All about Talve. So talcuitumab or Talve is a first in class bispecific molecule that targets GPRC5D. So why is this important? First bispecifics are off the shelf, which means that they're ready to go and it's the same product that's given to every patient for the indication. The second reason it's important, other than being off the shelf, is it's the only bispecific and actually the only therapy right now of any kind targeting GPRC5D. Because this is a first in class bispecific molecule that's off the shelf, I think there's going to be a huge need for this product. How do bispecific antibodies work? The way the bispecific works is it's almost like a handcuff or double-sided tape. One side binds to the myeloma, the other side binds to the T cell, and it takes these T cells and brings them to the cancer. What is GPRC5D? On which cells is GPRC5D expressed? Are there any on target off tumor side effects? So GPRC5D is important because it's a protein that's overexpressed specifically in myeloma cells but not so much other cells, and that means this specificity makes it an ideal candidate for immunotherapy. Here, because GPRC is preferentially overexpressed in malignant or cancerous plasma cell, we have some data that we think we can kill the bad stuff but not so much the good stuff. And so what that means for the side effect profile is one of the most challenging things and the most common cause of complications in myeloma and death in myeloma is infections. And so this particular therapy seems to have a much better profile when it comes to deaths and serious infections than other drugs in this space. And that's what's nice. Now, of course, every drug does have its side effects, and some of the side effects of this particular agent are related to what other cells are expressing GPRC5D. And those include what we call heavily keratinized tissues, which means keratin is a protein that's expressed in certain soft tissue cells, so in skin and in nails in particular. So we do see rashes, we see peeling of the palms and the soles, and we see nail changes. And then the other thing that we see that's a little bit, we're still trying to understand the mechanism, is loss of taste. So it could be oral things, it could be dry mouth, difficulty swallowing, loss of taste, those can lead to weight loss. So I would say those are the two major compartments, kind of the cutaneous skin and nails and then the taste. But what you don't see with this product is those serious infections. What is accelerated approval? What trial led to the FDA giving accelerated approval to Talve? Who is eligible to receive Talve? The approval of this drug is currently based on the monumental one, which is an accelerated approval. And accelerated approval means that health authorities are willing to give access to patients to a drug, even before the pivotal randomized phase three study is done, because it's filling an unmet need. But the pivotal phase three study is going to be monumental three. But right now, because there's such a need for this product, it's approved on this accelerated approval for patients who've had four or more lines of therapy and are what we call triple class exposed, which means proteasome inhibitors, immunomodulatory drugs and CD38 monoclonal antibodies. Is monotherapy the approved indication for Talve? So the current approval for Talcretamab is a monotherapy, but I should mention that there are preliminarily very exciting data that we heard this past year in Congresses combining Talcretamab. How is Talve administered? Talcretamab is a subcutaneous administration drug, which means that it's typically injected into large areas of the body where you can inject a needle under the skin, typically like the abdomen. And the drug can be given either weekly or every two weeks. What should be considered when making the decision to have a weekly or bi-weekly dosing schedule? So in terms of the dosing and deciding between weekly and every two week dosing, initially it wasn't clear. And of course there's this intuitive thought that why give a drug more frequently if you can get away with it less frequently? And that has a lot of implication for convenience for patients with respect to how often they need to come to the cancer center. This product is unique because we now have some more mature data, particularly in the last year or so, that to me has given a clear answer to this question. So the drug is approved at weekly at 0.4 milligrams per kilogram. So the milligrams per kilogram means that this is a weight-based dosing. Or you can give double dose, 0.8 milligrams per kilogram every two weeks. And so how do you pick between those two? Well good news first is to me there's not a difference so far in this side effect profile because that might be one of the concerns. If you double the dose, are you going to get more side effects? And so far we haven't seen that. Conversely, do you see a difference in efficacy? And the answer is yes, but surprisingly better efficacy for the every two week dosing. And so what I mean by that is there's a term called progression free survival, which means from the day you start the drug, how long is the typical patient going to be benefiting from the drug until they progress or have to come off the treatment for lack of benefit. And that is about seven and a half months for weekly dosing and it's nearly double to 14.2 months for every two week dosing. And you might wonder, is there something that explains this difference? Why would the same drug being given every two weeks give such a doubling