CAR-T-cell Therapy for Multiple Myeloma: Who's A Good Candidate?

Transcript of Presentation.

(00:00): [Michelle Kosick]: Hello, and welcome to the workshop CAR T-cell Therapy for Multiple Myeloma: Who's a Good Candidate? My name is Michelle Kosick, and I will be your moderator for this work group.

(00:12): Speaker Introduction. It's my pleasure to introduce today's speaker, Dr. Tara Gregory. Dr. Gregory is a Physician at the Colorado Blood Cancer Institute, where she is a part of the Plasma Cell Disease Group. Her research focuses on treatments for patients with multiple myeloma, including chimeric antigen receptor (CAR) T-cell therapy. She also participates in clinical trials to improve outcomes after bone marrow and stem cell transplants. Please join me in welcoming Dr. Gregory.

(00:43): [Dr. Tara Gregory]: Thank you, Michelle, for that introduction and thank you so much for joining us today. As Michelle said, my name is Tara Gregory, and I am one of the Physicians at the Colorado Blood Cancer Institute. We specialize in treating patients in the Rocky Mountain region with blood cancers and also specialize in what we call ‘cellular therapeutics’, which includes bone marrow transplants or stem cell transplants, and other ways of modifying people's immune systems.

(01:19): By way of disclosure, I have participated in advisory boards for both Johnson & Johnson and Legend.

(01:29): Overview of Talk. Today we’ll talk about why we would use chimeric antigen receptor (CAR) T-cell therapy to treat multiple myeloma. What exactly is CAR-T therapy? What are the steps to undergo CAR-T-cell therapy? What are the potential outcomes after CAR-T-cell therapy, and is it potentially a cure for myeloma? Conversely, what are some of the potential short- and long-term risks that can be associated with CAR-T-cell therapy? We'll talk about the impacts on quality of life and ultimately discuss who is a good candidate.

(02:21): I want to first talk about multiple myeloma. I think of the immune system as a big military operation – like homeland security – trying to keep foreign invaders out. When foreign invaders like infections infiltrate us, the immune system’s job is to fight that off.

(02:51): The immune system is constantly surveilling our bodies for any abnormal or cancerous cells, and its job is to clear those guys out.  

(03:11): Multiple myeloma starts from a type of white blood cell called a plasma cell. The job of the plasma cell in the immune system is to make immune proteins, or antibodies, that can seek out and attack specific infections. Typically, you want a lot of different kinds of plasma cells, because each will make a specific antibody that's going to fight off a unique infection.

(03:55): In multiple myeloma, instead of a diverse array of antibodies, your plasma  cells make a single identical antibody over and over, so it doesn't fight infection well, we end up with too much abnormal protein, and the buildup of that protein can hurt us.  

(04:58): This graph shows a timeline of disease presentations and treatments for multiple myeloma.  In the first box, labeled ‘asymptomatic,’ you see the terms ‘monoclonal gammopathy of undetermined significance’ (MGUS) and ‘smoldering myeloma’. This is describing the ‘pre-myeloma’ phase. Everyone who has multiple myeloma had pre-myeloma first and oftentimes just didn't know it because they weren’t experiencing any symptoms – or were ‘asymptomatic’. Sometimes doctors can find it within their routine tests and decide to order further specialized testing from there, but otherwise it can remain undetected.

(05:30): In multiple myeloma treatment, we try to identify patients with pre-myeloma, to decide whether the pre-myeloma is mild or aggressive and whether we should treat you.  This is an area that's really changing. For patients who have MGUS or smoldering myeloma, we want to be able to predict the point when we think their myeloma is going to start causing problems.

(06:06): Prior to 2014, if you had myeloma but were asymptomatic, we would just monitor you and wait until you developed a problem before we treated you. We later decided that's probably not a great idea – people shouldn't be breaking hips, having kidney problems, or be exhausted because their red blood cells are too low – we should go ahead and treat them before they develop problems.

(06:26): Now, we have criteria that helps indicate when your myeloma requires treatment, and can be useful in predicting potential issues for you as well.  

