Cristina Gasparetto, MD, Duke University
Mark Newman, OD, Optix Eye Center
Interview Date: October 4, 2021

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SUMMARY

All cancer therapies come with some type of side effect. One newly approved therapy called BLENREP, by GSK, is an antibody drug conjugate targeting BCMA that can cause a condition called keratopathy. Keratopathy is an eye condition that can be mild, so patients don't even know they have it, or it can be more severe and cause blurriness or impaired vision. Learn from myeloma specialist Dr. Cristina Gasparetto, MD from Duke University and Mark Newman, OD of OPTIX Eye Center share in this show how keratopathy can be successfully managed for patients on BLENREP.

They share the process to coordinate care between the myeloma doctor and the eye doctor, how they determine when to hold the drug or reduce the dose and share the impact of the drug on myeloma. The first piece of good news is that any changes to vision can be recovered in full when the drug is stopped. The second piece of good news is that when the drug is held, patients are still seeing durable myeloma responses. As myeloma experts gain more experience with BLENREP, using it with additional treatment combinations may change the dose and frequency to make keratophathy more manageable. 

Thanks to our episode sponsor

Jenny: Welcome to today's episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. We'd like to thank our episode sponsor, Takeda Oncology, for their support of Myeloma Crowd Radio Show program.

Now we're so fortunate in myeloma to have access to a wide number of new treatments. An increasing number of them are targeting BCMA or B-cell maturation agents. The first antibody drug conjugate to target BCMA is BLENREP, which is also called belantamab mafodotin. And when we think about incorporating new drugs into our treatments, we also always will think about side effects because I don't think there's a drug yet out there that is without side effects. Many myeloma patients are familiar with common side effects in myeloma therapy like gastrointestinal issues or neuropathy or things like that. But with each new drug approval, which we're very grateful for, it comes with a new learning curve about what to expect.

So on today's program, we'll be talking about a side effect called keratopathy, which is an eye condition. We are fortunate to have with us two experts, one in myeloma and one in eye care. So Dr. Gasparetto and Dr. Newman, welcome to the program.

Dr. Newman: Thank you.

Dr. Gasparetto: Thank you, Jenny.

Jenny: Now before we get started, I'd like to just give a very brief introduction for the two of you.

Dr. Gasparetto performs laboratory and clinical research in the field of multiple myeloma. She works on developing immunotherapy approaches to treat myeloma, particularly in conjunction with stem cell transplant. Her ongoing laboratory research projects include the development of dendritic cell vaccines and antibody therapies, and her clinical studies include a recently approved trial involving vaccination with autologous dendritic cells and included with transplant. Her upcoming trials include new therapies for myeloma. She's an investigator that has used BLENREP in the clinic and has expertise with that.

And then Dr. Newman has been an optometrist in private practice since 1992 and was educated at Ohio State University and Duke University. So we're thrilled to get the dual perspective, I think, because most myeloma patients, there are some side effects I know with dexamethasone that can affect your eyes. But other than that, I think we haven't had a lot of expertise or experience with this kind of thing.

Dr. Gasparetto, let's start with you. Maybe you want to explain what BLENREP is and how it works.

Dr. Gasparetto: Sure, of course, I would love to do that. So BLENREP is a conjugated antibody. So first of all, it targets a membrane protein that is overexpressed, so myeloma cells, it's called the BCMA, the B-cell maturation antigen. This protein is overexpressed in the myeloma cells specifically, in fact, is no elevated is present at a very low level in healthy cells. So it is very good target. It appeared to be one of the newest target that we have for myeloma, for treatment of myeloma.

So BLENREP was designed to target this particular protein, the BCMA protein, and is conjugated with what we call is linked so with what we call a cytotoxic payload. It's called mafodotin. And this payload, this cytotoxic, the mafodotin disrupt the microtubule. I don't want to be very complicated, but what it does is that the antibody link binds to the BCMA protein which allows this mafodotin, this toxin to be released inside the cell and cause the cell that induced the cell death. So the myeloma cells will start to grow, to proliferate, and eventually they go to apoptosis, the cell dies. It is enhancing the immune system in different ways. But the major mechanism of action is linking to this protein that is overexpressed in the myeloma cells and the release of the toxin, the mafodotin, into the cells and then eventually the cells will die because the disruption of the microtubule network. It's very clever. It's unique to this drug. We have other conjugated antibodies also available for other diseases with other hematologic malignancies, but this is unique for myeloma.

Jenny: Okay, wonderful. Thank you so much. I think everybody is wondering why this drug affects the eye. You're saying it's the mafodotin portion, actually.

Dr. Gasparetto: Yes.

Jenny: Can you explain why it does?

Dr. Gasparetto: Yes. Actually, the mafodotin is kind of what we call an off-target toxicity, so there is an accumulation of this toxin. It's a characteristic of this particular linker. It's the mafodotin toxicity. That's the reason why you don't see this type of eye toxicity with other anti-BCMA targeted therapies. You're familiar with the bispecific antibodies with the CAR T cell. So it's specific of this particular, and other actually, conjugated antibodies because the cytotoxic payload is causing the toxicity associated with this.

Jenny: Interesting. I know there's another antibody drug conjugate being developed in myeloma that seems to cause eye issues. Is it related to all antibody drug conjugates or just kind of specifically the way this one works in myeloma?

