What is CARVICTI? CARVICTI is the trade name for siltocaptogen autoleusel or siltacell. And this is actually a CAR T cell product that's made from patients' own cells. And so the way it works is patients have their T cells collected, and T cells are part of our immune system. They normally help us fight bacteria or viruses. But in this case, a small proportion of T cells are collected, and then those T cells are engineered outside the body to now recognize the cancer cell, in this case a myeloma cell. And then it's grown up to large numbers, these myeloma-specific T cells. And then the CARVICTI is actually that CAR T cell product, that sort of package of cells. So that's shipped back to the treating center, and then it's re-infused into the patient. And so that's what CARVICTI is. It's a T cell product made from the patient's own cells. 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. And 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 from collection of T cells to re-infusion of the CARVICTI product? It's usually about four to six weeks from the time that we collect the T cells to the time they're manufactured and go through quality testing and then get sent back to the center. What is the current indication for CARVICTI? So right now patients have had to have four prior lines of therapy. And line can be a little tricky. It's not just four different drugs. It's sort of four treatment programs. And the disease, unfortunately, has come back after those. And it has to include what's called an imid, which is a drug like Revlimid or pomelist or thalidomide, a proteasome inhibitor, which are drugs like Velcade and Kyprolis or Ninlaro, and a CD38 antibody, which is like Daratumumab, Darzalex or Esotuximab. So you have to have had at least one of those three categories and have gone through at least four different treatments. On April 5th, 2024, the US Food and Drug Administration approved CARVICTI for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent and are refractory to lenalidomide. With this approval, CARVICTI becomes the first B cell maturation antigen-targeted therapy approved for the treatment of patients with multiple myeloma as early as first relapse. Are there any age restrictions or comorbidities that may exclude you from CARVICTI therapy? So there's certainly no age, upper age limit. And we have done CAR-T cells in patients in their 80s. I do think comorbidities are important, though. We really need to be able to withstand the CRS or the neurologic issues if it happens. And so we often will exclude people who have advanced heart failure or advanced emphysema or COPD if you're chronically on oxygen. Those patients may not have the cardiac or pulmonary reserve to manage this. And again, this should be a discussion with your doctor. And if there's any question, I would still say refer them to the CAR-T center so we can assess. We usually do echocardiograms, which is the ultrasound of the heart, and pulmonary function testing to measure lung capacity to see if someone would qualify. But those would probably be the main ones. I also think patients who are really just so sick that they're really unable to get out of bed, they're in a wheelchair, they're in a stretcher or really unable to walk, those patients would be difficult to treat, but again, not impossible. And I think we'd have to discuss that on a case-by-case basis. Can you explain the harvesting process, also known as leukophoresis? Is it similar to harvesting stem cells? The process may seem similar to stem cells. Patients sit on this machine called an aphoresis machine, and blood goes out, they suck off the T cells, and the blood goes back in. You're on the machine about three hours. The big difference, though, is that to get stem cells, patients have to take medicines first, typically shots. One is called neupogen or GCSF, another is called mozabil. And those shots are taken for several days, and that gets the stem cells out of the bone marrow into the blood. The good news is that for carvicti and other car T cell products, you don't need to take those extra medicines. We all have plenty of T cells that are already circulating in our blood, and so you can just sit on the machine, take the blood for a few hours, get off the stem, the T cells, and put the blood back in, and you're done in one day. There's no need for any other treatments or medicines. Is it possible to not collect enough T cells to successfully manufacture the carvictic product? It is possible. Fortunately, that happened very infrequently on the trials. It's really usually only one or two percent of patients, at least on the trials, that weren't able to manufacture. So the vast majority could. But now that we're in the real world, and we'll have to see sort of how well it works in practice, but hopefully that won't be a common problem. What is bridging therapy, and why might it be necessary? So the bridging therapy refers to the treatment you get while the car T cells or carvicti is being manufactured. So during that four to six week period while you're waiting, you don't want to let the myeloma to start to take