(06:37): This graph represents a typical myeloma treatment timeline. We give the initial treatment, and get rid of the myeloma, which we call ‘remission.’  Then, after some time the myeloma starts to come back and does what we call a ‘relapse.’ Since we are monitoring you, it’s our goal that we see this relapse within your blood tests before it starts causing any problems. Sometimes the myeloma numbers aren't bad, but we are seeing changes in organ function, or something, and decide to treat again. This cycle of treatment, remission, and relapse can continue, but we start to see the responses to treatment are lessened, and the amount of time between each remission and relapse gets shorter. Ultimately, we see myeloma start to get out of control.  

(07:41): The treatment of myeloma has evolved throughout the years. In the 1940s, we started treating with single chemotherapy agents, and in the 1960s, we added on and administered combinations of chemotherapy. In the 1980s, we came up with a stem cell transplant which was a much stronger treatment, with a very strong chemotherapy regimen administered prior.

(08:07): This chemo treatment is very effective in killing myeloma cells, but it also kills and wipes out your bone marrow.  Your bone marrow makes those special blood cells that fight off infections (white blood cells), or stop bleeding (platelets), and that carry oxygen around (red blood cells). Therefore, after chemotherapy is finished, we need to help stimulate your bone marrow to regrow. We do this with a stem cell transplant. We collect your own stem cells, prior to your chemotherapy treatment, and then reinfuse your stem cells back after treatment to help boost your bone marrow as it repairs and regrows.

(08:37): In the 1990s we started treating patients with progressive myeloma disease with stem cell transplants, and found that the transplants were often very effective.  So we started treating more myeloma patients with transplants sooner in their treatment plan, and it was during this time that we decided to integrate transplants within myeloma treatment.

(09:19): In the 2000s, we started coming up with specialty drugs that worked differently than intensive chemotherapy. New drugs called 'immunomodulatory agents' (IMiDs) were produced, and proved to be very effective.  These are drugs like lenalidomide (Revlimid) and pomalidomide (Pomalyst), and primarily help enable the immune system to specifically identify cancer and foreign cells to destroy them.

(09:42): We also created drugs called 'proteasome inhibitors' (PI) that block the myeloma cells from being able to rid itself from the protein it is making. Once it gets blocked, the cell fills up like a water balloon and eventually is destroyed. Some common proteasome inhibitors include bortezomib (Velcade) and carfilzomib (Kyprolis), and we have seen a lot of success with these.

(10:08):  By the 2010s, we started to use other immune proteins that could identify the foreign cancer cell and lock onto it. Examples of these immunotherapy drugs include isatuximab (Sarclisa) and daratumumab (Darzalex), which are anti-CD38 antibody drugs.

(10:32): These monoclonal antibody drugs work in many ways, but they can grab onto the myeloma cell and signal to the immune system that they need to be destroyed.  

(10:59): Myeloma treatment options just exploded in the 2020s, and within the last five years, we have seen exciting advancements. Since those immunomodulatory agents and anti-CD38 antibody drugs were so effective in helping the immune system recognize and fight off the cancer cells, we tried linking a different immune cell called a T-lymphocyte -- or T-cell -- into this situation.

(11:37): We've come up with two different ways to do that. One is with bi-specific antibodies, and the other is CAR-T-cell therapies. These treatments have only been FDA approved for the last three years, and we're already looking at more ways to expand and utilize these treatments.

(11:57): Before 2010, if your disease came back, I didn’t have many other treatment options to turn to. Now when your disease comes back, I actually have options to choose from for how your treatment should proceed. We're constantly researching new treatment options with the goal of giving patients the best quality of life, and the most amount of time possible.  

(12:30): This slide shows an important study done in the United States, called the MAMMOTH Study. This study looked at response rates to drugs if the myeloma became refractory after being treated with those anti-CD38 monoclonal antibodies. We classify myeloma as ‘refractory’ if the disease gets worse either while taking a drug or within two months of stopping a drug.  

(12:50): Within myeloma treatment, we have three important drug classes: the immunomodulatory agents (IMiDs), the proteasome inhibitors (PIs), and the monoclonal antibodies (MoABs). Within those classes we have two different kinds of PIs and two different kinds of IMiDs.