Dr. Gasparetto: No, it's not. So there are several antibody drug conjugates like brentuximab, but for lymphoma that they don't cause the eye toxicity. So it's based on the particular type of linker associated with the antibody. And yes, you're correct that there was another conjugated antibody that was presented recently in a major Congress and there was eye toxicity, which was a little bit different than what we observe with this drug. Fortunately, you can choose a different link, but you may have different types of toxicity. I know that some are associated with severe peripheral neuropathy, which is something that we like to avoid. It comes to the myeloma territory and a lot of other drug very well that carry the peripheral neuropathy. That's the reason why this particular linker was chosen to avoid adverse events like excessive peripheral neuropathy in patients with myeloma. So it's new for the myeloma world, but it's not new for this type of drugs.

Jenny: Interesting. I think it's something we just have to get used to, right?

Dr. Gasparetto: Understanding the toxicity, yes, exactly. Because we get familiar with a lot of drugs, that we use in myeloma, so we know that every drug has their own toxicity. We know what was bad, the GI, the gastrointestinal toxicity, and the neuropathy, cardiovascular of this or that particular drug. So we are learning how to manage and how to prepare patients and how to mitigate this eye toxicity as much as we can.

Jenny: Absolutely. And the reason that I ask both of you to be on this show is because you work together with myeloma patients. So I think that's a wonderful partnership, and you can share with us together what you've learned from your myeloma patients and in the eye clinic. So Dr. Newman, maybe you can explain what is keratopathy, because this is a phrase that most myeloma patients have never heard before

Dr. Newman: True.

Jenny: And how and where does it affect the eyes? So let's start with that.

Dr. Newman: The term keratopathy itself is a rather generic term just meaning pathology or disease of the cornea. A keratopathy could affect different layers of the cornea. A keratopathy could be caused by a bacteria, a virus. So you can have bacterial keratopathy, viral keratopathy. You can have dry eye keratopathy. So the term keratopathy itself is very generic and it may affect, like I said, different layers of the cornea. The main layers of the cornea are the epithelium, the very top layer, which is regenerated very quickly. It's why when people get a little abrasion or scratch, by the next morning, it's typically gone because that layer, the cells regenerate very quickly.

The stroma or central layer of the cornea, that's what creates most of the thickness of the cornea and that layer, if there is a keratopathy or something that affects the stroma, that's where you can have scarring and something that could cause permanent damage. Then you have what's called the endothelium or very bottom layer of the cornea, the layer of the cornea that is against the fluid or aqueous humor that fills the eye and that layer of the cornea is the pump for the cornea to keep it clear and make sure that fluid doesn't penetrate from the anterior chamber of the eye into the cornea. So there are certain things, conditions, pathologies that affect the endothelium, which result in a cloudy cornea because fluid gets in from the chamber of the eye into the cornea where it doesn't belong.

Now in the case of BLENREP keratopathy, it seems to affect just the epithelium, which is very good because, like I said, the epithelium regenerates very quickly, and so the effects are not permanent. It does not seem to cause any kind of scarring or effects to that stromal layer where you could have scarring, and so that is good. Now, however, the effects of the epithelium can certainly blur the vision and cause irritation and burning sensitivity to light. So those things do happen with a keratopathy such as we see with the BLENREP. So that kind of gives you an idea of of what's going on there.

Jenny: How do you diagnose keratopathy?

Dr. Newman: Yes. So to diagnose the keratopathy, we use what's called a slit lamp, and most people who've had an eye exam would certainly have been in this instrument, but it's essentially a biomicroscope. It allows us to magnify the surface of the cornea. Usually, I'm using about about 25 to 30 times or 30x when I do these examinations, and we're able to see the cornea in detail, look for clarity, look for irregularities. So that's the instrument we use to diagnose the keratopathy and to grade it and see how severe it is. That, in combination obviously with looking at the patient's acuity, how their vision is, those are the two factors we look at.

Jenny: Okay. You talked a little bit that there are different severity levels or grades of keratopathy. Do all patients even know when they have keratopathy?

Dr. Newman: At the early stages, and if we're talking about BLENREP, this would be, say, after the first dose of BLENREP, we see the patients back at three weeks. Many times, they will say, I'm seeing fine. My eyes feel normal. And I will look in the eye and I will see some keratopathy. It just hasn't become symptomatic, but you can have keratopathy without symptoms. Again, it would be mild because as it gets worse, you do start to have symptoms. But yes, at the early stages, it can be asymptomatic but present.

Jenny: Okay. Do all optometrists and ophthalmologists have experience with keratopathy, like if I'm a myeloma patient, does seeing my regular eye doctor will then know what to look for?

Dr. Newman: Right. Well, anyone looking, of course, yes, all eye care professionals have experience with many different keratopathies. Now do they have experience with BLENREP keratopathy? The answer is probably not. I didn't have experience with it until I started seeing the patients. They're coming out with more and more, but there are resources from GSK for eye care professionals to look at to have an idea of what they might see when they see these patients, because the keratopathy is unique. It doesn't emulate any other condition like a bacteria or even the dry eye or all these keratopathies that we know from our training. This one doesn't look like it. So it's not going to ring a bell to anyone because it's new, and it was new to me.

