I am not going to concentrate on the cellular production and I will move to the cellular clonality. In terms of cellular clonality, I will not spend any time in immunohistochemistry or ASO PCR. Immunohistochemistry because of its long sensitivity level and ASO PCR because, although available, is not applicable to all patients with multiple myeloma. So I will concentrate in flow cytometry and next-generation sequencing.

This is the Spanish approach, while almost 500 newly diagnosed myeloma patients treated with bortezomib, lenalidomide, dexamethasone, six induction cycles, followed by transplant and two cycles of consolidation. MRD was evaluated at different steps, but when we concentrate on the MRD evaluation by next-generation flow, before maintenance, you can see here we were able to identify a sub-group of patients with an excellent outcome.

These patients were in minimal residual disease negative, and according to the prior discussion, the sensitivity level reached here in this study was 10-6. When we evaluate how the impact of the sensitivity level matters in the outcome, we can see that, when we consider MRD negative sensitivity level 10-6, I think that the group of patients who reached this level had, I would say, an excellent outcome.

You can see here another trial conducted by the French group, while similar approach with VRd induction, followed or not by autologous stem cell transplantation, followed by consolidation with two cycles of DRd after transplant or five VRd for those patients who were allocated to non-transplant. MRD was also evaluated at some steps, but when we evaluated minimal residual disease negative rate before maintenance, you can see here a similar progression-free survival curve that I previously presented according to the Spanish experience.

Again, in this study, next-generation sequencing was the assessment selected for the evaluation of minimal residual disease, 10-6, but again this technique in this study as group of patients with an excellent outcome was identified and this group of patients and this outcome, I would say, that is similar to that reported by the Spanish myeloma group. Concerning the sensitivity level, I would say exactly the same and when the sensitivity level is 10-6, the outcome is much more better. This study supplied to newly diagnosed myeloma patients transplant eligible, but now in the older patients, in the non-transplant eligible it is also possible to achieve complete response and also minimal residual disease negative.

One example is the ALCYONE study in which daratumumab, the monoclonal antibody targeting CD38 was added to the conventional regime bortezomib, melphalan and prednisone. And here you can see where patients achieved complete response, minimal residual disease negative, next-generation sequencing, 10-5, the outcome is much more better in terms of progression-free survival.

And I think that one important concept is that this is applicable to both the experimental and the control arm. Put in context, that minimal residual disease negative is an important surrogate marker predicting progression-free survival. When we evaluate how many patients were able to achieve minimal residual disease negative, after VMP, only seven patients when we added daratumumab, this rate increased up to almost 30%.

And there is another trial, the MAIA trial, in which again under the use of lenalidomide and dexamethasone as continuous therapy, daratumumab was added. In this study minimal residual disease was also evaluated with the same concept. Minimal residual disease negative is an important surrogate marker predicting progression-free survival and up to almost 25% of patients receiving DARA plus LEN/DEX achieved minimal residual disease negative.

So this would be the conclusions of this talk and I would say that progress in myeloma treatment and patient outcome has been remarkable in the recent past and continued progress will require the use of minimal residual disease. MRD negativity is a powerful indicator for progression-free survival and overall survival. And I think that the next step is of course to incorporate the minimal residual disease evaluation into our clinical trials because this is the only way to answer these relevant questions that we will answer for sure in the trials that are coming.

We will be able to define the timing of high-dose therapy in transplant eligible, and maybe minimal residual disease evaluation will allow us to identify patients in which we can defer the transplant at the moment of relapse. We will be able to answer to the question about the consolidation, do all patients have to transplant and need consolidation, maybe minimal residual disease can help us to answer to this question. The same for the optimal duration of maintenance therapy and also why not to identify the need for change in therapy anywhere along the continued treatment scheme.

And I finish here, thank you very much.