CAR T-cell Therapy in Myeloma: What to Expect and Late Effects

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CAR (Chimeric Antigen Receptor) T-Cell Therapy in Myeloma: What to Expect, The Process and Late Effects

Presenter: Nausheen Ahmed, MD. Assistant Director of Cellular Therapeutics Program, Medical Director of Transplant and Cellular Therapy Survivorship Program, The University of Kansas Cancer Center.

Presentation is 44 minutes followed by 16 minutes of Q&A

Summary: CAR T-cell therapy is an exciting second-line option for patients living with relapsed multiple myeloma. In this presentation, Dr. Ahmed reviews each step in the CAR T process and discusses a number of studies that support its use. Potential side effects are reviewed, and exciting future trends are discussed.

Key Points:

• Studies have shown that patients treated with CAR T-cell therapy experience improved overall response rates, progression-free survival, and overall survival.
• Potential side effects of CAR T-cell therapy include cytokine release syndrome (CRS), Immune effector cell-associated neurotoxicity syndrome (ICANS), movement disorders, low blood counts, increased risk of infections, and secondary malignancies.
• Patients who receive CAR T-cell therapy are required to adhere to strict monitoring guidelines, which include staying close to the treating facility for at least 2 weeks, refraining from driving for 8 weeks, and having a caregiver at home to assist with monitoring for side effects.

Highlights:

(02:37): CAR T therapy is approved for patients with relapsed or refractory myeloma. It recently moved from fourth-line therapy to second-line therapy, meaning patients may be offered this therapy earlier in their disease course.

(04:41): B-cell Maturation Antigen (BCMA) is expressed on plasma cells and is a target in myeloma. Abecma (idecabtagene vicleucel or Ide-cel) and Carvykti or Cilta-cel are both FDA-approved, BCMA-targeted CAR T therapies for myeloma.

(07:44): Insurance coverage, fitness, comorbidities and disease characteristics are factors to consider when deciding which CAR T product best fits each patient.

(08:27): T-cells are collected by a process called leukapheresis. The collected T-cells then go to a lab and are genetically modified. While this is being done, patients often receive bridging therapy until their T-cells are ready.

(11:10): The CAR T pre-evaluation includes scans, labs, a bone marrow biopsy, an echocardiogram, cognitive and neurological exams, and a social support evaluation. 

(19:33): Disease characteristics such as high-risk cytogenetics, extramedullary disease, high disease burden, and high-stage disease may be factors that affect outcomes with CAR T-cell therapy. 

(20:35): Patient characteristics such as performance status, age, comorbidities, and frailty may also affect outcomes of CAR T-cell therapy. 

(37:21): Despite potential significant and serious side effects, the most common cause of death in patients who receive CAR T-cell therapy for myeloma remains the disease itself.

(38:15): The future of CAR T-cell therapy includes new targets such as GPRC5D. Studies are in progress to explore allogeneic CAR T-cell therapy, which involves using someone else's genetically modified T-cells to combat your myeloma.

(42:14): Disparity in accessing CAR T-cell therapy presents challenges, with geographical location, socioeconomic status and insurance playing significant roles.

Transcript of Presentation

(00:00): [Michael Riotto] Introduction. Thank you. Good afternoon or good morning, depending on where you're at today. Welcome to the workshop, CAR T-Cell Therapy in Myeloma: What to Expect and Late Effects. My name is Michael Riotto, and I'll be your moderator for this workshop.

(00:14): It is my pleasure to introduce today's speaker, Dr. Nausheen Ahmed. Dr. Ahmed is a board-certified hematologist-oncologist at the University of Kansas Cancer Center, where she serves as the Medical Director of the Transplant and Cellular Therapy Survivorship Program. Her primary focus is on providing expert and compassionate care to patients with blood cancers, including lymphoma and myeloma. Her research interest involves quality and process improvements, care delivery with respect to CAR T-cell therapy and increasing diversity in clinical trials. Please join me in today's workshop in welcoming Dr. Ahmed. Dr. Ahmed, go ahead.

(00:59): [Dr. Nausheen Ahmed]: Overview of Presentation. Hello, and thank you all for having me. I will get right into it. Today's talk is about CAR T therapy in multiple myeloma. We'll go over what CAR T therapy is, who should be considered for it and what the patient journey look like? And we will go over some efficacy, toxicity, and future directions.

(01:24): Multiple myeloma is a cancer of plasma cells. First of all, what is multiple myeloma? Multiple myeloma is a cancer of mature plasma cells, which you see over here in the picture. These are cells that live in your bone marrow. Multiple myeloma can be detected by your physician, either because of abnormal blood work, maybe kidney function abnormalities, or symptoms such as bone pain, fractures, unusual fractures, confusion, or any other symptoms similarly.

(01:56): Frontline treatment is not curative and includes chemo-immunotherapy combinations. The treatment for a newly diagnosed patient, which we call frontline treatment, is typically a combination of chemo-immunotherapy, as well as a stem cell transplant. Now these therapies are generally not considered curative, and many patients might still end up having refractory disease or progressive disease at some point in time, which may be even years after they were initially diagnosed. And what we are going to focus on are CAR T therapies, is one of those treatment modalities for relapsed or progressive disease.

(02:37): CAR T therapy is approved for patients with relapsed or refractory myeloma. Here's just an idea. This graph shows that the prognosis in patients who have relapsed refractory or progressive disease and who've had several lines of therapy, the prognosis can be poor. This is a graph by Gandhi et. al. in 2019. This is before the time of CAR T therapy. This defines that there was a need to get better therapies, and that is how we got CAR T therapies approved for patients with refractory disease.