Now I will say once you've seen three or four patients and followed them for a few months, then you get a feel of how this affects a patient and what it looks like. So yes, it is a unique pattern on the eye. When it starts, just to describe a little perhaps, often it starts as a ring-like pattern that spares the center of the cornea. So now we don't know why. Obviously, the toxin gets to the eye probably through the tears, and why there's kind of an odd pattern of this, we don't really know. But that kind of spares the central vision. So the patient is seeing well, but yet, they have some keratopathy, but it's in a ring-like fashion around the mid-peripheral cornea. That kind of pattern is unique to this. There really aren't other things that you see this pattern with. I mean, there are several different patterns I see in these patients, but that's one that I see quite often and also kind of explains why a lot of these patients will come in. They feel fine, they still have good vision, because it didn't affect the center. And then the ones where it affects the center, that's where the vision starts to become a bit blurry.

Jenny: Can you describe or elaborate a little bit more on the symptoms? So there's this ring-like fashion that you may or may not have any difference in your vision. You could get some cloudiness, and you could get some, you mentioned kind of like irritation, eye irritation. Can you just elaborate on what other symptoms you could see?

Dr. Newman: Typically, if they're past the mild keratopathy and say a more moderate, we would call it moderate keratopathy, then you do see, the patients will often be a little sensitive to light. They'll describe eyes as burning a bit, and blurriness. Those are the main symptoms. They really don't describe, say, a constant pain per se. We're not really seeing that, which is good. The blurriness has certainly an impact. I try to educate the patients. First we do a baseline visit. At the baseline visit, I do a complete check of eye obviously to see if they have any other underlying conditions or predisposing issues with their cornea that may make them a higher risk for a more severe keratopathy as they go on the medication. At that visit, we definitely -- as has already been discussed with with Dr. Gasparetto's office about the potential vision effects, and then I elaborate a little more and I definitely let them know.

It is true and patients should know this. I tend to see the worst keratopathy usually about a week or two after the second dose. We see them every three weeks. After that second dose is when I tend to see the worst of the keratopathy (about six weeks in). A lot of times people, they might not be able to drive for a bit because of the blurriness in their vision. But almost all our patients, again, informing them ahead of time and letting them know, because of the response they've typically had on the myeloma side, they've been pretty accepting. Again, almost all of them have someone with them or caregiver. So they're okay. Someone has to drive them for a bit.

And then often the patients will have to miss a dose because of the eye findings. What we find is as we go further out, they sort of reach a level kind of steady state, if you will, with their vision and where it's not what it was a baseline, typically, but it's not what it was after that second dose, and they might have some mild to moderate effects. But for the most part, most of them are able to resume their activities. Obviously, also with the success of the medication with their myeloma, they're feeling better.

Of course, I'm an eye doctor. I am certainly not a myeloma specialist at all, but I ask them every time, well, how is this compared to where you've been? They all say, oh, well, the only thing about this medication is the eye effects. They're like, I don't get nauseous. I feel great. It's been a very positive thing overall. I think, well, Dr. Gasparetto can comment if, you know, obviously, the feedback on her side is similar. I suspect it is. But I always ask them that, even though I'm focusing on their eyes, just to see how their overall frame of mind isn't how they're feeling systemically, which tends to be quite good.

Dr. Gasparetto, can you just comment on that on your side compared to other treatments?

Jenny: Yes, before we do that, I want to have you walk us through this process because you kind of referred to the every three weeks pattern. Just practically speaking, Dr. Gasparetto, can you first say how you consult with a patient who starts BLENREP? And then how does this process work? How do you connect with Dr. Newman in your area?

Dr. Gasparetto: Yes. Well, I feel very lucky and pleasure to work with Dr. Newman. Our process is now quite easy. So I generally see a patient. I think of the patient might benefit from initiation of BLENREP. So I do my part. I counsel the patient, explain in my way what keratopathy is and what the potential side effects and like Dr. Newman mentioned, actually other than that is an extremely well-tolerated drug. So we talk about the risks and benefits and then we set up, but we submit to insurance, and we set up an initiation of therapy. We try to send the patient to Dr. Newman the same day -- well, the baseline assessment takes a little bit longer, but then the subsequent visits are relatively short of about 20 minutes. So we try to set up the appointment with Dr. Newman the same day of the infusion, so the patients go there first. And then they come to our office with the paperwork. We have fax of course. We have the form that we have to complete and then we make an assessment in clinic to determine if it would be safe to continue the infusion or if we need to hold a dose, etc.

So we work very well because no matter what, the patient sees us and Dr. Newman, the same time every three weeks, so even if the patient is keeping the same dose, we like to have this continuity so we can actually see the improvement, the stabilization of the keratopathy, the symptoms and improvements. So we work very well together. So we do it on the same day. So they don't have to come to see us more than once every three weeks. We track labs and make sure that everything else is okay, of course. So that works very well for us and Dr. Newman is accommodating our patients phenomenally.I can't thank him enough, but they feel very reassured that a care team has overseen this particular toxicity together.

Jenny: You have this wonderful partnership and collaboration. If a patient shows up at any clinic, whether it's an academic center or a general oncology clinic, the patient doesn't necessarily have to find their own oncologist, right? I mean, you're either helping them find an ophthalmologist or optometrist that can help when you're doing this clinic because that very efficient, it sounds like, to go on the same day.

