Could you give us some background on the Isa-KRd quad regimen in newly diagnosed multiple myeloma?
We are now using, more and more, as frontline treatment, as induction therapy, a quadruplet combination. There are different quadruplet combinations, some of them are based on bortezomib as a backbone, the VRd CD38 antibody regimen, or the VTd plus a CD38 antibody, and we can also use carfilzomib-based quadruplet combinations. With carfilzomib we can use KRd, carfilzomib, KRd daratumab or KRd isatuximab. So probably those two combinations with KRd daratumumab or KRd isatuximab are the most potent combinations before autologous stem cell transplantation. Unfortunately, those two combinations are not yet officially approved and we cannot use them outside clinical trials.
Could you talk us through the IFM 2020-02 Minimal Residual Disease Adapted Strategy (MIDAS) study?
The MIDAS study was presented for the first time during the International Myeloma Workshop 2024 in Rio de Janeiro. This is a very large study; we did enrol almost 800 patients. All patients did receive a quadruplet combination with KRd plus isatuximab and subsequently we systematically assessed minimal residual disease within the bone marrow with a threshold of 10-5. Then when patients were MRD negative, they were considered as good risk patients because they did achieve a very deep, very good response, and we did compare KRd isatuximab alone versus autologous stem cell transplantation.
For those patients that were remaining MRD positive, what we are considering as high risk, poor risk, because there were still a minimal residual disease positivity after a very strong induction, we have compared a single versus a tandem autologous transplantation.
So here in Rio we have heard about the first part of the treatment, the induction results. MIDAS is one of the first studies looking at the adaptation of the treatment according to the results of MRD negativity. So MIDAS means Minimal Residual Disease Adapted Strategy for young patients eligible for autologous stem cell transplantation.
What could be the impact of these results so far?
The results are outstanding in terms of MRD negativity rates. The depth of response is really incredibly high after six cycles of KRd plus isatuximab, showing again that this quadruplet combination is very, very active in fact. We are reaching 60% of MRD negativity at 10-5 in the intent to treat analysis and we also looked at a deeper response, 10-6, and we have more than 40% of the patients that are reaching 10-6. So outstanding response rates showing that this quadruplet combination is very, very active in fact.
What is important to note is that the death rate is very, very low, in fact. So the feasibility of the quadruplet combination, six cycles, 28 day cycles, six cycles up front, is very feasible and, from a safety point of view, we didn’t have any issue in fact. So for patients less than 66 years of age definitely we can use in routine this quadruplet combination to achieve very good responses.
Where does this study sit in the treatment landscape?
Now we have to wait for a longer follow-up to have the updated results for the current comparison of stem cell transplantation versus no stem cell transplantation for patients with a good risk. For patients in the poor risk group we need as well to wait for single versus tandem stem cell transplantation. So the study is still ongoing. That was the first report of this induction phase but we need a longer follow-up to look at the final outcome and progression free survival. So we will need more time definitely.
But this study is really showing that in routine, in fact, you can adapt the treatment probably according to MRD negativity after induction in the future.
Tell us about the CONCEPT study.
The CONCEPT study is a German study that started quite a long time ago now, in fact. This German group was one of the first to propose a phase II study focussing on patients with high risk disease. In the CONCEPT study our colleagues did enrol not only young patients but also elderly patients but few patients were elderly. So let’s focus on young patients that are really the majority of the patients enrolled in this large phase II because almost 150 patients were enrolled.
The idea is to use a very aggressive quadruplet combination, stem cell transplantation and a long duration of consolidation and maintenance in order to avoid early relapses.
What could be the impact of these results?
The German group is showing that the quadruplet combination up front, and again that’s KRd plus isatuximab, so carfilzomib, lenalidomide, dexamethasone and isatuximab, before stem cell transplantation is associated with a very high rate of MRD negativity – above 50% as well 10-5. So the results are very similar to what was described in the MIDAS study; MIDAS maybe the response rate was slightly higher but nevertheless. That patients are, all of them, receiving stem cell transplantation and the difference here in this phase II is that they are proposing a consolidation based on carfilzomib, lenalidomide, isatuximab, a strong one, and then a long duration of maintenance with carfilzomib and isatuximab. So the goal here is to have a strong induction and then a long treatment duration. The treatment duration is almost three years so that you are really reducing the risk of relapse for these high risk patients.
So we don’t have a lot of studies focussing on high risk published recently. We only have three trials that looked at high-risk patients, one from the UK, one from France and the CONCEPT study from Germany.
Where does the CONCEPT data sit in the overall treatment landscape?
When you are looking at the overall results that were updated after quite a long follow-up now during the International Myeloma Workshop in Rio in 2024, you see that the progression free survival is very good for this poor prognostic subgroup of patients with a median PFS that is not reached at six years. So those results are really unprecedented in terms of efficacy.
We have to keep in mind that the treatment is very aggressive and very long indeed but, nevertheless, this is really showing that for high risk patients we need to use a quadruplet up front and to have a long treatment duration.
