Published on January 7, 2021
What Is the Latest News on CAR T-Cell Therapy for Myeloma Patients?
How can CAR T-cell therapy be used to treat multiple myeloma, and what is the latest in CAR T-cell research? Is it getting closer to being an approved treatment option? What are we learning from clinical trials? And finally, what should patients know?
In this segment of Answers Now, host and patient advocate Cindy Chmielewski talks to myeloma expert Dr. Sergio Giralt, MD, of Memorial Sloan Kettering Cancer Center about the latest news in CAR T-cell therapy for multiple myeloma. Keep watching to learn more.
Transcript | Latest News on CAR T-Cell Therapy for Multiple Myeloma
Cindy Chmielewski: My name is Cindy Chmielewski and I'm a retired fifth-grade teacher who has been living with multiple myeloma since 2008. I am joining you from rainy Lawrenceville, New Jersey. I am here as your host today for our myeloma Answers Now program.
Today, we're going to be learning the latest about CAR T-cell therapy. Joining us is Dr. Sergio Giralt, who is the Deputy Division Head in the Division of Hematological Malignancies at Memorial Sloan Kettering Cancer Center, and he's also a Professor of Medicine at Weill Cornell Medical College. He is joining us from New York. Will you start off just by explaining a little bit about what CAR T-cell therapy is?
What Is CAR T-Cell Therapy?
Dr. Giralt: Well, thank you very much, Cindy. If I can ask, I brought a couple of slides to just illustrate some very important points about CAR T therapy. I think the myeloma community really has to be, I would say grateful for all the research that has happened in the myeloma field. We now have a new drug that just approved by the FDA, belantamab mafodotin-blmf (Blenrep), which is an antibody-drug conjugate that targets BCMA. We expect that by mid-next year we will have a CAR T therapy, which is an adopted-cell therapy.
There are two types of adopted-cell therapies that are being explored in multiple myeloma. One is the CAR T therapy. What is CAR T? It is a chimeric antigen receptor modified T-cells. How does it work? As you can see on the left side of the slide, we take cells from the patient, they get genetically modified. What does genetic modification mean? Our T-cells have receptors. Those receptors are there to identify proteins on the surface of a cancer cell or on a surface of the cell that has been infected by a virus. When the T-cell recognizes that there is a protein that shouldn't be there, then it has a signal that tells them, destroy this cell and call up other cells to make sure you get rid. Remember, this was created so we could defend our body against virally infected cells.
What have the researchers done in this? Part of this research was pioneered here at Memorial Sloan Kettering. The one for myeloma was pioneered by Dr. Michel Sadelain, Renier Brentjens, and Eric Smith. It targets, again, BCMA. What they do is they insert a gene that has an antibody against BCMA, so it's an antibody that recognizes BCMA. Then what happens is it takes the T-cell straight to the myeloma cell, which is one of the few cells in the body that has a lot of BCMA antigen on the surface. What it does is, it kills those cells. It's really targeted therapy and it's a very powerful targeted therapy. The results of the first trials have been dramatic, 60 to 70% response rates in patients who have failed four to five lines of treatments.
There's another adoptive-cell therapy that's being developed, which is called the TCR engineered T-cells. Now, these cells are cells in which the T-cell receptor is engineered to be able to recognize specific proteins on another protein that's expressed by all cells, which are the HLA proteins. I'm not going to talk about that because we do not yet have a product in myeloma, although they are being explored in clinical trials.
Now CAR T therapy is very complex. It can only be delivered in specialized programs because you have to have a very careful intake procedure, not everybody is eligible. You have to collect cells. Collecting cells is like donating blood. For those of you who had a stem-cell transplant, it's a similar process except you don't give yourself GCSF. In the meantime, the product takes about four to five weeks, three to four weeks to make. The cells are sent to a manufacturing facility. One of them is in New Jersey. Others are in California or they're all over the place. The company does the genetic modification. It ships it back to the place where the patient is, which again usually has to be an accredited center for CAR T therapy.