Dr. Gasparetto: Oh, yes. In order for us to prescribe BLENREP, we have to go through the training program. It comes with the box and this particular toxicity. So we have to be trained, the prescribers to the facility, everybody. So GlaxoSmithKline has done a phenomenal job on coordinating all this process for us, and they are capable of identifying eye care providers that can collaborate with the oncology closely in monitoring following these patients. So you know, I think that they're trying very hard to simplify the system for our patients. So all oncology, all of us are registered to prescribe and able to prescribe a BLENREP. We have to go to the REMS programs, and we have to establish a relationship with our eye care provider before we start. So it becomes simpler. So the patient does not have to found his or her own, I can provide. We will set it up for them and we want continuity.

So you know, it's very important for us that Dr. Newman does the baseline assessments. So he has an idea of what's going on, and also the continuity. So he can determine the improvement throughout the treatment, and so it will be bad if the patient has a baseline assessment elsewhere, I believe, right, Mark?

Dr. Newman: Yes.

Dr. Gasparetto: I think you have everything there to follow the progress, the improvement, or the deterioration, because you see the patient from the very beginning.

Jenny: Yes, great. I just wanted some new patients to know that it's not on them if they want to take this drug.

Dr. Gasparetto: No. And I think that our job is to make sure that we have this partnership, so it's not difficult for the patient to be seen on the same day for both of us. I have a team of APPs. They and the PA help me in clinic. They can follow the patients and they help with the coordination of care. Absolutely.

Jenny: Yes, that's very nice because then you walk into the clinic for your next infusion. And the infusions for BLENREP are just every three weeks, right? I mean, that's why you're checking it out.

Dr. Gasparetto: Yes, exactly. Well, and also because we want to have the continuity. I think the keratopathy and looking all the data of the DREAMM study which led the FDA to approve this drug for the treatment of patients with relapsed refractory myeloma. So we learn. Mark and I have also learned a lot treating our patients and following them longitudinally. It takes about three weeks for the visual acuity to improve while the keratopathy takes longer. And so I think the three weeks is for now, for the single agent is the interval, but we're learning more about can we actually go less frequently to minimize, to mitigate the keratopathy, particularly in combination? Can we adjust the dosage? Can we go rather than every three weeks a little bit longer? We're learning about that from the follow-up of some of these patients.

Dr. Newman was talking about all the patients. They may have to hold therapy, but what is unique of this drug, what we see that even when we hold therapy, we see durability. The responses are remain stable and actually in the DREAMM II study they were following longitudally the patients that were responding. What's interesting is some patient held therapy for up to more than three cycles, and they still had an improvement of the response which is not very common, otherwise, when you stop therapy the response ends. So we were all very excited by these follow up of these data because I always reassure the patient and tell them, look, if you develop the keratopathy and other ocular symptoms, don't worry about because even if we are missing a dose of two, you are not going to lose the response. It's true. It's absolutely true.

Dr. Newman: It's been remarkable.

Dr. Gasparetto: Yes, right?

Dr. Newman: We've had patients have to miss nine weeks, and we even have one recently we're working with that has missed 12 weeks because of the keratopathy but still maintain their response.

Dr. Gasparetto: Absolutely. So it's the value of the drug. We were talking about other side effects before Dr. Newman was asking me the question. You have about 20% that can develop some infusion-related reaction or the first infusion, but the majority is mild. About 20% or more patients developing low platelets, but we don't see that much but is one of the potential side effect of the drug. Other than that, it is really well tolerated, and we don't need to use the dexamethasone as a single agent and a lot of symptoms are related to the eye dose steroids. So it's very well tolerated, very well and convenient because you are to come back to the doctor office every three weeks. You don't need the central line. So is also very patient, friendly, convenient. So you don't want to affect the quality of life tremendously, right?

Jenny: Yes, absolutely. It's been almost a year since it was approved, and I think there's so many things to learn when a new drug is approved. And sometimes you just don't understand that until you have some time with it. So now the both of you are seeing what is it really like, and, yes, it's very well tolerated and effective. So that's really great.

Dr. Newman: Now we have a good handful that have been on it a year and have maintained in response. I realized that has to continue to stand the test of time and course we'll see going forward. Hopefully, these people will continue to do well. But again, these are people that have exhausted many, almost all their options, and now they're doing fantastic. So it's a great thing to see.

Jenny: Wonderful. Dr. Gasparetto, in the myeloma patients that you've see, many patients -- well, maybe you can kind of break it up into percentages? You both talked about this. How effective is this drug? And then what's the level of side effects? As a patient who is picking and choosing therapies, I take both of those things into account. So maybe you want to break it up with just the patients that you've seen. How have they fared on the eye conditions?

Dr. Gasparetto: When I counsel a patient at the beginning of initiation of therapy, I always tell them, look, the chance of you developing keratopathy is very high, is a little bit over 70%. And like we mentioned earlier, not necessarily all patients with keratopathy will have symptoms, but I would say that 50% of patients will develop some decrease of the visual acuity. And then about 20%, 30% will have the blurry vision.

