All about Blendrep or Bilanetimab mafidotin. On August 5th, 2020, the Food and Drug Administration granted accelerated approval to Bilanetimab mafidotin BLMF or Blendrep for the treatment of adult patients with relapsed or refractory multiple myeloma. The Dream 3 trial did not meet the criteria for accelerated approval leading to GSK, the manufacturers of Blendrep, to withdraw it from the market. The Dream 3 trial was an open-label, randomized, head-to-head superiority trial evaluating the efficacy and safety of Blendrep compared to pomalidomide in combination with low-dose dexamethasone. Although Blendrep was proven safe and effective, as a monotherapy it did not statistically show superiority. The observed median progression free survival was longer for Blendrep at 11.2 months versus pomalys plus dexamethasone at 7 months. GSK is actively developing and testing Blendrep in combination with other drugs with positive results. For example, GSK is exploring Blendrep in combination with Bor-Tezomib and dexamethasone and pomdex. On April 17, 2025, GSK's once-withdrawn multiple myeloma therapy, Blendrep was granted authorization in the UK. The remainder of this video was made prior to this re-approval. Health Tree will update this lesson once the FDA rules on Blendrep's re-approval application. The PDUFA date for Bilanetimab mafidotin in combination with other therapies for relapsed refractory multiple myeloma is July 23, 2025. This date marks the deadline by which the FDA is expected to make a decision on the biologics license application for these combinations. So Blendrep is the commercial name for Bilanetimab mafidotin. Blendrep is part of a new class of drugs. Can you tell us how Blendrep works? Blendrep, or Bilanetimab, is what's called an antibody-drug conjugate. And it's the first available drug that targets B-cell maturation antigen. And this is a protein on the surface of almost exclusively plasma cells, and those are the cells from which myeloma cells are derived. And it also looks like BCMA, or B-cell maturation antigen, expression or amount of that protein on the cells goes up as a person moves from, say, monoclonal gammopathy to multiple myeloma. So that means that it's an excellent target for multiple myeloma patients. And there's lots of drugs out there that are targeting BCMA, but Bilanetimab is the first one that's been FDA approved. So it is tied to a drug called Arastatin, or MMAF. And this drug is actually really what is one of the mechanisms of action. So that drug enters the myeloma cell and interferes with that cell's growth. And there's some other activities we think of this drug, including some antibody-dependent cytotoxic killing that's happening as well. So there are a number of different mechanisms. But the antibody is what delivers the drug to the actual myeloma cell. Is BlendRep attached to the antibody? This MMAF is attached to the antibody, and that antibody gets it to the myeloma cell, and then the drug gets inside the cell. It's taken and moved from the surface where it can start doing its action and interfering with that cell growth. What are some side effects of BlendRep? In the DREAM2 study that was published earlier last year, there were a number of side effects that you can see commonly. So some of them are we see with many types of myeloma drugs, and that's hematologic toxicity, meaning side effects that occur against blood cells. So there is some anemia and some lowering of platelets. But probably the one everybody has heard about is this side effect called keratopathy. And what keratopathy is, it's irritation of the cornea, which is the lining on top of the eye. And so keratopathy side effects can be things like dry eyes or blurry vision, or in more extreme cases, there can be some irritation and actually pain. And keratopathy turns out to be a relatively common side effect with this particular drug. How is keratopathy diagnosed? Well, there's two different ways in my experience with this drug. So one is as patients come in and tell you, they come in and they say, boy, my eyes feel a little irritated, or they really will say I've got some dry eyes when normally I don't. Or sometimes people have absolutely no side effects at all. And one of the restrictions about using this drug is you have to have an eye doctor involved in the care of the patient who is receiving BlendRep. So that means that the eye doctor is examining that person between each dose and looking for signs of keratopathy. So that sometimes patients have no symptoms whatsoever, but the eye doctor, the ophthalmologist, or perhaps the optometrist tells us that there is some eye irritation. And that's actually graded. There's a scale that's used to try to decide if the irritation is significant enough to require either holding the dose of Bilantimab or cutting the dose. There's one of the most common one is called a slit lamp exam. And this is a technique that probably anybody who's been to the eye doctor knows where they have this sort of semicircle, looks like a little cage and you put your chin to rest on that little platform. And then they use actually a slit of light. And that's where the slit comes through to basically be able to look at different components of the eyeball. They can look at the surface, the cornea, or they can look at the lens or they can look all the way in the back of the eye with this technique, including the retina. So anybody who is on BlendRep will be getting the slit lamp examination. And sometimes they do it without dilating your eyes. That's when they put those drops in if you have ever had that done. And sometimes they do it without. And then they'll also check your best visual acuity. And that's usually done by having you read off either numbers on a screen or sometimes on a card and then seeing what distance you can read those comfortably. So those are really the two big components of what's done. What is photophobia and is it a side effect? Photophobia is actually having, you know, everybody, if you've been out in the bright sunlight notices that you have some sort of eye irritation and you look away. People who have photophobia means with just sort of normal degrees of light that they're feeling some discomfort or in some cases even pain, you know, that they must look away or put on some dark glasses or they're uncomfortable. If you wear contact lenses, should you stop wearing them? That's the recommendation right now because there's some concern that we want to make sure that the cornea, you know, stays healthy and gets fluid spread out over it. There is a recommendation to use moisturizing drops when you're on Blend Rep. And so there is some concern that contact lenses could interfere with just