The cells are infused. During the first 30 days... Before the cells are infused, excuse me, people get what's called lymphodepleting chemotherapy. It's important that people get the lymphodepleting chemotherapy so that the lymphocyte count within the patient goes down to very low levels and the substances that make lymphocyte grow to get released. These substances also make the CAR T's expand and grow and persist, so you actually get a significant growth of CAR T-cells after they infuse due to the effects of the lymphodepleting chemotherapy.
But that CAR T-cell expansion and that lymphodepletion can cause serious side effects that will go on later. But usually, after 30 days, patients return to the community. You can see one of the other things that happens is patients need to stay within one or two hours of the CAR T center. For patients who are coming out of state, they have to find lodging. Most of the accredited CAR T centers have found what we call residential solutions or help patients to find residential solutions.
If I could have the next slide, please. The current generation of CAR T therapies is associated with side effects. There's something called cytokine-release syndrome, which usually is patients getting high fevers for a couple of days. On rare occasions, it can be severe and patients need to go to intensive-care unit. But generally speaking with early recognition and rapid treatment, these complications are reversible and the chances of serious life-threatening complications are relatively low when this is done in a specialized center that has a lot of experience doing this. The treatments for CRS and the neurologic toxicities are steroids and tocilizumab (Actemra). The bottom line in, we now have a cell therapy that's not a transplant, that can be very effective in treating patients with multiple myeloma whose disease has come back after multiple lines of treatment.
Cindy Chmielewski: That was a great overview and I'm going to have to put... What was that called TCR therapy? That's going to have to be on my radar next.
Dr. Giralt: Yeah.
Cindy Chmielewski: Earlier this week, we talked to Dr. Krina Patel, who's also a myeloma specialist at MD Anderson in Texas. We asked her what her thoughts about CAR T-cell therapy are and this is what she had to say.
Dr. Patel: I'm biased because I do CAR T research. But I think the fact that we have seen such a great response, meaning that 80 to 90% of patients actually get a response to CAR T in our myeloma patients with our current version. Those patients have had eight lines of therapy, so they've had seven to eight lines, meaning they've had a lot of therapy already. Most of the time, most of the new drugs that come out, usually in that time point show a 30% response rate. To see something that causes an 80 to 90% response rate, is pretty phenomenal and it tells us something.
Then the bigger part of it is that my patients who get CAR T and get responses, different patients do differently, but the ones who get what's called MRD negative where their myeloma is completely gone and we can't find it based on the technology we have, they get 22 months of sort of a hibernation period. They've only had one dose of CAR T, no other therapy. There's been no maintenance. They get almost two years where they're not on any therapy. I think we have a long way to go, but that's huge.
Some of the trials right now, we're doing it earlier and earlier because we think that your T-cells are better when they haven't seen so much chemo and likely it's going to work better if we do it earlier. Hopefully, we'll have results from that in the near future. But based on that and based on the little bit I've seen with my patients on trials, I'm going to try to get all my patients to CAR T at some point, as long as they're eligible for it.
Cindy Chmielewski: Okay. Dr. Giralt, what do you think about what Dr. Patel has to say? Is there anything you would like to add to that or do you agree?
Dr. Giralt: I think Dr. Patel is correct. Our experience has been that every time we find a drug that works in the patients who have multiply relapsed, when we put it in the frontline setting, it works even better. I think that's a testament that the average survival for a myeloma patient 40 years ago was only three years. Now, the average survival of myeloma patients is more than 10 years.
People talk about, oh do we cure myeloma? There are a substantial fraction of patients, never large enough, who have been without their disease for 10 years. With our current treatments, which do not include CAR T-cells, we think that with including CAR T's and some of these newer agents that will become available, we really think that the time will be that we will be able to cure, hopefully, a substantial proportion of myeloma patients. If we can't cure them, we'll be able to control their disease for a substantial period of time.
