Amrita Y. Krishnan, MD, and Paula Rodríguez-Otero, MD, PhD, on Multiple Myeloma: Findings From the PERSEUS Trial on a Regimen for Transplant-Eligible Patients

Amrita: So Paula, very exciting results. PERSEUS is the trial that keeps on giving. What was your biggest surprise from these longer follow-up results? Paula: I think that the main message in the presentation is that responses really deepen over time, particularly during the maintenance phase. In PERSEUS, there is this lenalidomide in the standard arm until this is progression and then there is the Daratumumab plus Len in the experimental arm for at least two years. Then, there is this response-adapted approach based on MRD and patients that have MRD negativity can stop the Daratumumab. What we clearly see is that responses go deep and deep during the maintenance, more in the experimental arm, in the DVRD arm. And also higher rates of MRD negativity tend to the minus six, which is a very stringent threshold for MRD and also high rates of sustained MRD. This is really reinforcing this continuous, let's say, therapy. That the responses really go further into the maintenance phase. Amrita: I'm going to be really provocative and ask, PERSEUS is two years of DARA and you've said MRD can deepen. Do you think two years is enough, or maybe should it continue? Paula: Yeah. I think that this is a very important question, because we truly don't know. The study design was planned like this. At least two years of DR maintenance or Dara plus Len maintenance, then patients who achieve MRD negativity that was sustained for one year could stop Daratumumab and they remain on Len until disease progression. So far, two-thirds of the patient had already stopped Daratumumab. It's the majority of the patients somehow that stopped Daratumumab. I think this is interesting because it allows you eventually to reuse the Daratumumab in the future. Because, if these patients relapse, they will relapse outside Daratumumab and maybe you can use it again. So I think it's interesting to see, you know, that in our Spanish trial also, after two years of maintenance patients who were MRD negative, they could stop, also, the treatment. So, it's difficult to say whether it's two, three, four years, but definitely I think two is a good number. Amrita: I'm going to go even one step further the other way. You're going to stop Dara. The majority of your patients, as you've shown, have become MRD negative in the Dara arm and de-escalated to Len. So, why not stop the Len too? Paula: Yeah, this is probably the next step because we want to stop, sometime, the treatment. Here we do not have the answer to that. In fact, for patients that lose MRD negativity, they could be re-treated with Dara, not patients with progression, but patients with reappearance of MRD. But they will continue on Len. So, we do not know whether Len can be stopped. But eventually, maybe in the future CAR-T26 is really aiming for a fixed duration of maintenance. And maybe in that platform we will be able to also stop completely all treatment for the maintenance part. Amrita: And then I had another question, which I never understood from the first PERSEUS, the patients over age 65 didn't seem to show the same benefit and was it just a patient number? But looking at your data in terms of MRD, in fact it's completely the opposite. Paula: Yeah, exactly. Here we see that for MRD 10 to the minus 6, 10 to the minus 4, sustain MRD 10 to the minus 6, 10 to the minus 4, all groups do favor the DVRD plus DR combo age over 65, high-risk cytogenetic IS history. So yeah, I think that for the first, so for the analysis of the ITT population, this was more some hazard finding that probably it's related to the small numbers. There was also a disbalance in the high-risk cytogenetic groups. So there was more patients over the age of 65 with high-risk cytogenetic abnormalities. So maybe all this came into this weird finding because there is no reason to believe that this is not working in age over 65. Amrita: And then, finally, do you think this now cements that DARA alone should be the sort of standard of care maintenance? Paula: I think so. I think that this study does not have the second randomization, but for sure the data that is being shown clearly suggests that there is deepening of the responses during the maintenance phase. And probably this should be considered the newest standard. Amrita: Thank you. It was a great presentation. Paula: Thank you.