COMy 2025 | An update on CELMoDs in myeloma: the promising activity and safety of iberdomide & mezigdomide

As part of maintenance, a new kid on the block, so to speak, is iberdomide. And iberdomide is distinct as a CELMoD from the immunomodulators. It’s a cereblon E3 ligase modulator. It’s truly a degrader, and in that context, it’s that much more active. But what’s really impressive is it’s that much better tolerated. And what we’ve seen in the trials so far is a very favorable and manageable side effect profile. And very interestingly, pre-clinically, there’s strong evidence that it’s going to be not associated with the second malignancy risk that unfortunately does occur with lenalidomide, and that may be a key advantage going forward. 

So I reviewed that as part of the maintenance talk. But I also think it’s worth mentioning that obviously we’ve had talks at this meeting about mezigdomide. Mezigdomide is the most potent cereblon E3 ligase modulator we have and is arguably the most potent degrader currently under clinical trial, recognizing other degraders are being investigated, but so far, the most mature data and most impressive combination data has come from the mezigdomide work that it’s been a privilege to be part of. 

In that space, it’s worth sharing with the audience, you know, why is that? The thing that I think is remarkable about mezigdomide is it’s a 100% closure of the cereblon E3 ligase complex. To give people a frame of reference, pomalidomide closes that complex by about 20%. Iberdomide by 50%. Mezigdomide – 100%. That results in the remarkably rapid and intense degradation of key transcription factors, specifically Ikaros and Aiolos. And we know this from really elegant work done preclinically. And we know that that translates to patients because we’ve done the correlative science in patients to show that’s exactly what’s happening. 

So with mezigdomide, combining it with other drugs has been a really remarkable experience in terms of activity. And I think what’s been really encouraging too is the actual excellent tolerability profile we’ve seen, aside from myelosuppression, which is again very manageable. So with all of that in mind, we’ve had data with combination strategies using mezigdomide and proteasome inhibitors, be it bortezomib or carfilzomib. We’ve had really great data with mezigdomide combined with daratumumab and with elotuzumab. We’ve also then had excellent data combining mezigdomide and dexamethasone with other novel agents, such as trametinib. And this particular experience has been particularly interesting because our patients in whom we’ve offered that combination have been classically quadruple class refractory. That doesn’t just mean PI, CD38, and IMiD, it means also BCMA refractory. And these patients have benefited from this approach. So we’re very excited by the promise of that. 

And in that same space, we’ve been using mezigdomide in combination with selinexor under the leadership of my colleague, Dr Clifton Moe, as part of the so-called STOMP study. And in that trial to date, although obviously data will be presented shortly in due course, so far so good. We’ve seen remarkable activity and we’ve seen a manageable safety profile. So all in all, the mezigdomide story continues to grow and look, I think, very promising.

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.