having that smooth surface of fluid over the top, which we think is important in preventing irritation. So we really do recommend not wearing contact lenses when you're on it. How was keratopathy managed? Yeah, so typically the one of the most important things to do is use those drops. There was a study with Blend Rep done trying to see if steroid eye drops would mitigate the problems, like get rid of it. And that didn't seem to be that helpful. So typically what we do is we use hydrating drops, but we usually hold a dose of Blend Rep if the keratopathy is severe enough. And then following that dose hold, we tend to drop the dose of Blend Rep from 2.5 milligrams per kilo down to 1.9. In my experience, almost all of the patients who go through those steps, so holding the drug, using their eye drops, going then onto a lower dose, don't seem to have the keratopathy come back. There is a small percentage of people in whom this unfortunately does end up being a bit of a problem. One of the things though that we've noticed in our patients is that during these dose Very seldom is it that patients actually seem to show progression of their myeloma. So that's one thing that we can reassure people about is as we are holding their doses, it doesn't seem like their myeloma is getting worse. Do eye drops need to be preservative free? And what does that mean? Just as you could imagine, food additives, there are additives, particularly in solutions that are used in the body. Often eye drops have additives that are supposed to keep them from having bacteria grow in them. So one of the common ones is benzyl, alconium, and preservative free drops are felt to be less irritating. So that's usually what we recommend, but it means that you're going to want to get fresh bottles pretty frequently to make sure that there isn't any contamination. And of course, when you're using those drops, you want to make sure that you're not touching the tip of the dropper directly on the eyeball. We want that to be held away. But they're felt to be somewhat less irritating because they don't have those additives in them to keep them from having a bacteria or fungal growth in them. Are there any other rare or serious side effects? Those are really the big ones. Unfortunately, before I think people knew about the ocular toxicity at the very beginning, there were some patients who had some pretty severe corneal injuries. They eventually recovered. But it's very important if people do have that eye irritation, that they should follow the advice of their ophthalmologist. And when your doctor is prescribing BlendRep, one of the very nice safety features is as they go through what's called the REMS program, they have to put in information from your most recent eye exam to make sure that it looks okay for you to receive that dose. But of course, if the eye exam results are not what they should be, then you actually are not allowed to go ahead and get that dose. There rarely, in terms of other side effects, there have been some infusion-related side effects. But compared to, for example, the anti-CD38 antibody drugs, those infusions-related side effects are much less common. The most common side effects of BlendRep include vision or eye changes, such as findings on the eye exam, decreased vision or blurred vision, other side effects such as nausea, low blood cell counts, fever, infusion-related reactions, tiredness, and changes in kidney or liver function. What is a REMS program? Can you talk about the REMS program and compare it to the REMS program at Cellgene? That stands for risk evaluation and mitigation strategies. And that's a moniker that the FDA uses for these various programs. They exist in actually all sorts of fields, not just oncology, that allows that they can make sure that the practitioners and the patients who are receiving certain drugs are aware of particular side effects. And so there's a REMS program for lenalidomide and pomalidomide and thalidomide for that matter. And now there's a REMS program for BlendRep as well. It's a little bit more involved because just like the REMS program for lenalidomide and where each person sort of has a component. So the physician does, the patient does, the pharmacist does. In this case, the three people involved are the patient going to get the eye exam, it's the ophthalmologist or optometrist who is filling out a specific form of talking about the slit-lamp findings and the best visual acuity. And then there's the physician who actually has to be authorized to prescribe BlendRep and then they have to be able to put in that information directly into an online form before the dose is essentially approved or released. So it's a little bit more involved, say, than the lenalidomide REMS program. But of course, the purpose is that one's eyesight is very, very important. And we want to make sure that particularly if some individual or maybe some prescribers don't have as much experience with this drug, we want to make sure that they feel very comfortable and understand what some of the precautions need to be when they are having their patients on this drug. It is. And so as a theme that will be very relevant to many myeloma patients, what typically happens with new drugs is that we try them out on their own. And then because they have a different mechanism of action, perhaps of existing drugs, it's a very easy next step to combine that with some of the existing drugs. And so there have already been two clinical trials out there with preliminary results. One was presented last year at the American Society of Clinical Oncology, combining Bilantamab with Bortezomib, that's the drug Velcade, and showed some very promising results. And then just a few months ago at the American Society of Hematology, Bilantamab was combined with pomalidomide and dexamethasone and also showed some very encouraging responses. And there is a trial actually looking at Bilantamab as part of initial therapy combined with Bortezomib, Revlimid, and dexamethasone. So I think you're going to be seeing more of those combinations with the drug as time goes on. We've been hearing about these BCMA targeting drugs for a long time now for years, and it's just fantastic to have one available to patients. And we really have seen people benefit from this drug where they have really failed other treatments. One of the very nice things about Bilantamab, if you're looking at other future BCMA therapies we're waiting for, such as CAR T transplants, Bilantamab is available off the shelf. So if there's a patient who we think needs this kind of therapy, they're able to get it very quickly without having to wait for CAR T manufacturing. So that's a terrific part of this. you