(13:08): If all five of those drugs aren't working, or even if three or four of them aren’t effectively treating the myeloma, then the average patient’s life expectancy significantly decreases. It's important that we have other options for people, because once these drugs stop working, or the disease is refractory, then we need to turn to a different treatment option.

(13:38): Another important factor that is considered when choosing a treatment option, is whether the myeloma is aggressive and classified as high-risk. We can look at the behavior of the myeloma and see if the response rates and remission times are as we expect them to be, or if they are ‘functionally high-risk’ due to how aggressive the myeloma is acting. For example, those who do not respond well to treatment in the first place, or transplants lasting less than two years before relapse are considered high-risk. A more aggressive myeloma requires a more aggressive treatment approach.  

(14:24): This next class of therapy is called immune effector cell therapy (IECT) and there are two different types of IECTs. These include bispecific antibodies and CAR T-cell therapy. Let me explain these therapies with female superhero analogies.  

(15:20): Imagine your T-cell is Wonder Woman. We give her a lasso to grab the bad guy (cancer cell) so she can drag him in and pound on him. That is what bispecific antibodies do – they’re like lassos where one end is latched to Wonder Woman, the other end grabs and drags the cancer cell together, and Wonder Woman is then able to pound that cancer cell. But, we need to keep giving Wonder Woman new lassos all the time.

(15:39): CAR-T-cell therapy is more like Captain Marvel. She’s stronger, doesn’t need a rope to grab the bad guys, and can go in and bind to them directly. That's the difference between a bispecific antibody and CAR T-cell therapy (CAR-T). Bispecific antibodies are drugs that you must take all the time to keep binding to the cancer cells, and CAR-T is what we call a ‘one-and-done’ treatment.

(16:10): CAR stands for ‘chimeric antigen receptors’.  A chimera is something that has two different types of DNA. The antigen is a protein that lives on the surface of the myeloma cell.

(16:25): On this slide, the purple cell represents your myeloma cell and the little half-moon sticking out of it titled ‘BCMA’ is the antigen protein. The yellow thing coming down from the green cell is our superhero receptor T-cell. The goal is to get the receptor and the antigen to snap together like puzzle pieces, so that the T-cell can then fight and destroy it.

(16:55): In CAR-T therapy, instead of collecting our patients’ stem cells, we collect their T-cells, and then modify the DNA of those T-cells so that it can grow a new receptor that specifically binds onto the cancer cell. These protein receptors need to be unique to just cancer cells – to ensure they bind only to cancer cells –  and also be a protein that is made by the majority of people with that cancer.  One such receptor – which has FDA approval in multiple myeloma treatment – is the B-cell maturation antigen (BCMA) that we can see on the slide.

(18:28): Let’s discuss the process of making CAR T-cells and the patient’s journey. When a patient needs CAR-T-cell therapy, we utilize the same machine that collected your stem cells, called an apheresis machine. A positive thing about T-cells is that they live in your blood already and do not need to be moved from your bone marrow to your blood. This differs from stem cells, where we have to give a series of shots to help move your stem cells from your bone marrow into your blood prior to collection. There are no shots during T-cell collection, and once you have been connected to the apheresis machine for approximately six hours, we then ship them off to a company that makes them into CAR T-cells.

(19:08): The company finds activated T-cells within what was collected and grows more of them. They then put new DNA into your T-cell, using a particle that was re-engineered utilizing knowledge acquired from studying the HIV virus. The particle carries new DNA that is going to make this T-cell grow new little prongs – antigens – that hopefully fit your myeloma specifically. Once the engineered T-cells are developed, they grow more of them, freeze them, and ship them back to us.

(20:04): Meanwhile, once the patient has completed their apheresis collection, while they wait for the T-cells to be manufactured, they continue receiving treatment to make sure the myeloma doesn’t progress. by continuing treatment. This is crucial, because if there is a lot of myeloma when the CAR T-cells are infused, it can make the CAR T-cells too reactive and cause more harm than good. I've made patients get treatment for four months before I let them have their CAR-T infusion, because I really wanted the myeloma under control.