So I always remember these numbers from the DREAMM-2 study, and it's really reflecting what we see in clinic. Always I tell them, if you look by keratopathy, the grade, we can divide it by grade 1, 2, 3 and 4 with 4 being the worst, the percentage of patients developing the worst at the grade 4 is less than 1%. And with the majority of patients developing between grades 2 and 3. If you break it down by numbers, I will say that 20% will be grade 2 and 40% grade 3. Like Dr. Newman said before, we hold the therapy and we make some adjustment if necessary until we wait for the improvement. And then when we restart the drug, it is more kind of a stabilization of their mild keratopathy, I want to say.

Again, I don't think I had any patient that I had to completely interrupt treatment because the keratopathy. I had a couple of patients with Mark that were more bothered and I guess was the underlying keratopathy, but the blurry vision was bothering them. I had one patient that didn't want to continue therapy because the blurriness. The decreased visual acuity seems to improve faster, at least, from my point of view, from the DREAMM-2 study (and Mark can say a little bit more about that). We had a couple of patients recently that had a severe decrease of visual acuity. But in the study, there were no patients that developed blindness so that they they didn’t have an improvement of the visual acuity, correct?

Dr. Newman: Yes. Definitely, as you've said, after the second dose is when we kind of see the worst effects, and then we discussed, they might have a dose pause, and then things improve. And we get to a level where, let's just say, to put an example that people could understand, like when someone comes to me for a baseline and their vision is 20/20. So they have the first dose, and most of the time, they'll come back in. They'll say they're doing pretty well. And they might have some keratopathy that's asymptomatic, and I tell them about it, then they go have their second dose. And I tell them before they go for it that it's after the second dose that we tend to see it mostly effectuous, so they're prepared. Then they'll come back, and they might be let's say 20-70 or 20-80, which is significant. And they will say yes, my vision is blurry. You told me that might happen. And then that level would make it so they would have a pause in their treatment, then they might come back three weeks later. They may still be at that level, so they may improve to have, say, about 20, 30, which at that level, though, have a repeat dose. If they're still at 20/60, 20/70, 20/80, they might wait and then it'd be a six week pause. Then typically they'll come back and they're at that 20/25, 20/30. Some people return to 2020. The one caveat to that, which we haven't discussed yet, is that that's what we call the best corrected vision. So someone might have a certain prescription when they come in here or no prescription and be 20/20.

Part of a BLENREP keratopathy is it does kind of alter the actual prescription to see better. So I put them in my machine that we use when people come to the eye doctor and they look through the lenses. And we generate what is the best vision we can get for this patient today? So it might be back to 20/20 or 20/25. But, of course, they can't leave the office with that because if we did put that in a pair of glasses, it might work for a week. And then what we notice is each time we see them the number or prescription to correct their vision is different. And that's something I want to make sure people are aware of.

So it's still reassuring to the patient that they look through the machine and they're like, "Oh, I can see now, but I can't see without it." And unfortunately, like I just said, it's not something, you know, they will ask oh well can you give me glasses like that? And then I can see and of course we say, yes, we could but it might only work for a week or so. So we just wouldn't do it. So I hope that additional information helps too because we look at what's called the best possible vision which is not how they're seeing day to day because they don't have that prescription to wear. But most people stabilize to, you know, let's just say between even 20/20 to 20/30, 20/40, which is still vision that you can drive with and do most of your activities. Again, somewhere in the two to three-month timeframe after starting the treatment.

Jenny: Okay, that's very helpful. Dr. Gasparetto, when you do hold the drug and then you say, Okay, let's check you next time in three weeks. And let's check you next time in three weeks. That's how you're looking at it too, from a myeloma specialist point of view, and then you're watching labs and everything?

Dr. Gasparetto: When they come to clinic, we check their myeloma labs, even if it's only three weeks, and there are regular labs, particularly as I mentioned for a potential low platelet count and other lab abnormalities. And so we monitor the myeloma, of course. And so we know every three weeks, we look for the markers of the myeloma, and we know if the patient is responding or not. Patients have a response immediately after the first dose and after the second dose. And so when they develop the keratopathy, they already have achieved the response. And when we hold the drug, we don't lose that response.

So that is, as I mentioned earlier, very unique and then if you develop more than a mild keratopathy, we make a determination if there is not a complete improvement, complete resolution, sometimes we decrease the dose. So we go from 2.5 milligrams to 1.9 and that helps. And that's the reason why that future clinical trial, the combination of assessing different dosage and also a longer interval between the dosage, but it's too soon to say. I think right now it works in this way. And we have longer follow-up of the patients in the DREAMM-2 study which are very encouraging, showing the durability of the responses.

Jenny: Great. And how frequently do you have to hold drugs? I mean, what percent of patients?

Dr. Gasparetto: What I can say that probably 50% of the patients will require holding the dose even more, and then we'll say that maybe 30% (and if you look at the data of the DREAMM study) that will require a dose or reduction. But the discontinuation, the permanent discontinuation of the drug is actually very low. I believe it's less than 10%. In the study, in my clinic, we have patients that discontinue because they lost the response. But because the visual problem, as I say, I think a couple of patients for the blurry view, but not because they were not responding, or because they have severe keratopathy. They just didn't like it. So the permanent discontinuation of the drug is actually very low. But yes, I would say that more than half of the patient swill require some dose interruption at some point, absolutely. For even more than three doses continuing like we say in our clinic, we had a patient holding for 12 weeks, but still maintaining the response which is better.

