All about BLENREP (Updated)

What is belantamab mafadotin or BLENREP? BLENREP, or belantamab mafadotin, or as we like to call it for short, Belamaf. Doctor Usmani refers to Belenantamab mafadotin as Belamaf. Some health care professionals use this shorter name when talking about the drug. The full name is belantamab mafadotin, also called BLENREP, is an antibody drug conjugate, and the idea of an antibody drug conjugate is you have the antibody part that can recognize a certain surface marker on the cancer cell, and it's laced with drugs that can be delivered to that cancer cell.

So it delivers a targeted payload to the cancer cell. And that payload is many times a chemotherapy drug. Sometimes it can also be an immune therapy approach as well. Belantamab works in more than one way. It delivers a toxic payload that kills cancer cells, and it can also activate the immune system. Belamaf is an off the shelf treatment option for myeloma patients.

The reason why we call it off the shelf is because it's readily available, so you can essentially take it from the pharmacy shelf and give it intravenously to patients the very same week. And there's a distinction between this treatment and say something like Car-T cell therapy, which require many weeks of preparation and orchestration. What is the surface marker that belantamab mafadotin targets Belamaf targets the B-cell maturation antigen, or BCmA, which is highly expressed on the plasma cells to deliver its payload, or the drug conjugate part that delivers the toxic payload, which is MAF or the maf part, to those cancer cells.

To learn more about antibody drug conjugates, be sure to watch the lesson on this topic and Health Tres Antibody course. What was the trial that confirmed belantamab mafadotin's current approval, and what were the findings of that trial? The trial that led to the current approval for Belamaf is called dream seven. It was the combination of Belamaf with bortezomib and dexamethasone, comparing it to daratumumab, bortezomib, dexamethasone.

So this was a phase three clinical trial done in patients who had received, at least one prior line of treatment. The patients were randomized or assigned either the Belamaf arm of the study or the daratumumab arm of the study, and the primary endpoint of the clinical trial was progression free survival. So seeing how long the remission period last in each of the arms.

And this was a global study, there were many sites around the world, including the United States, that participated in this trial. The results of the dream seven trial were quite impressive for the belamaf arm of the study. The progression free survival was roughly three years, and for the daratumumab bortezomib dexamethasone arm of the study, it was a little over a year, around 13 months or so.

So very impressive. Almost tripling of the progression free survival benefit was seen with the bela arm of the trial. After further follow up, there was also overall survival benefit seen for the belamaf arm of the study, which again was quite remarkable. If you look at the current landscape of myeloma treatment, with all the options we have on the back end, in more recent trials where progression free survival has been the primary endpoint.

Most of the clinical trials don't have that enough sample size to actually show overall survival benefit, but it was demonstrated in the dream seven study. Was the belantamab mafadotin arm of the dream seven trial. Equally effective across all myeloma patient subgroups? There were several subgroup analysis done looking at not just the high risk patients looking at patients who were older, looking at patients who had renal insufficiency.

And it looked like the benefit was uniform across all of these subgroups in favor of the belamaf triplet arm of the study. Is belantamab mafadotin, approved as a monotherapy or as a combination therapy. So the approved combination is belantamab mafadotin or belamaf with Bortezomib and dexamethasone. And the way that these treatments were given the belamaf was given every three weeks during the first eight cycles of treatment, and then after the eight cycles of the combination, patients could continue the belantamab during the maintenance phase.

Velcade or bortezomib dexamethasone was given on a twice weekly schedule as part of this clinical trial in both the Bela arm of the trial, as well as the daratumumab arm of the study, and patients who did develop side effects had dose reductions or scheduled reductions to weekly dosing along the way. I can share my own caveat here that for the most part in the United States, we utilize weekly dosing of bortezomib, and that helps in managing some of the neuropathy side effects we see less frequently.

And so from a practical standpoint, even though the clinical trial required twice weekly dosing of bortezomib for our patients, we would typically be doing weekly. Velcade and dexamethasone were both stopped after the initial eight cycles on the clinical trial and on the bela arm of the study the belamaf was given from cycle nine on its own, and daratumumab was given on the standard of care arm of the study every four weeks.

In the BVd arm of the Dream seven trial, 87% of patients required a dosage modification of BLENREP. The dose and the frequency of belamaf can be changed. The recommended dosage modifications for eye related side effects based on ophthalmic exam findings are as follows. Reduce dosage level 1 1.9mg/kg every three weeks. Reduce dosage level 2 1.9mg/kg every eight weeks.

