iwHRMM 2024 | An insight into designing randomized studies in high-risk myeloma

Francesca Gay:

Good morning, my name is Francesca Gay and I work in the University of Torino in Italy. I’m here with Sham Mailankody from New York and with Binod Dhakal from Wisconsin. We are here discussing how we can run and design trials for high-risk patients. 

So we had a long discussion. I think the first key point, if you two agree, is that we should first identify the groups of patients that we want to enroll and that we really define high-risk, and we face many challenges in enrolling these patients in clinical trials. What are your thoughts on this? 

Sham Mailankody:

So I think, yes, I think this is the right time to design studies for high-risk myeloma because of all the new treatments, but the two critical challenges are having precise definitions of what high-risk is so that they’re uniform and we can enroll patients quickly and true high-risk patients get enrolled on the study and and so I think the new IMS consensus guidelines is a good place to start. We now have a consensus definition for high-risk and hopefully all can agree and if future studies start using that as the eligibility criteria I think that will go a long way in harmonizing the kinds of trials we’re doing. 

Binod Dhakal:

No I agree. I think that will help us to identify you know potentially all high-risk patients but also we have to understand that you know there are some functional high-risk patients who, despite our best effort, may not be identified at that time. It’s not that they are not high-risk, they are high risk but there are limitations of our technology to identify them. 

So I think, it is two parts. There are challenges and two parts, one is identifying them and with the IMS IMWG definition we potentially can include the majority of them, but at the same time we also need to look at the trial, I agree with Sham, because we have so many now tools in the toolbox, I think we can potentially look at those functionally high-risk patients who will have relapsed very early after highly effective treatment. So I think I would like to take that into two different kind of studies. 

Francesca Gay: 

Yes, I think these are two key points: sort of a static definition, a baseline definition, of high-risk and then something that you learn ongoing, you’re not able to capture this as a dynamic definition of what is high-risk. That is a way to acknowledge that we have limitations and there are many things that we don’t know. 

And also the key point is how can we approach this patient, what is the optimal treatment approach? I think we all believe that there is a role for the immune therapies, the novel immune therapies. Most of them gave beautiful results in late lines, even unexpected results I would say. So most of us want to incorporate this early on in the course of treatment for standard-risk and particularly for high-risk. 

So, Binod, I think you have some nice trials that are now wanting to explore what is the optimal setting to incorporate this immune therapy, right? 

Binod Dhakal:

Yeah, so as you already pointed out, I think, you know, given how effective this immunotherapy is, I think we want to introduce this earlier, especially in high-risk patients. I think this is the perfect platform to use that and I think the question that you brought up very beautifully in the morning was, what is optimal timing for these patients? Because it’s not that these patients don’t respond. They respond but the responses don’t last that long. So I think we have to introduce these kind of innovative therapies very early on, when they are still responding, when the disease is still sensitive to the treatment, and if there is potential resistance down the road, you could probably salvage with immunotherapy by introducing it early on. 

So I think there are two approaches that we are doing right now. One is looking at all biological high-risk patients, and you heard that TRIUMPH is one study that we are planning on. It’s a cooperative group study, and now we have a, I would say, much more effective control arm than what we used to before because we have more long-term data from PERSEUS and GRIFFIN using dara-VRd and the transplant data, our maintenance, I think we have a little bit longer data that actually could, you know, play a role as a good control arm in the absence of other effective control arms, and now we are using immunotherapy on top of that. Cilta-cel and cilta-cel followed by talquetamab, two different targets. So I think that is one. 

The other one that what we are right now enrolling is the MASTER-2 study. Independent of the biological risk we’re looking at the dynamic risk patients, like who are MRD positive after six cycles of dara-VRd. So I think the capturing both the subset of patients, which probably wouldn’t have been captured initially. So I think they’re also very interesting, immunotherapy early on after transplanting subset of patients who are MRD positive. 

So I think these kind of trials, I hope, would help us at least answer some of the questions of how to improve upon these patients who probably wouldn’t have been eligible for other available therapies. 

Francesca Gay:

Yeah, I think a nice point also to highlight is that we think about these new trials, thinking about the new therapies that we can implement. When we want to explore these new therapies, there are some very nice trial designs that you showed this morning and that can help us gather more data referring to different agents with trials that show some flexibility in the design and can explore different course. So would you like to explain to us a bit these trial designs? 