(21:02): Once the CAR T-cells are manufactured, and the myeloma is under control, the patient receives a specific chemotherapy regimen to help prepare their body for those CAR T-cells. We call this process ‘lymphodepletion chemotherapy’ because we're depleting the other lymphocytes within the immune system to prevent the immune system from attacking the new CAR T-cells. Both chemotherapy drugs – fludarabine and cyclophosphamide – are given for three days in a row, typically in the outpatient setting. Then, there are two ‘rest days’ to continue to let the chemotherapy effects continue, before the CAR T-cell infusion. Your CAR T-cells come back in a bag that’s about 60 or 70 mls, and we watch you closely for side effects during and after the transfusion.  

(22:50): There are currently two FDA approved CAR T-cell products right now,  idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti). We’ll discuss two different spaces in which we utilize them, the difference between the two, and then discuss whether CAR T-cell therapy is actually curing cancer.

(23:28): Let’s first discuss Abecma. There was a clinical trial called the KarMMA-2 Trial that looked at how effective Abecma was in treating patients who had already undergone six prior lines of treatment, and were needing another option. When these patients received the Abecma CAR-T, we saw an overall response – meaning their myeloma got at least somewhat better – in 81% of patients. That is really impressive to see; after exhausting six other lines of treatment, their myeloma at least responded to Abecma. Importantly, we found that the better the response, the better the patient did and the longer their remission or response to treatment lasted.

(24:19): This trial saw complete remission rates of about 28%. The light blue curve on the top right of this graph shows the patients who had complete remission. The purple line represents people who got 90% better from where they started. The gray line represents patients who got 50% to 90% better. For those with complete remission, their remission lasted for an average of 19 months. For those who experienced a partial remission, their responses last for about four and a half months.  

(25:17): We then looked at how patients responded when they were given the CAR-T earlier in treatment than if we had followed the standard of care treatment plan, and compared this to other patients who continued with standard of care treatment.  

(25:35): We saw myeloma relapse within about four months in the group who received the standard of care. In the group that got the Abecma CAR T-cell therapy, the myeloma stayed away for about 13.3 months, which indicated that treating with CAR-T earlier than the standard of care created more favorable outcomes.  

(25:55): We did a very similar clinical trial with Carvykti called the CARTITUDE-1 Trial. Once again, the trial was treating patients who had already undergone six prior lines of treatment, and were needing another option. The overall response rate was 98%, with a complete remission rate of up to 83%. For these patients who achieved remission, their myeloma stayed under control for 35 months.

(26:24): For those who did not have any minimal residual disease, there was no average relapse rate at three years, and we continue to follow these patients as the years go on.

(26:41): Carvykti was developed in China and purchased by Johnson & Johnson, so we have longer-term data out of China showing that those survival curves flatten out at about a 30% response rate at a six-year follow-up. Looking at the data from China, it seems Car-T might have the potential to cure about 30% of patients, but we currently do not have an average life expectancy for myeloma patients because we are continuing to study these treatments, and are finding new, effective treatment options as well.

(27:30): The CARTITUDE-4 Trial followed this study, and involved patients who had one to three prior lines of therapy, and had also taken lenalidomide (Revlimid) and were still refractory. About 15% of patients within the study were triple refractory and fit these requirements, compared to 65 patients in the other study.

(28:08): One group received Carvykti, and the other group had a list of standard of care regimens that they could receive. Of the patients who got standard of care, about 80% of them relapsed within 30 months. With the group who received early line CAR-T therapy, there was no average relapse rate at 30 months. The trial is almost at three years old, and we still don't have an average relapse rate.

(28:43): I do want to add, looking at the graph it looks like the standard of care group did better in months zero to three of the trial. This is because we had some patients in the CAR-T group with very aggressive myeloma, and unfortunately a few patients passed away from their disease during that time.

(29:10): While it does not look like CAR-T completely cures myeloma, it does seem to allow patients long periods of disease control without needing any form of treatment. We are continuing to wait for long-term data from these studies, to determine the percentage of people it does cure. We do know that the better the response – such as being negative for minimal residual disease (MRD) – the longer the survival rate and time in remission.  