of the remission duration? And I think what we are trying to figure out is there's probably a dose that you need to start with and then there's a dose that you need to keep the disease under control. And when you have heavily treated patients, if you don't give enough drug at the beginning, you may not be able to capture the disease and get it under control. If you repeatedly give these drugs called bispecifics, we may be creating T cell exhaustion. And we've seen that and by exhausted I don't mean like, you know, they sit on the couch. I'm talking about biological markers of exhaustion that tell us that these T cells are not as angry and not as able to kill. Is the overall response rate dependent on the dosing schedule? When we look at the overall response rate, there also does not seem to be a major difference between weekly and every two week dosing. Both are in around 70%. What is step-up dosing and why is it used? Step-up dosing is basically to try to decrease the risk of CRS. And other things we do to decrease the risk of CRS is we give pre-medications like with dexamethasone. I know patients hate that drug, but it's one way of suppressing that inflammation that we see. Dexamethasone is a pre-med, Tylenol or acetaminophen is a pre-medication. Sometimes additional oral medications like antihistamines are added. That's one strategy. And then if somebody does get CRS, you can give either additional dexamethasone or a medication called tocilizumab, which is an intravenous medication to block that side effect. So rather than giving the full dose of the Bi-specific all at once, you gradually work your way up to the full dose, thinking that as you give these low doses, you get the drama over with and then as you follow up, that's mitigated. So for the talcretumab, there's the two dosing schedules. So the weekly dosing of 0.4 has two step-up doses and then the every two week dosing, which is double dose, has three step-up doses. So the program that requires everybody to be trained called the REMS program. So because these drugs are unique and rare and we're learning about all of them, the health authorities like the FDA have mandated that anybody who prescribes these drugs does a program called REMS, which is a risk mitigation strategy. And the risk mitigation strategy says that patients should be observed in the hospital for 48 hours after each step-up dose. So once you finish the step-up dosing, that's when the frequency of the dosing on the label kicks in. So if you're going to that lower dose, then you go to weekly after the step-ups or if you're going to the every two week dosing after the total of three step-ups in the first full dose, then you go to every two weeks. Are pre-medications required after the step-up dosing? Once the step-up doses are complete and there's no issue of CRS, the pre-medications can be admitted in particular. The dexamethasone does not need to be continued indefinitely by any means. Do not drive, operate heavy machinery, or do other dangerous activities during and for 48 hours after your talvi step-up dose is completed or at any time during your treatment with talvi. If you develop dizziness, confusion, tremors, sleepiness, or any other symptoms that impair consciousness until your signs and symptoms go away. These may be signs and symptoms of CRS or neurologic problems. How soon can responses to talvi be seen? In terms of the timing of responses, the time to first response is usually officially on the literature one month and the time to best response is about three to four months. But I would put in my caveat that I've seen responses occur very quickly with all of these therapies, bispecifics and CAR-Ts. And part of the challenge with saying how quickly do people respond is how quickly can you see changes in the measurement. And so what I mean by that is if somebody has myeloma and you took a magic wand and waved it, the evidence of myeloma in their blood is not going to clear immediately because those proteins like antibodies that are made can linger for up to three to four weeks. So if somebody has only light chain myeloma which clears very quickly, we see light chains going down even within one to two weeks. What is tumor flare? And one other thing I should mention in this context that's not a lot of public information about is this concept of what we call tumor flare. Tumor flare is when you're doing those initial step-up doses, wherever a patient has myeloma and the T cells are trafficking to that area to kill the myeloma, sometimes patients can transiently get worsening pain. And so I make the analogy, it's like pushing on a bruise, right? Like if you have an area of tumor and then you're punching at it with the T cells, it could hurt more. That's actually not always a bad thing. And that's why I think it's important that patients know that. In those priming doses particularly, worsening pain may actually be a sign of a very robust immune system that's actually doing its job. What are the major side effects associated with Talvay? One of the side effects of Bispecific as a class of drugs and also CAR-T's is what's called CRS, cytokine release syndrome. And what that has to do with is when you activate T cells and make them angry to kill the target here, which is the myeloma, they do their job, but the way they kill is the T cells, when they're trafficked to the cancer cell, they release chemicals that essentially cause the death of the target nearby. And so those chemicals can poke holes in the cancer membrane and then the cells basically will die. But those