(03:13): T-cells are immune cells that usually identify and destroy cancer cells. Now, just to give you an idea of what CAR T therapy means, what is it? Our T-cells are the soldiers in our bodies that should help clear up all cancer cells. T-cells are part of our white blood cells. They're part of our immune system, which you see here depicted in that blue cell with a blue ball. That's a nucleus.

(03:38): Normal T-Cell activity can be disrupted by cancer cells. Now these cells rely on other cells to activate them. So, there are different T-cells involved in activating these cells, which then go and find the cancer cells. And therefore, it's a process that can easily be disrupted by the cancer cells. They can figure out a way to blind these T-cells so they cannot get activated to find the cancer.

(04:02): CAR T therapy genetically modifies a patient’s own T-cells so they may recognize the cancerous plasma cells and destroy them. What we do with CAR T therapy is we genetically modify these T-cells so that now, they are able to express these receptors, which you see over here. These receptors, they pop up on the surface of these T-cells, which make them a CAR T-cell. And these receptors can directly recognize the plasma cells, which are the cancer cells, and that can lead to activation of the T-cells and destruction of the plasma cell. So now the T-cells can independently do the whole process. And makes it a much stronger cell.

(04:41): B-cell Maturation Antigen (BCMA) is expressed on plasma cells and is a target in myeloma. Now the next question is, how do they recognize those plasma cells? For your understanding, plasma cells have multiple markers on their surface, some of which may be unique to the plasma cell, and some of which may be shared with other cells. There's a particular one called BCMA, which all our CAR Ts are focused right now presently on BCMA. This marker is found on the plasma cells and hardly found on any other cells in the body, which makes it a really good target, because it can allow killing of the plasma cells which cause the myeloma, and not affect other organs or other cells. Our currently approved therapies all target BCMA.

(05:30): Abecma (Ide-cel) and Carvykti (Cilta-cel) are FDA approved, BCMA targeted CAR T therapies for myeloma. The therapies that are presently approved, there are two of them. There's Abecma, which is also known as Ide-cell, and then there's Carvykti, also known as Cilta-cel. If you look at the way they're engineered, they have some similarities in what we call the 4-1BB costimulatory domain. That's the way the T-cells get activated. It's similar when you look at the binding sites, how do they recognize the plasma cells? That's a similar binding site as BCMA. There are some differences in the way it's engineered to bind to the BCMA, but this is what they generally look like.

(06:14): Patients with myeloma who have progressive disease after first-line therapy may be considered for CAR T therapy. So now the question is who should consider BCMA CAR T? At present, that since April of 2024, it's any patient, really, who has progressed or relapsed after a single line of therapy should be considered for CAR T therapy. There will be some nuances about whether they have had exposure to Revlimid (Lenalidomide) or whether they've had exposure to Daratumumab (Darzalex), but that's the time when we start thinking about CAR T therapy. This would be regardless of age, regardless of how frail they might be, regardless of comorbidities, and regardless of whether they've had BCMA therapies in the past. Because many patients might've had others like Teclistamab (Tecvayli) or Belantamab (Blenrep). They still can get CAR T.

(07:02): Now I've been asked whether patients who are not fit for auto autologous transplant, could they get CAR T? And the answer is yes, they should at least be considered for an evaluation, even if they've not been previously fit for an autologous stem cell transplant.

(07:23): Both products are approved for patients as second line. Until a month ago, both of these products were only available only in four lines or later setting. The question many patients ask is, which product is best for me? Would it be Abecma (Ide-cel)? Would it be Carvykti (Cilta-cel)? There are many things that dictate that.

(07:44): Insurance coverage, fitness, comorbidities and disease characteristics are factors to consider when deciding which CAR T product is the best fit for each patient. All right now, it's line of therapy, because now both of these are approved in earlier lines of therapy. It could be insurance coverage, availability at the center. It might be disease characteristics that your doctor would discuss with you, such as the time to manufacture, any bridging therapies, any high-risk features. There might be patient-specific factors such as risk of movement disorders and risk of toxicity. What are the fitness and comorbidities that would make one product more suitable versus another? These are typically the factors that we think of.

(08:27): CAR T Process overview. T-cells are collected by a process called leukapheresis. Just to give you an overview, what happens, so this is a broad overview of how we get the CAR T process started. The patient first has to go through a process of leukapheresis, which is where we collect the T-cells from the patient. For people who are aware of the dialysis procedure, it looks like that, where a patient's pretty much sitting in a chair and is attached. There are two things that come from your veins into a machine, and that machine is able to filter out the part that's reaching the T-cells, and the rest of the blood just goes back to the patient. For some people, it's probably easier to think of a washing machine, right? You're sitting in a chair. There's a machine that looks like a washing machine, and there's tubing that goes from the patient to that machine and back. And that machine again filters up the part that's reaching the T-cells.

(09:35): The collected T-cells go to a lab and are genetically modified. What happens to those cells? Those cells go to a central lab. They are genetically modified, like we discussed. They go through a whole process in the lab. The cells expand. They have to reach certain quality parameters before they're released. And that whole process can take anywhere from four to eight weeks. In the meantime, the patient would just wait for those cells to get manufactured. And sometimes your doctor might recommend that you get some interim therapies to keep the myeloma controlled.

(10:07): Chemotherapy is given to allow CAR T-cells to expand. Once the cells are ready, the patient will get lymphodepleting chemotherapy. The chemotherapy allows those CAR T-cells to expand in the body, and then you get the CAR T infusion.