Jenny: That is really remarkable.

Dr. Gasparetto: Maybe that's the reason why we're looking at maybe we don't need it as often. In the future, I don't know. We don't want to lose the responses. So we don't want to jump to conclusions and say, okay, everybody is going to receive the drug less often because we don't have the data. For now, we have to continue these those, this interval because we have all the data and then eventually in the future, we may learn more from clinical studies and see if we can we can mitigate the toxicity with different intervals.

Jenny: Do you need to have frequent communications and be really open with your doctor about what's happening with you? I'm sure Dr. Newman, you're giving her suggestions too because it sounds like the patient takes a report back to their physician, so you can really see what's happening from here.

Dr. Newman: Right. There's a pretty formalized report. I mean, it's a brief report, but it has all the critical information, and then I often add some information to try to let Dr. Gasparetto and her team know how things are trending. Perhaps someone is stable and in a dose hold, but, but it's looking a little better, but they're still in the category where they have to wait three more weeks for us to reevaluate. Yes, we communicate immediately.  I always give the patient a copy of the report as well, just in case fax, email, whatever doesn't quite get to the right person, they have it in their hand. So there's no delay yet. For us, of course, a lot of our patients do come from out of town or from far away. So being able to time everything on the same day definitely helps. And I'd imagine a lot of your other patients around the country here that might be listening to this also that go to say, a major medical center, they may have to travel some distance. So being able to coordinate it such that we have the eye exam in the morning, and then they see their oncologist two or three hours later, and having that achieved in one day is certainly the ideal for this for following patients on this medicine.

Jenny: Yes, it has its advantages for sure. I want patients to know that we talked about how it works in the beginning. It's very different from how other BCMA-targeted therapies work because this is almost like your immune system is helping delivers this toxic payload. But your immune cell is not the working tool here to kill the myeloma, right?

Dr. Gasparetto: Yes and no. I think the antibody works linking to the BCMA and delivering the payload, the cytotoxic payload, but also that there is an announcement of the immune system. BLENREP brings or recruits and activates other cells of the immune system that affect the myeloma in different way. And so it is this immunotherapy. I think is it works directly linked into the BCMA. But it is also immune mediated, inducing cell death through the new system. Absolutely.

Jenny: Oh, okay. That's great. I didn't know that.

Dr. Gasparetto: I will say that it has multiple mechanism of action, absolutely.

Jenny: Okay, that's wonderful. It makes it more effective. When you put patients back on, do the same symptoms come back? Do you decide to lower the dose when you put patients back on? How do you do that?

Dr. Gasparetto: So if a patient develops just Grade 2 keratopathy, which is kind of a mild keratopathy, we generally restart the drug at the same dose with the prompt improvement, the resolution of the keratopathy. If a patient develops more severe like Grade 3 keratopathy, we tend to decrease the dosage, at the time of re-initiation of the drug.

Jenny: Okay, that makes sense.

Dr. Gasparetto: We generally tend to restart the lower dosage for Grade 3. For Grade 4, which we don't see very much, and that's good, you could resume a reduced those, so one that is a resolution and improvement to a great one or better, but sometimes when you have a grade 4, that is when you may want to discontinue the drug. But as I say, we don't see it very often. We don't see this type of severe keratopathy, the corneal defect, the ulceration, very much. But, yes, if the patient develop grade 3, which is more kind of moderate, we tend to resume at a lower dosage. We don't lose the effectiveness of the drug.

Jenny: Dr. Newman, so I just want to reemphasize because -- we talked about this in the beginning of the program -- because this is the top layer of the eye, this drug cannot make a patient go blind, right?

Dr. Newman: Well, it has not. I mean, could I say 100% that that couldn't happen? I guess I really can't. But everybody who's been on it so far and even in those studies, the DREAMM-2 study and the 30 patients or so that I've seen in the last year, I've seen no effects beyond the epithelium (the top layer). So yeah, it just doesn't seem to be there. It seems to only affect the epithelium, in which case, yes, someone might have very blurry vision, and they might have to be off the medicine for three months even or four months, sometimes up to six months for it to fully go away, but they will return to their pre-medication baseline. I try to reassure the patients that we've not seen anyone with permanent damage from this. No damage to what we call that stromal layer where you could have scarring. So we have just not seen that and no, I've not seen it reported anywhere at this point.

Jenny: Okay, great. Well, I think that's the most essential question the patients want answered. I mean, that's what we all think about.

Dr. Gasparetto: Yes, that's the most important conversation. Yes. I think I totally agree. We were saying, we were commenting earlier that that is what the patient needs to know from the very beginning when we start the drug. And so having me counseling and then Dr. Newman counseling them is very important from our different perspective.

Jenny: Absolutely. Dr. Newman, is there anything else that provides relief? Like, let's say you have itchy eyes or kind of that burning that you're talking about, are there other things like drops or things like that that patients can use? I was reading that steroid drugs don’t really work, right?

