All about Abecma or IDA cell. The most recent addition to the myeloma armamentarium is quite exciting. This is a CAR T cell product that's called Abecma. Those of you may have heard of this in the past as BB2121. You also may have heard of it as IDA cell, but this is the first FDA approved CAR T cell therapy for relapsed refractory multiple myeloma. How does CAR T cell therapy work? As far as CAR T cell therapy is concerned, CAR stands for, it's an acronym that stands for chimeric antigen receptor. So what the heck is a chimeric antigen receptor? So what this is, is actually a gene, a man-made or human-made gene that's typically inserted into a T cell through a viral vector in most cases. And this gene encodes a protein that's called a chimeric antigen receptor. This protein will sit on the surface of the T cell. The reason it's called a chimeric antigen receptor is because the portion of the protein that's sticking out from the T cell is actually a portion of antibody. This antibody is designed to bind to anything that has something called BCMA on it, or B-cell maturation antigen. Now importantly, B-cell maturation antigen is highly specific for plasma cells. So we see expression on all plasma cells, and that includes normal plasma cells, and that's an important issue which we'll talk about later. But we don't see BCMA expression on other tissues of the body, and that's important because the concern that we have with CAR T-cell therapy is that if the CAR, chimeric antigen receptor, can actually recognize normal tissue, it might accidentally go after that normal tissue. So the part of the chimeric antigen receptor that sits out in the breeze on the surface of the T cell, again, that's an antibody or a piece of antibody that recognizes BCMA. And then the tail of the chimeric antigen receptor which sits inside the T cell and kind of triggers activation of that T cell is actually derived from a T cell receptor. So we're basically creating this antibody T cell receptor hybrid that sits on the surface of these T cells, allows these T cells to actually bind to plasma cells, and when that CAR engages the myeloma cell by binding to BCMA, it triggers a signal through the CAR inside the T cell that basically tells that T cell to activate, to grow and expand and go after more plasma cells. How long does it take to complete CAR T-cell therapy? So the entire process for CAR T-cell therapy is complicated. So the first piece of this is apheresis. So the patient will go to an apheresis center where they'll have blood drawn for actual collection of the T cells. Now this is different than transplant. If you think about transplant, we're collecting stem cells. We're not collecting T cells in the setting of a stem cell transplant. And the other important thing is that there are plenty of T cells floating around in the circulation, whereas there's very few stem cells floating around in the circulation. So when patients go through stem cell transplant, they require growth factor support to get large numbers of these stem cells to spill out into the bloodstream. None of that is required for apheresis for CAR T-cell manufacturing. You just get the blood and there's enough T cells in there to isolate and actually create the CAR T cells. So the T cells are then sent to the manufacturer. The manufacturer, again, will have a viral vector in most cases. There's a number of different CAR T-cell products that are in clinical trials right now. Most of them use a viral vector to get the CAR gene inside the T cell, but there are other ways of doing it as well. But in the case of IDA cell, again, it's a viral vector. They sprinkle these viral vectors on the T cells that have been collected. The virus will go inside the cell. The virus will integrate into the genome, into the DNA of that T cell and will start expressing the CAR protein that's encoded by the gene that's inserted into the T cell genome. At that point, what they'll do is they'll use a number of different, basically a cocktail of growth factors to expand these T cells into much larger numbers. At that point, they're actually returned back to the center for the patient. Now, when you give CAR T-cell therapy to a patient without any kind of preparative regimen, they don't necessarily take and expand in the manner that you want. So we actually will use in most cases a two-drug combination, something called fluderabine, and the other drug is cyclophosphamide or cytoxin, which a lot of myeloma patients are familiar with, and we'll give these two drugs together over three consecutive days prior to administration of CAR T-cell that typically occurs approximately two days later. The idea behind this is to just temporarily reduce the number of T cells, non-CAR T cells that are still left behind in the patient, to make way, if you will, or give room for those CAR T cells once they're infused to take and expand when they encounter myeloma cells. So it takes weeks. So it can take anywhere from 10 weeks or so. It depends on the product that's in clinical development, and there are strategies that are actually being utilized now to kind of try and reduce the manufacturing time, but that's a particular issue. So it does take time to generate these CAR T cells, and a lot of patients with relapsed refractory multiple myeloma who have disease, that's not going to wait. So oftentimes we'll have to use what's called bridging therapy to kind of maintain control of the myeloma to the best of our ability while we wait for those CAR T cells to be manufactured. Are there any bridging therapies that should be avoided? As far as specific bridging therapy is concerned, I don't think that there are specific bridging therapies that have been shown to be more detrimental than others. I would avoid a BCMA targeted strategy as a bridging