(10:24): Going into this, we'll go into this in a little more detail, specifically from the patient standpoint. For the patient journey, the first step is referral to the CAR T center. Then they get a pre-CAR T evaluation to make sure that they're fit for CAR T, and are good candidates for CAR T, and they're appropriate for CAR T. Then they go to that leukapheresis procedure, where they're hooked onto that machine that we discussed. The manufacturing procedure with possible bridging, what we call bridging therapy, that's where your doctor decides, "Okay, we might want to keep you on something in order for this myeloma to stay in control while we're waiting for the four to eight weeks." Then the lymphodepletion, which is three days of chemo, typically, followed by the CAR T infusion.

(11:10): CAR T pre-evaluation includes scans, labs, bone marrow biopsy, echocardiogram, cognitive and neurological exams and a social support evaluation.  Now after the infusion, there's typically four weeks monitoring that's done close to the center by the CAR T team. And after that, the patient can be monitored by either their referring oncologist or primary oncologist for long-term monitoring. The first step is referral to the center. The referral, the pre-evaluation, what to expect? You can expect disease evaluation, so scans, PET scans, bone marrow biopsy labs. The patient can expect to get a fitness evaluation, which may include echocardiogram, cognitive function evaluation, neurological evaluations, such as an MRI, testing the spinal fluid, a frailty evaluation interview and basic movements, as well as an oncology-psychology evaluation. Now this all does not have to be done, but this is what you may expect.

(12:10): Also, the social workers would evaluate the social support. Is there a caregiver available for up to 30 days or 28 days, which is pretty much a prerequisite for most centers to give CAR T? What does the insurance coverage look like? Is a financial counselor needed? And then I just put it down here, smoking cessation and other things to minimize the risk of infection and complication, as indicated.

(12:40): During leukapheresis, the T-cells are filtered out of the patient’s blood. Temporary side effects may include blood pressure fluctuations, dizziness, numbness, tingling, and electrolyte imbalances. The leukapheresis, we talked about this, but this gives you a better visual. This is a machine where the patient's sitting in a chair, hooked onto the machine. And that machine, the blood is circulating back and forth continuously. The machine is filtering out the part that's rich in the T-cells, and the rest of the blood just goes back in the patient. This typically can involve a few hours' stay in the apheresis unit. It may involve using a central line, and monitoring during this time. I mean, it's a monitored process. There are nurses there watching while this is happening. There could be blood pressure fluctuations, dizziness, lightheadedness, numbness, tingling, electrolyte imbalances, and a bruising tendency. But those are usually just temporary during the time that this is ongoing, and the nurses usually are vigilant and watch for any side effects and complication during this procedure.

(13:41): Patients often receive bridging therapy for 4-8 weeks while their cells are being processed. The bridging was the next thing while the cells are gone for manufacture. This is just therapy used to keep the disease at bay. And this may involve chemotherapy, immunotherapy, radiation, steroids. The choice really depends on the pace of the disease, as well as prior therapies used. And it's called bridging, because it bridges the period between collecting the cells and delivering the cells back into the body.

(14:11): Lymphodepletion chemotherapy is used to dampen the immune system before the CAR T-cells are reinfused. Then I use the term lymphodepletion. That's the chemotherapy that's given right before the CAR T. Now the purpose of this chemo is basically to dampen the immune system so it does not try to fight the CAR T-cells. It's given a few days prior to the CAR T, usually outpatient. Usually it's three days, and the chemotherapy used is Fludarabine and Cyclophosphamide.

(14:35): The side effects can be fatigue. Blood counts can go low. There's a risk of infection. I was specifically asked about hair loss. And hair loss is not profound with the doses used in this chemo regimen or with CAR T, as compared to an autologous transplant.

(14:55): The CAR T infusion itself is a one-hour infusion through a PICC or central line. Here's a CAR T infusion itself. The infusion, it can be given inpatient, it can be given outpatient. Usually takes less than an hour. It's literally just given as an IV. Potentially, immediate issues can be infusion reactions, but it's not very common. Monitoring is done throughout the infusion for reactions.  Preferably a PICC (peripherally inserted central catheter) line or a central line would be used in order to give this infusion.

(15:27): In the KarMMA – 1 study, patients treated with Ide-cel (Abecma) had an 81% overall response rate with a median overall survival of 24.8 months. So now that we understand the process of how CAR T is done and administered, we will talk about the approvals in the myeloma space. Starting with 2021, when we had the first approval, which was Ide-cel, also known as Abecma, based on the KarMMa-1 study, this was the first approval of CAR T in myeloma. And we see here that it's based on an overall response rate that is 81%, with complete response rate 39% or better, which was much better than historical controls. And the median overall survival was 24.8 months.

(16:16): In the Cartitude-1 Trial, patients treated with Cilta-cel (Carvykti) had an overall response rate of 98% and the 18-month overall survival rate was 81%. After that, the next year in 2022, we had the approval of Cilta-cel, also known as Carvykti, based on the Cartitude-1 trial. And here, you see that the overall response rate of 98%, with 83% being complete responses are better. The 18-month overall survival was 81%. A median progression-free survival and overall survival were not reached. There's no head-to-head comparison between these two trials because the populations are slightly different, but these are just to give you an idea of the general outcome.

(16:57): In the phase 3 trial KarMMa-3, patients who received Ida-cel (Abecma) had improved overall responses and progression-free survival compared to patients who received standard therapy. Now the exciting thing this year, in fact, within the last month was that both of these products got approved in earlier line. So really hot off the press is that Ide-cel, which is also known as Abecma, is now approved after two lines of therapy based on the Phase 3 trial, the KarMMa-3 trial. The KarMMa-3 trial was a study of 381 patients who have had two to four prior lines of therapy. Such patients were randomized to either get the CAR T Ide-cel, or to get standard-of-care therapy. And we see here that the overall responses with Ide-cel were far better than that of standard regimen. So, the response was 71%, compared to 42%. And when we look at the progression-free survival, Ide-Cel had a 13-month median progression-free survival, versus 4.4 months with just the standard regimens.