(29:56): We are utilizing these studies to look at further CAR T-cell therapy options and asking questions, like maybe a CAR-T should have two targets rather than one. We have a new product called anitocabtagene autoleucel (anito-cel), which we expect is going to get FDA approval in the next year and is looking to be even more effective. More people are becoming MRD negative faster with lesser side effects.

(30:24): We are also continuing to collect data regarding an individual’s quality of life post-treatment. This slide shows a quality of life study done by Dr. Cohen at UPenn, looking at CAR-T patients at a six-month follow-up. 60% of patients had decreased pain, fatigue, GI issues, and nerve pain. 71% of patients felt like their expectations were met by CAR-T-cell therapy. 21% said treatment was better than expected, and 71% of patients said CAR-T was better than their previous treatments.

(30:55): Other data looking at quality of life post- CAR-T showed improved physical functioning in activities of daily life – such as showering, toileting, and food preparation – as well as improved emotional and social well-being. Ultimately, CAR-T patients felt like they were experiencing a better quality of life.

(31:14): Patients undergoing CAR T-cell therapy will most likely experience toxicities. These toxicities might be side effects from the lymphodepleting chemotherapy given prior to your therapy. This chemo will not be as intense compared to the chemo regimen given prior to stem cell transplant, and you will not lose your hair, but nevertheless it is still chemotherapy. This might include nausea, and decreased blood counts (cytopenia). Cytopenia can put you at risk for bleeding, needing blood transfusions, and infections.    

(31:54): These toxicities can also be specific to the T-cell therapy, and can include cytokine release syndrome (CRS) and neurotoxicity. We are learning that there are all different kinds of neurotoxicities – one is ‘immune effector cell-associated neurotoxicity syndrome’ (ICANS), which generally happens within the first week of CAR-T treatment,  and there are other neurotoxicities that may occur later on. Depending on the product you get, we can anticipate when we think these toxicities will happen and how long they will last. Your doctor can discuss that timeline with you.

(32:33): Due to the risk for toxicities – in my program –If you are doing an outpatient CAR-T, we need to see you every single day for 14 days, because that's the period of time with the greatest risk for side effects. These late effects may include low blood counts, infections, a reaction called ‘hemophagocytic lymphohistiocytosis’ (HLH) – which we will discuss in a moment, – low antibody levels, late neurotoxicity, and even other kinds of cancers.

(33:04): We recommend that blood counts are monitored for three to six months after the CAR-T.  If we don't see the blood counts coming up, we might need to do a bone marrow biopsy to further assess what’s going on. Sometimes we need to boost your immune system, and if you have frozen stem cells stored, we can add them to a blood transfusion to help boost your immune system. You will take medications while your immune system is recovering to help prevent infections. You may also need intravenous immunoglobulins (IVIG) to help boost your antibodies as well.  

(34:15): Hemophagocytic Lymphohistiocytosis (HLH) is a side effect that causes incredibly severe inflammation, high fevers, organ damage and increased risk for bleeding. It's incredibly rare, but very severe and your CAR-T doctor needs to be involved immediately.

(34:42): Within the first week or two we also monitor for any kind of confusion or neurologic changes you might be having that might indicate the T-cells are causing inflammation in the brain. If this occurs, we can treat you with steroids to help decrease the inflammation. As time progresses, we monitor for other neurological issues like tremors, Parkinson's-like movements, or facial drooping. These issues are seen in less than 10% of patients, but if their myeloma is not fully under control going into a CAR-T, we see these bigger issues.

(35:30): Cytokine release syndrome (CRS) occurs when cells release inflammatory proteins (cytokines) and those cytokines can cause issues like high fevers, breathing difficulty, and low blood pressure. CRS can be treated with steroids or with specialized medicine that blocks these inflammatory proteins, and help the T-cells calm down. It's easier to shut down this inflammatory syndrome earlier versus later.

(36:11): To help safely monitor and treat any of these potential side effects, most CAR-T centers require you to live or stay within an hour of your CAR-T-cell center for the first 30 days, so that you have quick access to these special medications. Also, due to these potential neuro side effects, you cannot drive for 60 days.  