therapy prior to administration of IDA cell, for example. So I would not use Bilanetumab mafidotin or BlendRep out of concerns that that might somehow mask some of the therapeutic target for the IDA cell. I would generally, if I can, avoid therapeutics that might cause significant low blood count issues in the lead up to IDA cell administration, because one of the things that we see, particularly in the short term, after IDA cell administration are low blood count issues. And part of that has to do with the fact that we do the lympho-depleting chemotherapy for three days with fluid, air, and encyclophosphamide, but there's also probably an indirect effect of the IDA cell itself on the counts. So imagine a patient who has a large amount of myeloma in their bone marrow, and here we are giving them these weaponized T cells or CAR T cells that are basically designed to recognize and attack what's in the bone marrow. So you can see a scenario where there's a large amount of inflammation that is generated as a result of these CAR T cells engaging myeloma inside the bone marrow, and that massive inflammation that you see can cause some of the side effects that we'll talk about, such as cytokine release syndrome, but can also have a transient effect on the counts as well. How does the infusion process work? In the clinical trials for IDA cell, at least in the initial clinical trials for IDA cell, and in the clinical trials for a large number of other BCMA targeted CAR T cells in development and multiple myeloma, the administration of the CAR T cell product is done in the hospital. Now I know that there's a very strong interest in potentially being able to do that on the outpatient side of things, but at least initially the studies did it on an inpatient basis, and certainly at our center, our plan is to use commercial IDA cell therapy initially in the hospital. So in the initial clinical trials, patients receiving IDA cell in the CARMA trials, for example, were hospitalized for two weeks for observation purposes, but we do know that the median onset to cytokine release syndrome is actually one day with a range anywhere from less than one day to 12 days, and then the neurologic side effects that are sometimes seen, the median time to onset was actually two days, so shortly thereafter the cytokine release syndrome, and the median duration of cytokine release syndrome and neurologic side effects are on the order of several days. You can count them on one hand. So the overwhelming majority of patients who experience cytokine release syndrome or neurologic side effects are going to experience them early. So for now, our plan is to keep patients in the hospital for seven days and then to assess their status at that point. The overwhelming majority of patients will have experienced cytokine release syndrome, but if we have that treated and controlled and there's no lingering neurologic side effects, our plan would be to discharge them at that point. What are the common side effects of a BECMA? Cytokine release syndrome or CRS is the most common side effect of CAR T cell therapy, including IDA cell therapy, and in the CARMA 2 trial that led to FDA approval of this particular product, the incidence of cytokine release syndrome was in the 80% range. What is cytokine release syndrome? So cytokine release syndrome is basically a robust amount of inflammation that occurs as a result of these CAR T cells engaging myeloma cells throughout the body and activating in the presence of these myeloma cells. The more myeloma you have in you, the higher the likelihood it is that you're going to have cytokine release syndrome. So what are the symptoms of cytokine release syndrome? So the most common would be a fever. If it's more severe, you might actually see a drop in the blood pressure. If it's even more severe than that, you might actually have a patient run into respiratory trouble. When the blood pressure is dropping and we're requiring to administer medications to support the blood pressure, an additional therapy to support their breathing, that would be considered severe cytokine release syndrome. Thankfully, the overwhelming majority of cytokine release syndrome that we've seen in myeloma patients with IDA cell has been grade one or two in severity and generally well managed, typically with an anti-interleukin 6 receptor antibody called tocilizumab. So with that, very successful management of cytokine release syndrome. And we found that when we intervene promptly with lower grade cytokine release syndrome, that the overwhelming majority of patients will not go on to develop a more severe cytokine release syndrome that was sometimes seen in the earlier trials. Question always comes up, do you need to have experienced cytokine release syndrome in order to respond to CAR T cell therapy? And the answer is no, you don't. Again, the burden of disease in part is going to dictate whether someone has clinical symptoms of cytokine release syndrome. So if a patient is going into CAR T cell therapy with a relatively low burden of myeloma, they may have a much less severe case of CRS or perhaps they may not have any CRS at all. Now in other blood cancers, where CAR T cell therapy is approved, there is some link between cytokine release syndrome and achievement of response. So those that do get cytokine release syndrome are more likely to respond than those that don't, but those that do not get cytokine release syndrome are not doomed to no response. What is immune effector cell associated neurotoxicity syndrome or ICANS or neurotoxicity? So ICANS is a unique side effect of CAR T cell therapy. ICANS is an acronym that stands for immune effector cell associated neurotoxicity syndrome. So what exactly is that? This is something that oftentimes occurs in close proximity