Sham Mailankody:

So one of the challenges, I think, is the field is moving so quickly that if you take too long to run these studies, the results of the study become somewhat outdated I guess, or no longer relevant necessarily. So we do have to have a way in which we can get these results generated relatively quickly. The challenge, and it’s a good challenge to have, is that we have many different agents to test in many different settings. And so do we add these new drugs to induction, consolidation, maintenance? Do we target one protein or others? Do we target both of them together? Do we use a CAR? Do we use a bispecific? Not to mention some of the genetically targeted therapies that we also discussed here, t(4;14), other subsets. 

So there’s a lot of questions to answer and many different ways in which to answer them. So I do think that we have to start thinking about trials that are not just single arm studies, which certainly we should do some of, but maybe more platform approaches where you have multiple arms that are all enrolling in parallel to each other, that have maybe some kind of adaptive design, a Bayesian approach, that tells you early on which arms are promising which ones are less promising so we stop enrolling patients on non-promising arms and meanwhile prioritize the treatments that seem the most promising ways to treat high-risk myeloma. And this kind of adaptive design also allows to add new arms as new information becomes available and close out arms that are not meeting the benchmark that we want to. 

So I think this would be the right time. We have a uniform diagnosis. We have a lot of tools. We have an endpoint that we can measure early on in MRD and sustained MRD negativity. So I think hopefully as a group, meetings like this one will allow us to design those kinds of studies in the coming couple of years. 

Francesca Gay:

Yeah, I think this is a great point. And I think this is the way to go. So speaking about endpoints, I like the fact that you mentioned the possibility to have an early endpoint. So for two reasons. One is that we all think that PFS could be a good endpoint for high-risk patients, because unfortunately with all the regimens that we have, this is suboptimal. Nevertheless, if we want really to have some information early on and not go ahead, treating patients waiting for the PFS with a therapy that might not be optimal, I think MRD and particularly sustained MRD, I think you mentioned this, Binod, this morning, is extremely important. Because many high-risk patients, they can even turn into MRD negative, but MRD negativity does not last. So for these patients, I think really we need to use MRD, we need to look at MRD at specific time points and we need to look how much the MRD lasts. 

Binod Dhakal:

Yeah, no, that’s an excellent point and I’m very interested in looking at the how these patients do at MRD progression you know, before their clinical progression or IMWG progression how these patients do. I think that is where there’s a beautiful spot for us to intervene before this disease becomes out of control, right? And and we have now, again, so many options. I think definitely we have to switch target and that is a perfect time, I think, that even those patients who have sustained MRD and have done well, they could still flip the coin very quickly and we need to think about the trials how to intervene at this stage. We have some data coming at ASH, where we looked at these patients treated in MASTER, because we have MRD at different time points, and you will be surprised. This MRDp, or MRD progression, a resurgence of MRD is quite different when you look at the cytogenetic profiles of these patients, so I think there is another good platform for us to intervene with these new therapies.

Francesca Gay:

Thank you for mentioning this, because, again, the MRD monitoring in MRD negative patients is another key factor to try to improve the outcome of these patients in two ways. One is do we really need to treat all these patients until progression? Because we all believe that high-risk should be treated until progression, but maybe we can end up with an excessive toxicity so it’s worth to explore, if not stopping treatment, maybe treatment de-escalation that is enough to maintain the disease under control. 

And the other key point is what we do when the MRD clone, I mean, it reappears again. So I like the fact that you mentioned the progression criteria for myeloma, which now are totally not considering the MRD, are clinical progression, but the first setting where we should explore probably the retreatment at MRD or at biochemical progression is indeed high-risk. 

Binod Dhakal:

You know in our clinical anecdotes, of course it is anecdote, clearly we have seen that somebody who is MRD positive and they’re clinically high-risk to begin with, their time to progression is very very fast and the kinetics are much faster than standard risk. Again we haven’t looked into that with the new therapies, but I think that’s what at least tells you that this is probably going to behave differently when it comes back. 

Francesca Gay:

Yeah, no, in our case series, in our data, it’s exactly the same. So the high-risk patients, and you can consider many high-risk factors, are the ones that have a higher risk of MRD-reappearance, even if they are MRD-negative and if they stay MRD-negative for a while. So this is particularly important. 

So I think we had a very nice discussion. I’d like to thank my co-chairs in this discussion together. And thank you all.