(18:05): In the Cartitude-4 trial, patients who received Cilta-cel (Carvykti) had both an improved overall response rate and progression-free survival compared to standard of care with Daratumumab (Darzalex) based therapy. The other news, on April 5th, the very next day, was the approval of Cilta-cel or Carvykti, again in early lines of therapy. This was based on the Cartitude-4 trial, in which there were 419 patients. And they had to have one to three prior lines of therapy. All of them had to be refractory to Lenalidomide (Revlimid). Now those patients were taken in either they were randomized to get Cilta-cel, Carvykti, or standard-of-care therapy, which was a Daratumumab (Darzalex) based therapy. And as you see again over here, the response rates were much better with Cilta-cel, 84% versus 67%. Progression-free survival was clearly superior in the Cilta-cel group as compared to the standard-of-care group. And based on these outcomes, the FDA approved it after one line of therapy in the Lenalidomide (Revlimid) refractory patients. This is all just all very recent progress, that we've had very exciting advances.

(19:11): A lot of patients wonder that is CAR T the right thing for them. What are the factors that would affect outcome? I looked at several trials to try and synthesize, what are the things that might be high-risk, and what are the things that we think about? In general, we think about disease characteristics.

(19:33): Disease characteristics such as high-risk cytogenetics, extramedullary disease, high disease burden and high-stage disease may be factors that affect outcomes with CAR T-cell therapy.  and here may be certain characteristics which may affect outcomes. That may mean that the disease has a higher risk and may not respond as well. There are still studies ongoing to look at exactly how these would affect outcome. But things to consider are the presence of extramedullary disease, which is disease outside the bone marrow. Patients who have high-risk cytogenetics; those with high disease burden, such as a high percentage of plasma cells; those with high risk, the R-ISS III, that's the high-risk staging at diagnosis; as well as prior BCMA therapy. If someone has just gotten, for example, Teclistamab, which is a BCMA therapy, how would they do if they got CAR T therapy? Would the responses be less than what we expect or not? We are still looking at that data.

(20:35): Patient characteristics such as performance status, age, comorbidities, and frailty may also affect outcomes of CAR T-cell therapy.  Other things that might be associated with slightly inferior outcomes might be low physical status or performance status of 2. That means that their patients are not very active. And younger patients, those that are less than 70. The question comes up about comorbidities such as cytopenia, those with low blood counts, renal impairment, poor performance status. The studies have shown that they may have higher toxicity. But again, some studies have shown similar efficacy. As far as frailty, which means taking into account age, performance status, and comorbidity index, there was a paper published showing similar toxicity and outcomes being similar.

(21:30): Now, I wanted to give you all an idea of what the toxicities are that we look at, and how do we follow for toxicity. I’m just outlining some general toxicities that we look at over here, with the first being CRS, cytokine release syndrome, and we'll talk about this in more detail. Then immune effector cell therapy associated neurotoxicity syndrome, ICANS. And some others such as cytopenia, non-ICANS neurotoxicity, which are motor disorders due to the CAR T. Other effects include infections, second primary malignancies, B cell aplasia and macrophage activating syndrome.

(22:16): Cytokine release syndrome (CRS) is a toxicity associated with CAR T-cell therapy. We'll talk about the major ones. Firstly, CRS. CRS is caused by a cytokine storm. What happens when these CAR T’s get activated is that they just rev up the immune system. It causes a hyperinflammatory state, and that can lead to the patient having a fever. They may experience low blood pressure, low oxygen levels, depending on the severity, and this is typically treated with some special medications, such as Tocilizumab and other medicines that can dampen the cytokine storm. This can reduce the amount of cytokines.

(22:55): To give you an idea based on the KarMMa-1 and the Cartitude-1 data here, I've shown you most patients receiving Ide-cel (Abecma), or Cilta-cel, which is Carvykti, most of them will experience some degree of cytokine release syndrome. Grade 3 or more, which means high-grade, which means pretty serious cytokine release syndrome, that's around 5% or less. Neurotoxicity, what I just called ICANS, immune effector cell associated neurotoxicity syndrome, that it can be a change in mental status. Again, because of all that inflammatory response and all those cytokines that are generated by the CAR T.

(23:44): Immune effector cell-associated neurotoxicity syndrome (ICANS) is neurotoxicity that is associated with CAR T therapy. For the patient, that might mean that they could be confused. They may be slower to answer questions. We ask the patient to count backwards or count from 10 backwards. They might not be able to do that. It might be more serious, and it could be a seizure. It could be coma. It really depends on the severity. It could be very subtle, but it could be all the way, where there's coma. Patients are in the ICU.

(24:08): Movement disorders have been seen as a side effect to Cilta-cel (Carvykti). There's also an entity which is a neurotoxicity, but it's not really ICANS. And that has been seen with Carvykti. There are some incidents of that. It's movement disorders. It's Parkinsonism. So again, based on the studies, the KarMMa-1 and the Cartitude-1 studies, we see that any degree of neurotoxicity can be in close to 20% of the patients, but severe is just 2 or 3%. Non-ICANS neurotoxicity is described with Carvykti, that's around 12% of patients. And again, just symptom management with that. Otherwise, for ICANS, so we have to sometimes treat with steroids and other medications to help, depending on how severe it is.

