Identifying and managing ocular toxicities in patients with MM

Multiple myeloma (MM) is the second most prevalent hematologic cancer with a vast majority of patients requiring subsequent lines of therapy, leading to limited treatment options. Ocular toxicities are common adverse events (AEs) associated with molecularly targeted therapies and immunotherapies, as many of the essential signaling molecules that drive cancer growth are also expressed in ocular tissues.

An unprecedented case of transient myopic shift induced by daratumumab was reported in 2019 and the U.S. Food and Drug Administration (FDA) updated the drug label for daratumumab in 2021 to include ocular toxicity.¹ With the advent of many novel therapies, the complexity of ocular pathology and understanding around ophthalmologic AEs occurring due to targeted therapies is important for the management of ocular toxicities in patients with MM.

During the 3rd European Myeloma Network Meeting, Marc Labetoulle discussed the early recognition and management of ocular toxicity to improve patient outcomes.² Here, we present a summary of the ocular toxicities associated MM including recommendations for early detection and clinical management.

Ocular AEs associated with MM therapies

There are a range of ocular toxicities (Table 1) associated with both conventional chemotherapeutic agents as well as more recent agents such as belantamab mafodotin (belamaf), an antibody-drug conjugate (ADC) approved by FDA in 2020 for the treatment of relapsed and refractory MM. Figure 1 shows how specific MM drugs lead to ocular toxicities affecting different parts of the eye.

Table 1. Ocular AEs with MM therapies*

ADC, antibody-drug conjugate, AE, adverse event; BCMA, B cell maturation antigen; CD, cluster of differentiation; NOS, not otherwise specified; MM, multiple myeloma. *Adapted from Labetoulle M.2 †Allergic reaction. ‡Grouping of >1 Medical Dictionary for Regulatory Activities preferred term. §Post-marketing adverse event regardless of indication. ‖Based on eye examination, characterized by corneal epithelium changes with or without symptoms. ¶Includes diplopia, blurred vision, reduced visual acuity, and visual impairment. #Includes dry eye, ocular discomfort, and eye pruritus.
Drug class	Main side effects	Others
Alkylating agent
Cyclophosphamide	Blurred vision Visual impairment	Conjunctivitis Eye oedema† Lacrimation increased
Carmustine	Ocular toxicities Transient conjunctival flushing and blurred vision Retinal hemorrhages	Neuroretinitis
Proteasome inhibitor
Bortezomib	Eye swelling‡ Vision abnormal‡ Conjunctivitis‡ Eye hemorrhage‡ Eyelid infection‡ Eye inflammation‡ Chalazion‡ Blepharitis‡ Diplopia Dry eye‡ Eye irritation‡ Eye pain Lacrimation increased Eye discharge	Corneal lesion‡ Exophthalmos Retinitis Scotoma Eye disorder (including eyelid) NOS Dacryoadenitis acquired Photophobia Photopsia Optic neuropathy§ Different degrees of visual impairment (up to blindness) §
BCMA-targeted ADC
Belantamab mafodotin	Keratopathy‖ Microcyst-like epithelial changes Changes in visual acuity Blurred vision events¶ Dry eye events# Photophobia Eye irritation	Ulcerative keratitis Infective keratitis
MEDI2228	Photophobia
CD138-targeted ADC
Indatuximab ravtansine (BT062)	Dry eye Lacrimation increased Vision blurred	Angle closure Cataract Cystoid macular edema

ADC, antibody-drug conjugate; BCMA, B-cell maturation agent; MEC, microcyst-like epithelial change; MM, multiple myeloma.
*Created with BioRender.com.

Mechanism of action

ADCs can reach the cornea either through the tear film or the vascularized area of the limbus, and may cause ocular toxicity either via on- or off-target processes. On-target ocular toxicity is caused by non-cancerous cells expressing the target antigen, binding of the monoclonal antibody leads to the release of the cytotoxic drug (such monomethyl auristatin F and ravtansine). Off-target ocular toxicity results from proteases, esterases, and other blood enzymes inducing premature deconjugation of the drug, leading to endocytosis and pinocytosis; this exposes neighboring cells to cytotoxicity.

Belamaf

For belamaf, ocular toxicity may occur via macropinocytosis by corneal epithelial cells. Epithelial stem cells can internalize the ADCs, causing cytotoxicity, and their migration to the cornea leads to keratopathy and blurred vision. Some ADCs, such as trastuzumab, may also have an on-target mechanism and cause ocular lesions similar to belamaf.