to those patients that have undergone cytokine release syndrome. It usually occurs one to several days after the onset of cytokine release syndrome, and it's a constellation of neurologic side effects, and we don't fully understand why it happens, but thankfully we're much better at identifying it and treating it when it does occur. The most common clinical manifestation of ICANS for a patient who's gone through CAR T cell therapy would be confusion. We actually will run the patient through a battery of tests to understand exactly whether or not ICANS is occurring, so we'll do it at baseline before they have the CAR T cell infusion, and we'll actually monitor their score on this test over time. If we see it drop or if we see other signs of confusion or what have you, that's the signal that ICANS is beginning to occur and that we need to intervene. Typically we'll intervene with steroids, and dexamethasone is the most commonly utilized corticosteroid to treat ICANS, and it is actually quite effective. As long as you intervene early, you can actually head it off at the past, which is good, but unfortunately in very rare instances, patients might actually develop severe ICANS, and that might actually lead to a much more significant decline in mental status to the point where a patient can actually become comatose and need ICU level care, and in some instances has been associated with seizures. For that reason, it's very important to identify it early and intervene with steroids so we don't get into a situation where the patient is encountering a severe manifestation of ICANS. Now thankfully with IDA cell, the rate of ICANS is actually not that high, and the rate of severe ICANS is very low, well under 5%. But again, it speaks to the need for monitoring the patients very closely after CAR T cell therapy, both the healthcare team as well as the caregivers, and looking for any subtle signs of neurologic changes that might indicate that ICANS is rearing its ugly head. So a common question is whether or not dexamethasone will somehow impair the effectiveness of the CAR T cell product for patients, and that's something that we're actively investigating in the myeloma space, but I will let you know that with other CAR T cell therapies, so for example with B cell acute lymphoblastic leukemia and B cell non-hagic lymphomas, utilization of corticosteroids like dexamethasone to treat ICANS does not have a negative impact on response to the CAR T cell product. The most common side effects of a becma are fatigue, fever, chills and shivering, severe nausea or diarrhea, decreased appetite, headache, dizziness or lightheadedness, confusion, difficulty speaking or slurred speech, cough, difficulty breathing or fast or irregular heartbeat. A becma can lower one or more types of your blood cells, such as red blood cells, white blood cells or platelets, which may make you feel weak or tired or increase your risk of severe infection or bleeding. After treatment, your healthcare provider will test your blood to check for this. Tell your healthcare provider right away if you get a fever, are feeling tired or have bruising or bleeding. Using a becma in your blood may cause a false positive human immunodeficiency virus or HIV test result by some commercial tests. As the FDA investigates a safety signal for approved CAR T therapies, the agency has upgraded a warning about secondary cancers following the use of a becma. In November 2023, the Food and Drug Administration posted a safety communication to provide information about reports of T cell malignancies including chimeric antigen receptor CAR positive lymphoma in patients who received treatment with BCMA or CD-19. Directed at all August CAR T cell immunotherapies. A boxed warning is the FDA's most serious safety related warning for drugs on the market. Previously, the risk of secondary malignancies was listed in the warnings and precautions section of a becma's label. This section is lower and not as prominent as a boxed warning. What is the indication for a becma? The FDA label for IDA cell is very similar to that of PAPAXTO with dexamethasone and BALANTIMAB mafidotin. It's patients with relapsed refractory, multiple myeloma who have received at least four prior lines of therapy for their disease. Again, these are a group of patients that largely have what we call triple class refractory disease. In other words, their disease has become resistant to at least one proteasome inhibitor, one immunomodulatory drug, and one CD38 antibody therapy. On April 4th, 2024, the FDA approved a becma for treatment of adult patients with relapsed or refractory multiple myeloma after two or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. What should be considered before trying CAR T cell therapy? So I think there's a couple of important considerations before considering treatment with IDA cell. I think it's important that patients recognize that cytokine release syndrome is a real side effect. They need to understand that. They need to recognize the signs and symptoms of cytokine release syndrome so they and their caregivers can recognize it quickly, alert their health care team, and intervene quickly. Similarly, ICANS is something that needs to be understood very carefully before receiving this product because the caregivers need to be able to identify that ICANS is going on so they can again alert the health care team and intervene appropriately. I think it is important to recognize that there are low blood count issues that occur after receiving IDA cell, and again, that's in part due to the lympho depletion chemotherapy that's given before the CAR T cell infusion and some of the inflammatory changes in the bone marrow that occur as a result of the mechanism of the therapy. So counts need to be monitored very