Dr. Newman: Right. Again, steroids are typically used for inflammatory type conditions when used on the cornea and this is not an inflammatory condition. It's a toxic condition due to the medication. So things that dilute the medicine, so to speak, on the eye like the artificial tears, we use preservative-free artificial tears, and actually those are, which is great, they're provided by GSK. They provide drops to the patients and that way they don't have a cost in that aspect of their treatment, which is definitely a big incentive for compliance. The drops can get expensive. It's another expense that the person would have. So it's wonderful that they supply those. The protocol for the treatment advises four times a day.

We start people with drops four times a day. If they start to develop keratopathy, we go to every two hours on those drops. And sometimes also, I will add ointment at night, which a lot of patients have found that comforting and helpful. Cool compresses sometimes give people a little symptomatic relief. But, yes, the steroids I have not prescribed them for anyone. Yes, you're correct. In the initial studies, it was shown to be equivocal, basically not effective.

Jenny: Are there other eye conditions when somebody can have that might be a problem for somebody starting?

Dr. Newman: Yes, I would mention that people who have had a history of prior LASIK vision correction, and we have, I think, four patients that I've seen on BLENREP that have had prior LASIK. And those patients, their corneas tend to be a bit drier, and so they're going to be a little more prone to the BLENREP keratopathy. Indeed, in these patients, it was a little worse initially than what we would see with patients who had not had LASIK. So I do give those patients a little extra counseling like, hey, this could be worse for you than for some other people. But actually, they're still on the treatment. They're doing well and their keratopathy was a little more severe. Again, not to this severe stage, but more significant, say, after the second dose, then someone who didn't have LASIK, they still have recovered to a pretty good steady state after, let's say, three months or so.

The other kind of red flag or thing I watch for is people with significant dry eye at baseline because those people, their epithelium is already disrupted a bit because they've had cells that have dried up and died. So the patients will be familiar when they go to the eye doctor with the eye doctor putting a yellow dye in the eye, and the yellow dye called fluorescein, it will stain where the dead cells, in other words, the space left by a dead cell. So it shows up when I look at it under a blue light, we'll see this peppering on the cornea where all these dead cells are. So when we see that at baseline, that makes us more concerned that this patient may develop a little more keratopathy than someone who doesn't have this. But again, and we've seen patients both with the LASIK and dry eye a baseline, they've still done well. They've just maybe had their level of blurriness or level of symptoms was definitely a little bit higher as they've gone through this than someone who did not have those predisposing factors.

Jenny: Interesting. And what about patients who have contact lenses?

Dr. Newman: Right. You're not supposed to wear contacts while you're on this treatment. Truthfully, I have not had anyone yet of the 30 or so patients I've seen that was a contact wearer. So I didn't have to take the contacts away from them. But, yes, if you read in the BLENREP literature, it specifically states not to wear contacts while you're on BLENREP, which makes sense because that lens could be a reservoir for the BLENREP that's coming through to the eye and perhaps increased contact time to the cornea and make things worse. So yeah, we would tell patients that they should not wear their contacts while they're on this treatment.

Jenny:  Okay, I have other questions for you. Dr. Gasparetto. If you combine BLENREP with other myeloma therapies, do you see anything making things better or worse?

I know sometimes you may have seen this in selinexor, maybe you combined it with Velcade and actually makes your neuropathy better. Or if you combine BLENREP with other types of myeloma therapies, which is perhaps where treatment will head next for BLENREP,

Dr. Gasparetto: When we combine drugs together with a different mechanism of action, we see an increased rate of response with all the drugs. That's the reason why we treat patients with a cocktail to increase the effectiveness and also to decrease the chance of the rate of resistance. So we have all this combination that they become more potent, more effective. So there are actually a lot of different combination and their evaluation, the different, you know, DREAMM, they have DREAMM studies. They have a different name and different number based on the different combination that the BLENREP has been testing with. We had some preliminary results presented with bortezomib, with pomalidomide.

I think what is going to be interesting, like we mentioned earlier, when it's given in combination and so maybe more effective because the synergistic, the dual effectiveness, maybe we don't need to give it a BLENREP every three weeks. Maybe we can give it less often and have less of the eye toxicity. So there are studies ongoing to evaluate different dosage, lower dosage in combination, longer intervals. So we're all excited about that.

And then, of course, when it was tested very heavily pretreated population and approved for patients with very resistant disease, and so then the drugs are going earlier into the line of therapy. And so we're going to see BLENREP become more effective or when it's given earlier on during the course of the disease. I think we're all waiting for different combination and the evolution of this very important drug. They just entered the myeloma world. And this changing, like Dr. Newman was saying from his perspective, in my perspective, that means it's changing the dynamic of the disease that some of these patients didn't have any other options. But we don't want to keep it just for those patients. We want to bring it earlier on and use it earlier to target. The BCMA is the new target for myeloma. So we do have a lot of new agents coming up.

And the only other thing while Dr. Newman is on the phone, we discussed together if we have a patient with cataracts, maybe it's better to do the surgery before the cataract removal, before we start BLENREP, right?

Dr. Newman: Yes. We've had a few patients who were able to have their surgery and then start the treatment because the compromise to the cornea with the keratopathy, they would not be able to have surgery while on the BLENREP. So yes, that was a great point to bring up, so people can know that.