(36:50): There are different guidelines and requirements that patients need to meet in order to be a candidate for CAR T-cell therapy. First, you have to have relapsed myeloma. You can't get diagnosed with myeloma and immediately get a CAR-T. You have to have been treated with the three different kinds of drugs – the CD38 MoABs, IMiDs, and PIs – and you have to be refractory to Revlimid.

(37:14): You need to be healthy with good lungs, good kidneys, and a good heart. You must be able to take care of yourself, be functional, and have a caregiver available to be with you for 30 days. It doesn't have to be the same person the whole time, but we need a caregiver to monitor for confusion or any sudden changes.

(37:36): When we use CAR-T-cell therapy early in treatment, we are getting better and longer responses. We are just now starting to understand which patients are going to have side effects, what problems they're going to have, and how to predict them and prevent them from causing serious problems.

(38:31): Not everybody will be able to collect healthy T-cells. If you've been through a lot of treatments, sometimes your T-cells are weak. But we can collect T-cells from other people and create what we call ‘off-the-shelf’ products. And, we can determine a combination of treatments to ensure we find the best treatment plan for you.

(38:55): With that, I will let Michelle lead us through some questions. I appreciate everybody's attention.

Question and Answer.

(39:05): [Michelle Kosick]: Thank you, Dr. Gregory. That was an excellent presentation. Let's go ahead and get started.

(39:23): For patients who work a flexible remote job, do you recommend that they take a leave during CAR-T-cell therapy or continue working? If you recommend time off, how long?

(39:38): [Dr. Tara Gregory]: I do recommend that people take at least two months of time off. If you can't drive for two months, you probably shouldn't be working for two months. That being said, I have plenty of patients who have gone through CAR-T and have had no issues.

(40:10): For my patients who do work, I’ve advised that they let their job know that at any moment you could be operating just fine, and then something might happen and the next day you won’t be able to get work done. If they're going to be dependent on you, and they can’t cover for you at the last minute, then you really shouldn’t be working. But I would say, most patients feel like they can go back to work at the 60-day mark.

(40:51): [Michelle Kosick]: "How does each center select which CAR-T product to use? Is it patient-based or what the center is approved to deliver?"

(41:02): [Dr. Tara Gregory]: That's a great question. Like we talked about, there are two CAR-T products – Abecma and Carvykti. Our center only carries Carvykti because we think the data supports that it lasts longer. However, that's my personal opinion.

(41:35): I will say that Abecma has a lower side effect profile than Carvykti. So some centers opt for Abecma for patients who are not as healthy, and Carvykti for people who are healthier.

(42:00): The center must also be approved by the product, and by insurance plans, so that plays into it as well.  

(42:12): [Michellel Kosick]: "Are there any complications if you've been heavily pretreated – especially with Revlimid – going into CAR-T-cell therapy?"

(42:20): [Dr. Tara Gregory]: There are two big pieces to think about here. The first is if your T-cells are weakened because you’ve been through tons of treatments, that will influence how robustly the CAR-T is going to work.

(42:53): Revlimid doesn't negatively affect the T-cells down, so we don't worry about that as much. We worry more about patients who have had a lot of chemotherapy or have a history of transplants. In people who have been heavily pretreated, their bone marrow gets weak, so it is much harder for the bone marrow and immune system to recover.

(43:45): We do have a system, called a CAR-HEMATOX score, that assesses this risk, and determines if the bone marrow will be able to recover, or if you aren’t a good candidate as the treatment will be too hard on your body.  

(44:12): [Michelle Kosick]: "Do you recommend similar vaccination guidelines as those followed after a stem cell transplant or are there different ones that you recommend after CAR-T therapy?"

(44:23): [Dr. Tara Gregory]: Patients likely need to be vaccinated after CAR-T, but we don't currently have any standard guidelines through our national or international organizations regarding what schedule that should be. A lot of centers have determined that a year after your therapy, you should probably receive a similar schedule to transplant patients. This includes polio, Haemophilus influenzae type b, DTaP, hepatitis B, hepatitis A, pneumococcus, flu, and COVID.

(45:13): CAR-T patients must have healthy T-cells to respond to a vaccine. Your CD4 count needs to be over 200. Everybody's worried about measles right now, so once your CD4 count is over 200 we can give you your MMR a little earlier than the two years that we typically wait.