(25:05): Prolonged low blood counts can be a side effect of CAR T-cell therapy. Prolonged low blood count, which is called prolonged cytopenia, is another side effect of CAR T therapy. And basically, it's beyond 90 days, can be seen in approximately a third of all patients, which means that there's low red blood cell count, low white blood cell count, low platelet count. That could mean an increased risk of infection. It can also mean that there may be more need for transfusion over a longer period of time. The treatments for this include supportive care, which is giving transfusions, giving growth factors. Growth factors such as Eltrombopag, other thrombopoietic agonists. And when available, stem cell boosts also can be helpful. There are many patients with myeloma, when they first are evaluated for a transplant, they get stem cells collected for two or more transplants. If there are any stored stem cells from that time, they might be utilized at this time.

(26:13): Patients who receive CAR T therapy have an increased risk of infection. Again, giving you an idea of infections and prolonged cytopenia’s with both Abecma and Carvykti, we see at one month with Abecma, a high-grade neutropenia was seen in around 52 patients. That's around half of the patients. And Grade 3 or higher thrombocytopenia, that's high-grade thrombocytopenia, was also seen in a fair number of patients. Any grade infections were seen in 69% of patients. But really high-grade infections were in a fourth of the patients that got Abecma. With Carvykti, around 30% of the patients did have high-grade neutropenia, significant neutropenia at day 30. And 41% had significant thrombocytopenia at day 30. And then going down to day 60, 12% still had significant neutropenia, and 6% had Grade 3 or higher thrombocytopenia. Again, infections, any grade and high-grade was similar for Carvykti.

(27:30): What type of infections are we looking at? Infections, this is a depiction of just general CAR T. This is not restricted just to BCMA CAR T like the ones that Abecma and Carvykti are. We see, if you look down, you see day zero. Day zero is the day that the cells are infused. Day minus seven, that's when the lymphodepletion chemo is being given. And then moving forward, we have day 14, 28, 90, and one year. There's a constant risk of respiratory viral infections. There's also a risk of bacterial infections, more so in the first month, and then that gets less and less. In the first month, many patients have neutropenia, a low white blood cell count. And that increases the risk of bacterial infection.

(28:19): Other things such as fungal infection, there's a risk initially. And then later on, that risk decreases. PJP infection, that's a particular kind of pneumonia, Pneumocystis pneumonia, that's seen in patients that have a low immune system. We typically give our patients some medicines to prevent these, like acyclovir for some of the viral infections, as well as PJP prevention. Many people would be on Bactrim or other similar agents. The acyclovir is for basically to affect the other viral, not the respiratory viral, but other viral such as herpes virus, HSV, VZV, which is highlighted here in the yellow.

(29:10): The concurrent use of steroids in myeloma increases the risk of infection. Risk factors with myeloma. The risk of infection is higher than lymphoma, which is a different disease altogether, still being treated with CAR T. Risk factors can be prior therapies, low white blood cell count, even at the start of CAR T.  Use of steroids. If there's a complication, steroids are used. If there is ICANS, that can increase the risk of certain infections.

(29:39): Strict monitoring guidelines are in place for the first 4-8 weeks after CAR T-cell therapy. Monitoring, it's pretty structured in the first four weeks. The patients have to be close to the treatment center. The exact distance may vary from center to center. There is no driving from the day that the CAR T is infused until eight weeks post-infusion. All patients are required to have a 24/7 caregiver if their patient's not in the hospital. And the caregiver can help with driving the patient, helping managing medicines, and activities of daily living. And most importantly, to monitor and report any issues, any, for example, confusion or change in mental status. Report that immediately. Call the treatment center.

(30:24): Monitoring is daily for the first 2 weeks. The early monitoring period can be inpatient or outpatient. Some centers have a dedicated number of inpatient days.  I would say most centers do. And then there's the outpatient after that. Visits, if not in the hospital, are daily initially and then they're spaced out after two weeks, typically. What is done during the visits? There is monitoring for cytokine release and neurotoxicity.  They will check the vitals and ask the questions that check for neurotoxicity. They will check labs to see how you are doing with the blood counts. The use of growth factors, transfusions and TPO agonists, which help support blood counts as needed will be considered. And then prevention and prompt treatment of neutropenic infections and other infections.

(31:15): Hospitalization may be required if there's fever, because fever could be from a number of reasons, such as cytokine release syndrome. It could be infection. And rarely, it's what we call hemophagocytic syndrome, which is a hyperinflammation of the immune system that needs some even more specialized treatments. It can also be required if a patient has altered mental status, which could mean neurotoxicity amongst other things as well.

(31:51): After 4 weeks patients can be further away from the treatment center, but still no driving for 8 weeks. Now what happens beyond four weeks? Ongoing monitoring for late effects beyond four weeks. What to expect? There is myeloma disease assessment, which is typically done at the four-week mark, the three-month mark, six-month mark, and twelve-month mark. Most patients, if they do live far away from the treating center are able to go back home after four weeks. We still advise no driving for a total of eight weeks from the day the CAR T was given. One might expect their own local oncologist to get several labs and visits done. The frequency would be determined based on how the blood counts are doing and how is the patient recovered from the CAR T. The purpose of the visit is to monitor the blood count and organ function, which can be monthly or more frequent if there are any abnormalities, monitor the myeloma markers monthly, or it could be spaced out, depending on how the markers are doing.