Dr. Gasparetto: Exactly. We see a lot of patients developing even earlier cataracts because the steroids that we use. So that's not important. In the study, we had a lot of patients older than 70 and the rate of keratopathy was very similar to the younger population. So it's actually very well tolerated even in a more frail and elderly population of patients. But because they start with already decreased visual acuity, sometimes we have to be cautious about that. And the cataract surgery is also part of the discussion, I think.

Dr. Newman: Yes.

Jenny: Great.

Dr. Newman: That helps maximize their acuity going into the treatment.

Dr. Gasparetto: Exactly.

Jenny: Wonderful. Well, I have one final question for both of you. Dr. Newman, do you have any other comments from an eye specialist perspective? You both said that this is a very well-tolerated drug. Dr. Newman, you're asking patients how they're doing with their myeloma. But do you have any other thoughts that you'd like to share?

Dr. Newman: Yes, just that people, if it's proposed to them, I don't think they should be afraid of it. You know, there just haven't been any permanent negative effects to the vision even though you'll have some temporary effects or perhaps a low grade of effect that will stay with you through the treatment. But the benefit of the treatment, at least what we've seen so far, has definitely outweighed for, again, almost all the patients we've seen, outweighed the side effect to the vision.

Jenny: Great. Wonderful. Thank you. We're so grateful that you're on this show. I'll thank you both in a second. Dr. Gasparetto, I know that many myeloma patients need all available drugs on the table when they're considering care. So do you just want to close with how and when you use BLENREP in the clinic?

Dr. Gasparetto: Yes. It's becoming a very important drug in our clinic, in the community. We have, in addition to BLENREP, we have the other drugs in the development or recently approved with the same target, the BCMA target. So definitely we're trying to figure out, can we use all these drugs and what is the best sequence? Particularly with the CAR T cell that was recently approved. But the problem with the CAR T cell is very important procedure drug, if we want to call it drug, you're very familiar with the CAR T cell, the problem that we have with the CAR T cell, it to be done in an academic center or in a larger hospital. Patients have to be in very good performance status, be able to manage the toxicity of the CAR T cell.

What I'm trying to say is it's a phenomenal addition to our pool of drugs that we have available for this complex disease, but we cannot bring it to all patients, right? It's not there available for all patients. So particularly, myeloma remains a disease of the older population. I'm always surprised because in my clinic I see a lot of young, young patients, but then when you read, the statistic remains more prevalent in the older population. So you're not going to be able to do the CAR T cell in the majority of patient older than 70. You could. There are some patients that have very good performance status, but not necessarily. It's not available for everybody. So that's the reason why this drug is going to be very important for this more frail population of patients, patients that don't have access to the academic sites. We're going to see what's going to happen in different combinations. So that really changed our treatment over the last year since approval because I have to say that it is effective. It works. We are learning how to manage the toxicity.

I like this drug. I really do. I think it's one of the new drugs that really has impact on the course of the disease. I've been doing this now for a long, long time, for 20 years, so I saw the introduction of all the major drugs for myeloma from thalidomide to lenalidomide, to bortezomib. I have to say that this is another big admonition that we have to fight the disease, prolonging probably the life of many patients. It works. I'm glad I'm here with Dr. Newman because I think if we are able to mitigate the toxicity and outpatient to be able to tolerate the drug, it seems like we don't have a lot of issues. As soon as you learn how to manage the toxicity, I think it is obvious that that is doable and feasible for a lot of patients including the older patient and more frail patients, which sometimes we can't treat in the same way because they're not going to be able to tolerate therapy, right? So this is very important for that population of patients. So I'm very excited to continue to treat patients with myeloma and having more and more options available.

Jenny: I think it's really stunning what's happening. I'm grateful for all these new approvals and for the companies that are making them possible because like what you're saying, not one therapy is the right thing for every single patient.

Dr. Gasparetto: Exactly. You have to tailor. You have to adjust therapy based on the individual, the age, the type of myeloma, the other medical issues. So we need to have more and more options so we can apply to all our patients. Again, the old patient that we're treating with BLENREP could be eligible for the CAR T cell. The CAR T cell might not have worked for them.  So it's another option. My hope is that we can sequence this drug, including the CAR T cell, go early and then sequence and being able to reuse the same target with a different drug. We do have other drugs in myeloma with the same targets, right?

Jenny: And they can be reused in different combinations or after different therapies.

Dr. Gasparetto: Exactly. So we just have to wait for the data to become more mature. We have a longer follow-up of the DREAMM-2 and learning a lot. And very exciting. I know one of the things that is very difficult is to counsel the patient. So I'm glad that Mark mentioned about the fact that all the symptoms are reversible because it's a new work for us. It's a new toxicity.

Jenny: Right, we just have to gain experience. Well, I'm just so grateful for the both of you that you are willing to take your time to share all your experience with patients because you not only have the academic side and the studies, but you have the practical, real-world experience as well with patients coming to your clinics every day who are taking this treatment. So we're just so thankful that you took the time to share your experience with us.

Dr. Gasparetto: Absolutely. Anytime.

Dr. Newman: Yes, our pleasure.

Jenny: Well, thank you and keep up the great work. Patients will continue to come to you and be glad that they are. So we're thankful for you both. We're thankful for our audience.

Thank you for listening to Myeloma Crowd Radio. We invite you to join us next time to learn more about what's happening in myeloma research and what it means for you.