Ocular toxicity associated with belamaf can be observed by slit lamp microscopy to identify superficial punctate keratopathy, microcyst-like epithelial changes and whorl-like keratopathy. The ocular lesions are diffuse and presented bilaterally, with patients reporting blurred or decreased vision and dry eye. Other tools used to measure structural changes in the corneal epithelium include:

• optical coherence tomography
• in-vivo confocal microscopy

Changes in the corneal epithelial thickness may cause refractive shifts (myopic or hyperopic) as well as changes in the corneal curvature. The DREAMM-2 trial (NCT03525678) showed that ocular AEs associated with belamaf were frequent, with keratopathy observed in >70% of patients; however, only 18% of patients showed best corrected visual acuity change to 20/50 or worse. In total, 3% of patients discontinued the study due to corneal events. Belamaf ocular toxicity is managed either by dose delays, dose reduction, or discontinuation. Table 2 shows the incidence of keratopathy and treatment changes in the DREAMM 1, 2, and 6 trials investigating belamaf.

Table 2. Treatment changes due to ocular toxicity in DREAMM (1, 2, and 6)*

NA, not applicable. *Adapted from Wahab, et al.3
	DREAMM-1 (NCT02064387)	DREAMM-2 (NCT03525678)	DREAMM-6 (NCT03544281)
Incidence of keratopathy	69	70	100
Median time to onset of keratopathy (range), days	23 (1–84)	36 (19–143)	NA
Median time to resolution of keratopathy (range), days	35 (5–442)	71 (57–99)	NA
Treatment gap	49	47	83
Dose reduction	46	23	39
Discontinuation of treatment	2.9	1	0

Ocular AEs grading scale

Based on the corneal epithelial thickness and location of the cyst, the ocular AEs can be graded as shown in Table 3.

Table 3. Ocular AEs grading scale*

AE, adverse event; BCVA, best corrected visual acuity; MEC, microcyst-like epithelial change. *Adapted from Labetoulle M.2
Ophthalmic assessment	Changes in visual acuity from baseline	Change in corneal epithelium	Complementary objective criteria	Recommendation
No ocular AEs	No change	No	No	Continue treatment at current dose
Mild ocular AE	Decline of 1 line	Mild superficial punctate keratopathy	Density: non-confluent   Location: predominantly (≥80%) peripheral   Microcyst: few if any	Continue treatment at current dose
Moderate ocular AE	Decline of 2 or 3 lines (and not worse than 20/200)	Moderate superficial keratopathy with or without MECs, sub-epithelial haze (peripheral), or new peripheral stromal opacity	Density: semi-confluent   Location: predominantly (≥80%) paracentral	Withhold treatment until examination findings improve or BCVA reaches mild severity or better   Consider resuming treatment at a reduced dose of 1.9 mg/kg2
Severe ocular AE	Decline > 3 lines	Several superficial keratopathy involving central cornea Corneal epithelial defect	Density: confluent   Location: predominantly (≥80%) central	Withhold treatment until examination findings improve or BCVA reaches mild severity or better   For worsening symptoms consider treatment discontinuation

Management

The following recommendations can be made for the clinical management and advise to patients to reduce the frequency of ocular AEs and increase the tolerance to the antimyeloma drugs.

• Use of keratopathy and visual acuity scale to decide future treatments of belamaf
• Recommend to patients not missing any planned ophthalmic examinations (at baseline, before subsequent three treatment cycles, and in case any symptoms occur during treatment)
• Prescribe preservative free lubricant eye drops to begin from Day 1 of Cycle 1 until the end of the treatment
• Advise using cooling eye mask during drug infusion
• Preservative free and low-grade steroid eye drops may be useful in short term pulses to relieve side effects
• Educate patients to declare any new ocular symptoms that may occur during treatment
• Advise patients to pay attention when driving or operating machines
• Avoid contact lenses until the end of the treatment

Conclusion

The ocular surface is prone to AEs during the treatment of patients with relapsed/refractory MM with ADC’s and, while these AEs are not severe, they are a common occurrence in many patients. The frequency of ocular AEs can be reduced by educating patients in the self-management of their symptoms and the early identification of any signs, educating physicians on the management of ocular toxicities, and planning regular check-up visits appropriately. In addition, drug developers and medical professionals should be aware of these possible ocular toxicities, facilitating early recognition and intervention in both preclinical and clinical settings.