(45:43): [Michelle Kosick]: "Can I have a second CAR-T treatment if the first one doesn't work?"

(45:48): [Dr. Tara Gregory]: We have patients on clinical trials who've gotten the anti-BCMA protein CAR-T, where it doesn't work right away. Typically we don't have extra cells made and ready to go, and we can't collect healthy T-cells anymore to make a new CAR-T, so that ends up being a problem.

(46:25): We have patients whose myeloma came back within the first year or so after CAR-T-cell therapy, and because these patients were all on clinical trials, the study had extra CAR-Ts they could give them. They had about a 50% response rate, but it lasted only a couple months. They tried the same thing for people who relapsed a couple years later, with similar results. It just doesn't work as well.

(46:57): There are some newer products using combinations of different receptors that are showing positive responses. We discussed the BCMA target, but there’s a product that’s a combination of BCMA and a receptor called CD19 that seems to be having positive results. Another one is called GPRC5D, but we are seeing neurological problems that need to be addressed. Finally, there's one that's a combination of GPRC5D and BCMA.  

(47:38): So, the answer is yes, you can. Chances are you'll collect T-cells better if it's been well over a year since your first CAR-T, but we do need to change the target.

(47:52): Sometimes patients ask if they could be treated with one of the bispecific antibodies first, because CAR-T scares them. The problem with that is, if you give somebody a bispecific antibody, such as elranatamab or teclistamab, – our two anti-BCMAs – you burn up that receptor. Then, if you have to use the CAR-T afterwards to target the same receptor, it doesn’t tend to work because the CAR-T doesn't have anything left to go after.

(48:28): Conversely, if you do the CAR-T first, if the patient relapses, they can still be treated with elranatamab or teclistamab and see equal response rates compared to the patients who've never had that therapy before. I really encourage patients who think they ever want to have a CAR-T to not get the bispecific antibody to the same target first.

(49:06): [Michelle Kosick]: "If a person is taking medication to keep depression and anxiety under control, will that affect the risk for CAR-T-cell side effects?"

(49:15): [Dr. Tara Gregory]: We do not see side effects with depression and anxiety medications. It's hard to go through treatment, so a lot of CAR-T centers have strong social work and psychology teams checking in with you to ensure you feel supported, but those medications are not an issue.

(49:43): Medications we are concerned about are blood thinners, because while your medication is thinning your blood to prevent a clot, treatment is lowering your platelet counts, so the risk for bleeding is increased.

(50:10): [Michelle Kosick]: "How long do you have to be on IVIG infusions after CAR-T-cell therapy?"

(50:17): [Dr. Tara Gregory]: You can expect to be on IVIG for at least a year before your immune system makes healthy antibodies, and a lot of patients have to be on it for at least 18 months after CAR-T-cell therapy.

(50:32): [Michelle Kosick]: "Are there studies looking at sequential CAR-T and repeat stem cell transplants in either order? If so, what interval?"

(50:41): [Dr. Tara Gregory]: There are lots of studies with lots of pieces to this. There are studies where patients got a stem cell transplant first – which was planned when they first got diagnosed – and then got the CAR-T right after they recovered from transplant. Some of those studies have been closed because it didn't look effective, and it makes me wonder if the CAR-T-cells need to see at least some myeloma so that it can act against it. But it's kind of a double-edged sword because you also don’t want to wait too long, and have it become super aggressive and cause significant CRS.

(51:23): China is doing sequential CAR-Ts, where they give you a CAR-T targeting one antigen, and then a couple of weeks later they give you a CAR-T targeting a second. Here in the United States, we stopped focusing on that because technology is evolving so rapidly, we can now make a CAR that will hit two targets at the same time, – called ‘dual CARs’ – so now our studies are utilizing these dual CARs.

(51:50): I will say, second transplants have now been largely replaced by CAR-Ts, so it's pretty rare to see a patient get a second transplant these days.

(52:03): [Michelle Kosick]: "Do you see greater cytokine release syndrome and neurotoxic issues with people who have autoimmune diseases like rheumatoid?"