closely. Patients may need transfusion support temporarily. They may need growth factor support to support their neutrophils. There's going to be a requirement for prophylactic antibiotics to reduce the risk of infection, so it does require a very close monitoring after administration. And those first 30 days are absolutely critical. So while the initial piece of this is going to be given in the inpatient setting, at least initially, it's important that the patient is being monitored very carefully on an outpatient basis, particularly for those first 30 days. Does a patient need a caregiver with them 24-7 to have CAR T cell therapy? So from my perspective, a patient who's been through CAR T cell therapy should have a caregiver at their side 24-7 for the first 30 days of therapy. So the caregiver that would monitor a patient after CAR T cell therapy, I mean, at least initially, for those patients that receive it in the hospital is going to be the medical team that's taking care of the patient. So once they're discharged from the hospital, the caregiver should be someone who's very familiar with the patient and could recognize, for example, very subtle neurologic changes that perhaps someone else would not be able to recognize. Are there any comorbidities or age restrictions that would prevent a patient from getting CAR T cell therapy? So there are no age restrictions with regards to administration of CAR T cell therapy. This has actually been looked at more carefully just because it's been around longer in the B-cell non-Hodgkin lymphoma space. And there's actually very nice data that older patients are actually doing very well after CAR T cell therapy without a significant difference in the rate of cytokine release syndrome or neurologic side effects, for example. I think that there's probably several underlying medical conditions or comorbidities where I would need to think very carefully about the safety of administering CAR T cell therapy. So someone who has severe heart condition, so, for example, severe perhaps suboptimally controlled congestive heart failure, somebody who has severe underlying lung disease, these are the kind of patients who might not be able to tolerate a bad case of cytokine release syndrome were it to occur. The other group of patients that I would use it very cautiously in is someone who has a significant underlying neurologic disorder that has already created problems for them as far as confusion and those sorts of things. That might be the kind of patient that does not tolerate an episode of ICANS, for example, terribly well. So those would be the main things. But if we have a patient in their 70s or early 80s, for example, who does not have significant heart lung disease, you know, has good neurologic function, I mean, I think that that's as good of a candidate for IDA cell as a 50-year-old patient with the same profile. What is hypogammaglobulinemia? What is the likelihood of getting it during CAR T cell therapy? An important side effect to recognize after IDA cell therapy is acquired hypogammaglobulinemia. What that means, hypogammaglobulinemia basically means low antibody levels. Now this is actually something that a lot of multiple myeloma patients contend with anyways. So patients who have suboptimally controlled multiple myeloma may actually have low normal antibody levels to begin with. A lot of myeloma patients are on monthly IVIG infusions as a result. Some of our other therapeutic strategies can sometimes affect normal antibody levels. Some of the CD38 antibodies like daratumumab and isotuxumab can affect normal antibody levels. As I mentioned before, IDA cell targets BCMA, B cell maturation antigen. That is a plasma cell specific marker. So these CAR T cells, these weaponized T cells, are very good at killing cancerous plasma cells or myeloma cells, but they're also incredibly good at killing normal plasma cells. Your normal plasma cell pool is what's responsible for making antibodies to fight off infection. So severely low antibody levels, immunoglobulin G, M, A, serum-free capillite chains, serum-free lambda-light chains, all of that drops very low after treatment. And the overwhelming majority, I would say 100% of patients, will wind up on IVIG therapy at least for a period of time, at least a year after receiving therapy as a way of reducing the risk of infection because of those low antibody levels. And IVIG is basically a transfused, it's a blood product basically. It's an antibody pool that's been derived from donors. So I think that the duration of IVIG therapy that's required for the hypogammaglobulinemia that occurs after BCMA targeted CAR T cell therapy, the duration remains to be seen, at least from personal experience, and this is with IDA cell as well as the Janssen product CILTA cell, I would say that the majority of patients will require therapy for at least a year. But as you get further out from CAR T cell infusion, particularly if you're still in complete response, we are beginning to see signs of normal plasma cell recovery and improvement in immunoglobulin levels and at least again, and this is anecdotal, from my experience, from the one to two year mark is when we really start to see that normal plasma cell population start to recover. A BECMA is only available at certified treatment centers that are trained to monitor and manage potential side effects if they occur. Cell Therapy 360 offers assistance programs for you and your care partner that are designed to support you throughout treatment and the initial post-infusion monitoring period, at least four weeks. To learn more about the support offerings available through Cell Therapy 360, talk to your healthcare team for more information. Visit celltherapy360.com or call 1-888-805-4555 Monday through Saturday, 24 hours a day.