Hi, my name is Anu Kumar. I'm one of the myeloma physicians at UCSF. And today I'd like to talk to you about a project that I've been working on on delayed neurotoxicity after CAR-T. In our project, we wanted to collect cases around the world of some of these delayed neurotoxicities. We've seen a handful of those cases at our institution and we know that our colleagues had it as well. But given that these events are rare, we still don't understand what causes this, what predicts these toxicities. And so we collected data across 15 different institutions and wanted to collect data on what we're calling sort of delayed Parkinsonism, cranial nerve palsies, and Guillain-Barre syndrome, which have been seen after CAR-T. We noticed that there are certain patterns in terms of demographics, particularly with the Parkinsonism. It was older men who were more predisposed to those toxicities. Also in general, patients who had higher disease burden of myeloma going into it had more of those toxicities. And patients who developed those Parkinsonism symptoms particularly had higher inflammatory markers. We saw different patterns for treatment. So for the Parkinsonism, centers have been using steroids, have been using IVIG, IT chemotherapy, and even IV chemotherapy with cyclophosphamide in certain cases. Those have been a little bit harder to treat, although some patients who've gotten the IV cyclophosphamide have had a full recovery. The cranial nerve palsies, patients are generally treated with steroids up front and the majority of patients had partial or full response to the steroids. We did see that some of these toxicities also happened in patients who are not heavily pretreated and who didn't have a high disease burden. And so we continue to collect data and are continuing to work with centers around the world really to understand more about these toxicities. We think that more patient education, caregiver education about what these toxicities are like, early recognition, will lead to faster treatment and better outcomes. I think over time our practice pattern has changed such that now we are being more aggressive about bridging because not only are patients with higher disease burden more likely to get CRS and ICANN, they're also more likely we're finding to get some of these toxicities, particularly Parkinsonism. One question that's unanswered is, you know, some patients have a high peak expansion, meaning their ALC count goes very high. And is there a particular threshold as which we should give medication prophylactically like steroids or even something else like anakinra to help decrease that peak expansion? You know, in the past our understanding was that the higher the peak expansion the better, but now we're finding that actually maybe there's a middle point which is sort of the sweet spot where patients still get response to the CAR-T but are not as predisposed to these toxicities. Cranial nerve palsy, so like a Bell's palsy. And then also a couple of cases, we're calling it sort of Guillain-Barre like syndrome where it's a neuropathy and ascending neuropathy. Those have been quite rare. In our data we had 52 total cases, 30 plus where cranial nerve palsies, about 15 were Parkinsonism and we had four cases of peripheral neuropathy or Guillain-Barre, keeping in mind that actually a lot of myeloma patients going into it already have some neuropathy, but that this was distinct from that neuropathy. And I think the key message we really wanted to get across is early recognition and some of these things, particularly the Parkinsonism, it can present very subtly. So it can be slight change in personality or stiffness and sometimes actually the caregivers are the first to recognize. So I think that we have noticed pattern as well where now we are educating patients and caregivers and that people are calling us, calling the on-call line quickly within 24 hours of these toxicities and we're getting them admitted. At least for now we are doing pretty broad workup. We're looking for infection. We are often doing lumbar punctures and scans, but that's why I think it's important to recognize quickly and get attention and workup. For the Parkinsonism we say that there's sort of three categories of symptoms. One is cognitive and sometimes that can be subtle. Two is stiffness, kind of movement disorders. It can be a change in gait. It can be difficulty with tasks like using a fork and a knife, tasks that people had previously been able to do. And then third is sort of like a personality change as well. So those are the things to look out for. For the Bell's palsy or other cranial nerve palsies, sometimes it can be very subtle, like an asymmetric smile. Sometimes it can be decreased ability to close one eye. It's usually unilateral, although we've seen it sometimes bilaterally as well. Sometimes lack of tear formation, you know, some very subtle things like that. And for the neuropathies in Guillain-Barre, it can be more like a numbness or sensory or motor issue that may start low, like in the feet, and then move up. This does not mean that patients should not get CAR T. We still think that it's the best particularly in patients who have relapsed myeloma. I think we just need to be more cognizant as physicians as to choose patients correctly. One for CAR T. So if patients have underlying neurological comorbidities, maybe this is not the best therapy. So this may affect patient selection in a small subset of patients. I think more important is, you know, more aggressive bridging as we were discussing and then just close attention to the symptoms. One of the next steps of our study is also to develop a screening tool to screen patients, ask questions to patients, ask questions to caregivers to try to detect some of these changes early even before they might become more obvious.