KRd vs RD: Reducing Progression in High-Risk Smoldering Myeloma | Annemiek Broijl, PhD | #ASH24

My name is Annemiek Poyl. I'm from the Erasmus MC in Netherlands, Rotterdam actually, and I'm working on multiple myeloma precursor diseases. I have presented this year at ASH the research, the study, EMN 15, Hovenland F47. It is a phase two randomised trial which compared carfilzomib, lenalidomide and dexamethasone versus lenalidomide and dexamethasone in high risk smoldering multiple myeloma patients. Patients with high risk smoldering myeloma were included in this study and they received immunotherapy with carfilzomib and lenalidomide, dexamethasone. These are agents that are used for myeloma treatment, but different than myeloma treatment, we give that for a certain period of time. So nine cycles in total, then lenalidomide for 12 cycles. And the other group receives lenalidomide, dexamethasone and lenalidomide for again two years and then it stops. So it's a limited period of time that patients receive immunotherapy. And we look at what works best for patients that have high risk smoldering myeloma. And this is a group that is normally outside clinical trials not treated. Studies before, we had a long time, we had no good agents that can indeed get a better disease free or a period two disease with the agents that we had. But there was this study, the Kiridek study by Marie V. Mateus, that for the first time showed that giving immunotherapy, lenalidomide, dexamethasone to patients with high risk smoldering myeloma. And these are the patients that have within two years, 50% gets myeloma. And then it makes sense to try to treat them to prolong that interval to myeloma. That was one of the first studies. We also saw a study from the Sloan-Kettering hospital, Ola Landgrenen, they added carfilzomib to LenDex that even got more people completely free of disease, also for a very long period of time. And that makes us wonder what would work for high risk smoldering myeloma to really get rid of their disease for a very long time. They do not have the known CREB or slim criteria, but they do have sometimes issues. And you do not want to get them into trouble with getting CREB or MDE criteria. So then it sometimes can make sense to try to treat them. But we have to also be aware that if we treat them, we also introduce toxicity. And so we have to really be aware, what are we doing? Is that really helping the patients or only giving them more toxicity? And then it doesn't make sense to treat them. And those are important things to look at. So with high risk smoldering myeloma, high risk is always a little bit difficult to define. The definitions have changed over the years. But in general, you see that 50% of the high risk smoldering myelomas will evolve to multiple myeloma within two years. And so that makes sense to if you know that these patients, 50% will get myeloma, can you already do something to not get them to the multiple myeloma, CREB or slim issues that they would then normally have without treatment? In the trial, we looked at several things. The most important thing is, can we really get rid of the disease? And then in the sense that you in a bone marrow measure no malignant plasma cells anymore, we call that MRD, measure minimal residual disease in a sensitive to one to the minus five. So one in a hundred thousand cells does not include any more a malignant plasma cell. That is really to try to get rid of the disease. This was the first goal. But then you also want to have that minimal residual disease to be durable. And that is something that you can measure by several things. We looked at one of the things we looked at was progression free survival. And as there was quite some comment, yeah, that is difficult. Progression free survival also means a rise in an M protein. And for a small myeloma, that does not mean that they have to start treatment. So I showed the progression free survival, as I said, with also by chemical progression. But what we also will look at is the time to really progression to myeloma. Those events were so few yet that we cannot give a statistical significant benefit in one or the other. But we did see that progression also by comical progression or cures much faster in patients treated with Landex than with carfilzomid Landex. So that is anyway what we can see. And most of the time, but that is something that we have to show, that will also result in that more patients will need than treatment after a while. But that can take sometimes a year or two years. But we think that it would be more when patients receive Landex, that they will progress to myeloma than when they receive carLandex. But we have to really show that and that will be there, I think, in the coming year. About this study, I would like to say that this is one of the few randomized studies. I mean, we actually already know that doing treatment in small myeloma, especially in the high risk makes sense. That is what the Kiridex and E-coctrion from Loneo already have shown. So and we try to build up on that with adding a new agent, adding a third agent to the equation to see, can we even deeper the response and prolong the time to progression to myeloma. On the other hand, it does not, it is also coming with then more toxicity. So that has to be really weighed, what is the best. And this is one of the study showing indeed more efficacy, also more toxicity. And there are quite some great trials that have been presented here looking at what could be the best for patients in high risk model myeloma. And actually, I do not think directly that carLandex or Landex are the ways to go. I would even go for maybe a agent that is even less toxic, always limited time of therapy. And with again, the, at least try to expand or prolong the time to progression to myeloma with something that is not too much toxic, but effective.