BLENREP is not re escalated after a dosage reduction is made for isolated side effects based on ophthalmic exam findings.

Can individuals that have had previous velcade exposure still try BVd? So for this clinical trial, patients who were refractory to bortezomib, in the past were excluded. And so, you know, patients who had prior bortezomib, if they were not refractory to it, you know, they could have participated in the clinical trial. Many of our patients in the United States do get bortezomib as front line treatment.

But then it's only for, you know, fixed duration of period of time. So, practically speaking, one can apply this clinical trial to our patients in community practice or our general practice. How is belantamab mafadotin administered? It is given as an intravenous infusion over 30 minutes. Belamaf is typically given at a dose of 2.5mg/kg for the purposes of this clinical trial, but based on the patient's tolerance, we can reduce the dose as well as the frequency of the of treatment.

Belamaf does not require step up dosing. We typically start off with the 2.5mg/kg IV dose. Belamaf is given in the outpatient setting, and that's the off the shelf part of it that patients, all they need to do is to come in to the outpatient infusion center. They get their bortezomib subcutaneous shot, they get their belamaf IV infusion and go home.

How soon can a response be seen? So typically we would know if patients are responding to the belamaf combination within one cycle of treatment. We would also gather by that time if patients are having any side effects, so we can actually manage the schedule according to what happens in that first cycle of treatment. What are the eye related side effects associated with belantamab mafadotin?

Belantamab mafadotin utilizes the mafadotin part of the drug conjugate. It's a very well known side effect of the maf part of it, that it can cause corneal ulcers or breakdown of the cornea. And what is cornea? It is the top layer of epithelium or skin over the eye. So our patients, when they get the belamaf they can have irritation in the eye.

And those side effects start to happen from the periphery or the white portion of the eye, and then come into the center. They start noticing any blurriness of the vision. The healing starts from the center and goes towards the side. The blurriness is the first one to go and then the irritation. And this is a well-known side effect of the mmaf component.

And that's something that that patients can observe. I would say if there were 100 patients getting this treatment, 75 to 80 of them would have some degree of it. But really the side effects, the grade three or higher side effects would be seen in about a third of the patients. The good news, however, is that almost all of those patients, once they develop it and you hold the next dose, have resolution of those symptoms, they get better.

Can they come back with subsequent doses? Yes. And that's the reason why we reduce the dose as well as change the schedule. If someone is getting this every three or every four weeks, we can change it to every eight weeks and even every 12 weeks. Does the cornea constantly renew itself or does it only regenerate after injury? All of us know that skin is the largest organ that we have.

The skin doesn't just cover our face, it actually is the epithelial or skin part that covers over our eye. And that's what we call the cornea. And the cornea regenerates very quickly. And so even on a daily basis our cornea is generating layers when it gets affected by drugs like mmaf, heals very quickly. So there's a very rapid turnaround of the epithelial cells to to help with the healing.

So once you stop the belamaf drug and extend the treatment schedule, that healing occurs on its own. It's a natural process. The symptoms of the eye related side effects that Doctor Usmani just described include decreased vision, blurred vision, dry eyes, sensitivity to light, feeling like something is in your eyes, eye irritation and eye pain. What is a Rems or Risk Evaluation and Mitigation Strategies program?

So once a drug is approved by the regulatory authorities, in this case the FDA, if there are certain safety concerns that were brought up during that approval process, the FDA requires a Rems program to be placed so that you can mitigate that safety concern or watch out for it. This has been done for many different drugs. In fact, for myeloma, Rems is established for thalidomide, lenalidomide and pomalidomide.

All of our patients have to do those monthly surveys before we can prescribe those treatments? And it's the same program that has been set up the belamaf program as well, because it's important for patients to have eye exams during this period of time. The physicians have to be part of the REMS program before they prescribe the treatment as well.

So it's a safety measure that's been put in place. In addition to doctors needing to be certified in the Rems program, doctors must counsel with the patient on the risks of eye related side effects with belamaf and why eye exams are so important. What is being evaluated during the eye exams that are part of the BLENREP Rems program?

