A New Multiple Myeloma Drug Is Here: What to Know About Zenbexus

Dr. Joseph Mikhael:
A new generation of myeloma medicine is here. For the first time, the FDA has approved a CELMoD agent for multiple myeloma, but what does that really mean?
Hi, everybody. Dr. Joe here from the International Myeloma Foundation, a nonprofit committed to improving the lives of patients and accelerating the cure for multiple myeloma. Today, we'll be discussing a new FDA approval of a CELMoD agent for relapsed and refractory multiple myeloma.
To help us understand this better, I want to go through five areas that'll help us understand CELMoDs. Number one, what is a CELMoD? Number two, who is Zenbexus or iberdomide approved for? Number three, how did Zenbexus or iberdomide do in the clinical trials? Number four, what are the key side effects of CELMoDs? And number five, what questions should you be asking your doctor about CELMoDs?
But before we begin, let me encourage you to subscribe to the International Myeloma Foundation's YouTube channel. The science of myeloma is changing every day. And at the IMF, we are empowering you to be educated about multiple myeloma so that you can bring the right questions to your doctor and make the right decisions about your care.
CELMoDs are a new class of drugs in multiple myeloma. The word CELMoD is actually an acronym for a longer phrase, get ready for it, cereblon E3 ligase modulators. You can see why we call them CELMoDs. A CELMoD was just approved for relapsed multiple myeloma, a drug called Zenbexus or iberdomide.
Well, how do these drugs work? Well, what's really important inside a myeloma cell is this thing called cereblon. We've known about cereblon for many years because another class of drugs that you know, IMiDs, drugs like Revlimid and pomalidomide, they trigger a pathway, what I think of as a death pathway, when they squeeze cereblon. So cereblon inside the myeloma cell, when it gets squeezed, it triggers a pathway that leads to the destruction of the cell. Well, whereas the IMiDs like Revlimid and Pomalyst, if you will, pinched the cereblon, these CELMoDs really squeeze it comprehensively. So they really make use of that pathway to help to destroy the cell, which is one of the reasons why they're so effective.
And the first of them, iberdomide, was just approved by the FDA, and I'll tell you more about that coming up soon. We have another drug in this class called mezigdomide, which also works in this way of squeezing cereblon to help trigger the death pathway to destroy the cell. But importantly, CELMoDs also have other effects. They also engage the immune system to help destroy the multiple myeloma cell. And interestingly, they have a bit of a nourishing effect on other parts of our immune system, namely T cells that are so important in the treatment of multiple myeloma.
So there you have it. CELMoDs, this new class of drugs, they squeeze cereblon, which triggers a pathway to destroy a myeloma cell. They engage the immune system and they help nourish your T cells. You're now an expert in CELMoDs.
This new myeloma therapy is approved by the FDA, but it's not for every patient right away. Who is Zenbexus approved for? Zenbexus is the first CELMoD drug that we have for relapsed multiple myeloma. Zenbexus, also known as iberdomide, was recently approved by the FDA in combination with Darzalex, also known as daratumumab, for relapsed multiple myeloma. Well, what is that? Well, of course, we use the word relapse when someone's myeloma has been treated and then unfortunately it comes back. This approval is for patients who have relapsed myeloma. So they've been treated, their diseases come back. It could be that their diseases come back once, twice, or more times.
The Zenbexus approval is for all patients with relapsed multiple myeloma. Remember that Zenbexus is a pill. So unlike a lot of other therapies that have to be given intravenously or through the skin, this is a pill that we take 21 days on and seven days off, a lot like we did with the IMiD drugs like Revlimid and Pomalyst. So patients will be familiar with this, and it'll make it very accessible to them because patients don't have to go into their doctor's office or into the hospital to receive Zenbexus. So in summary, Zenbexus is now approved in relapsed multiple myeloma for anyone who has relapsed disease, and it is used in combination with Darzalex as this combination of Zenbexus, Darzalex, and dexamethasone for relapse disease.