same chemicals that are released can also cause side effects like fever, and that's the most common symptom of CRS or cytokine release syndrome. They can also in more serious situations cause low blood pressure, low oxygen level, and rarely also a condition called ICANS, which is neurologic side effects like confusion, lethargy, seizures, or even death. What I can tell you is that CRS is quite common, not that serious stuff. CRS and Bispecifics can range from 40 to 90% of patients. Talcretumab tends to have about 70 to 80% of patients can get CRS, but most of it is what we call low grade, meaning not serious. High grade CRS is very uncommon, probably we're talking about less than 5% across various studies. One other thing to be aware of with CRS is in my about 20 years of practice in myeloma, I have not gotten as many phone calls overnight in the entire 20 years compared to the last few years of these T cell redirection. Because these drugs are injected subcutaneously, the peak absorption doesn't necessarily happen immediately, right? When you inject a drug under the skin, it's slowly distributed compared to an IV that just goes right in. What that means is the time to CRS can be anywhere from one to two days after the injection. If you think about what timing that could be, it may be at an inconvenient time. That's why I think that if a patient's in a hospitalized setting, it's not a big deal because the patient's there. If somebody's going to be doing it as an outpatient, I think there's a few important criteria. Now again, the label says should be monitored, but it's not must be. So there's a little bit of nuance that the health authorities have put in there. But if somebody is thinking about doing it at home, I would suggest that they first have a caregiver because if somebody's having fever, low blood pressure, or is confused, a confused person is not going to know to call. So a caregiver is important. Having home vital science equipment like a thermometer, a blood pressure machine, and a pulse oximeter, I think those are good to have in the era of COVID anyway. You should have that equipment if you're a myeloma patient. But those are things that could be done, but just be prepared that these CRS can occur at inconvenient times. What is ICANs? ICANs stands for Immune Cell Associated Neurotoxicity. And it's that spectrum. It could be kind of a little lethargic, sleepy, to confused, to like having seizures, and in severe cases, death. With bispecifics, we usually don't see those severe cases. There are reports of ICANs with bispecifics, in particular like talconeumab, can be as high as 10%. What does that mean? In my experience, I haven't seen major problems in speaking to other experienced investigators. I think what it is is that we were required in the phase two portion of the study to monitor for ICANs with things like mini mental status score, which asks you to count, spell the word world backwards, or count by seven and keep adding seven or subtracting sevens. And if you're being asked to do that in the middle of the night, you may not be as alert, right? And so if somebody's having a fever, fevers can cause confusion. So most of the time ICANs I think was occurring in the step-up doses and it was transient and resolved. But steroids can be used for ICANs. But to me it was not a major issue with talconeumab. I should mention though that there are rare reports of what we call cerebellar toxicity. So what does that mean? There's slight expression of GPRC5D in the cerebellum, which is a part of the brain that controls balance and coordination. It's been seen with GPRC targeting CAR-Ts, but with the bispecific it's been exceedingly uncommon. I'm only aware of one patient out of several hundreds that had that. But it's something that patients should bring to the attention of their healthcare providers if they experience any balance or coordination issues. But I personally have not seen that. However, I will mention that sometimes we see balance issues not because of targeting the brain, but in some patients who lose weight, if their blood pressure medications aren't adjusted their blood pressures can be a little lower and that makes them dizzy and imbalanced. So to me that is probably more common than having brain toxicities, which I've never seen. You will receive a patient wallet card from your healthcare provider. Carry the patient wallet card with you at all times and show it to all of your healthcare providers. The patient wallet card lists signs and symptoms of CRS and neurologic problems. Get medical help right away if you develop any of the signs and symptoms listed on the patient wallet card. You may need to be treated in a hospital. Signs and symptoms of CRS may include a fever, dizziness or likeheadedness, chills, difficulty breathing, feeling anxious, headache, or a fast heartbeat. Symptoms of neurologic problems with Talve may include a headache, feeling confused, being less alert or aware, feeling disoriented, trouble speaking or writing, shaking or tremors, numbness and tingling or feeling like pins and needles, feeling sleepy, feeling very sleepy with low energy, slow or difficulty thinking, seizures, muscle weakness, memory loss, or burning, throbbing or stabbing pain. What is hypogammaglobulinemia? Is hypogammaglobulinemia a frequent side effect of Talve? What is hypogammaglobulinemia? Hypogammaglobulinemia is basically low antibody levels that are important to help protect us from infections. Interestingly, we're not seeing it very often with talcuetamab and I think it's