From the Ophthalmologist’s Eye: Managing Ocular Toxicities With Belantamab Mafodotin in Myeloma

Shaily Shah, MD

Ophthalmologists are filling a critical role in the collaborative management of patients with relapsed/refractory multiple myeloma who are receiving belantamab mafodotin-blmf (Blenrep), said Shaily Shah, MD, who added that the potential ocular toxicities that can occur with the antibody-drug conjugate (ADC) require consistent screening and management.

“As a junior attending, what opened my eyes has been how incredible the field of medicine is in general, and how eager people are to work together to do what is best for the patient,” Shah said. “It is very exciting, in general, [that] oncology is a multidisciplinary specialty.”

On August 5, 2020, the FDA approved belantamab mafodotin for use in patients with relapsed/refractory multiple myeloma who have received 4 prior therapies, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 agent.¹

Findings from the DREAMM-2 trial, which served as the basis for the approval, demonstrated a 31% overall response rate (ORR) with the recommended 2.5 mg/kg dose of belantamab mafodotin (n = 97).² The ORR was 34% among patients who received the 3.4-mg/kg dose (n = 99).

Grade 3/4 keratopathy was observed in 27% of patients who received the 2.5 mg/kg dose versus 21% of patients who received the 3.4 mg/kg dose.

At 13 months of follow-up, deep responses were seen; more than half of responders in the 2.5 mg/kg (58%) and 3.4 mg/kg groups (66%) achieved a very good partial response or better.³

No new safety signals were identified with longer-term follow-up. Although keratopathy was common, only 6 patients discontinued treatment due to corneal events, suggesting that they were well managed with dose modifications.

According to Shah, with this ocular safety signal, patients treated with belantamab mafodotin should receive prophylactic treatment for dry eye, as well as have routine eye examinations to ensure ocular changes are identified early.

“There is still a lot to be learned here,” said Shah. “Of course, the studies have been done, but now that belantamab mafodotin is going to be prescribed on a larger scale, there is going to be so much that we learn specifically regarding that agent, as well as how we can improve collaborative management for these patients.”

In an interview with OncLive^®, Shah, an assistant attending ophthalmologist at NewYork-Presbyterian Hospital and an assistant professor of ophthalmology at Weill Cornell Medicine, discussed disease and treatment-related ocular toxicities that can arise in patients with cancer, specific management strategies for patients receiving belantamab mafodotin who develop ocular toxicities, and the importance of collaborative management of these patients.

OncLive^®: What is the frequency of disease-related ocular toxicities among patients with cancer?

Shah: I don’t have an exact percentage offhand, but [ocular toxicities] are more common than one may think. Oftentimes, it is not related to the cancer itself but, there are certain types of cancers that manifest with ocular findings, such as some lymphomas and leukemias. Multiple myeloma in itself can produce crystalline keratopathy, but it is uncommon that we see that.

How frequently are treatment-related ocular toxicities observed in oncology?

Treatment-related adverse effects (TRAEs) are fairly common to see. At Cornell, we are right next to Memorial Sloan Kettering Cancer Center, so we see quite a few patients with graft-versus-host disease (GVHD), as well as patients who have received bone marrow transplants for leukemia. Those patients will often develop significant ocular toxicity from their systemic GVHD. Patients will sometimes come in with severe dry eye, lack of tear production, corneal haze, or corneal opacities. Patients could eventually develop limbal stem cell deficiency and go down a path of significantly decreased quality of life and visual acuity.

We have gotten good at having a protocol in place for our patients with GVHD. We know that patients may not respond to typical dry eye management, so we have steps to help them.

There are also certain medications such as chemotherapeutic agents that can cause cancer treatment-related ocular toxicities. We know that treating breast cancer with tamoxifen can cause retinopathy—changes in the retina of the eye where crystal-type deposits [form] in the macula.

We may also see radiation-related toxicities in patients who had radiation near the face or around the chest and neck. Oftentimes, these patients will have problems with their tear ducts, tear drainage system, and sometimes, their tear production glands. They may develop significant dry eye either from scarring of the eyelids where they can’t blink easily and the eyes dry out from exposure, or from a problem with tear production or drainage.