(32:56): Prophylactic antimicrobials are used to help prevent infection. These are often stopped when CD4 level reaches 200 or more. And then clinically, see what's going on. Is there fever? Are there any new symptoms? Is there any movement disorder? If there are low blood counts, they may require supportive care transfusions, TPO agonists or stem cell boosts. For infection prevention, we do continue, as I said, the antimicrobials to prevent infections for at least six months. Your doctor will be checking labs such as CD4 levels, which are a marker of how the immune system is recovering. And some of these medicines will be stopped based on that CD4 level, as long as it's recovering. Typically, a CD4 level of more than 200 is what we look for. Also, time-sensitive infusions are given.

(33:47): Patients require re-immunization after CAR T-cell therapy. Immunizations are also done. Usually starting from the six-month mark, patients start getting their baby shots, because the CAR T really reboots the whole immune system. Responses to prior immunizations diminish, your body has likely forgotten them. Re-immunization starts at six months and continues for two years. There are certain immunizations, such as influenza and COVID shots, you may receive even earlier.

(34:18): Secondary malignancies have been seen after CAR T therapy. The next thing that I wanted to spend a little time on was second primary malignancies. There've been a lot of questions about this. And I would just like to share some data which Sidana presented at ASH 2023, on Abecma (Ide-cel). Just to give us an idea of what we see now, this was a study from the CIBMTR Registry of 821 patients with a median of 11 months follow-up. There were 33 patients who had second primary malignancies. Out of these, the most common was skin cancer, basal cell or squamous cell skin cancer. Then, there were cases of myelodysplasia and acute myeloid leukemia. There were other cases as well, such as malignant melanoma, breast cancer, CNS, and genitourinary malignancies

(35:18): Myelodysplasia (MDS) and acute myeloid leukemia (AML) were the most common secondary malignancies. The FDA did announce in November 2023, it alerted us about the risk of T-cell malignancy with CAR T therapy. There are reports that looked into that specifically. There's this big study that looked at the incidence of malignancy in all patients who received CAR T. And this was our myeloma CAR T, which was BCMA-CAR T, and the CD19 CAR T, which is used for lymphoma. They looked at this database where all adverse effects are reported to the FDA database. There were 536 such events noted. Most of them were myeloid malignancies. Myelodysplasia (MDS) was 38% of all second primary malignancies. Acute myeloid leukemia, which was 19.8% was the second most common primary malignancy.

(36:16): And coming to T-cell malignancies, there were two cases of T-cell large granular lymphoma, which was only two cases out of all those cases. Skin cancer was 10%. It was 10% of the second primary malignancies. When we look at non-Hodgkin's lymphoma, specifically the T-cell type, there were 17 cases, two of which were anaplastic large cell lymphoma from Cilta-cel. I highlighted that because it is relevant to what we are seeing. Two cases, really, out of the hundreds and hundreds that have been treated. The FDA obviously is like, "We worried about this, because it's a CAR T. And so, we want to be sure that the treatment itself is not causing malignancies."  There are   many reports looking into this. But so far, the incidence of T-cell malignancy is relatively very low.

(37:21): The most common cause of death in patients who receive CAR T-cell therapy for myeloma, remains the disease itself. I also show Abecma data, the CIBMTR study. This looked at all real-world patients within the United States, around 821 patients. It looked at the primary cause of death. And it seems that the main cause of death for patients after CAR T, if anything, is the disease itself. It's still myeloma. Other than that, there are some deaths from infection. There's around a 1% or so death from the immediate toxicity of the CRS in the ICANS. And deaths from second primary malignancies was around 1.7%. Just to give you an idea of the causes of death.

(38:15): The future of CAR T-cell therapy includes new targets such as GPRC5D. Now the next thing to talk about is where is this all headed? What is the future of CAR T therapy? And what we are excited about is the fact that other than BCMA, other targets are identified that would be great targets that are found on plasma cells. These targets are not found really on other organs as much. So good targets, such as GPRC5D, is a new target. And there are clinical trials out there using this target. I just highlighted here a study reported in ASH 2021 and NEJM, which shows this for myeloma. You see this hot spot lighting up myeloma over here in the chest on the baseline scan. Then, after treatment, it's completely gone. After treatment with this CAR T, which targets GPRC5D.

(39:14): Studies are in progress to explore allogeneic CAR T-cell therapy, which involves using someone else's genetically modified T-cells to combat your myeloma. Another advancement that we are excited about is using new platforms, trying to engineer these cells better. So perhaps using an allogeneic platform. There are trials coming around looking at allogeneic CAR T. What about allogeneic and autologous? Autologous basically means that the cells, the T-cells come from the patient. Allogeneic means that these T-cells, they come from another source, whether it's a healthy donor, whether it's fibroblast, whether it's cord blood. There's another source for these cells.

(39:50): There are several advantages of allogeneic CAR T, such as the fact that you don't have to do any of the collection process; waiting, process, bridging. This is ready off-the-shelf, available therapy. Theoretically, the T-cells that come from an allogeneic source have never been exposed to chemotherapy. They would be high-quality starting material. There's an ability to standardize a product and potentially decrease production costs.

(40:22): There are some challenges that are still being overcome. There are many different products that are designed to overcome some of these challenges, such as the risk of graft-versus-host disease that come with allogeneic products. Graft-versus-host disease is where the cells from the third party might think that the patient's own normal cells shouldn't be there, and so they attack that. That's graft-versus-host disease. There's also a risk that the host, that the patient's body rejects those cells, and doesn't allow them those cells to grow. That's decreased persistence. So more to come on that. You'll see many clinical trials that are developing the allogeneic platform, as well as in the autologous platform, like shorter manufacturing time.