because of that restricted expression on bad plasma cells but not good plasma cells. So we're able to kill the bad myeloma cells but we still see antibodies being made from the good plasma cell. What evidence do we have of that? Well, we're not seeing deaths from infections, which is huge and that's the number one thing. Number two, we're not seeing high-grade infections, meaning patients who not need to be admitted to the hospital for intravenous antibiotics. We haven't seen that. We haven't seen complications from COVID like admissions or death from COVID and that's important. All of the things I just mentioned have been seen with BCMA targeting therapies, particularly BCMA bispecifix. In fact, I have patients whose COVID antibodies have actually responded to the vaccine. So in patients who are getting talcuetamab, they have good antibody production. And it's almost an interesting controlled study because when you look at talcuetamab studies that were enrolled during the pandemic and comparing to BCMA bispecifix studies that were enrolled during the pandemic, we didn't see those COVID complications with talcuetamab. We didn't see COVID related deaths. We didn't see COVID related severe complications. The need for IVIG, which is nearly 100% with BCMA bispecifix, is here guided more by the frequency of infections. What are the other common side effects seen with talve? In terms of other common side effects, we did discuss at a high level, but basically There's GPRC 5D overexpression in heavily keratinized tissue. So one of those is the skin. So what kind of skin changes do we see? Generally, a little bit of dryness I've seen. Very rarely redness and like discrete rashes. Those are usually managed with emollients. So just things to keep your skin hydrated like Vaseline, any ointment that's hydrating, not taking too long a dry shower. If somebody does have more of a rash, not just dryness, then we can add topical steroids, to help control that. If the rash is quite robust and extensive, like let's say high percentage of the body surface area, then we can also do a short course of oral steroids. To me, the rash is a minor inconvenience in the sense that it tends to happen very early, say within the first cycle or so. And with the interventions of topical treatments and rarely oral treatments, that's usually behind us after the first cycle. The next keratin-related side effect would be nails. So those can happen within the first few weeks. And basically the nails can become friable, look maybe even slightly discolored. But what's happening is that as the nails grow relatively quickly, you can actually see a line in your nails where when the talcumab was started, you can see that that's the date that the nail damage started. Honestly, we haven't found a magic bullet for this. We found some of my nursing team, and I shout out to the nurses because they do all this great supportive care management. There are nail hardening solutions that people can think about or gels to try to harden the nails. But good news is it's not painful, it's more of a cosmetic issue, and it can improve with time, and definitely improves off therapy. So it's not like these changes are permanent. And then the third side effect I would say that's also related to keratin is peeling of the hands and feet. That like the skin rashes tends to happen early, so it can be managed with topical steroids and rarely dose reductions. And then the last side effect that's common is dysguisia or loss of taste. So we don't completely understand the mechanism, but in the mouth we can see dryness, we can see loss of taste, we can see difficulty swallowing because of lack of saliva. So it's important to keep up with good dental hygiene because if you don't have good saliva that can increase bacterial buildup. So keep up with dental appointments, rinsing, flossing, hydrating, just because you have dry mouth or difficulty swallowing you've got to keep up with your fluid intake even if things don't taste good. And for the taste, trying to supplement with high caloric foods, so like shakes that have peanut butter or ice cream, things to maintain the weight and that are easily swallowable. None of those have really reduced the rate of the taste and oral toxicity. I think the only thing that I've found that has helped is really reducing the dose. And one thing I'll mention to our listeners I think is super exciting and probably the most exciting research that's going to be coming out this year is we have seen that people who have these side effects, whether it's the nail changes, the loss of taste, the palmar plant or peeling, any of those three things seem to be actually happening in people who are responding and responding for longer duration and potentially even living longer. So what's exciting about this is these side effects may actually be a biomarker or a sign that these patients are going to do well. And so what that means is that these things are a good prognostic sign and also it means that probably we can reduce the dose a little bit because all of these side effects are related to the dose. And as an investigator who participated in the initial Phase 1 dose escalation study, I can tell you that when we started at those really, really low doses, we didn't see that much of these side effects. We only saw it at the higher level. Now you need these high doses initially for advanced myeloma, which can be, you know, if somebody has heavy bone marrow involvement and a lot of disease, you need to get adequate drug to kill the cancer. But perhaps once