ASH 2024 | Outcomes of patients with high-risk myeloma treated with Isa-VRd in the BENEFIT trial

In 2024, there has been an incredible development in the newly diagnosed myeloma transplant ineligible setting with the development of this quadruplet-based regimen, the Isatuximab, Bortezomib, Lenalidomide, Dexamethasone, and how when we put all these drugs together, we improve the survival of the patient, we improve the depth of the response for the patients and we do not compromise the quality of life and the safety issues of the patients. That’s for sure two studies, IMROZ for registration and BENEFIT as sort of supportive complementary. 

The thing is that myeloma is not the same disease for all patients. You always have the vast majority of the patients, we usually say 70-80% of the patients, that are non-high risk so very likely to improve, benefit from the treatments and get the best from these new treatments. But you always have a percentage of patients often 20 to 30 percent of the patients that always benefit in a lesser extent, we call that high-risk myeloma. 

So two things here, number one in the past, up to this year, the definition of high-risk myeloma was very much different, it was not completely different but quite different, across studies, across centers, across groups, across countries and there has been an incredible international effort under the IMS, International Myeloma Society, and the IMF, IMWG groups, International Myeloma Foundation and International Myeloma Working Group to homogenize the definition, at least one of the high-risk definitions based on the genomics of the tumor cells. And so the new definition is not yet published and in the process of being published but we thought it would be great to take back our study BENEFIT and to look into how the high-risk performed but using the new definition, number one. 

Number two, BENEFIT is similar to IMROZ, a comparison of the quadruplet-based regimen – Isatuximab, Bortezomib, Lenalidomide, Dexamethasone – but instead of using bortezomib-len-dex as one of the standard of care in the control arm, we picked a new standard of care daratumab-lenalidomide-dexamethasone, the so-called MAIA-like, which historically has provided the best median PFS and results in that population (65-80 years old). So we have looked at how the quadruplet that globally beautifully performed in the study whether they would beautifully perform in high-risk similarly to non-high risk or only to the non-high risk, and the high risk would again have a benefit but in the lesser extent to the non-high risk, and so we have been using the new definition that I just spoke about. 

And so the results that we are presenting definitely concluded that in terms of MRD, the primary endpoint of BENEFIT MRD negativity rate at time to minus 5 by NGS and the EF-NGS failed by NGF, the primary endpoint was the same. So it’s at 18 months at one time point, the high risk benefit to the quadruplet to the same extent that the non-high risk. This is true at 18, at 20 minus 5. This is true at 18 months at 10 to minus 6. This is actually true at 12 months at 10 to minus 5, 10 to minus 6 in complete response and non-complete response MRD patients. So this is really, really a good start. 

We looked at the safety profile across high-risk, non-high risk and the two arms, and we found out that the high-risk patients actually had the same safety profile than the non-high risk, which again is very important and reassuring. So what we don’t know yet for sure is whether that good safety profile, at least similar across the different groups and the similar great MRD impact we’ve seen will translate smartly and nicely into a prolonged survival and maybe an equally prolonged survival in the non-high risk similar to the high risk. This we don’t know yet. 

Now we have reason to believe that the the high-risk might not do as good as a standard risk in the end, despite the quadruplet, even though we do believe that probably the quadruplet will have improve the high risk but maybe not rescue this patient and take to this high risk myeloma back the same survival as to the non-high risk. But again too early to say for that final part. The survival is not mature yet in the study, we have to wait one or two more years to conclude on whether what we have seen in MRD will be translated into survival for the high risk similarly to the non-high risk. 

In the end, the conclusion is the same. Today, we believe that this Isatuximab-Bortezomib-Lenalidomide-dex is the new, a new, possibly the new standard of care for this newly diagnosed myeloma transplant ineligible patients 65-80, maybe 80 plus, but at least 80. And if you’re high-risk, you should receive that regimen because the data we have at hand now, although not entirely complete, but the data we have at hand now tend to say that you will benefit as a patient family to this treatment.

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