What ocular toxicities have been observed with belantamab mafodotin specifically? What sort of issues could arise if these AEs are not managed correctly?

Certainly, now with [the approval of] belantamab mafodotin, we have been seeing corneal toxicities [in patients with myeloma]. Throughout the clinical [trial] process for belantamab mafodotin with the DREAMM-1 and DREAMM-2 studies, the ocular toxicities [observed were] specific to the ocular surface. When [investigators] studied that further, they found that it [has] a corneal epithelial pathology. The cornea is the most superficial layer of the eye, and the epithelium is the most superficial layer of the cornea. Therefore, it is really [on] the most superficial layer of the ocular surface that we are seeing the majority of these toxicities.

Even just being confined to 1 portion of the tissue, the range of symptoms that the patient can feel is broad. Patients could be completely asymptomatic [although] the [ocular] changes are seen on the exam from the physician’s standpoint, or the exam may not show changes, but the patient could have significant ocular surface-related complaints.

In general, these complaints will be similar to dry eye–related complaints, including burning, grittiness, a foreign body or sandy sensation, an achy sensation, redness, and significant tearing. Oftentimes, patients may experience decreased visual acuity, so they may come in with complaints of blurred vision.

Our exam findings can range from no findings at all, to mild or moderate dry eye. We would see signs of dryness on the surface exam where a dye used to stain the surface of the cornea can pick up changes that correlate with dry eye and highlight dry spots in the corneal epithelium.

In terms of parameters, we look at whether there are any staining patterns. Are there any punctate epithelial erosions? An interesting finding that we have seen, and that was reported after the DREAMM-1 and DREAMM-2 studies, is microcystic keratopathy. These are small microcysts that we can see just underneath the surface layer of the epithelium.

[Microcysts] usually start in the periphery of the cornea and work their way in toward the center. That is consistent with what the studies had shown. Initially, the 2 patients I had seen who developed microcysts were completely asymptomatic. They came in for a routine follow-up with no visual complaints and their vision hadn’t changed on their exams. It was an incidental finding.

Corneal exams [can also show] corneal haze. Again, this very fine opacity starts around the edges of the cornea and can eventually progress to the center. Sometimes the exam findings are correlated with patient symptoms such as blurred vision or discomfort, but again, patients may be completely asymptomatic.

It is important to screen these patients. If they do not have symptoms, they won’t necessarily come in of their own accord. We have a great system in place where right before every infusion, we see patients for screening exams.

If a patient on belantamab mafodotin does develop ocular toxicities, what are some of the management strategies that can be used to treat these AEs?

With this expanded access [program] that I have been part of at Cornell through GlaxoSmithKline, the protocol that we have in place is to treat our patients prophylactically with artificial tears. We will start patients on preservative-free artificial tears anywhere from 4 to 6 times a day, or more if patients get [relief] from them. The idea is to lubricate the eyes and keep them as healthy and wet as possible to try to minimize discomfort and surface level toxicity.

One of the proposed pathophysiologic mechanisms for why corneal toxicity occurs is that some of the drug may be carried in through the tear film of the patient. Then every time that patient blinks and produces tears, the drug sits on the surface of their eye. In addition to keeping patients comfortable and preventing dry eye symptoms, artificial treats help to dilute their natural tear film and potentially prevent toxicity from building up.

Even if patients don’t have dry eye, but they have any other eye conditions that can contribute to dry eye such as meibomian gland dysfunction (MGD), I will oftentimes have them start treatment for that ahead of time. The treatment [for MGD] is simple. At home, patients are asked to use warm compresses to try to open up the glands to increase oil production and improve the quality of their natural tears.

At this point, most treatment is preventative, and we try to maximize patients’ ocular health before they even start treatment. As soon as I see them for screening, I will go over the details of what the [potential] toxicities are and why it is so important to start these preventative treatments.

Additionally, some studies have shown that putting a cold compress on the eye during the time of infusion can increase patients’ comfort levels and potentially improve the ocular toxicity profile. That is also something that is built into our protocol.