(41:22): Time to access for autologous CAR T-cell therapy is improving but remains a challenge. Lastly, is improving access. When in the autologous space, where the cells are made from the patient, there have been several challenges. As these therapies rolled out in 2021, we found that there were very limited slots for the patients. The centers would get maybe between two to four slots per month to treat the patients. And there were many patients that were on a wait list in our own center. This is a report that we got out from our center. We saw the patients that were on the wait list for a long time had worse outcomes than those that were able to get CAR T therapy. There were other results out there of similar reports essentially, and how patients were selected.

(42:14): Disparity in accessing CAR T cell therapy presents challenges, with geographical location, socioeconomic status and insurance playing significant roles. Thankfully, that is now getting better and better. This was back in 2021. And now with having two products and with more production slots, this limited slot issue is now much improved. But there's still more to do. The slot limitations are getting better. There may still be geographic limitations. In certain states, there may be only one or two centers that are able to do CAR T. There may be some limitations by insurance for disparity in accessing CAR T cell therapy that presents challenges, with geographical location and insurance playing significant roles, like more than one CAR T, for example. If someone gets one CAR T product, insurance might not approve them getting a second product that has the same target. And there is data again that we have looked at that does support that. There's a disparity in access based on socioeconomic stauts; minorities may have less access because of barriers to CAR T.

(43:16): Improving global access to CAR T-cell therapy is a goal of the future. There was a question early on about global access as well. What does it look like outside the US? There's a lot of room for improvement, a lot of room for growth of CAR T outside the US. There was a study done, a report where we talked to oncologists treating myeloma in different continents, in different countries. Most of them perceived that access to CAR T was limited. In fact, we tried to see whether Teclistamab (Tecvayli), which is a bispecific targeting BCMA, might be restricted or not. And we have results out here. Some places feel that Teclistamab (Tecvayli) may be more easily accessible. But in general, the theme is that there are resource limitations, and there's a lot of work to be done globally.

(44:18): In summary, we went over some of the indications, who to treat, when to treat. Some common toxicities, what does monitoring look like? And then future directions and areas of unmet need, including access. I'll leave it open to questions.

Question and Answer Session

(44:39): [Michael Riotto]:  All right. Thank you, Dr. Ahmed, for this incredibly great presentation. We'll now begin the question-answer session. If you have a question for Dr. Ahmed, please use the chat box on the left side of your screen to submit your question. We'll answer as many questions as possible.

(44:55):

Our first question is, and this one came up quite a lot, there's multiple questions about it, it says, "Can I do a CAR T therapy if I do not have a caregiver? And if I do not have a caregiver, does your facility help facilitate getting a caregiver?"

(45:18): [Dr. Nausheen Ahmed]: Yeah, that's a great question. And the answer, I mean, in very simple terms is that a caregiver is required. It is one of the requirements because of all the side effects that might happen, which we just discussed. Many facilities will go through a rigorous process where the social workers talk to you about potential caregivers. In our own facility, most patients, when they first hear about CAR T, they haven't thought about caregivers. It comes as a surprise. We help them think through who potential caregivers could be. Look at friends, sometimes church families and other people that might be helpful. And then there may be some resources. Again, this may depend on insurance and payment, but there may be some resources available. I would encourage all patients to definitely talk to the social worker at the facility that they're being treated at, or that they're being evaluated at.

(46:28): [Michael Riotto]:  Great, thank you. Next question, Doctor. "Can you compare the CAR T therapy compared to an autologous transplant as far as post-therapy recovery time?" In other words, they want to know the difference. Does it take longer to recover from CAR T than transplant, basically?

(46:50): [Dr. Nausheen Ahmed]: That's a great question. Again, so most of my patients in this, I'm going by their experience, find that the autologous transplant may be harder initially. Physically, there are more GI symptoms like mucositis, nausea, diarrhea, and others. You may not see that with CAR T, right? Even hair loss, you may not see that as much with CAR T. CAR T has its own set of side effects, which patients may cruise through completely, or they may have complications, which again affect how long it takes to recover, such as that neurotoxicity or cytokine release syndrome and infection. So again, physically, if everything's going well, some people really cruise through CAR T. But there are things to think about even in the long term with CAR T, infections in particular.

(47:45): [Michael Riotto]:  All right, thank you, Doctor. Our next question. "Can you have another CAR T after the first one if the first one doesn't work or fails, or you get 18 months, can you do another one?"

(48:01): [Dr. Nausheen Ahmed]: Yes. The answer is if it's the same target such as BCMA, which is Abecma (Ide-cel) and Carvykti (Cilta-cel) both target BCMA, the standard-of-care. If insurance allows, technically, you could get it. But sometimes that in itself can be a barrier. There are CAR T trials, also. Some of these trials may have more than one infusion. So please talk to your center about any CAR T trials that might be out there. Many of those trials might still take patients who've had previous CAR T. There's also CAR T s that are coming out, as I showed, with different targets such as GPRC5D, and others. You might still be eligible for those CAR T s. And all of that right now is in the context of a clinical trial.

(48:53): [Michael Riotto]:  All right. Thank you, Doctor. There's lots of questions about secondary cancer, and you touched on it a little bit. And basically, a few of the questions revolve around, is the incidence higher to get secondary cancer? Is it greater with CAR T than with a transplant?

(49:13): [Dr. Nausheen Ahmed]:  There is no head-to-head comparison right now with CAR T and transplant. There is a risk of secondary cancers, including MDS and AML, any of those that can happen with transplant, with exposure to Revlimid or Lenalidomide, the duration of exposure to lenalidomide. And then also with CAR T. I think we are learning more about this. We still have to see how it is. We need longer follow-ups.

(49:44): [Michael Riotto]:  Okay. And then there's several questions about age. People want to know, "Is there an upper age limit? If I'm 70, can I do this? Can I not do it?" Can you talk more about the age factor in CAR T?