Cindy Chmielewski: That sounds good to me now. I know that we were really, really hopeful about CAR T-cell therapy. We saw that in some of the other cancers, it was almost a curative treatment. Unfortunately, the results in myeloma had been more that it's kept your disease under control maybe for 12, 18 months, but then your disease seems to relapse. Could you talk about any research? Well, first of all, do we know what's causing the relapse? Are there different things that are causing the relapse? Could you talk about any research that is being done to help extend that or get rid of that?
What Can Cause Relapse in Myeloma Patients After Receiving CAR T-Cell Therapy?
Dr. Giralt: We do know that the quality of the T-cells that are used to make the product is important for the efficacy of the product. We know that T-cells that have not been heavily exposed to chemotherapy are T-cells that you can make a better CAR T product, that they expand more. That means that when they go into the body, they grow to a larger number and they persist a longer period of time. That means they don't get exhausted. We do know that the myeloma also lives in an environment that helps surround itself with substances that may protect it from immune effects. Although initially, the CAR T can get into the myeloma micro-environment, sometimes the myeloma starts creating substances that inhibit the activity of the CAR T.
Finally, although in myeloma we haven't seen it as much as we've seen it in lymphoma and acute lymphoblastic leukemia. Remember the CAR T just targets one specific protein, the BCMA. If the myeloma loses the expression of BCMA or significantly down-regulates it, the CAR T cannot identify it and attack it. What are we doing to attack? There's a lot of research in this area. Dr. Patel already mentioned we're trying to treat patients earlier in the course of the disease to hopefully make better CAR T-cells. Two, we're trying to make substances that will make over-expression of BCMA, that enhances the expression of BCMA. Three, we are studying strategies that can inhibit that immune-suppressant micro-environment in which the myeloma cells protect themselves.
Cindy Chmielewski: Now a burning question on everyone's mind is, is CAR T-cell therapy going to replace stem cell transplant in the future? What do you think about that?
Dr. Giralt: The answer is we don't know. There are studies being done at this time to try to answer that question and to try to see how best to sequence CAR T therapy with high-dose therapy. I think we need to remember that stem cell transplant, autologous stem cell transplant is basically a vehicle that we use to be able to deliver high dose melphalan (Evomela). High dose melphalan was the first strategy we ever used for patients with multiple-relapsed-refractory multiple myeloma. It was the first strategy that would get a significant proportion of patients in complete remission.
Now it's interesting that CAR T actually has more complete remission, a higher complete remission rate than high dose melphalan had in its time when it was done to patients with multiply-relapsed disease, but they work in two different mechanisms. One damages DNA. The other works through the immune system. They may actually complement each other. I recognize I'm a transplant-er. I'm a believer in high-dose melphalan. I believe in dose intensity, but again, if we can find ways that we can... Remember, our goal is always to give patients the longest life with the best quality of life, with a minimum amount of treatment. In myeloma, to be able to get a long life, a good quality life, it is essential to get a good deep response. The earlier you get it, the less likely we have of having a patient develop resistant disease.
Cindy Chmielewski: Sounds good. Now, can you talk about who qualifies for a CAR T-cell transplant or therapy? It's not a transplant per se.
Who Qualifies for CAR T-Cell Therapy?
Dr. Giralt: At this moment in time, you obviously have to have a relatively good performance status. You have to be independent in your activities of daily living. You have to have good organ function, good kidney function, good heart function, good pulmonary function tests. The studies that are being done have very strict eligibility criteria. We expect when the commercial drug becomes available, when ide-cel (idecabtagene vicleucel) becomes commercially available, some of those strict eligibility criteria will be loosened. But it's important to recognize this is a treatment that has significant toxicities and how you come in will determine how you come out. One thing we've learned from this CAR T and from other CAR T is if patients have an active infection, even if it's just a common cold, we have to delay CAR T until that infection gets resolved.