How did Zenbexus do in clinical trials, and why did the FDA approve it? Zenbexus, the first CELMoD agent that we have in relapsed multiple myeloma, was approved by the FDA based on a very important trial called the Excalibur trial. We have great names for trials in multiple myeloma. And in this Excalibur trial, the combination that got approved, which is Zenbexus plus Darzalex and dexamethasone, was compared to another combination that we typically use in multiple myeloma of Darzalex, Velcade, and dexamethasone. So these two combinations of three drugs each were put head-to-head to see if one was better than the other. And there was no doubt that the Zenbexus, Darzalex, dex combination did better.
How did it do better? Well, it did better by something we call MRD or minimal residual disease. We know when patients respond to a treatment, the burden of their myeloma goes down. All those things that we measure in myeloma go down, down, down. We know that the lowest point when we can't measure disease anymore means they have minimal residual disease negativity. We can't even find one in a million cells that are multiple myeloma. That test for MRD negativity is what led to the approval of this drug. When patients got the combination with Zenbexus, 41% achieved MRD negativity. With the other combination, it was only 21%. So we pretty much doubled the number of patients that have no measure of myeloma anymore.
This is fascinating because this is the first time the FDA has ever approved a drug based on MRD instead of waiting to see over time how long patients stayed in remission. I'll talk more about that later, but it's important to understand that that depth of response predicts the duration of response later. So these patients that got into a deeper response are going to stay in that for longer than in the other combination.
So in summary, Zenbexus was approved based on the Excalibur clinical trial, and the Excalibur clinical trial compared Zenbexus, Darzalex, and dexamethasone versus a standard triplet in patients with relapsed multiple myeloma. And in that comparison, we doubled the number of patients that got into MRD negativity, 41% versus 21% achieved that deepest level of response, and that's what led to the approval of Zenbexus.
Before I go any further, let me pause on something very important. These kinds of breakthroughs are not by accident. This takes patients going on to clinical trials, researchers asking very important questions, and most importantly, the myeloma community coming together to work together. A great example of that is how the IMF brought together the i2TEAMM. This was a group of experts and statisticians and industry partners that wanted to prove to the FDA that MRD testing or minimal residual disease testing is actually predictive in clinical trials of patients having progression-free and overall survival benefit. So instead of having to wait for years in a clinical trial for progression-free survival and overall survival, we can predict it by the fraction of patients that get into MRD negativity, and we proved it.
The FDA agreed with us. They voted 12-0 in favor of this and started a process to allow drugs to be approved more quickly through an accelerated program where MRD, instead of waiting for PFS and OS, can lead to the approval of a drug. And sure enough, it happened with Zenbexus. Instead of waiting years for the results of a clinical trial, early on in the trial, we can have that proof and we can have drugs approved. And we expect that Zenbexus is only the first of many drugs that will go through this accelerated approval program so we can get the most important therapies to our patients faster so they can live better and longer with multiple myeloma. If this has excited you about clinical trials, then that makes me happy because without clinical trials, we wouldn't have these major advances.
But you may wonder, how do I participate in a clinical trial? The IMF has made it easy for you. Come to our website, myeloma.org/sparkcures, and we have a search engine there that can help you understand what clinical trials are available, and even the ones that are close to you. We want you to be an active partner in your care, and the more you're aware of the treatment options available to you, the better your conversations will be with your healthcare team to decide what's best for you.
All right, let's get back to talking about CELMoDs. A new treatment option for myeloma is exciting, but we have to be aware of the risks. What are the side effects of Zenbexus? Zenbexus is the first CELMoD to be FDA approved and it, like all drugs, come with some side effects. And when we think of those side effects, we typically put them into two buckets. The first bucket is what happens to the blood, and secondly, what does the patient feel?
When it comes to the blood, the most common thing we saw with Zenbexus is that it lowers the white blood cell count. This is actually not surprising because the way Zenbexus works, we expect people's white blood cell counts to come down. For those of you who remember, Zenbexus works on cereblon, and when we squeeze cereblon, we trigger a pathway that helps destroy the multiple myeloma cell. That same pathway is actually involved in white blood cell production. So when we target the multiple myeloma to kill it, sometimes it takes out some of the white cells as well. But thankfully, this typically only happens for the first two cycles and we have ways to overcome it, like giving patients drugs to boost their white blood cells. So although we saw white blood cells go down, we pretty much can control this side effect.
