Emerging Iberdomide-Based Combinations in Multiple Myeloma

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Dr. Lonial:
Hello. My name is Dr. Sagar Lonial and I'm from the Emory University School of Medicine in Atlanta, Georgia. And this presentation is going to really focus on emerging iberdomide-based combinations in multiple myeloma. So what we know about both iberdomide and mezigdomide also previously known as CC-92480, is that they clearly synergize with other anti-myeloma agents. And what you see on the left is cell line data combining iberdomide with either bortezomib or with carfilzomib, suggesting that you get synergistic cell death. Far more potent than what we see with either pomalidomide or control media on the left. When you look at xenograft models, what you're clearly seeing is that the iberdomide combinations, as well as the mezigdomide combinations with bortezomib are clearly very potent. And in fact, result in the greatest degree of tumor reduction using in vivo models today.

Now we know that this has clearly been an effective combination with both LEN and POM partnering with bortezomib, carfilzomib, and daratumumab. And so in the CC-220-MM-001 trial, iberdomide was combined with bortezomib, daratumumab, and carfilzomib in cohorts E, F, and G. And while the numbers of patients are not as large as the expansion cohort of IBER-DEX alone, what I think is really quite encouraging is the synergy data that you're seeing from these. Where many of these patients were resistant to either bortezomib, carfilzomib, or daratumumab. And yet in the IBER-DARA-DEX combination you're seeing an overall response rate of 45.9%. In the IBER-bortezomib DEX you're seeing an overall response rate of 56%. And in the IBER-carfilzomib DEX you're seeing an overall response rate of 50% in general. And that cohort is actually much larger now than just the original eight patients that we've reported on at previous meetings. This suggests that not only is this very active, but that you are likely helping to overcome drug resistance and seeing deeper responses than with IBER-DEX alone. Particularly in the context of partner drug resistance; whether that partner drug is DARA, bortezomib, or carfilzomib.

At the same time, I'm showing you additional data for mezigdomide or CC-92480, in combination with bortezomib and dexamethasone. And again what you're seeing here is an overall response rate of 73%. Far higher than any drug given on its own, where you would expect to see a much lower response rate in a heavily pre-treated patient population. A fraction of whom is in fact resistant to bortezomib and dexamethasone already. And what you're seeing is not just deep responses but that these responses can in fact be quite durable as you can see in the swimmer lane plot, where many patients are beyond a year of therapy for this combination, and in fact doing quite well.

So, I think when we think about cell mod-based combinations, it's clear that there's pre-clinical synergy with common myeloma agents. Not a surprise, particularly considering that LEN, POM, and THAL also had similar efforts of synergy for those combinations, but with the cell mod agents it's likely more potent. Clinical trial data already suggests that IBER combinations are active and safe, and are currently being tested in expansion cohorts and potentially even in randomized phase three trials. Hopefully leading to further data and ultimately we hope regulatory approval. Clinical trial data also suggests that MEZI combinations are active and safe. And these are further being tested in larger phase two with the goal of ultimately going to larger phase three trials as well. Further validating this data in a larger data set as well. Thank you again for your attention.

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