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What’s the Latest in Emerging Myeloma Research?

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What’s the Latest in Emerging Myeloma Research? from Patient Empowerment Network on Vimeo.

Myeloma expert Dr. Benjamin Derman shares research updates from the 2022 American Society of Hematology (ASH) annual meeting, including information about newly approved CAR T-cell therapies and a bispecific antibody therapy, as well as research on the new target, GPRC5D (G protein-coupled receptor 5D).

Dr. Benjamin Derman is a hematologist and oncologist specializing in multiple myeloma at the University of Chicago Medicine Comprehensive Cancer Center. Learn more about Dr. Derman.

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Transcript:

Katherine:

Joining me is Dr. Benjamin Derman. Dr. Derman, welcome. Would you please introduce yourself?  

Dr. Derman:

Yeah. Thanks so much for having me. As you said, my name is Ben Derman. I’m an assistant professor at the University of Chicago. And I specialize in actually, plasma cell disorders, which is mainly multiple myeloma, amyloidosis, Waldenstrom’s. If a plasma cell is the problem, then I address it. So, that’s what I do. And that’s my clinical and research focus as well.  

Katherine:

Excellent. Thank you so much for taking the time to join us today. Before we get into our discussion about available myeloma treatments, let’s talk about emerging therapies. And I know there are many. 

The American Society of Hematology or ASH annual meeting took place in December. What are some of the highlights from that meeting?  

Dr. Derman:

Yeah, ASH is always a very exciting time because it’s when we get to see all the latest and greatest of what’s on the way or what’s already here to stay.  

I think the biggest focus in the myeloma field, if I could really pin it down, was more in the later stages of the disease and focusing on treatments in that setting. We already have two FDA-approved chimeric antigen receptors, or CAR T-cell therapies, in Ide-cel (Abecma), and Cilta-cel (Carvykti). Those are the brand names. And then more recently, we just had a bispecific antibody, which is another type of immune therapy that was approved. But there are actually many under investigation.  

And so, at this ASH we heard a lot. Not only about the target that’s been most popular in this setting, which is something called BCMA or B-cell maturation antigen.  

That’s what the CAR T-cell therapies that I mentioned are going after and the teclistamab (Tecvayli) bispecific antibody that I mentioned.

But there are a lot of other candidate drugs that are also targeting that same molecule. So, we heard a little bit about – more about those. We’ve been hearing about them pretty much at every conference these days.  

So, there’s a lot of competition in that space. Which is good for patients because ultimately, what we’re trying to figure out is, is one of these better than the others? Or at least, if we have multiple options, there may be different side effect profiles that we have to think about.

But now as BCMA therapies are getting used more and more, one of the questions is, well, is there any other target that we could go after? And really, the one that was hot at ASH this year was something called GPRC5D, or G-protein coupled receptor 5D. This is expressed pretty strongly in myeloma cells, and not in many other tissues. Maybe the skin, nails, tongue. So, basically, that’s what you want, is you want a target that’s not going to be expressed elsewhere.

So, there were a couple of different types of therapies that were discussed. One was a CAR T-cell therapy going after GPRC5D, and the others were – there were two bispecific antibodies actually targeting the same GPRC5D. And that’s actually already in addition to another GPRC5D-directed bispecific that’s in development.

So, basically, the idea is that if patients may experience progression on one of these BCMA targeting agents, we’re going to have another target to be going after. And I think that part is really, really exciting.

And as far as other highlights, I think the other thing is, how do we reduce the toxicity from these drugs? And exploring avenues in order to be able to decrease sort of the inflammatory effects of these drugs, which are important.   

What Treatments Are There for Myeloma Patients Who Relapse After CAR T?

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What Treatments Are There for Myeloma Patients Who Relapse After CAR T? from Patient Empowerment Network on Vimeo.