off, and then the patient might get too sick or develop organ problems like kidney failure and not be able to get the actual car T cells. So the bridging therapy is treatment that's given during that four to six week period, sort of hold things in check. And bridging may be different for every patient. It depends a little bit on what treatments you've had in the past, what your doctor thinks is most likely to control your myeloma. And so typically this is a decision that's made sort of as a collaboration between your primary treating oncologist as well as the car T cell physician who's going to be administering the cars. They often will work together and look at your treatment history and come up with the plan for bridging. Are there any treatments you should avoid as bridging therapy? I don't think there's any absolute rule saying you must not get this, but the main things are we try to avoid things that could lead to some sort of complication. So things that are going to severely suppress your immune system and perhaps lead to an infection or cause any risk of a blood count not recovering, et cetera. So I don't think there's anything that you can't use, but you have to take those things in mind. You really want to make sure the patient's recovered in that four to six week period so they're able to go for the cars when they're ready. Blend rep hits the same target as carvicti and other car T cells. And so it hasn't really been studied as a bridging therapy to know what happens if you give that and then give the cars. So again, I don't think it's an absolute contraindication. It wouldn't be my first choice. I would probably want to try something else just because we don't have much experience really with Bilanthamab as bridging. But in some cases, if that's all you got, that's all you got. If your bridging therapy is so effective that you no longer have any detectable myeloma left, can you still receive carvicti? So you actually can. And I'll say, first of all, right now these cars are approved for patients who have really progressed on multiple treatments and often their disease is resistant. So it would be really unusual to sort of totally eradicate the myeloma just with a couple weeks of bridging. So in almost everybody, there's at least some disease left. But I will say we have done a study here at Penn led by Al Garfo, one of my colleagues, where we actually did car T cell treatment in myeloma patients who were responding to their treatment. And some patients responding very well. They had less than 5% plasma cells in the bone marrow, had a really low burden trying to limit that toxicity. And we found that the cars could still expand and we actually still could get responses and we did see less toxicity. So to answer your question, even if somebody had a great response to the bridging, I would still take them to the car T cell therapy. Because if we're doing it, it means their disease has come back, unfortunately, several times already. And we wouldn't expect the response to last that long just from the bridging alone. What is lympho depleting chemotherapy or lympho depletion? Lympho depleting chemotherapy. It's typically two drugs. One is called Cytoxan or cyclophosphamide, which some of you may be familiar with. Another one called Fludarabine that we don't usually give in myeloma. But these are both intravenously administered chemo drugs. They're typically given three days in a row and we do it as an outpatient. And that's designed to temporarily lower sort of the white blood cell count in your body to allow the car T cells to go in and really expand. And so it's been shown that that actually augments the expansion of the cars and their activity. So you get the three days of the lympho depleting chemo. We do that as an outpatient, typically on a Wednesday, Thursday, Friday. You then tend to get two to three days off. And then you would come in and get your car T cells infused. How is the Carvicti product infused? The way those are infused may differ from center to center. You may get some Benadryl or Tylenol ahead of time as a pre-med. But most of the time the infusion itself is fairly anticlimactic. So here at Penn, we have a lot of experience with outpatient car T cell infusions and we have a whole setup for that. So we would actually give your Carvicti typically as an outpatient in one of our infusion rooms or in our aphoresis suite. And it would be given by one of our nurses who have experience giving these products. And they typically tend to go in fairly quickly. They can go in through a peripheral IV or through a port or a PICC line. And they're in probably between 15 to 30 minutes. There are other centers though that only give car T cells as an inpatient. And so they actually would admit you to the hospital and you'd have an inpatient bed. And then they would administer the cars. And there's very little in terms of immediate reactions. Some people can feel a little flushed maybe from the cryopreservative. If patients receive Carvicti as an outpatient, would they need to be admitted to the hospital at some point? So again, it depends a little bit on the