(52:16): [Dr. Tara Gregory]: No, actually, people with autoimmune diseases actually feel really good. This is because when you get the lymphodepleting chemotherapy – fludarabine and cyclophosphamide – it knocks down your immune system. Then, for the first six months the CAR-Ts replace your T-cells and are focused solely on fighting that target in the myeloma cells, and stay away from other tissues – like the synovial tissue in your joints. After that, it takes another six months after the CARs die out for your T-cells to grow back, so they get a little hiatus from their autoimmune symptoms.  

(53:28): [Michelle Kosick]: "Is there something called CAR-T brain? Is it different from chemo-brain?"

(53:35): [Dr. Tara Gregory]: As you go through more and more treatments, you definitely can get chemo brain. This often looks like increased forgetfulness and is fairly minor. One of the late neurotoxicities that we worry about is if those CAR-Ts are in the spinal fluid and the brain. If this is the case, these neurotoxicities from CAR-T are profound. CAR-T associated neuro changes are much more significant and severe, and generally occur during the first couple weeks. Patients will do an ICANS assessment daily,  where we screen for any kind of subtle differences.

(55:08): [Michelle Kosick]: "My daughter had a CAR-T for multiple myeloma and has had Parkinson's-like symptoms for a year. Are you familiar with this? Is there a chance she'll recover?"

(55:20): [Dr. Tara Gregory]: I'm sorry to hear that. That's incredibly rare and really tough. We don't know if people recover. That can happen at any stage, which is frustrating with CAR-T. We tend to see it more with Carvykti, and less with Abecma. We're not seeing it with anito-cel yet, but it's still the early days in terms of that research.

(55:46): We've tried a lot of things for patients here at Colorado Blood Cancer Institute that haven't been particularly helpful. We've learned we should not over-immunosuppress patients, but instead shut down the CARs completely, because usually there are active CARs in the spinal fluid causing this issue. If it does look like the CARs are still sticking around long term, then we need to kill them. To do that we use high dose chemotherapy called cyclophosphamide (Cytoxan), and for that we need stem cells available in the freezer to recover the bone marrow. That's where we are right now in understanding. We also utilize a lot of the Parkinsonian medications, but at this point we don't know how to make Parkinsonism go away.

(56:58): [Michelle Kosick]: "Are there tests to find out how many T-cells remain one year post CAR-T therapy?"

(57:05): [Dr. Tara Gregory]: There is not a commercial assay or test that we can do to look at specific CAR-Ts, but we have a couple tricks up our sleeves. We can use HIV testing because the CAR T-cells are reengineered using an HIV vector, so sometimes a positive HIV test can find them.

(57:28): Our pathologists here at CBCI have come up with some testing that they think can differentiate between a normal T-cell and a CAR-T-cell but, unfortunately, there's no mechanism that counts T-cells in a blood sample. We're hoping that is something that will be readily available to all of us in the future.

(57:55): [Michelle Kosick]: "Is there a certain diet that one needs to follow after CAR-T?"

(58:05): [Dr. Tara Gregory]: The best diet on earth is nothing any of us want to do, because it's way more fun to eat French fries and hamburgers and that kind of stuff. We think the closest thing is the Mediterranean diet. We want our diet to increase our gut microbiome and provide our bodies with enough protein to grow good healthy cells. We're learning more about the bacteria that live in our intestines and how that interplays with our immune system. There are studies that show that when you have a healthier gut biome, you actually have better immune function and your T-cells regulate themselves better.

(58:47): The closest we can get to an anti-cancer diet is the Mediterranean diet which includes lots of variety, lean protein, and complex grains in your diet. Instead of white bread, opt for wheat or nut and seed bread, and lots of healthy fruits and vegetables. Half of your plate should be fresh fruits and vegetables.

(59:30): Everything that you love can be had in moderation. If you want to have some wine or dessert, that's great. Whatever makes you happy in moderation, because where you are mentally is equally as important.

(59:45): [Michelle Kosick]: Closing. On behalf of the BMT InfoNet and our partners, I'd like to thank Dr. Gregory for an extremely informative presentation. And thank you to our audience. You sent us some wonderful questions. Please contact BMT InfoNet if we can help you in any way.