Cindy Chmielewski: Okay, great. Now you talked a little bit about the toxicities and you did talk a little bit in your introduction slides. But can you go over what some of those toxicities of the CAR T-cell therapy are and how they're currently being managed?
Dr. Giralt: I'm just going to put, let's say Mrs. Smith has had four lines of treatment, is now getting ready for a CAR T. What happens? Let's say, come November first we put Mrs. Smith on the apheresis machine so she can have her lymphocytes collected. Her lymphocytes are collected. The apheresis machine is like donating blood. The blood is taken out. It's spun. The white cells, where the lymphocytes are, are taken out. They're put in a bag and they're shipped to the manufacturing facility. Four weeks later, those cells that have now been genetically modified will be shipped back to Memorial, in the case of Mrs. Smith. Mrs. Smith is not a true patient - I'm not disclosing anything. December the first Mrs. Smith comes in and she gets what's called lymphodepleting chemotherapy. She gets three days of a drug called fludarabine (Fludara) and three days of a drug called cyclophosphamide (Cytoxan).
We can do this if Mrs. Smith is in good condition and she's eating, drinking, walking, talking, and she's comfortable, we can do the chemotherapy as an outpatient. We can actually do the CAR T infusion as an outpatient, but after the CAR T infusion we admit Mrs. Smith to the hospital to be observed for the next 14 days. Why do we do this? Because we expect that on the fourth day after the CAR T, Mrs. Smith is probably going to have cytokine-release syndrome manifested either by a fever, which we can treat with Tylenol. Or if it gets very high, then we will start her on the anti-CRS medications, which is a combination of steroids and tocilizumab, or tocilizumab alone. On rare occasions by day five or six, Mrs. Smith may start being confused.
Actually, while patients, after patients are getting CAR T for the next 14 days, they have what's called a regular neurologic, and we do what's called the [inaudible] score. Patients are asked what day it is, to recognize five objects, to write a sentence on a piece of paper. They're asked if they can remember five objects that they were shown, so a fairly structured exam of neurologic function. If there's any deterioration on the baseline score, that is a sign that there may be neurologic toxicity that is one of the complications of CAR T. Then Mrs. Smith will start on steroid therapy, which rapidly reverses this. Now, remember Mrs. Smith got fludarabine and cyclophosphamide, so her white counts are expected to go down. If she gets a fever, she has to start on antibiotics just because her white count is very low, similar to those patients who underwent the stem cell transplant. But usually, by 14 days after the chemotherapy here white counts should, her neutrophil count should start recovering back to normal.
By that time, she has recovered from the effects of the CAR T-cells and we're getting ready to send her out. Though we send her out, she still has to say close by for the next two weeks, for the whole month of December, to be monitored routinely at our center here to make sure that there are no late toxicities. After day 30, she is sent back home to come back around day 100, three months after the infusion, so we can do all the disease assessments, check her bone marrow, check her PET, and check the urine and the blood for the myeloma markers. We are hoping and expecting that, as Dr. Patel says, she'll be in complete remission without the need for any further therapy for a long period of time.
Cindy Chmielewski: Yes. Yeah. Now we have an audience question. Actually, it's from my friend Chrissy. She couldn't be here today.
Chrissy: Hi, my name is Chrissy. My question is if I've already had a CAR T-cell transplant through the bb2121 trial, is there another CAR T that you would recommend for me?
Dr. Giralt: Chrissy asks a very important question. What happens if you've had a CAR T and your disease came back? The answer is, we're not sure. But patients who've had long remissions, there have been anecdotes of responding again to another BCMA directed CAR T. You could say the reason why she relapsed was that the CAR T's disappeared. There are other targets that are being explored. None of these are yet commercially available. There is a GP5, which is another protein that's expressed primarily in the myeloma cells. That one would be one that she would qualify for. Then there are protocols with these T-cell receptor engineered T-cells, but these are specific for certain patients who have certain tissue types. You have to have a certain tissue type for the T-cell receptor, for the engineered T-cell receptor product to work.
