BCMA as a Target in Heavily Pre-Treated RRMM - Episode 4
Sagar Lonial, MD, FACP: One of the unique adverse events associated with belantamab mafodotin is an ocular toxicity: keratopathy. Functionally, what that means is that patients develop microcysts in the cornea, and those microcysts cannot be seen by you or me unless we have a slit lamp examination. To give belantamab mafodotin, it is important that you partner with an eye care professional so that they can do slit lamp exams before each dose of belantamab mafodotin is administered. One may say, “This sounds complicated. Do you have to have a specific ophthalmologist to work with?” One of the important take-home messages is this: if you can find an ophthalmologist to work with, that is great, but even an optometrist can see and grade the keratopathy as evidenced by microcysts using a routine slit lamp exam.
If you look at all the patients who were treated at the 2.5 mg/kg dose, roughly 70% of patients had some form of keratopathy as demonstrated by an exam from an ophthalmologist. It is important to recognize that every exam finding does not correlate to clinical findings, so finding that intersection between exam and clinical findings is what you do in partnership with your eye care professional before you give a dose of belantamab mafodotin. As an example, if we look at the DREAMM-2 study, in the 2.5 mg/kg group, as I mentioned, 70% of patients may have keratopathy as measured by an exam finding, but only 50% have any true symptoms at all. The most common symptoms that we see are dry or itchy eyes, which can sometimes be alleviated through lubricating eye drops, which are recommended at the time you start belantamab mafodotin therapy.
If you drill further down in the data, only 18% of patients had changes in visual acuity, which means a reduction greater than 20/50 in their best eye. While you may see 50% of patients who had some symptoms like dry or itchy eyes, only 1 out of 5 patients will have any true changes in visual acuity. In the DREAMM-2 study, only 3%, or 3 patients, had to discontinue belantamab mafodotin because of ocular issues. The keys to managing ocular issues are dose holding or dose modification. This is unlike other medications where, when you hold the dose, you have this fear that you are going to lose control, particularly in the context of refractory myeloma. Because the half-life of belantamab mafodotin can be so long in some patients, only 10% to 15% of patients lost control of their disease during dose holding or dose modification. It is OK to hold the dose until the keratopathy or symptoms improve such that you can reinitiate therapy. In some patients, the dose was held 6 weeks or longer, so that is OK. Allow the keratopathy to resolve with dose holding and dose modifications.
We know from longer-term follow-up that almost no patients had irreversible ocular changes: they almost all recovered. The ones for whom we cannot say that with clarity are because they progressed or came off study and had other treatments that were administered to them at that point. It is not like there are patients who have irreversible ocular toxicity. From what we know about the data, that is not a significant concern with appropriate dose holding, dose modification, and partnerships with eye care professionals.
Asim V. Farooq, MD: The DREAMM-2 trial for belantamab mafodotin showed us the ocular adverse effects. In terms of ocular safety, it was important to develop an understanding of what the rate of ocular toxicity that occurs with this drug is, as well as what the impact on visual acuity and visual function is. What are the short-term and long-term implications for patients?
In general, the DREAMM-2 study showed from an ocular safety standpoint that a significant proportion of patients develop ocular adverse effects. Most predominantly, this includes the finding of microcyst-like changes within the corneal epithelium, which in our University of Chicago Medical Center recent paper, we have called microcyst-like epithelial changes, or MECs. Roughly 70% of patients in the DREAMM-2 study developed these MECs.
We also know, based on looking at both the location data, meaning location within the cornea that these lesions were present, as well as the impact on visual acuity, that in a significant number of patients who develop these microcyst-like changes, there is no impact on visual acuity. That is reassuring. In other words, for a number of patients who will develop these lesions within the cornea, they will continue to have their baseline vision or vision to pursue their activities of daily living. However, a significant portion of patients, closer to about 50%, had some decrease in vision associated with these lesions.
We have some parameters by which that decrease in visual acuity was defined. For anyone with a decrease of greater than 1 line of visual acuity, we would pick them up using our visual acuity metrics in the DREAMM-2 study. With that being said, the patients who developed both MECs and a decrease in visual acuity, at the time of data cutoff for all those patients for whom there was adequate follow-up, these lesions and their visual acuity returned. The lesions resolve and visual acuity returned back to baseline.
From a safety standpoint, what we are seeing with belantamab and what we saw in the DREAMM-2 study was that a significant majority of patients developed cornea lesions, which we call microcyst-like epithelial changes. A significant portion, although not all of them, roughly 50%, also had some level of decrease in visual acuity, but the patients for whom we had follow-up at the time of data cutoff, they resolved. We also saw that, with a number of patients—and I have seen on my own anecdotal experience—with dose holds and dose reductions, these lesions also tend to recover. That was valuable information that was provided as a result of the DREAMM-2 study.
Transcript Edited for Clarity