Hi, my name is Ajay Chari. I'm a professor of clinical medicine and the director of the Myeloma program at UCSF, San Francisco, California. So when we think about the side effects of talcuitamab, which is targeting GPRC5D, what we know about this drug is that it is remarkably active. The response rate is 70 percent and the remissions or progression for survival can be as long as about a year. And what's also very unique about the efficacy of this drug is it's the only drug in myeloma where high-risk patients remission lasted as long as standard risk. Now, of course, there's always side effects of any drug and this drug's side effects we describe as on-target off tumor, which means when you're trafficking a bi-specific antibody where one side binds to the myeloma cell and the other side binds to the T cells, the target is GPRC5D so that when the molecule goes to the T cell and attaches to anything that expresses GPRC, first and foremost it's the myeloma which it kills. But we think there are other tissues in the body that also express this GPRC5D, which explains the side effects. And broadly speaking, the side effects are loss of taste, which we call dysgousia and that can lead to difficulty swallowing and weight loss. We see skin changes because GPRC is expressed on heavily keratinized tissues, meaning thick skin, particularly the palms and the soles. Also we see some rashes and the third is the nails because nails also have a lot of keratin. The nails is a cosmetic issue and maybe nail strengthening solutions can help. With the skin, quite manageable. It's really in cycle one and you can give topical steroid creams for rashes and sometimes brief course of oral steroids if the rash is quite distributed. And also same thing for the peeling, that if that happens you can put topical steroid creams. I think the biggest concern has been how do we manage this dysgousia, difficulty swallowing and weight loss. Now certainly you can do salivary substitutes. It's important that if you lose saliva that you maintain good hydration because otherwise you can have dental issues and so it's good to keep up with a dentist, do oral hydration and rinses and try to keep up your weight. So beyond that, what else do we know? Well first is I think we need more work because dysgousia, the one we grade is side effect. We typically use this clinical toxicity criteria or NCICTCAE which goes from 1 to 4. And the problem is that dysgousia is a side effect that we don't have a lot of information about but we only have low grade so we can't even characterize it well because we only have grade 1 and 2. So the first thing is we need to do a better job because taste is mediated by salty, sweet, sour, bitter and so we need to understand which tastes are really being affected and how long. But as we work on that and as we do also a randomized study with different potential solutions that have been tried, how do we manage that in the interim? And so the first thing I'll say is we think these side effects are actually relating to response. So studies have shown that if you get these taste, skin, rash, nail, palm or plantar peeling, hand and foot peeling, there's actually about a 20% higher chance that the patient is responding in the first few months meaning this may actually be what we call a biomarker. We don't have a lot of examples of this in myeloma but in other diseases when patients for example have a rash, it usually means that the patient is responding. Here I wouldn't say it's that one to one because the good news is 70% of patients respond which means a vast majority of patients respond but also about 70% of patients will have loss of taste. So it's not one to one but chances are if somebody is responding, probably those side effects are going to be present in that setting of response, maybe they're more sensitive. So then what do we do next? Well we can actually decrease the dose intensity and I can tell you participating in the phase one study where we studied very low doses of the drug and worked our way up because as with all phase one studies you need to find out what's the active drug level. The first 30 to 40 patients had none of these side effects that we just described and it was only as we were getting to the higher doses and in fact when we have these early phase studies you're asked as an investigator is this side effect related to the drug or not and when it first happened we said maybe not because we dosed 40 patients and we didn't have any of these side effects but then as we got to these higher doses it became clear that there was a relationship. So these side effects are related to the dose and what we've shown in prior presentations is that when you skip or reduce the dose intensity, skip a dose, reduce the frequency or reduce the amount of the dose, these side effects actually improve and the good news is that the efficacy is not compromised. So at this point I probably treated about 150 patients with talcretumab on and off clinical trials and I can think of only one patient that we weren't able to find the right dose and schedule to keep them on this treatment and benefiting. And lastly I'll say when I'm consenting patients and talking about these side effects I don't by any means want to minimize the impact of taste on quality of life and that is a patient perspective and as I said we need to do a better job of understanding the patient perspective but what I start with is you know what I didn't tell you as side effects? Death. We don't see deaths with this drug like some of the other products where patients myeloma may be controlled but they're dying of infection so we're not seeing that. In fact in New York we were in the epicenter of COVID and we did not lose patients to COVID with talcretumab and we've shown that actually if you're getting talcretumab you can actually still respond to vaccines so we don't see deaths, we don't see heart issues, we don't see lung issues, we don't see diarrhea, we don't see neuropathy, we don't see kidney issues. We see these other side effects but they're manageable by changing the dose and schedule I think that's what makes this drug so unique and these side effects also don't overlap with other drugs so you're seeing a lot of exciting combinations. You can combine talcretumab with almost all the available products. We're seeing talcretumab plus dara leading to a progression free survival of 19 months, talcretumab plus ticlystemab, 20 months, talcretumab plus pomalidomide over 90 percent response rate so I think this drug is able to be combined with our other drugs because we know in myeloma single agent therapy is not the way to go. Myeloma is too smart to be throwing one drug at a time. You have to mix and match and throw the myeloma off its game and this drug can actually allow you to do that and what I'm really hopeful for is that in the future as we do more combinations, two drug, three drugs, maybe we can back off on the dose so that you don't even have to have those side effects at the beginning and then we can get this great amazing synergy with efficacy without those side effects but I think it's really exciting to have this option and it's the only GPRC targeting therapy. We have a lot of BCMA targeting therapies but this is unique and I think that's why I hope that patients and providers take advantage of it because one other place we've used it a lot is we know that CAR T's are really effective but if you have CAR T's, if your disease is exploding CAR T's are more risky at that point and so what we sometimes do is we collect people's T cells and give talcretumab as a bridging because we've already collected the T cells, we don't want to give bispecifics before collecting the T cells because that might impair the CAR T but collect the T cells, have it manufactured and in the meantime don't let the disease go out of control, use talcretumab for whatever one to three months to knock the myeloma down and that way when you do the CAR T you can actually get those benefits without the side effects that we worry about like Parkinson's and secondary cancer so I think it's a great molecule to have and I'm glad that we have more options for our patients.