How do these ocular toxicities affect the use of belantamab mafodotin?

It depends on the level of toxicity the patient is experiencing. If patients have mild toxicity with a little bit of dry eye on the exam, no significant haze, no microcysts, and they are asymptomatic, we would call that grade 1 toxicity. Patients can usually continue with their treatment as planned.

If they start to develop peripheral microcystic changes or corneal haze, with or without changes in their visual acuity, oftentimes we will dose reduce or halt the next dose of belantamab mafodotin until they resolve back to grade 1 or baseline.

If a patient has cysts in the central portion of their cornea, their vision has [declined] significantly, or they have haze in the center of their cornea, those are definite indications to hold the next treatment. If patients get back to a certain healthy baseline, we can start belantamab mafodotin at either a decreased dose or full dose depending on the patient’s corneal health.

In the DREAMM-2 study, [investigators] evaluated whether the use of corticosteroids would help in [preventing the] development of these changes. The toxicities associated with a drug are often thought to be related to the inflammation that they induce in a certain tissue.

However, it was found that prophylactic corticosteroid use did not make a difference in the ocular toxicity profile, so that is no longer recommended for patients starting on belantamab mafodotin.

Could you speak to the collaborative efforts required between oncologists and ophthalmologists to manage patients receiving belantamab mafodotin?

One of the really beautiful things about the expanded access protocol, as well as the DREAMM-1 and DREAMM-2 studies and the FDA approval, is that it encourages and requires collaborative management of patients. It is about collaborating with the patient, their oncology team, including the infusion specialist, nurses, pharmacists, and the ophthalmology team.

With the FDA approval, [we have seen] a lot of outreach into the community [regarding this agent and this collaboration]. Community oncologists are going to be prescribing this medication now, so community oncologists and community ophthalmologists [need to be educated on] what these toxicities are, how frequently patients should be screened, and how frequent follow-ups should be. The lines of communication between the ophthalmology team and the oncology team need to be kept open.

What are some of the challenges that remain in this space?

In an academic center, it is much easier to collaborate with other departments. For example, the ophthalmology department is in full collaboration with the oncology department [at Cornell] so that we can get these patients seen quickly and get the [treatment] decision over to the oncology department. Once community doctors are prescribing belantamab mafodotin more, the challenge will be getting patients quickly to an ophthalmologist or having ophthalmologists ready to see these patients. Additionally, making sure that the ophthalmologists are communicating efficiently, quickly, and clearly to the oncology team could become a challenge as well.

What would you like to emphasize regarding the management of ocular toxicities among patients receiving belantamab mafodotin?

The most important thing is to make sure that all parties are equally aware of the importance of communication with one another, as well as communication with the patient. Oftentimes, patients [receiving belantamab mafodotin] may feel like this drug is their last resort. Patients may ignore certain AEs that they are having or may not be aware of what AEs are important [to report]. Keeping those lines of communication open, not just among providers, but with the patient, as well as educating patients on the potential toxicities that could manifest is important. Additionally, making sure that patients follow up with the ophthalmologist, even if they are asymptomatic, is important.

It is a really exciting time because it affords us, as ophthalmologists, the opportunity to collaborate on a truly systemic disease. It is also exciting to be able to be part of a larger treatment team and to work within other specialties.

References:

1. FDA approves GSK’s BLENREP (belantamab mafodotin-blmf) for the treatment of patients with relapsed or refractory multiple myeloma. News release. August 5, 2020. Accessed September 23, 2020. https://bit.ly/3gxEXB1
2. Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study [published online December 16, 2019]. Lancet Oncol. https://doi.org/10.1016/S1470-2045(19)30788-0.
3. Lonial S, Lee HC, Badros A, et al. Pivotal DREAMM-2 study: single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) refractory to proteasome inhibitors (PIs), immunomodulatory agents, and refractory and/or intolerant to anti-CD38 monoclonal antibodies (mAbs). J Clin Oncol. 2020;38(suppl 15):8536. doi:10/1200/JCO.2020.38.15_suppl.8536