Corneal microcyst-like epithelial changes (MECs) are frequently associated with antibody–drug conjugates (ADCs) containing monomethyl auristatin F, which have been studied in a variety of cancers, including belantamab mafodotin (belamaf, GSK2857916) currently being investigated for the treatment of relapsed or refractory multiple myeloma. |
In this report, the authors further characterize belamaf-associated MECs and provide a representative case report. MECs typically are seen early in treatment, are manageable with dose modifications, and tend to resolve after completing treatment. |
Presented images demonstrate that MECs appear as bilateral, diffuse, microcyst-like lesions on slit lamp photography; however, on confocal microscopy the affected areas appear as hyperreflective material that is (at least predominantly) intracellular. |
Available literature on corneal events with other ADCs supports the observations with belamaf treatment and confirms the need for additional research on the underlying pathophysiology and optimal management. |
The authors propose a mechanism whereby MECs represent an off-target effect of belamaf in the cornea leading to apoptosis of epithelial cells, which are eventually replaced with new epithelial cells, leading to the eventual resolution of MECs and symptoms after completing treatment. |
Digital Features
Introduction
Methods
Eye examination findings per KVA scale | Recommended dose modifications | |
---|---|---|
Grade 1 | Corneal examination finding(s) | Continue treatment at current dose |
Mild superficial keratopathya | ||
Change in BCVAb | ||
Decline from baseline of 1 line on Snellen Visual Acuity | ||
Grade 2 | Corneal examination finding(s) | Withhold treatment until improvement in both corneal examination findings and changes in BCVA to Grade 1 or better and resume at same dose |
Moderate superficial keratopathyc | ||
Change in BCVAb | ||
Decline from baseline of 2 or 3 lines (and Snellen Visual Acuity not worse than 20/200) | ||
Grade 3 | Corneal examination finding(s) | Withhold treatment until improvement in both corneal examination findings and changes in BCVA to Grade 1 or better and resume at a reduced dose |
Severe superficial keratopathyd | ||
Change in BCVAb | ||
Decline from baseline by more than 3 lines (and Snellen Visual Acuity not worse than 20/200) | ||
Grade 4 | Corneal examination finding(s) | Consider treatment discontinuation for a Grade 4 event. Based on a benefit:risk assessment, if continuing treatment with belamaf is being considered, treatment may be resumed at a reduced dose after the event has improved to Grade 1 or better event |
Corneal epithelial defecte | ||
Change in BCVAb | ||
Snellen Visual Acuity worse than 20/200 |
Results
Eye examination findings per KVA scale | CTCAE scale | ||||
---|---|---|---|---|---|
MECs (n = 95) | BCVA change (n = 95) | MECs + BCVA change (n = 95) | Blurred vision (n = 95) | Subjective dry eye (n = 95) | |
Any grade, n (%)a | 68 (72) | 51 (54) | 68 (72) | 24 (25) | 14 (15) |
Maximum grade | |||||
Grade 1 | 8 (8) | 7 (7) | 7 (7) | 11 (12) | 9 (9) |
Grade 2 | 16 (17) | 15 (16) | 14 (15) | 9 (9) | 4 (4) |
Grade 3 | 43 (45) | 28 (29) | 45 (47) | 4 (4) | 1 (1) |
Grade 4 | 1 (1) | 1 (1) | 2 (2) | 0 | 0 |
Median time to onset of first occurrence (range), days | 37.0 (19–143)b | 64.0 (20–213) | 36.0 (19–143) | 51.5 (6–339) | 42.0 (12–151) |
Median duration of first event (range), days | 86.5 (8–358)b | 33.0 (8–127)b | 96.0 (8–358)b | 42.5 (6–441) | 39.0 (12–316) |
First event outcomes,c n/N (%) | |||||
Recovered | 46/60 (77)b | 34/44 (77)b | 45/61 (74)b | 16/24 (67) | 12/14 (86) |
Not recovered | 14/60 (23)b | 10/44 (23)b | 16/61 (26)b | 8/24 (33) | 2/14 (14) |
Event outcomes as of last follow-up,c n/N (%) | |||||
Recovered | 29/60 (48)b | 26/44 (59)b | 30/61 (49)b | 15/24 (63) | 11/14 (79) |
Not recovered | 31/60 (52)b | 18/44 (41)b | 31/61 (51)b | 9/24 (38) | 3/14 (21) |
Dose delays due to event, n (%) | – | – | 45 (47)d | 7 (7)e | 3 (3) |
