Point number one， we have to focus on newly diagnosed myeloma patients， maybe young or fit patients who are here for optimal drugs without many comorbidities. And， in addition， we have to also incorporate a standard for these patients in order to plan a cure for multiple myeloma， and to introduce the role of undetectable measurable residual disease inside and outside of the bone marrow， increasing the sensitivity threshold， and maybe tend to the minor six， at least， and then to include what we call undetectable measurable residual diseases and sustain it over time. So， it would put all of the information together. I think that we can convert the myeloma into a curable disease.

 

Dr. Mateos: When we are planning the population that could be eligible for cure， of course， if we plan newly diagnosed myeloma patients fit enough for receiving optimal drugs， we have to consider the transplant eligible population. And in these patients， their standard of care routine includes induction， followed by autologous stem cell transplantation， and maintenance therapy. And we know that transplant is a complementary strategy toward the induction regimen， and transplant with high dose melphalan is able to upgrade the quality of the response. And this is something that we have seen with all induction regimens. And， definitely， this is going to contribute to having more patients in—meaning more residual disease ineffective— and that in the end， maintenance is going to maintain this status and we can have some patients potentially cured. 

 

But， it’s true that we can potentially challenge autologous stem cell transplantation and we can find some patients that could be potentially cured without autologous stem cell 

 

transplantation. And these patients are definitely dosed again， at the standard risk and achieving undetectable measurable residual disease after an optimal induction regimen. And this is what we have observed in some clinical studies and， indeed， many clinical trials are ongoing trying to evaluate this question. I would say that today， the transplant eligible population has to continue receiving autologous stem cell transplantation. And some trials that are ongoing will finally answer the question of whether it is possible to select some patients in which we could potentially avoid autologous stem cell transplantation and they can be potentially cured. 

 

Dr. Mateos: Yeah， concerning the role of autologous stem cell transplantation， transplant is a complementary strategy. But the better the induction， the better the outcome. And， definitely， we are introducing another combination as part of the induction regimens. I would say that bortezomib， lenalidomide， and dexamethasone is the standard of care in many countries and in many centers. And bortezomib， lenalidomide， and dexamethasone is effective， but the next step is to monoclonal antibodies anti-cd38 in order to convert treatment drug combinations in quadruplet combinations. 

 

And we have information coming from some clinical studies—like the GRIFFIN study—in which daratumumab was added to RVd， and after induction， transplant and consolidation， approximately 50 percent of the patients achieved a complete response. And a minimal residual disease negative was found at the end of maintenance in approximately 60 percent of the patients. And the same information is coming from isatuximab in combination with bortezomib and lenalidomide and dexamethasone. And just after induction， 50 percent of the patients are in undetectable measurable residual disease. This news started， in principle， the novel combinations to be utilized as part of the induction regimens， which should incorporate proteasome inhibitor and anti-CD38 monoclonal antibodies. 

 

Dr. Mateos: Well， concerning the toxicity of the introduction of these novel agents-based combinations， followed by autologous stem cell transplantation， I think that this is not going to be a big problem overall because we are dealing with young and fit newly diagnosed myeloma patients. So， they tend to be without comorbidities， and overall， they tolerate the treatment very well. If we compare the novel combinations with the previous ones， basically the main difference is， to switch thalidomide， they’re all admitted by lenalidomide—the most common immunomodulatory drug in use right now. And lenolidomide has a better safety profile than thalidomide， basically， because it does not induce peripheral neuropathy. And when we added the monoclonal antibody anti-cd38， we are not going to increase the toxicity， because the anti-cd38 monoclonal antibodies are very well tolerated. 

 

It’s true that we have to take care about the respiratory infections， especially upper respiratory tract infections—that they are usually observed more frequently than with the combinations without the antibody anti-cd38. But we know how to manage this toxicity， and with antibiotics in majority of the patients， resolve these adverse events. And in the randomized clinical studies， at the end of the day， the discontinuation rate is quite similar， involve absent.But overall， the toxicity profile is quite manageable and the majority of the patients are able to receive these novel combinations.