Typically, the eye exams that are utilized are looking at visual acuity. So the ability for us to actually look at both near and far vision and reading and looking at the structural integrity of the cornea. So it's not just visual acuity, but also looking at the presence or absence of corneal issues in patients. Eye exams are required before starting treatment and before every infusion.

A follow up exam must be done within ten days before the next scheduled dose. Patients can have those corneal changes and not have any trouble with their vision, because those changes start from the outside coming in to the center.

So there are patients who will have those changes on the outside, but their vision would be fine. And then as these changes recover, it would be the same pattern. The center will heal first before you stop. You can still see the changes in the periphery, but they won't be having any symptoms. What eye tests are included in the BLENREP Rems program, and what should patients expect?

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, or they have this sort of semicircle, it 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 so they can look at the surface of 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 BLENREP 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 those are really the two big components of what's done. Do corneal changes need to be completely resolved before restarting blenrep, or can treatment be resumed earlier? If it's just the Keratopathy, and patients are asymptomatic, you can start the treatment. Most patients by the second or third cycle of treatment, you already know whether they're in a PR, VGPR so you can also kind of play it by ear depending on the response and how patients are feeling.

How are eye related side effects managed? We have employed different strategies. I think the biggest factor here is really stopping and delaying the dose. I think artificial tears are very important to keep the lubrication. In case of a lot of irritation, warm compresses to the eye can also help as well. It's better to avoid the contacts during this time, because they can be an high risk for infection and can cause further complications, whether it's viral infections or secondary bacterial infections, that can happen as well.

It's better to avoid them. The contact lenses can also are generally kept in a solution that may have preservatives, as well, and that can also contribute to the risk of infection and subsequent irritation. Patients do get sensitivity, so wearing sunglasses to avoid direct sunlight that can cause irritation would be important as well. These are just some common things that one can do.

Why is it important that when you use eye drops, they should be preservative free? We don't want the preservatives to cause subsequent irritation as well or cause the possibility of secondary infections? So it's important to have preservative free formulations of the eyedrops. Did any patients have irreversible damage? Does belantamab mafadotin cause blindness? Irreversible damage is not something that is observed with belamaf.

Patients can have severe side effects that require us to discontinue the treatment, but they lead to resolution of symptoms. Blindness is not something that's been observed with belamaf. Was there any data showing that the myeloma stayed under control even when doses were paused? Yes. So this was another very important aspect of figuring out what's the best way of dosing belamaf in combinations.

Once patients get those treatments and the disease is under control, delaying the dose did not lead to loss of response in patients. You were able to rechallenge patients with less frequent doses. In some cases, in fact, were patients who were receiving only 3 or 4 doses a year. And that was more than sufficient to keep the response going.

How did the eye related side effects affect day to day life? It depends on the degree of symptoms. Some of the patients have said, you know, when I'm having those symptoms, I just use a magnifying glass for reading sometimes, or I make sure that I'm using sunglasses. When we look at visual acuity, 2020 is the usual vision. If the symptoms get to 2050 or higher, that's when you want to avoid driving.

And so it really depends from one patient to the other. But most patients were able to get back to their usual routine after the first couple of weeks. Besides eye related side effects, what other side effects have been seen with this treatment? Are high rates of infection being seen. So infection risk is not the same as Car-T cell therapy or bispecifics.

Patients do not develop hypogammaglobulinemia. The same way as they do with bispecific or Car-T cell therapy, so the use of IVIg is not as common as those modalities. However, we know that many myeloma patients who have received anti-CD38 monoclonal antibody treatments in the past, they do develop hypogammaglobulinemia. So there are going to be patients who receive IVIg.

But it's not the same as one would expect with the other immune therapy modalities. Cytopenias is something that we pay attention to. When I say cytopenias it's really the blood counts. Looking at the white blood cell counts, hemoglobin and platelets in this combination, because bortezomib itself can also cause those numbers to go down. We don't see CRS or ICANS or other neurologic side effects with Belamaf that we have observed with Car-T cell therapies more commonly.

And then we can see CRS in infection risk with the bispecifics, but typically not in neurologic side effects. So belamaf actually has a more I would say, friendly profile from that perspective. And this is why I feel that for many of our patients who are out in the community who either don't qualify for Car-T or bispecific or do not have access to it, I think the belamaf combination is going to be very important for them to make sure that they get a BCmA directed option in that setting.