center. Carvicti is a little bit different than the other CAR product from iloma called the Beckma in that the timing of the CRS, the cytokine release syndrome, which is one of the side effects of when that CRS occurs. So with Carvicti, the CRS usually doesn't occur till around day seven after CAR T cells. And so that's why we do it as an outpatient and don't make patients sit around all that time. So they'll admit them to the hospital day five when we think there's a chance of the CRS starting. And then they're typically in the hospital from five to seven days while you're managing them for their CRS. Again, other places may admit them right from the start just so they can monitor them closely. And they may be in the hospital for seven to 10 days. So Carvicti, we expect it to come a little bit later. So when they're in the hospital, then the staff really is providing that 24-hour care. And you don't need to have a caregiver there with you. If you're doing it as an outpatient, you still have to come back and forth for visits almost every day and laboratory checks and exams. And there, it really does help to have a caregiver with you to be able to monitor you and bring you back and forth if necessary. With the lymphodepleting chemotherapy, those three days of chemo before the CARs, there can be some nausea and loss of appetite. And that tends to be short-lived and go away. I mentioned the CAR T-cell infusion is usually pretty anticlimactic. The big one, though, is what's called CRS or cytokine release syndrome. As I mentioned, this tends to occur about seven days on average after the CAR T-cells. It can be manifested as fevers and flu-like symptoms. People can just feel achy and fatigued and a little bit loss of appetite. And that's most common. So those mild symptoms, and they're managed with Tylenol and rest and fluids. But occasionally, cytokine release syndrome can become more severe. It can actually mimic more of a sepsis-like picture where your immune system gets over-activated. You can develop low blood pressure or trouble breathing. You might need oxygen, fluids, and medicines to bring your pressure up. And that, fortunately, is much less common than just the flu-like symptoms. But if it occurs, we do need to intervene and act on that. And we would give an antidote-like medicine called tocilizumab or TOSI, which is an infusion that's been shown to sort of calm down the cytokine release syndrome, calm down the overactive immune system after CAR T-cells, and relieve a lot of those problems. And so that's why you're in the hospital at the time that this is likely to occur, so that the doctors and nurses can really jump on that very quickly. So I think CRS would be the most common. The other side effect with carvicti and other CAR T-cells is called neurotoxicity or neurologic issues. And these were seen less frequently. Maybe about 20% of patients might get them. They tend to occur around the time of CRS or shortly thereafter. And this can be anything from just a little bit of mild confusion and bad headache, which can be self-limited, but in some cases can become more severe with delirium or even rarely seizures and other things. And in that case, again, we have to treat with TOSI and steroids like dexamethasone to try to reverse these. And we're fortunately able to reverse these side effects in the vast majority of cases, but not in every case. So that's something patients have to know and discuss with their doctors. We certainly were really worried about that in the very beginning. We were nervous about giving steroids because we know steroids can affect T-cells in a negative way. It turns out, though, if it's really only a short course of steroids, a day or two, that doesn't seem to have a major impact. And so we're much more liberal with using steroids if people are getting even any neurologic toxicity, if they're starting to get confused or have trouble with finding the words, that's called aphasia. We'll often start some dexamethasone and many patients will start to improve within a dose or two. Where we start to see problems if they get more severe side effects and they're really having problems and they have to be on steroids for weeks, then we worry maybe it's having some impact. But I wouldn't worry about a short course. If your doctor wants to put you on steroids briefly to help with toxicities, definitely do it. So not exactly, to be honest with you, and particularly with carvicti, where the response rate was 98 percent. So almost everybody responds. And honestly, almost everybody gets CRS, too. It's hard to sort of tease out those two things separately. But what we have seen is that the severity of CRS and even the neurotoxx may be correlated somewhat with the sort of burden of myeloma, the way your disease is behaving at the time you go into the car T cells. And patients who had unfortunately really aggressive disease, their disease was progressing through bridging therapy and was growing rapidly, may have a higher chance of more severe CRS. So that's why the bridging therapy is important. We really want to try to control the disease, keep it