Do multiple myeloma patients who relapse after CAR T have other treatment options? Dr. Sikander Ailawadhi from the Mayo Clinic explains patients who typically receive CAR T-cell therapy and options for those who relapse after CAR-T therapy.

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Transcript:

Lisa Hatfield:

So this next question has to do with the sequencing of treatments, which, again, speaks to the fact that it’s super important to see a myeloma specialist, but the question is what treatments are available for myeloma patients who relapse after CAR T?

Dr. Sikander Ailawadhi:

Very, very important question, and unfortunately a tough situation that we are dealing with because CAR T initially has been used for later lines of therapy as it is currently FDA-approved. With time, hopefully it will start making it may sooner in the treatment also, but when a person…when a patient has had treatment with CAR T, generally, they have already had treatment with most of the standard available drugs prior to CAR T, because the way CAR T is currently approved is the patient has to have at least four prior lines of therapy, and generally, at least in the U.S. system, with the first three to four regimens or lines of therapy, we’ve already seen and exhausted most of the available drugs.

So you can imagine most CAR T, there is less drug availability that the patient has not had before or may not be resistant to, but if the CAR-T response lasted long enough, sometimes we are recycling some of the drugs after previously used, and the patient may respond to them again.

Another thing to think about in that place is from my standpoint, clinical trials are extremely important and patients must seek clinical trial options, as you mentioned, again, important to see a specialized myeloma center, but one of the drugs that was approved in 2022 bispecific antibody, teclistamab (Tecvayli), and there are some other related by specific antibodies which have actually shown some benefit despite the fact that they also target BCMA, which CAR T targets, but patients who had prior BCMA therapy still had a very good response rate to, for example, teclistamab or some other…bispecific antibodies in clinical trials, so I don’t say that everybody who’s been treated with a BCMA CAR T should go immediately to a BCMA and bispecific may not be the best option in all cases.

But sometimes recycling older drugs in certain different combinations, clinical trials or options promising options like bispecific antibodies. We do have more options today than even what we had a year ago for patients who are progressing after CAR T-cell therapy. 

Myeloma Expert Gives an Overview of Novel Therapies

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Myeloma Expert Gives an Overview of Novel Therapies from Patient Empowerment Network on Vimeo.

What novel multiple myeloma therapies are available for patients? Dr. Sikander Ailawadhi from the Mayo Clinic shares an overview of novel therapies of CAR T-cell therapy, monoclonal antibodies, bispecifics, and immunomodulators and discusses therapies currently in rapid development.

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Transcript:

Lisa Hatfield:

We are going to jump right into a discussion about some of the novel therapies that there is much buzz about right now, and it’s kind of an alphabet soup these novel therapies. I actually was trying to digest all of this information and divide it into the general categories.

And correct me if I’m wrong, but we have monoclonal antibodies, we have bispecific antibodies like the CAR-T therapies, and they target different things. We have BCMA, we have GPRC5D, FcRH5, we have things called antibody drug conjugates and cell mods. So, Dr. Ailawadhi, if you can just give us kind of a broad overview of these therapies and how they may be used to harness our immune system, and how they come into play when you’re treating your patients, how and when they come into play when treating your patients.

Dr. Sikander Ailawadhi:

Surely, so I think thanks a lot for bringing up that discussion, this is extremely important, and I think it’s most important because if a myeloma patient goes online and wants to search for information or research, these things start coming up this term start coming up. So it’s extremely important for a knowledgeable and empowered patient to learn about these, understand them, so that they are able to digest that information. And I should mention that a lot of what we’ll talk about about these particular treatments may not be applicable to newly diagnosed patients or a recently diagnosed patient, but this is important enough and exciting enough that I would want every single patient to pick up this information. Learn it hopefully, and maybe park it for now somewhere, so that hopefully down the road it becomes important and handy.

