on OCT throughout the clinical course ( Fig. 3 ). No other AE was detected during the follow-up period.
2.2
Case 2
A 77-year-old male with a history of MM was referred to our clinic for ophthalmic evaluation before belantamab mafodotin therapy. He was initially diagnosed with MM about two decades ago. Relapsed myeloma was later treated with multiple therapies. Subsequently, the patient developed anaplastic large cell non-Hodgkin’s lymphoma (NHL) 7 years ago, which was treated with intensive chemotherapy that led to clinical remission. During the past three years, the patient had been treated for relapsed myeloma. However, four months ago, the patient had a relapse of MM, and was diagnosed with RRMM. The Hematology team then decided to initiate belantamab mafodotin therapy due to the previous multiple treatments (≧4). At the baseline evaluation, his pinhole VA was 20/40 in OD and 20/30 in OS. SLE revealed bilateral clear corneas and no abnormality of the anterior and posterior segments except mild nuclear sclerosis. The patient denied any ocular symptoms, previous ocular disease or surgery. The patient received his first belantamab mafodotin (2.5 mg/kg) infusion (day 0). He was also given the second infusion on day 21. There was no ocular AE after the first infusion. Subsequently, one week after the second infusion, the patient noted bilateral decrease in his vision despite using preservative-free artificial tears four times daily. At the follow-up visit on day 41, his pinhole VA had decreased to 20/60 and 20/40 in OD and OS, respectively. SLE and VA assessment established grade 2 (moderate) diffuse superficial keratopathy with involvement of the entire cornea according to KVA scale in OU; the findings were more severe in the peripheral cornea. AS-OCT also showed increased heterogeneous signal intensity and hyperreflective lesions in the corneal epithelium in the paracentral region in OU, which was more severe in OD ( Fig. 2 ). The mean of full CET demonstrated an increase to 60 μm from the baseline value of 48 μm in OD, while there was no change in OS ( Fig. 3 ). Therefore, belantamab mafodotin infusions were held until the re-initiation criteria can be achieved. There were no abnormal findings in corneal stroma or other components of the cornea except corneal epithelium, and no changes in corneal thickness without CET was observed in OU throughout the clinical cause ( Fig. 3 ). Given the decreased vision with moderate diffuse superficial keratopathy in both eyes, topical prednisolone acetate 1% was started bilaterally four times daily and artificial tears were increased to eight times daily to help to relieve visual symptoms due to superficial keratopathy. The patient did not experience any other AEs during his follow-up.
