Is it possible to predict who might have that delayed neurotoxicity?

Is it possible to predict who might have delayed neurotoxicity?

Yeah. So I think this is another big question, particularly for cilta-cel We're seeing the delayed neurotoxicity in these Parkinsonian like features. It's not totally clear. It's it's still fairly rare. So not many patients get it. So when you have a rare event, it can be hard to figure out exactly what the factors are that are associated with it. But we think some of the things may be high burden of disease at the time of the T cell infusion possibly other infections. So I think if at all possible, you want to try and decrease the disease burden before going into CAR-T cells.  So not waiting to the last minute, if possible. We certainly try and give bridging therapies to keep the disease under better control. And that seems to have helped maybe decrease the rates of of delayed neurotoxicity and then, you know, making sure that patients don't get additional infections that might trigger some kind of immune reaction. So we often give IV immunoglobulin or IVIG as a prophylactic treatment to help prevent infections. 
And patients have had CAR-T cells. So the question is, is it possible to predict who are the patients who might have that delayed neurotoxicity? 
And this is something that we have seen formally reported in the Cartitude-1 study which is cilta-cel so there were reports of with the initial cohort of patients out of the 97 patient dosed there were five patients who in the range of 1 to 3 months post infusion developed neurologic symptoms that were  different than the typical what we call, you know, neurotoxicity associated with cytokine release syndrome associated with the initial activities of the car T cells. And  these symptoms include  some what we call cranial nerve palsy. So that could involve some paralysis of some of the facial muscles on one side, both sides. And those were some of the presentation. We had a patient with Guillain-Barré syndrome, but probably the one that got the most media attention were of the five patients who had Parkinson like symptoms and the symptoms they were having were very classic for Parkinson's. So they would have difficulty initiating movements such as getting from sitting to standing. They would have what we call cogwheel rigidity. So if you try to move their arms, they literally it feels like you're trying to move cogwheel. So they would have these we call masked faces and be not as communicative. These features obviously are very alarming because these myeloma patients are in the age range where people would naturally be worried about “am I at risk for dementia” “am I at risk for Parkinson’s”, you know Parkinson disease that that might show up.  And so when patients develop these symptoms it's are these temporary, are these reversible. How do we manage them? What we have learned so far from the study is of the patients who did get them. It appears that these are patients who had higher risk disease burden coming into CAR-T treatment. So these patients also had more severe cytokine release syndrome. They've had more severe neurotoxicity associated in that same time frame when they had cytokine release syndrome. And so some of the preventative strategies that were used later on in other clinical trials with this CAR-T product included trying to use different types of myeloma treatment to reduce the disease burden before the patient is infused with the CAR-T cells. And also when patients do get that cytokine release syndrome after the CAR-T infusion to do early interventions so that these patients, the cytokine release syndrome, is not as severe to reduce the risk. And since then we've dosed hundreds of more patients on various CAR-T tuned studies. And it does appear that the incidence of this Parkinsonism is significantly reduced, I would say it seems, you know, at least of this current report is now closer to an average 1 to 2% of the time rather than the initial five cases we saw out of 97 patients dosed. We know that not perfect because that's a preventative measure. We know there are many more patients with high disease burden who don't develop right Parkinsonism. So it's not a perfect predictor. I would say, you know, if I see these patients with these risk features, I would warn them more about this risk. But I don't know that the association is so strong that I would say you should absolutely not get CAR-T product right. It's part of that, you know, discussion with the patient. The other thing I would caution too that, you know, we we have seen it formally under study and really tried to look at associations, risk factors, what we can do to prevent it. But this is not unique to cilta-cel or CARVYKTI. We have seen it with other CAR-T product as well. And actually, if you look back in the literature, this type of neurologic symptoms has also been associated or found in patients who are treated with checkpoint inhibitors. So I think this is a manifestation of some type of over immune activation that now somehow caused the symptom involving this part of the neurologic system. And we need to learn better.  And, you know, can we become even better at predicting who might get this and more importantly, what what's the best way to manage it? You know, if patients do develop these symptoms. So more work to be done. 
Are there any biomarkers to help predict who will have delayed neurotoxicity? 
That's a great question. So this is something that has been looked at on the clinical trial setting, not necessarily in the real world setting. And I can give you a bit more information on that so on the clinical trial. There are several features. So for example, having very high disease burden or what we call tumor burden. So this is reflected as having a high monoclonal protein or M spike like that, say beyond five, or having somebody with really high light chains or a lot of disease in their bone marrow.You know, these are patients that are increased risk for developing this neurologic toxicity.  We are currently working with Janssen on the commercial side to develop almost like a predictive model to look at certain features, not only, you know, clinical characteristics from the chart, but some biological markers. So some, you know, blood testing, bone marrow testing, sometimes spinal fluid testing or PET scans to see, you know, what are some predictors that can identify who these high risk patients are and what we can do to improve their outcomes. But generally, you know, one of the most important takeaways and one of the most important things that we do for these patients is we. debulk their disease. So we try to reduce their disease, give them bridging chemotherapy or chemotherapy before CAR-T to lower these numbers as much as we can to reduce the risk of immune mediated toxicities like neurologic toxicity. 
Is having a preexisting neurological condition a risk factor for neurotoxicity? this is a risk factor So having a prior CNS myeloma, which is a very rare but certainly, you know, having seizures, epilepsy, these are things that make me concerned for somebody to have a risk to develop it in the future. I can speak from our abecma experience certainly patients who have history of neurologic illness like seizures, epilepsy or even involvement by CNS myeloma, which is very rare, are at increased risk for developing neurologic toxicity.