Dose reductions due to event, n (%) | – | – | 24 (25)d | 2 (2)e | 0 |
BCVA of 20/50 or worse in the better-seeing eye (n = 95)a | BCVA of 20/200 or worse in the better-seeing eye (n = 95)b | |
---|---|---|
n (%) | 17 (18) | 1 (1) |
Median time to onset (range), days | 66.0 (20–442) | 21.0 (21–21) |
Event outcomes as of last follow-up, n/N (%) | ||
Recovered | 14/17 (82)c | 1/1 (100)d |
Not recovered | 3/17 (18) | 0 |
Median time to resolution in patients who recovered as of last follow-up (range), days | n = 14 | n = 1 |
21.5 (7–64) | 22.0 (22–22) |
Description of MECs and Imaging Findings
Representative Case
Literature Review of Corneal Changes with ADCs
Incidence and Description
Proposed Pathophysiology
Treatment Strategies
Discussion
Conclusions
The cumulative incidence of MECs (observed on slit lamp microscopy with or without symptoms or changes in BCVA) in patients receiving the 2.5-mg/kg dose of belamaf was 72%, with 69% of patients experiencing MECs by dose 4 and only 2 patients developing a corneal event for the first time after dose 4. Given the frequency of MECs observed in patients receiving belamaf, it is important to understand its clinical features to better inform the treating hematologist/oncologist so that he/she is able to make appropriate treatment decisions. |
Monitoring
|
Conduct eye examinations (visual acuity and slit lamp microscopy) at baseline (up to 3 weeks before), prior to each cycle (up to 2 weeks before), and promptly for worsening symptoms. |
Diagnosis and Staging of MECs
|
MECs are very small, hence capturing them by slit lamp microscopic photography takes special consideration. MECs are best observed using retroillumination or indirect illumination at medium to high magnification. In DREAMM-2, patients with MECs in the paracentral or central cornea have been likely to report symptoms (e.g., blurred vision). Table 1 provides guidance for assessing MEC grading based on eye examination findings and changes in BCVA. The eye care professional should provide the treating hematologist/oncologist with an examination report that includes worst grade for corneal examination finding(s) and decline in BCVA. Determine the recommended dosage modification of belamaf based on the worst finding in the worst affected eye. Worst finding should be based on either a corneal examination finding or a change in visual acuity per the KVA scale. |
Management
|
The treating hematologist/oncologist should determine the appropriate belamaf dosing based on the highest grade corneal event (based on slit lamp or BCVA assessment) in the most severely affected eye. For grade 1 events, continue treatment at the current dose (Table 1). For grade 2 events, withhold dosing until improvement in corneal examination findings and changes in BCVA to a grade 1 or better event. Resume at the current dose (2.5 mg/kg). For grade 3 events, withhold treatment until improvement in both corneal examination findings and changes in BCVA to grade 1 or better and resume at a reduced dose. Consider treatment discontinuation for a grade 4 event. Based on a benefit:risk assessment, if continuing treatment with belamaf is being considered, treatment may be resumed at a reduced dose after the event has improved to grade 1 or better event. |
Patients with a history of dry eye prior to starting belamaf were more likely to develop moderate/severe MECs compared with patients without a history of dry eye. Advise patients to use preservative-free lubricant eye drops at least 4 times a day starting with the first infusion and continuing until the end of treatment and to avoid use of contact lenses unless directed by an eye care professional. On the basis of available data from the DREAMM-2 study, corticosteroid eye drops are not currently recommended as a prophylactic treatment for MECs. Changes in visual acuity may be associated with difficulty driving and reading. Advise patients to use caution when driving or operating machinery as belamaf may affect their vision. |