somewhat in check as you're going into the car T cells. And that hopefully will limit the toxicities. So hypogammaglobulinemia, which I agree is a mouthful, refers to an inability to produce normal levels of immunoglobulins, which are your antibodies. So it's your you'll see these tests called quantitative IgG, IgM, IgA levels sometimes. And those sometimes can reflect the myeloma, but also reflects your body's normal antibody levels. And so most patients with myeloma actually have hypogammaglobulinemia, especially once they've gone through multiple treatments and have gotten to the point where they need car T cells. So it's actually very common even before car T cells. And the car T cell treatment and the chemo that goes with it definitely can worsen that. BCMA, which is the target for carvictin and the other car products in myeloma, is on normal plasma cells, which are the cells that make our antibodies. And so in addition to taking out your myeloma, you're going to take out your normal plasma cells for usually several months. And so that hypogammaglobulinemia worsens in almost every patient. Fortunately, we have a way to sort of combat that. We have something called IVIG, which stands for intravenous immune globulin. And these are infusions that can be given to the patient every four to six weeks that basically give you a boost of normal antibodies. It's sort of like a red blood cell transfusion. But instead of red cells, you're getting good antibodies. And we were using that even before car T cells, but we're certainly using it more often now. And many patients need that even up to six or nine months sometimes after the cars. But ideally, if they're in a good remission, their normal immune system starts to recover. And eventually we can stop that. There's several different formulations. And unfortunately, sometimes which one we give is dictated by the insurance coverage, because the insurance will say you get this formulation or that one. Some of them are subq. Some of them are IV. The subq. I feel like is used more in pediatrics than adults. Most of my patients end up with IV, but some of them do get it at home if they have a home in a porter pick line or sometimes even a nurse will come start an IV and get it. What should patients consider before they decide that car Vicky should be their next treatment? 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 Johnson and Johnson and Legend biotech's car Vicky. The boxed warning on Car Vicky's label includes a new item stating that secondary hematological malignancies, including myelodysplastic syndrome and acute myeloid leukemia, have occurred following treatment with Car Vicky. A boxed warning is the FDA's most serious safety related warning for drugs on the market. Previously, the risk for secondary malignancies was listed in the warnings and precautions section of Car Vicky's label. This section is lower and not as prominent as a boxed warning. What are the things you need to know before you decide to go to a car T treatment? So I guess the things you need to know. So one, have you had enough treatments to really qualify and been through a lot of the standard treatments, at least as it is right now, as I mentioned? Do I have sort of the lack of comorbidities as we talked about? And then the main thing is it is a bit disruptive of your life. You need to be able to come down to the car T cell center and get the collection and then after the infusion, be willing to be hospitalized. And even after your discharge, we usually ask patients to stay within an hour of the center for that first week after discharge, sometimes even up to two weeks just to monitor them for any late complications. And so it is a commitment. Most centers do have social workers to help with housing and reimbursements and things if if that's an issue. But you have to realize it is a time commitment. It's almost like stem cell transplant a little bit. You have to understand sort of that you need to be near the center for those first several weeks. And then you will need to continue to collaborate with the car physician even when you go back to your local oncologist. So they'll sort of take over again, but they'll be intermittent visits and discussions back and forth. So for our parameters, they have to be without a fever for 24 hours, not requiring any fluids or any IV fluids or support of their blood pressure. They're eating and drinking OK and no neurologic symptoms at all. So that's sort of our minimum threshold. And again, for car victi, we're usually waiting at least five days from their admitted day five. I'm usually waiting till day 10 for a Beckman, the other program where the CRS usually occurs much earlier on day one or two. You know, we're often letting them go home by day seven if they had their CRS early and they've recovered and everything else looks good. So it may vary from product to product and even program to program. They have a little bit different requirements. What is the role of the caregiver? Right. So I think particularly if you're doing outpatient cars like we are for those first five days, it's really important