you get the cancer under control, you can then back off. And that, in my experience, has been the main way of managing these side effects. Another class-specific side effect can be cytopenias, which is low white count red cells and platelets. We do see that with telcretomab, but it's usually restricted to cycle 1. And after that, we don't see that. And the rates are less common. So we're like, for example, white cell count dropping is only about on the order of 20 to 30 percent compared to like 60 percent with BCMA treating bispecifics. And I think, again, the reason for this is probably the specificity, right? So, I think that the PRC5D is really restricted to cancerous plasma cell versus BCMA is more broadly expressed. And I think the reason we do see some cytopenias is because, again, if your snipers are going to the bone marrow, because that's where myeloma lives and they release their chemicals, yes, they kill the myeloma, but the normal bone marrow that might be there may be temporarily stunned as well. But that improves because you don't usually see these after that first cycle. So that's another plus point for this drug because it makes it more combinable with other therapies that are already approved. So what if we take a break from therapy and should you take a break? Of course, things happen and people may need to go on vacations because now their myeloma is so well controlled, which is a great thing. The label says after 28 days, you should step up again. I think sometimes in clinical trials, we've gone up to 35 days. I think it really depends on the patient. You know, we kind of did this natural experiment during COVID in New York. We were in the epicenter of the pandemic. We did have to halt patients. Our plan there was if somebody's myeloma was in remission and it was peak pandemic, again, this is before the vaccines, we would skip the doses. But if their myeloma wasn't controlled, we would continue with the doses. And what I can tell you is in all those patients that we skipped, the majority of them when we restarted, we did do step up again. They did fine, maybe with one exception. I do think that if somebody's myeloma is not well controlled, I would probably err on the side of doing step up again, because again, if your T cells are now killing the cancer again, you could get CRS again. So I would definitely encourage re-treatment of patients who have residual myeloma to do Whether and how to do the re-step up in the non-heavily diseased patient is unclear. And that may be a population that could be managed as an outpatient and admitted if there's a problem. But I think we'll have to see how things evolve. If a patient had previous T cell directed therapy, can they still respond to Talve? Actually, the data that was submitted for the initial accelerated approval did include a cohort of patients that had prior T cell redirection. And what we saw in that subgroup is first, no major difference in side effect profile. So that was good. But in terms of the response, 63%, which is still quite good compared to the non-T cell redirection. But where we see a dampening is the duration of remission. So the progression for survival was shorter on the order of say, five to seven months. And I think the issue is more extreme with prior bispecific. So we saw pretty good responses and durability with prior CAR T. So if you have a CAR T and then you later need to have talcetamab, that seemed to be not as compromising as having a bispecific and then going to another bispecific. And so what I think is underlying that is target switch is important, right? So a lot of these patients, almost all these patients were prior BCMA. So if you have a prior BCMA CAR T and a prior BCMA bispecific, you can switch to a GPRC targeting agent. The problem is that the bispecific from BCMA, yes, you switch to target, but the T cells may have become exhausted. And so if you go from one bispecific to another just because you changed the target, may not overcome that. Whereas CAR T, because it's a one and done and you have a break, when those patients have a relapse, if they do after CAR T, you can go back to bispecific. So that's an area of active investigation is a sequencing. In my practice, I think if somebody has a progression on bispecific, I might try to come up with an interval strategy to let their T cells perhaps recover a little bit and then come back to another bispecific just to try to give them the best chance. But sometimes you can't do that because if they've exhausted all therapies, you've just got to do what you've got to do. Once you and your doctor have decided that Talve is right for you, Janssen has resources to help support your treatment journey. A Janssen Compass Care Navigator can help with free personalized one-on-one support over the phone throughout your treatment journey. Call us at 844-628-1234 Monday through Friday, 830 AM to 830 PM Eastern Time. You will talk to the same Janssen Compass Care Navigator on every phone call. They will help you in three key areas. Cost and affordability. Explore resources that may help you pay for your Janssen medication. Medication and disease education. Gain a better understanding of your disease and your Janssen medication. Some tips for how to have meaningful conversations with loved ones and your care team during office visits. Practical and emotional support. Learn lifestyle and coping skills to help manage stress. Get connected to resources for your practical and emotional support needs, including support groups and transportation-related services.