Paul G. Richardson, MD, on Multiple Myeloma: Mezigdomide Plus Dexamethasone in Relapsed and Refractory Disease

Well, it's my pleasure to present at this meeting the results of our mezigdomide dexamethasone combination dose expansion part of a phase I/II trial. This was exclusively in relapsed and refractory myeloma patients who were triple-class refractory. That meant that three classes of drugs had failed them and they were also allowed to have received prior BCMA therapy, which is an important new aspect of myeloma management. Because obviously BCMA has been a very exciting advance as the target. But the question obviously then arises when treatment fails in that space, what are effective agents there? What are the effective agents that can meet that challenge? So we allowed BCMA exposed patients as well as triple-class refractory patients to receive mezigdomide combined with low-dose dexamethasone. And the dexamethasone was given on a weekly schedule. mezigdomide was given three weeks on and one week off. And mezigdomide is this really very interesting oral agent. It's what's called a CELMoD. These are very powerful drugs that engage the cereblon E3 ligase complex inside the myeloma cell and result in profound pathobiologic changes within the myeloma cell through the targeted degradation of Ikaros and Aiolos. They also have enormous immune system effects. They stimulate specific T-cells and NK cells and have an immune effect on the tumor as a result. So really a very exciting class of drug. And in that context we were able to show a response rate of 40%, actually 41% to be precise overall for the whole 101 patients on intent to treat. What we were able to also show in the subgroups was a 30% response rate in patients with extramedullary disease. And what was really interesting, in about a third of patients who had BCMA exposure, we showed a 50% response rate. So really nice response data. In the original phase one portion of the study, we demonstrated a response rate in the small number of patients at the RP2D and there was the recommended phase two dose. We've shown a response rate of 55%. So all of this data was very consistent in terms of the safety. Again, very consistent, very similar to what we saw in the phase one portion with neutropenia, some thrombocytopenia, some fatigue. But beyond that everything else was very, very uncommon in terms of any non-hematologic side effects. And above all, we didn't see thrombosis, we didn't see neuropathy, we didn't see cardiac issues. We found that the drug was generally well tolerated. So in terms of future directions, we know that mezigdomide is extremely active in combination and there are trials ongoing combining the mezigdomide with bortezomib, carfilzomib and monoclonal antibodies. And these studies hopefully will bear fruit within the next three to four years or so in terms of a readout. In the meantime, to have this exciting data is really quite important because it tells us that we've got an oral agent with a convenience of that, that we can actually literally take off-the-shelf for our patients. And in that spirit, one of the other things that was important among the safety profile was to us we did have some infections. They were at a much lower rate than you would normally see with say, an antibody based therapy. And also we only had one COVID death despite seeing some COVID infection because of the timing of the trial. In that context of over 100 patients, there was only one person who died of COVID. So really important information to share with the community and hopefully very exciting new addition to the army in the relative near future.