Mezigdomide

What is mesignomide? So first up, there's a new drug called mesignomide and it's one of the salmones. And so, you know, this stands for a cereblon E3 ligase modulatory drug. And of course, nobody likes saying that. So we call them salmones. There's actually a couple of drugs in this class, the other being iberdermide that's actually been a little bit further along in development. And mesignomide got a little bit of play most recently at this last ASH meeting. Basically, what was presented at ASH was a phase two expansion cohort of about 100 patients or so. The idea is that these drugs are sort of like cousins of the drugs you may be more familiar with like lenalidomide and pomalidomide, the imides, for example. The idea is that these might be a little bit more potent and a little bit more efficacious, at least pre-clinically speaking, than the previous imides that are more often used in the frontline setting. And so in this dose escalation study, what ended up happening was a bunch of patients who had previously been exposed and were refractory to imides, either lenalidomide, pomalidomide, or both, were then able to get mesignomide in combination with dexamethasone. So just a doublet for patients with pretty relapse refractory myeloma. A lot of the patients had actually even received BCMA-directed therapy. So things like CAR-T cells and other antibody drugs directed at BCMA. So relatively relapse refractory. And the endpoint here in the dose escalation study was looking at overall response rate. And so we saw for patients that got this doublet that about 40 to 50% met that overall response rate criteria. That's pretty good, I would say. And what we really like to see is that we're desperately looking for drugs that are similar to imides because they work so well in multiple myeloma. We just really need to find stuff that is going to work once those imides stop working. The main issues that we're seeing, obviously, with these drugs are some things pretty similar to what we see with imides, and those are the toxicities related to low blood counts. So a lot of patients are having low white cells, low red cells, and low platelets. And that can be dose limiting. Actually on the trial it was a little bit surprising. A really large number of patients actually had to interrupt their treatment, and a fewer number but still substantial actually had to reduce the dose of the drug that they were taking because those toxicities were pretty high. And that's a little bit concerning moving forward because remember here, these drugs were just given in a doublet combination. So just the drug plus dexamethasone. And that's typically not what we do with imides in the relapse refractory setting. Most people are getting those drugs at least in a triplet combination with at least an anti-CD38 antibody like daratumumab or isotuxumab or with a proteasome inhibitor like carfilzomib or bortezomib. And so once we start combining those medications, we'll have to really see if the low blood counts are kind of tenable for the future, if we're going to really be able to combine those drugs and get the most play out of them. So there's a little bit of work in progress to be done there. And as I mentioned, the other drug, ibertamide, we don't have to say a ton about it. It's further along. There was a recent publication out in the Lancet Hematology just in November, so very recently. And this drug has very, very similar characteristics to mesignomide. And so what you'll see are the same kind of overlapping toxicities, the low blood counts, with very similar response rates, although on the ibertamide trial, the patients were even more relapse refractory and I think triple class refractory. So those patients were in an even rougher spot and we're still seeing responses. So definitely expect to see these drugs in further development moving down the line.