to have someone there monitoring the patients, helping them make sure they're eating and drinking OK, helping monitor temperature, looking for any fevers, which would be a sign of CRS, any neurologic issues, patients sort of just not themselves. They're not maybe thinking clearly or repeating themselves or there's something different that I think is is helpful. And then even after their discharge from the hospital, patients have gotten through the CRS and other things, but they still may be pretty wiped out and tired. They may need help with people doing sort of shopping and cooking and things like that until they get back on their feet after a couple of weeks. A caregiver will be needed to drive CARVICTI recipients for at least eight weeks after treatment. CARVICTI recipients are asked to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery for at least eight weeks after treatment and in the event of new onset neurologic toxicities. Are any remote monitoring devices used for CRS? No, we have not actually started doing that. I mean, most of our patients have blood pressure cuffs at home and can monitor that and they can monitor temperature. Some even have pulse oxygenation, you know, where they can look at their oxygenations. But we don't give them that or have that as an official program. That would be an interesting thing to think about, though. Is there any approved maintenance therapy after CARVICTI treatment? As it is currently approved, there's not. And the studies that got CARVICTI and ABEKMA, the other one approved, did not use maintenance therapy. But that's certainly a big interest of the myeloma community, research community, is trying to see, can we extend the duration of these remissions? Unfortunately, even though these CARV products work fantastically well, they don't appear to be cures in the majority of patients and the disease still can come back. And so there are those trials ongoing now. What if we add another drug afterwards as a maintenance? And we may be able to risk stratify patients saying people who may be at higher risk of it coming back, you'll get maintenance, whereas the other people maybe you'll do fine with just the CARVs alone. We're just not there yet. How quickly do you see a response to CARV T cell therapy? So if you look at the trials, they all say the median time to response, which is sort of the most common, is one month. And so that's really when often the very first restaging occurs. And most patients who have responded have responded by a month. But that response can deepen actually over time. So you may be in a partial response at a month, but then a very good partial response, which is a 90% reduction by two months and then a complete response by three or four months. We sometimes do check earlier. We'll sometimes check at day 14. And many patients, especially if they have light chain myeloma, the kappa lambda type, the half life of light chains is very short. And many patients will normalize their light chains even in 14 days. So it can be very rapid. But typically we tell people about a month. And that's when we do our official first assessment. How long do the CARV T cells persist? We know they go to the bone marrow. So there's been bone marrow biopsy done on all these studies. And they do traffic down there. And that's where we think they do most of the killing. How long they stay can vary from patient to patient and even disease to disease. Recently, Penn published a paper for a couple of patients with CLL, a different bone marrow cancer, that got CAR T cells in 2011 and still had CAR T cells in their blood 10 years later. And that's an extreme, but that's really fantastic. For myeloma, most of the CARs seem to be shorter lived. So again, somewhere between three and 12 months is what we typically see. And again, it depends on the product. For CARVICTI, it seems like the CARs stick around a little less than a Beckma, for instance. And again, these are small numbers. They haven't really been compared head to head. But I would say it's somewhere in the order of several months. They don't really stay forever, we think, in most of the myeloma patients, at least. What are your final thoughts about CARVICTI? I think really we're all very excited about this, to have this product on the market and actually have two different CAR T cell products. Hopefully we'll increase access. I think that's been one of the biggest challenges, is there's more of a demand right now than supply. And we're hoping with both of these now, there'll be more manufacturing slots and we'll be able to get more patients this treatment. I would just say, urge patients to be patient right now with us, just because, again, there's a big demand and there's still sometimes several months waiting list. But we're hoping that's going to get better as we get more slots and the manufacturing picks up a little bit. The myCARVICTI patient support program may help eligible patients along their journey. Call to discover what support is available and find out if you're eligible for the program. 1-800-559-7875, Monday through Friday, 8 a.m. to 8 p.m. Eastern Time.