So you asked about monoclonals, bispecific, CAR-Ts, cell mols, etcetera. Let’s take a step back, let’s think about these as strategies to target myeloma. Myeloma treatment is going through a change where immunotherapy and harnessing the body’s own immune system is becoming extremely important, and when we do that, the immunotherapy is typically very targeted, so what these drugs these agents, these terms, this alphabet soup is doing is it is targeting specific markers on the myeloma cell on the plasma cell.

For example, one of the markers is CD38. There is a monoclonal antibody. There are actually two monoclonal antibodies. Daratumumab (Darzalex), rituximab (Rituxan) that are FDA-approved, but there are other ways of targeting CD38, for example, CD38 targeting CAR-T cells, CD38 targeting antibody drug conjugates, etcetera. So CD38 is one important part. A very, very, very important thing in the past one year or a year-and-a-half has been what’s called B-C-M-A, B cell maturation antigen. BCMA is another target on plasma cells. Very effective, very specific.

So there are many, many drugs that are available and becoming available to target BCMA. Right now, there are three drugs that are FDA-approved that can target BCMA. Two of them are CAR-T cells, a particular way of going after BCMA in which the body’s own T cells are collected. These are not stem cells, these are T cells, T lymphocytes, these T cells are collected, they are actually genetically modified to go and fight against the BCMA, and then those modified T cells are multiplied in the lab and given to the person as a drug, they go and seek the plasma cells because of BCMA kill them harnessing the body’s immune system.

So there are two CAR-T cells against BCMA, one called ide-cel (Abecma) and one called cilta-cel (Avekti). There has recently been available a bispecific antibody against BCMA, we call it bispecific because it connects to BCMA from one end and from a second it connects to the body’s T cells again, bring the T cells close to the plasma cells to kill them. Then bispecific antibodies called teclistamab (Tecvayli). And until recently there was another drug available against BCMA which was what’s called an antibody drug conjugate. This drug is called belantamab (Blenrep) for the timing, belantamab has been removed or withdrawn from the market in the U.S., but there are ongoing clinical trials and down the road, it may come back again.

Now, antibody drug conjugate is another way of targeting something in which there is a seeker for the BCMA in this case, and it has a payload of some kind of a toxin, so that when the drug connects to the plasma cell through the BCMA in this case, that toxin is released, it can kill the cell, so either we harness the body’s immune cells, the T cells by CAR-T or bispecific, or we kill the cell by releasing a toxic payload from a drug, antibody drug conjugate, these are all different methods of targeting the myeloma cell. So I talked to you about monoclonal bispecific CAR-T and ADC as different strategies, CD38 and BCMA, some of these strategies are available, but there are other targets which are very exciting and new drugs are being developed against them, two of the very interesting targets there one is called GPRC5D, and the other is FcRH5.

These GPR5CD or FcRH5 are two different targets on myeloma cells. No drugs are currently FDA-approved, but they are being developed very rapidly, and we have a couple of extremely promising agents which will be coming down the pipe. And you also mentioned something called cell mods. Cell mods are some newer drugs in the family of what’s called IMiDs or immunomodulators, in which our patients may be aware of thalidomide (Thalomid), lenalidomide (Revlimid), and pomalidomide (Pomalyst). The cell mods are kind of the same family, and there are a couple of them that are also being developed.

So why is this important for everybody, whether they are newly diagnosed or relapsed or long-term survivor with myeloma, because this tells you that not only are we getting newer drugs in the same classes, we are also getting brand new classes of drugs, and you can imagine that means that those brand new strategies are ways to target the plasma cell, we know cancer cells are smart and they develop invasive mechanisms to become resistant to drugs, but every time something gets resistant if we have a brand new mechanism to go against the disease, but that’s exciting because that’s why we are seeing deeper responses, even in very heavily pre-treated patients, because we are using newer specific, relatively safe, convenient strategies to going after the plasma cell.

I know that was a lot of information, but I hope this helps our listeners learn a little bit about what you rightly said is an alphabet soup, but I would like us to think about it as an exciting time for being a myeloma doctor, and certainly a very hopeful situation for all our patients.