Besides eye problems, the most common side effects of BLENREP when given with bortezomib and dexamethasone include colds or other upper respiratory infections, liver problems, diarrhea, feeling very tired, pneumonia and cataracts during treatment, blood tests may show low platelet, low white blood cell, low hemoglobin, and higher liver enzyme levels. Call your health care provider right away if you have new or worsening lung symptoms, such as shortness of breath, chest pain, or cough, blenrep may affect fertility in both men and women.

This could make it harder to have children. Talk to your health care provider if this is a concern for you.

What prophylactic medications are prescribed while on belantamab mafadotin? In this particular combination, we do have patients taking acyclovir because in the bortezomib combinations there is always a chance of having shingles reactivation. So I think acyclovir prophylaxis. And of course the ocular side effects, we always encourage the use of preservative free artificial tears. When the velcade is dropped after eight cycles do you need to continue on acycovir? Typically not. But for many of our patients, it's a low risk kind of an intervention. Many would actually continue taking the acyclovir just to have that added protection. If you have had a previous BCmA directed therapy, can you still respond to belantamab mafadotin? That's a very important question.

And that question actually takes us back to the dream two clinical trial, because belamaf as monotherapy was approved, it was actually the first BCMA directed treatment approved back in 2020 as monotherapy for patients who had four more prior lines of treatment. So we have a lot of real world experience that belamaf can work in patients who have received a BCMA directed Car-T or bispecific or a clinical trial. So it can work.

It hasn't really been studied systematically. I do feel that a real world evidence that we will generate as a community will help us on that end. Does belantamab mafadotin cause T-cell exhaustion? Unlike the bispecific therapies or Car-T cell therapies, where the mechanism of action is really having the patient's T cells do the job with bispecific, you know, the T cells are directed to the cancer cell.

With Car-T cell therapy, we actually engineered the T cells to go after the myeloma cells. The antibody drug conjugate is very different. All it does is identify the cells or binds to the cells that have BCMA and just deliver the chemotherapy. So it's not affecting the T cell function in any way. So you don't get the T cell exhaustion or T cell dysregulation by using belamaf.

What is the role of the care partner? The role of care partner in general in myeloma is paramount, and looking out for symptoms. Myeloma patients are very resilient. They might downplay the symptoms. And many times it's the caregivers who are actually saying, hey, no, no, no, you have to tell the doctor what's happening. So I think that's the role that caregivers can play, bring those symptoms to the fore so that we can do make the adjustments to dosing and treatment for belamaf. it's the same concept with any treatment. But I think the more important thing to pay attention to is the eye side effects. Can belantamab mafadotin be given safely to older or frail patients? Are there any comorbidities that might exclude you from taking belamaf? I would say that, it's one of the easier treatments for the older patients, at least in the clinical trials.

The efficacy was the same regardless of age. But you have to be careful to make sure that the patients have adequate social support as they're starting the treatments. The other thing that I would say is patients who have existing eye issues, we have to be careful. So having a good initial exam to make sure that you're documenting their baseline is going to be important.

If someone already has corneal issues, it would be important to document exactly what they have. Also, have this proactive discussion to make sure that the patients are aware side effects can occur, maybe at a higher propensity than someone who would not have, preexisting corneal issues. It's not a absolute contraindication, but something that we have to be careful for.

Can individuals that have cataracts be prescribed belantamab mafadotin? It is not a contraindication because the cataract is a problem with the lens inside the eye that it gets clouded as as a function of aging. For many of our patients, actually, cataracts are an easy fix. In today's day and age, patients can get the cataracts removed and lenses placed, but that should not be a contraindication.

Are there any support programs to help people who are prescribed BLENREP? The together with BLENREP program is support made for individuals prescribed BLENREP. Together with BLENREP is designed to support patients during treatment with BLENREP. Together with BLENREP offers personalized help to get you started and stay informed. Key program features include coverage support: insurance, and coverage information to you and your doctor, including supporting your doctor if you face coverage challenges.

Cost support: help make paying for BLENREP more manageable with options tailored to your needs. Patient support: A dedicated Nurse Navigator through key steps in your treatment journey. The together with BLENREP program will also help you understand your insurance coverage, find an eye care professional for required eye exams and provide educational resources. You can enroll in two ways.

Complete a form with your doctor at your next visit, or use the button below to start your enrollment online. For current eligibility criteria, check the manufacturer's website. The link is in the description.