Hi, my name is Ajay Chari. I'm a professor of medicine and director of clinical research at the Multiple Myeloma Program at Mount Sinai, New York. And it's my privilege today to be telling you about Taquetamab. And let me begin by very exciting news that the phase one portion of the study just got published in the New England Journal. That study, to distinguish it a little bit from what we were discussing at ASH, shows this new bispecific antibody that targets a protein called GPRC5D. Many of you probably have heard about bispecific antibodies. The way I describe it to patients is it's either, depending on what you're more interested and into, either handcuffs or double-sided tape. One side binds to the T cells, the other side binds to the myeloma. And when you bring the T cells close to the cancer, the T cells release chemicals, poke holes in the membranes of the cancer cell, and the cancer cell dies. So there's one bispecific that just got approved for myeloma called Taquetamab. This is, if you will, a sister drug that targets different protein. And we need all of these because, unfortunately, patients, even if they get one, they can relapse. So this phase one study in the New England showed it was active at a variety of doses and it had a characterized safety profile. And so what's exciting in you at this year's ASH, we're presenting the results from the phase two study. So we knew from phase one what the right dose and schedule was, and now we're testing in larger numbers how do they work. So here in this study, patients were assigned one of three cohorts. They either got 0.4 milligrams per kilogram, so that's the dosing every week, and that was an injection in the skin, or double that dose, 0.8 every two weeks. And then there's a third group of patients, which is actually the unmet need in myeloma. And these are patients who had already had prior T cell redirection therapies. That means they had prior CAR-Ts or prior bispecifics. And why is that important? That's probably the new unmet need in myeloma, right? When those treatments work, what do we do next? And so those are the patients that we were studying here, and they were also quite high risk. And about 60% were high risk in one of three ways. They either had disease outside the marrow called extramedullary disease. They had ISS stage three disease, which we know can be a more aggressive feature in these T cell redirection errors. And finally, patients also had high risk genetics. They typically had had five lines of therapy over six years, and the majority of patients were heavily treated, sizable number of what we call triple class refractory and pentadrug refractory as well, which means ledalidomide, bortezomib, carfilzomib, pomalidomide, and daras, the big five drugs. And almost every patient, about 95%, they were progressing on their last line of therapy. So with this heavily treated patient population, the response rate was a very impressive 73 to 74%. And that response was maintained in patients who were triple class refractories, so the proteasome inhibitors, the imidazine CD38, and also patients who were refracted all five drugs. So that's really impressive. You know, I think we say that historically drugs were approved with a 20 to 30% response rate, and now 70 appears to be the new 20 to 30. And those responses were maintained also in ISS3, high risk disease, so these are really important. Patients with disease out of the marrow called extra medullary, they also had a response, but it was slightly lower, but still a very impressive 50%. So that's kind of one of the main points of this presentation at this year's ASH. That's generated a lot of interest. But we also have to talk about the safety profile, which is also very interesting. The rates of severe, what we call in clinical trials, grade three and four, severe side effects are quite uncommon. The most common grade three and four were blood-related issues. And even those, low blood counts occurred in less than a third of patients, and they tended to happen early, which is nice because that means that in the future this drug can be combined with other drugs without adding to the blood count issue. Second and huge issue, I think patients are probably aware of one of the things that we're really concerned about with these new T-cell redirections, particularly targeting BCMA, is infections. Patients are getting significant infections, and that's what's kind of nice about this agent. In three different ways, you can kind of distinguish this. The rates of severe infections were quite low, about 10 to 15% compared to some of the other compounds, which have as high as 45%. Secondly, while any death is terrible, COVID deaths in particular have been an issue with other products. And here in this particular study, there were two patients with COVID-related deaths and none in the entire, approximately 250 patients that were published in New England. This means that we have now over 500 patients who've been treated with this drug in a very uncommon COVID-related signal, which is great. And also in the laboratory, when we give these patients these drugs, we can actually measure COVID antibodies, which means the vaccines work. And the third and final demonstration is the need for IVIG, which is this immune boosting infusion, was only in about 10% of patients, which is quite low. So we have favorable blood counts, favorable infection. We do have some unique side effects with this agent that are worth talking about, because GPRC5D is expressed primarily in myeloma, and that's why this drug works and kills the myeloma that spares a lot of the other blood counts, et cetera. But it's also expressed on tissues that have a high expression of this protein called keratin. And so that we did see skin changes, which rashes, which were quite manageable, typically happened early on. Those resolved with steroids that we either applied to the skin or took by mouth. Nail-related changes. And then thirdly, the loss of taste, which we call dyscusea. That's important, and I think we have to keep in mind that this patient population had exhausted all available therapies. But I think we can, so even though we saw these side effects, those side effects are going to be important to figure out how to handle as this agent goes up to earlier lines of therapy, where patients will have other choices. So what we found is the importance of supportive care. Shout out to the great nurses that have been involved, because we know they're on the front lines with patients doing all of the supportive care work in collaboration with the rest of the team. But one of the things that's good about it is if somebody does lose taste, we can adjust the dose and schedule of the drug, and that seems to really help. And you don't have to take my word for it. At Mount Sinai, we treated 100 patients on this study over the last four to five years. But overall, in the global study, only 5% of patients came off for side effects and not for progression. So I think what this tells us in conclusion is that this is a really active drug in patients who've had a lot of prior therapies. It works in a completely new way. It's off the shelf. There's none of that waiting for a CAR T slot, waiting for your cells to be manufactured. It's ready to go. So it's an off the shelf, novel, bi-specific, that's showing excellent activity with a really good safety profile. And so where are we going next with this? First, there's a confirmatory study. We know that this would be considered, the application was submitted to the FDA called the BLA, which we hope means that the FDA will act on this within six months because of the sensitive nature. It got a breakthrough designation, which means that the FDA recognizes a completely novel way of treating myeloma. The other, so there's the randomized phase three studies going on to confirm these results from the single arm study, and it's being compared with other standard of care agents in earlier patients, not in the heavily treated. And then also, because of the safety profiles being studied with a lot of other drugs, standard myeloma therapies with the sister drug Ticlystumab, with new ways of augmenting the immune system called checkpoint inhibitors. So it's really exciting. I think it's great to have another option for patients. And it'll be interesting to see how this drug moves forward, not only in terms of getting approved, but even potentially moving earlier in combination. So stay tuned. So a couple of the other interesting things that I think came up at ASH is the use of Tocilizumab, which is a drug that we use to block fevers and cytokine release syndrome. Because we know that when we give these T-cellular redirection therapies, about 70% of patients can have CRS, which can be characterized by fever, low blood pressure, oxygen, et cetera. This Tocilizumab, which was given in one study, dropped that rate from 70% to about 30%. The second thing we saw is with the same agent, Sevastomab, which is one of the few bispecifics that's not given until progression, but for a fixed duration of a year. We saw that those patients who had a complete remission, many of them stayed in remission even off the drug, which is fantastic. Because I think in myeloma, patients need these treatment breaks. So that's really exciting. And then the third thing, perhaps patients' least favorite drug, dexamethasone, is finally being studied by the French group. They did a really cool study where they looked at Daratumumab with Revlimid or Lenalinamide and compared it to Revlimid with dexamethasone. And what they found was that the patients who got Daratumumab with Revlimid without the steroids did better. And so perhaps we don't need to torture everybody with these steroids forever, especially these frail older patients who don't tolerate drugs well. They still need myeloma control, but they're very sensitive to side effects. So it's nice to be able to kind of optimize the therapy for each patient based on their age, disease, and their other medical history.