SUCCESSOR-2 was built upon a comprehensive phase I/II programme and is the first phase III with mezigdomide to report in the relapsed/refractory setting. Mezigdomide is a highly potent cereblon E3 ligase modulator, or CELMoD, which has potency built on the fact that it thoroughly engages what’s called the cereblon E3 ligase pocket from a [??] effect, so it locks in. Very excitingly, it generates a 100% closure of the complex which in turn leads to profound degradation of Ikaros and Aiolos, these are key transcription factors that control myeloma pathobiology. Also, frankly, if you degrade them you trigger a profound immune response, both from T-cells and NK-cells, against the tumour. So it’s a remarkably potent oral compound.

So we explored the use of mezigdomide combined with carfilzomib and dexamethasone in a global study, truly real world, multiple countries, where we combined MEZI, carfilzomib and dex and compared it to a very active control, so-called carfilzomib and dex, which in itself has shown potent activity and probably is the most powerful proteasome inhibitor-based platform in this setting. So putting it together, with that in mind, we explored the value of these combinations, including a very exquisitely unmet medical need which are those patients in whom they’re experiencing relapse after prior lenalidomide exposure and/or refractoriness to lenalidomide. Most importantly, as well, they had to be CD38 monoclonal antibody exposed and/or refractory. Moreover, patients could have had prior pomalidomide, they could have had prior BCMA treatments etc. So all of them were heavily pretreated.

We allowed, however, one line or more to be enrolled, so the actual range was 1-9. We also were very permissive in terms of age and our oldest patients were in their mid-80s. So this was a real-world practice study, designed to address that need.  What was very exciting to see was that the median progression free survival exceeded our expectations – it was 18 months for the triplet compared to just 8 months for the active doublet. This is quite important because it generated a hazard ratio of 0.48 and there’s even with what we call progression free survival 2 estimates a difference of at least a year. This equally is important with a hazard ratio of 0.53 and it means that we’re likely to see an overall survival benefit. Whilst the data are relatively immature, with a median follow-up of about 11 months, we already see a hazard ratio for survival under 0.8, it’s about 0.79 or 0.78 to be precise. So in that context we’re seeing a trend towards survival gain which we hope will be sustained. The data on that should read out relatively soon.

Very encouragingly, we saw across specific subgroups, in every single subgroup that was prespecified, hazard ratios in the range 0.3-0.6 in favour of mezigdomide, carfilzomib and dex. Now, that in itself is quite remarkable. These hazard ratios dominated age, prior therapies, extramedullary disease, a very important subgroup, refractoriness to both lenalidomide and CD38 antibody, pomalidomide exposure and so on, and, very importantly, high-risk cytogenetics. So to see that consistency of signal was really quite encouraging. Remember, this is an oral therapy – 1mg daily, three weeks on and one week off.

Another strength of the study was we did it in two stages, stage 1 and stage 2. Stage 1 embraced FDA guidance on dose optimisation which I think is a very important thing to share with our audience because it allows them to have a degree of confidence around the tolerability of mezigdomide and of the combination. We were pleased to report there that neutropenia was the dominant side effect but was readily manageable with growth factor support and, when necessary, dose reduction. Although our dose intensity of mezigdomide in the study was striking at 83%, in other words it meant we were able to maintain dose with appropriate supportive care.

The other thing is we didn’t see any unexpected side effects. Sometimes with carfilzomib you can see significant cardiovascular toxicity, those rates were exactly the same across both sides of the study, both arms. What was really interesting is we were able to reduce the rate of hypertension, which is an important side effect of carfilzomib. The reason for that, probably, was because the mezigdomide allowed us to use lower doses of carfilzomib, so another benefit for patients.

So, in aggregate, manageable safety, in fact excellent tolerability, potent efficacy and the convenience of real community-based practice.

What impact could these findings have?

This is probably one of the most important new oral agents in myeloma for some time. The CELMoDs are profoundly active and they provide an opportunity to be combined, not only with standard of care agents such as carfilzomib, bortezomib and so forth, and antibodies for that matter, but really excitingly there’s real promise for them being integrated with current immunotherapies, including bispecifics, including antibody-drug conjugates and including CAR T therapy. I think the potency of the CELMoDs will allow us to do that in a way that we can really make an impact across multiple settings in myeloma.