(50:01): [Dr. Nausheen Ahmed]: Oh, yeah. There is no age limit. There is no age limit for CAR T. When we do an assessment, we look at the fitness. How fit is the patient, what are their comorbidities? Can the kidneys handle it? Are the blood counts going to recover? What are the risks of infection? What are the baseline counts, what is the patient coming in with? Age by itself is not at all a barrier. In fact, one of the studies shows that patients who are above the age of 70 might respond better to CAR T in terms of efficacy.

(50:40): [Michael Riotto]:  All right, thank you. Next question, Doctor. How long do you have to be on IVIG infusions after CAR T? Do you get them one every two months? Do you have to have them at all?

(50:56): [Dr. Nausheen Ahmed]: I typically do recommend checking IgG levels. And if the IgG levels are low, less than 400, which is what we use at our institution, then we want to treat the hypogammaglobulinemia. We want to treat it with IVIG infusion because there's still that risk of infection: viral infection, respiratory viral infection, non-respiratory viral infection. Possibly, the risk can be reduced if you have that IVIG replacement. Now the frequency of this, we check it monthly, and it can be replaced as frequently as monthly. However, if a patient is doing really well, not having any respiratory infection, you can definitely have a discussion with the doctor to see, do you need it at all? Do you need it every two months? Sometimes it can be more tailored to the situation. Is there a lot of respiratory viral infections going around or not?

(52:05): [Michael Riotto]:  Okay. Next question, Doctor. Are there tests to find out how many T-cells remain one year past CAR T therapy?

(52:16): [Dr. Nausheen Ahmed]:  That's a really good question. Yes, with CD19 CAR T s, we have a Viracor that does test to see CAR T persistence. We don't typically test for this, though. We do look indirectly at some B-cell aplasia, which would be low number of B cells or even plasma cells in the bone marrow to see if the CARs are persistent. But there are tests out there. There are many. The clinical trials use these tests, and they're coming out in the commercial space.

(52:54): [Michael Riotto]:  Okay, thank you. Next question. Can you talk a little bit about how effective, or is there a comparison out there or studies of how effective CAR T is concerning high-risk myeloma?

(53:14): [Dr. Nausheen Ahmed]:  There are studies out there showing that high-risk myeloma, which is extramedullary disease or high-risk cytogenetics, may have a lower response rate. But again, these are some retrospective studies. And I'm still looking, waiting for more data in the real world setting to get better answers on that. But right now, that wouldn't affect us using the CAR T at all.

(53:44): [Michael Riotto]:  Okay. This one's not exactly related to your presentation today, but maybe you can comment on it. A person asks, "Is multiple myeloma hereditary?"

(53:55): [Dr. Nausheen Ahmed]:  We typically think of multiple myeloma as environmental disease. So not necessarily hereditary. There are maybe rare cases of families having myeloma, but most of the time, it's because of environmental exposures over a lifetime which cause these plasma cells to have changes, and ultimately evolve into multiple myeloma.

(54:25): [Michael Riotto]:  All right, we have time for one or two more questions. This one talks about "Are there any complications if you've been heavily pretreated, especially with Revlimid, going into CAR T therapy?"

(54:42): [Dr. Nausheen Ahmed]:  No. The basic thing with Revlimid (lenalidomide) would be if there are any cytopenias. But I mean, no, there shouldn't be. We are not using stem cells from the patient, so it wouldn't affect necessarily the collection process. It shouldn't, no. The short answer is no.

(55:01): [Michael Riotto]:  Okay. Thank you. Sorry for the chuckle there but thank you. Next question, and this one's probably the most complicated one I see here. Lots of questions about "How do you choose between a bispecific, transplant and CAR T? How do you make that decision?"

(55:21): [Dr. Nausheen Ahmed]: The field is rapidly evolving. Just within the last four weeks on April 4th and 5th, the CAR T has jumped from being fourth line now up to first and second line. There may be many different ways in which we approach myeloma. Transplant for sure, we would consider it mostly in newly diagnosed myeloma patients. There are still studies coming out, that later on in the future, we might challenge the role of transplant. But right now, anyone that's newly diagnosed, they get their initial induction. Then they get evaluated for a transplant if they have a good response, and then go on to maintenance. So that's still all one line of therapy.

(56:11): How do I think of bispecific or CAR T in the relapse refractory setting? I would again take into account what is available, what's going on with the patient, what's the pace of the disease? What are the comorbidities? Does the patient have the support system ready, and are they ready for CAR T? Is there a slot available? A lot of those logistic factors, as well as the disease factors that I take into account. If the disease may be progressing at a faster rate, or we cannot get a slot in time, one may want to start with bispecifics. But my intimation is whenever we can, we should try and collect for CAR T if the patient meets criteria, and if the patient has a good social support system and everything in place.

(57:06): [Michael Riotto]:  All right. One final-

(57:11): [Dr. Nausheen Ahmed]: Yeah, sorry. These are just general ways that we approach this at our institution. We've taken all this information, and a bunch of experts, we discuss all this and try to come to the best answer for the patient. And taking into account what our social worker says, what our financial counsel says. Everything.

(57:37): [Michael Riotto]:  Okay. All right, Doctor. Thank you so much. We are out of time for questions. On behalf of BMT Infonet and our partners, I'd like to thank Dr. Ahmed for an extremely helpful presentation and for answering all those great questions.

(57:51): And thank you, the audience. I so appreciate those questions. It helped me. I'm a 12-year myeloma patient myself. Please contact BMT Infonet if we can help you in any other way. Enjoy the rest of the Symposium, and the rest of your day. Thank you very much.