Tailored to fit: New approaches in transplant-ineligible NDMM

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Published: 30 Oct 2024
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Prof Xavier Leleu - CHU de Poitiers, Poitiers, France

Prof Xavier Leleu speaks to ecancer about new approaches in transplant-ineligible NDMM.

In 2017, a new quadruple regimen was introduced for transplant-eligible patients, later found safe for those ineligible as well.

A phase three trial with 230 patients focused on an 18-month induction treatment using Bortezomib.

Results showed a significant improvement in MD negativity rates, highlighting the regimen's unexpected efficacy and synergy among the drugs.

The combination therapy managed side effects effectively, leading to its rapid adoption as the new standard of care.

In 2017 when we have started this notion that quadruplet-based regimens, CD38 monoclonal antibody, a PI, proteasome inhibitor – bortezomib, an IMiD – lenalidomide, and dexamethasone, that quadruplet-based regimen was launched and already started in the transplant eligible patients. But in 2017 we had experience in the transplant eligible patients and we knew the quadruplet was safe enough and we thought it could be applicable to transplant ineligible patients, although non-frail, the fit ones. The difference between a 69-year-old patient I would transplant and a 71-year-old patient that I would not transplant is almost nothing so it was logical to try to transfer that incredible regimen to a little bit more elderly patients but still very fit.

So Sanofi was very interested into launching that study. Now, the problem they had was that for their registrational study they had to demonstrate the add-on value of isatuximab to a standard of care, in the particular case in IMROZ bortezomib, lenalidomide, dexamethasone. But the thing is that in many countries in the world the standard of care, bortezomib, lenalidomide, dexamethasone, and in my country, the bortezomib, lenalidomide, dexamethasone was not a standard of care anymore because it was replaced by the daratumumab, lenalidomide, dexamethasone, MAIA, regimen.

So we proposed to Sanofi to do a sister study, a twin study, where we would run a phase III trial but instead of asking what is the add-on value of the isatuximab to bortezomib, lenalidomide, dexamethasone, we would then ask the question if you pick MAIA, daratumumab, lenalidomide, dexamethasone, as the standard of care can you improve that? Because it’s a much more difficult regimen, standard of care, to improve. And if you add bortezomib to it are you going to make much of a difference? Which is a completely different question from the IMROZ study but a very complementary one.

What was the study design?

It was a phase III study, 1:1 randomisation, stratified on, as usual, centres, high risk and age, because we recruited patients from 65 to 79 but we didn’t know too much if the 75-79 years old that are the most elderly population in our big population study would potentially have less of an effect from the treatment. So 75 was one of the stratification points.

So approximately 230 patients were recruited in either arm and we’ve been moving on with the treatments. Start of in induction and then maintenance, the primary endpoint being at 18 months. The induction had to last until 18 months and then the maintenance would start after that. So for the induction we wanted to be closer to real life because that’s what we think academic studies are meant for. They have to develop new approaches but stick to real life. In real life bortezomib in elderly patients, transplant ineligible patients, is used weekly. So in IMROZ they had to go by the Velcade, bortezomib, that is approved – twice weekly – but we, in BENEFIT, use it weekly. So for the first 12 months we gave it weekly, 1, 8, 15 and from 12-18 months to limit the risk of neurotoxicity we gave it twice monthly. So the patients received bortezomib for 18 months.

Now, patients stopped dexamethasone after 12 months because we wanted also to demonstrate that the addition of dexamethasone in the long run brought nothing interesting to the patients and it’s the other way around, it would bring potentially more safety issues.

What were the key results?

The primary endpoint was MRD negativity rate at 10-5 at 18 months. So the results are, number one, that the isatuximab, lenalidomide, dexamethasone control arm actually did as good, as well, as the MAIA historical daratumumab, lenalidomide, dexamethasone arm, MRD around 26% at one timepoint, 18 months. It was 30% in MAIA approximately. But, most importantly, in the quadruplet arm, the isatuximab, bortezomib, lenalidomide, dexamethasone arm, the MRD negativity rate jumped to more than 50%, 53%. That difference is really what we believe is most interesting and most intriguing and really the groundbreaking thing here. Because we expected the quadruplet to do better than the triplet, we never expected the quadruplet to do twice as better than the triplet actually by just adding one drug. So it really shows how there’s this incredibly synergy in that regimen across the different drugs we’ve been using for quite a reasonable safety profile, but we might get to that.

One other important point in BENEFIT was that we looked at 10-6 and without transplant one third of the patients at 10-6 negative. This is, again, incredible.  One last point is that we looked at 12 months as well. So the MRD was done at 12, 18 and 24 months so we also have the 12 month. Most of the patients already had MRD negativity level at 12 months which speaks to the fact that you don’t necessarily need to give Velcade for as many months as 18 months.

What did you see in terms of adverse events?

There’s no free lunch, as the US like to say. If you give four drugs you will have four different types of side effects that might pile on and you’re going to have to deal with that. Nothing new, there’s no side effect that is related to the combination. You sum up the side effects coming from each of the four agents and so as soon as you can decrease the dose or stop an unnecessary drug you immediately improve the side effects. Of course with lenalidomide fatigue, GI, neutropenia; of course with bortezomib neurotoxicity, peripheral oedema, in the lower limbs particularly, and GI sometimes. And, of course, with the CD38 monoclonal antibody a slightly higher risk of [??] and bacterial infection which are more upper respiratory. And, of course, with dexamethasone insomnia, hypoglycaemia, stuff like that.

But, first of all, the centres are very experienced with these four drugs because we’ve been using these four drugs for years. So really there was no major grade 3, 4, 5 side effects, number one. Number two, again, the combination did not create any new side effect. Number three, the relative dose intensity of either drug was more than 90% so it means that it might have been difficult from time to time for some patients and for some centres and teams but globally they were able to maintain the patient on treatment for the duration of the treatment as per protocol.

So that quadruplet you need to learn how to use it and make it right but it’s something that doesn’t seem to be too difficult to manage.

What do you think will be the clinical impact?

The clinical impact, at least in my centre, is that on the next Monday, so I gave my talk at ASCO on Saturday, the next Monday 100% of my patients have switched to quadruplet. I think in the coming months and I hope not in the coming years but definitely in the coming months the quadruplet is the new standard of care. For now, isatuximab, bortezomib, lenalidomide, dexamethasone is the quadruplet. At IMS in Brazil 2024 we will hear about a third phase III study, CEPHEUS, that I can tell you is confirmatory to the two first studies, IMROZ and BENEFIT.

So, yes, it’s definitely the new standard of care, it’s definitely the way to best treat the patients. The benefit for the patients, their families, is just gigantic. We have never been that close to transplant without a transplant. So, yes, I wish any patients from at least 65 to 79 could switch to this regimen because it’s just a groundbreaking change for them.