Efficacy of Reduced Dosing of Talquetamab in Relapsed Refractory Myeloma | Ajai Chari, MD | ASH 2023

Hi, my name is Ajay Chari. I'm a professor of clinical medicine and director of the myeloma program at the University of California, San Francisco. And at this year's ASH, I'm excited to present some new information on talcretumab. Talcretumab is a first in class, bi-specific antibody, which targets GPRC5D, which is a protein that's overexpressed in myeloma cells and attracts the T cells, the sniper cells, if you will, to the myeloma cells that express this target. We know already from prior data that was presented that this is a very active agent. The response rate is over 70 percent. What we call the progression for survival, which is how long patients stay on drug before progression or other side effects, is about 14 months, which is really impressive for an off the shelf product. Interestingly, we know that it works comparably well in both high risk and standard risk patients, which is very unique. And so those are the benefits of this agent for this off the shelf product. But as with all therapies, there are side effects which are unique to this therapy, and that's partly because of the expression of GPRC5D. So we know that some of the what we call on target off tumor side effects, so these are the kind of side effects from targeting this, include loss of taste, peeling of the hands or feet, rashes or nail changes. Importantly, we don't see serious life threatening things. For example, even though these studies were done in COVID, patients were able to mount COVID antibody response. We didn't see a lot of COVID related deaths. So that's really encouraging about the drug. And so the question we asked in this study is we have an active agent with these side effects and we know that loss of taste has an impact on the quality of life. And what we wanted to know is can we do anything about it as we figure it out? And what I mean by as we figured it out is that our tools are pretty rudimentary and we don't really understand the mechanism of this, but in the interim, what we do know is that these side effects are related to the dose. In fact, I can tell you as for participating investigator in the phase one dose escalation study where we started a low dose and keep working our way up, the first few patients we treated had none of these side effects because they were getting a low dose. And so what we found in this analysis that's being presented at ASH is that when we looked at patients who had had dose reductions after having a response and the reductions were side effects, there was no compromise in efficacy, which is great. So it means that if you back off on the dosing, you're not losing control of the myeloma. But we wanted to confirm that in what we call prospective fashion, because when you look at it backwards, one of my favorite terms is people who do better do better, right? So you're only going to reduce drug in people who are doing well. So can you do it in a prospective fashion? And what we found is that if you reduce the dose or schedule after approximately three months when patients have had a response, we again saw no loss of efficacy. Those response PFS were maintained. And most a lot of those side effects started improving, like the skin issues, the nail issues, the oral issues, the weight loss was still there. And also we found during this work that people who had these unique side effects in the first three months of therapy had a 20% higher likelihood of responding, which is a very unique finding in myeloma because we don't have any other drugs where the side effects actually correlated with a better likelihood of response. So I think the take home message here is Taquatumab is an active drug with high efficacy and including in high risk patients. It has some unique toxicities which seem to respond to dose reduction. So I think it's a great way of leveraging the risk benefit profile of this drug to give them maximal benefit. And we hope that this is helpful for patients and community doctors.