In terms of the side effects that patients feel, there were four things that we saw in the clinical trial with Zenbexus. Number one, upper respiratory tract infections. Number two, fatigue. Number three, rash. And number four, diarrhea. These side effects, although not very common, can happen with patients, and more often than not, we can manage them by managing an infection, by being able to dose hold the drug for periods of time, or that very often these side effects just lessened over time. It is always really important to talk to your doctor about any side effects that you're feeling when you are being treated with any drug, but especially now with Zenbexus. For those who recognize those side effects of upper respiratory tract infection, fatigue, diarrhea, and rash, we did used to see those and still see those with the IMiD drugs like Revlimid and Pomalyst, but thankfully with Zenbexus, we tend to see them in less severe ways.
So in summary, Zenbexus, like all drugs, come with some side effects, typically a lowering of the white blood cell count and things that patients can feel, including upper respiratory tract infection, fatigue, diarrhea, and rash. But more often than not, we can manage these side effects. Very few patients have to come off the drug because of those side effects, and that way we can continue treatment for our patients with relapsed multiple myeloma.
What questions should patients ask their doctor about CELMoDs? If you're wondering if this is the right therapy for you, what should you be asking your doctor today? CELMoDs are a new class of drug that we have in multiple myeloma and Zenbexus is the first in that class just recently approved in combination with Darzalex and dexamethasone for relapsed multiple myeloma. Sometimes with all these new approvals, it's hard to know what is the best treatment for me. That really depends on an important conversation you have with your healthcare team. We have demonstrated that when you have a strong relationship with your healthcare team and the ability to ask questions, that is going to impact how you do with the disease.
So asking questions of your doctor is a very important thing and we empower you to ask the right questions. Well, what questions should you ask? I would start with, do you know what CELMoDs are? With all of these new agents we have in multiple myeloma, it's hard for us as healthcare practitioners to keep up, and we want to make sure we know what is the latest and greatest, especially in multiple myeloma. You could ask your doctor, "Am I eligible for this Zenbexus treatment?"
Thankfully, Zenbexus has what we call an indication or can be used in literally all patients with relapsed multiple myeloma because it was approved for anyone who has relapsed multiple myeloma as long as they had already had one prior line of treatment. So discussing whether or not you are truly eligible for this becomes a very important question.
The next question I would ask is this the right therapy for me now? Very often when you're being treated and your disease is in a good remission, we don't want to change treatments, but when unfortunately the disease is waking up again, we tend to introduce new treatments and perhaps Zenbexus is the right treatment for you.
And then lastly, I would ask more about the potential side effects as we always should with any new therapy. Is this going to affect my quality of life? Does this match with the kinds of things I like to do and want to do in my life? So there are a lot of questions that you can ask your doctor about CELMoDs, and in summary they are, do you know what CELMoDs are? Am I eligible for CELMoDs? Is this the right therapy for me right now? And what side effects should I expect, and how might it impact my quality of life? With these questions in hand, you can have a great conversation with your healthcare team and decide if this is the right therapy for you right now or in the future.
So there you have it. You're now an expert in CELMoDs. We've covered these five areas together. What are CELMoDs? What is Zenbexus approved for? How did Zenbexus do in the clinical trials? What are the side effects we should know about Zenbexus? And what questions you should ask your healthcare team? It is wonderful to have a new option in our treatment of relapsed refractory multiple myeloma. If you do have relapse, please talk to your healthcare team so they can guide you through the process of deciding what is best for you. And remember, the IMF is here for you. Please come visit us at our website at myeloma.org. Call the info line and speak to someone about your multiple myeloma, join a myeloma support group, or join us in one of our virtual or in-person educational events.
By the way, if you want to keep learning about myeloma science, I really want to highlight an important video for you where we gave the updates of what happened at ASCO, the American Society of Clinical Oncology, and EHA, the European Hematologic Association. We talked about lots of things like high-risk myeloma, CAR T cell therapy, bispecific antibodies, and we answered a whole series of questions from patients. You can watch the replay linked here.