Cindy Chmielewski: Yeah, we have another audience question. This is from my friend Jack. He wants to know, what is lymphodepleting chemotherapy? Is that kind of like what you get before a stem cell transplant, or is that something different?
What is Lymphodepleting Chemotherapy?
Dr. Giralt: That's an excellent question, Jack. For the lymphodepleting chemotherapy… The stem cell transplant chemotherapy you have is called melphalan and it's myeloablative. It wipes out the whole marrow, all the cells sources, both the lymphocytes and the myeloid cells that produce the neutrophils. The lymphodepleting primarily attacks, lymphocytes and lymphocyte precursors. It still will make your white count go down, but the neutrophil recovery is much quicker without stem-cells than with high-dose melphalan. In the context of fludarabine and cyclophosphamide, which is the lymphodepleting chemotherapy that's commonly given for the myeloma CAR T-cells, your neutrophil counts will recover within 10 days, which would not happen with the high dose melphalan, unless you got a stem-cell transplant, obviously.
Cindy Chmielewski: Now, this is a question from me. They harvest your stem cells when you're newly diagnosed and they put them away just in case you're having a stem cell transplant as part of your therapy. Is there any talk about doing the same thing with your T-cells since now CAR T-cell therapies would be maybe coming up closer to the frontline? Another thing, could you explain, even maybe prior to that, I've heard of the term T-cell exhaustion. What does T-cell exhaustion mean?
What Does T-Cell Exhaustion Mean?
Dr. Giralt: Well, it's exactly that. Imagine, if you're a T-cell and you're working full-time just trying to kill all the myeloma cells in the body, eventually you get tired and eventually you get exhausted and eventually you die. There are ways that actually the myeloma actually stimulates T-cell exhaustion by producing certain substances called checkpoint - that's why you've heard about checkpoint inhibitors. These literally are substances that turn off the immune reaction and the tumor can sometimes produce it and surrounded itself with these substances to weaken the immune reaction against the myeloma.
The other question you asked about, should we collect T-cells? That's an excellent question because many patients have collected stem cells for two transplants. But the one thing we do know is, is that for many patients with myeloma who've had multiple treatments, their white-counts, marrow function is not very good, so having a stem cell source in the freezer for many of them helps them reboot their marrow system and reboot their white counts and their platelets.
Well, with T-cells, we really, although there have been some patients who have not been able to produce CAR T-cells, and many of us believe that the quality of the T-cells does get worse, there really is no, first there's no... The resources required to collect a lot of people for cells that we may never use is huge. At this moment in time, we're not doing it. There is the perception that eventually there may be an off-the-shelf product. If there's the off-the-shelf product, there really is no reason to collect the T-cells.
Cindy Chmielewski: I won't be going in to have my stem-cells and T-cells collected at the same time.
Dr. Giralt: Not at this time.
Cindy Chmielewski: Put them in one bag and another bag and put them side by side in the freezer. No?
Dr. Giralt: Not at this time.
Cindy Chmielewski: Okay. Wow, I think I've learned a lot today. My mind is starting to hurt me. Before we sign off, are there any final thoughts that you would like to say?
Dr. Giralt: I think, one, I'd tell all of the patients and caregivers of Patient Power, thank you for your trust. Thank you for all the support you've given the myeloma community, the myeloma researchers. One, stay healthy, keep a positive mind. There are more and more trials for myeloma patients. There are more new medications coming down the pike, and be open-minded about participating in clinical trials. We have what we have today because many patients like you have participated in clinical trials. It is the most efficient way of improving the care of myeloma patients. Spread the word. Spread the word about Patient Power. Spread the word about other advocacy groups that really they become your voice and your voice has power. Thank you very much for listening to me today, and it was a pleasure and a privilege to be here.
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