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*

Figure 1. Ocular toxicities associated with MM therapies and anatomy of the eye*

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)*

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*

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.