iwMPN 2026 | An update on combination strategies in frontline myelofibrosis

Raajit Rampal:

Hi, I’m Rajit Rampal from Memorial Sloan Kettering Cancer Center, and I’m joined by two of my esteemed colleagues. 

Pankit Vachhani:

I’m Pankit Vachhani from University of Alabama at Birmingham. 

Nikolai Podoltsev:

And I’m Nikolai Podoltsev from the Yale School of Medicine. 

Raajit Rampal:

So, you know, gentlemen, we had a session today talking about combination therapies. That was the focus of, you know, our session on ruxolitinib plus a number of other agents. And maybe just let’s spend a couple of minutes with a couple of key highlights of what we talked about. So maybe, Nikolai, maybe we’ll lead off. 

Nikolai Podoltsev:

Yeah, you know, there are three of us here because there are three different drugs which are in development in that particular space, all in phase three development. And so I presented Selinexor, which is an XPO1 inhibitor in combination with ruxolitinib, and was compared with ruxolitinib with placebo. In that particular phase three study, there was randomization two to one. And the co-primary endpoint was SVR35, which is spleen reduction by 35% by week 24, as well as absolute reduction in total symptom score. So this study showed a significant improvement in SVR35 endpoint, but didn’t show reduction in total symptom score. The reduction of symptoms occurred in both arms of the study, but it was not better in the study which looked at Selinexor as the drug which we are trying to develop for this disease. So the one outcome which makes this study different from other studies is early signal that overall survival may be better in an arm which used Selinexor in addition to Ruxolitinib. Again, it’s preliminary, and the duration of follow-up is about 12 months. And also the number of events is also quite limited. So we have to give more time to see if this benefit continues to persist with time. So certainly, an interesting finding and an exciting finding. And that, perhaps, in the race of three drugs, puts it somewhat ahead. So the company, which is making selinexor, submitted a supplementary new drug application for this medication at the end of August. We’re hoping to hear from the FDA in a few weeks, and we’ll see how it goes. But certainly, it’s a progress in the field where recently we had five competitors, and now we only have three. 

Raajit Rampal:

Survival of the fittest to some degree, right? 

Nikolai Podoltsev:

Yes. 

Pankit Vachhani:

Absolutely. And so I talked about navtemadlin. Navtemadlin is an MDM2 inhibitor. The story behind it is that MDM2 levels are high in patients with MPNs, especially so in patients who have myelofibrosis. And MDM2 negatively regulates P53. So if we had an MDM2 inhibitor, we could restore the P53 activity and therefore lead to cell apoptosis, reduce cytokine levels, decrease fibrosis, improve symptoms, splenomegaly. And that is where navtemadlin comes in. It’s an oral best-in-class MDM2 inhibitor. The drug was first studied in a study called 101A, which was then followed by the 101B study, which is a randomized study called BOREAS, the results of which we have seen, where navtemadlin led to nearly three times more spleen reduction and twice as much symptom improvement as compared to best-available therapy. Now, that was as monotherapy. There’s also a different study called the 109 study in which patients who were already on ruxolitinib, but had suboptimal responses deemed by the investigators for the protocol, they had an addition of navtemadlin to their stable dose of ruxolitinib. And what the study showed, the 109 study, was that there was additional and more spleen improvement, symptom improvement. There were decreases of variant allele frequencies of the driver genes like JAK2, CALR. There were reductions of cytokine levels. And very importantly, CD34 cell counts came down as well. These are the ones which are at the heart of the underlying myelofibrosis. After all, these constitute the stem cell and progenitor cell population. Now, these exciting results of the 109 study led to what is currently ongoing, which is the POIESIS study, a very uniquely designed study where there are two parts. One is the RUX run-in part, whereby patients who have intermediate 1, 2, or high-risk myelofibrosis with platelets of 100+, they go on to just Rux monotherapy initially. And then if they are deemed to have a quote-unquote suboptimal response, only then do those patients enter the next stage, which is the randomized portion, where either navtemadlin at 240 milligrams on days one through seven of a four-week cycle is added on, or placebo is added on. The study is ongoing. It’s one of the largest studies in our field, and the primary endpoint should be, the top-line results should be coming out at some point around quarter three or quarter four of 2027. What I find very unique about the study is, one, the design, and two, the fact that it isolates the benefit of navtemadlin as compared to an underlying JAK inhibitor, Ruxolitinib in this case. It also perhaps is much more in alignment with what may end up happening in the community if and when there were additional drugs with different mechanisms of actions to be approved. As stated more clearly, I think that there could be many patients who could just get a JAK inhibitor first, may have a very good response, and may not need a second drug initially. So why not identify the ones who truly need a second drug and then add that second drug, navtemadlin in this case, for those patients who have suboptimal response so that we can get them to a more optimal response. 

Raajit Rampal:

I think that’s a really important point. And I think, you know, I want to come back to that, right? Let me, I’ll talk a little bit about, you know, what we know from MANIFEST-2 that was also presented. But I do think this becomes a key discussion point. So, you know, we also talked about the MANIFEST-2 study, which is, at this point, the study with the longest follow-up to date of a combination study. And this is a combination study of a BET inhibitor, pelabresib, plus ruxolitinib in a randomized fashion versus monotherapy with ruxolitinib. And the top-line data has been presented, which is that clearly there is a better spleen response with a combination of pelabresib and ruxolitinib versus ruxolitinib. Symptoms statistically not different, numerically, a little bit more in favor of the combination. But I think importantly, you know, with the cutoff of the data at week 96, it was a sustained response, right? This is not just a quick thing at, you know, six months. This is something that we’re showing to be a durable response. And with long-term follow-up, there seem to be less deaths, less progression events. Again, these are not statistically significant events, but there are numerically some differences there. So having thought about all of these drugs that we just talked about, let’s come back to the question that you posed, which is, in a world where these drugs were approved, we don’t need to think about one drug in particular here, but are we going to use these in front line? If so, who’s the right patient? Or is it going to be, as Pankit has said, in all likelihood, these are going to be patients get JAK inhibitors as first-line therapy with these drugs being as an add-on? 

Nikolai Podoltsev:

Yeah, I can say that Selinexor, the drug studied in the SENTRY trial, is a little different because it is already approved and available. So I think the company which is making the drug is accumulating real-world evidence of its use in patients with myelofibrosis. And that will inform who is actually being treated. So even before the drug approval. So it is approved in the myeloma relapsed/refractory disease. And of course, it is not used commonly in that disease anymore because there are so many other drugs out there. But we have experience with this drug beyond clinical trials. So I think it is interesting that it may have single agent activity in this disease. And the question is what the SENTRY-2 study is going to show, which is going to be presented at ASH 2026, where the study was an add-on study. But here, instead of ruxolitinib being the frontline treatment, selinexor is. And then you add ruxolitinib to it or some other JAK inhibitor, depending on your platelet count or presence of anemia with hemoglobin less than 10. So I think the data from the SENTRYstudy shows that patients who were using very small doses of ruxolitinib still benefited from the standpoint of SVR35. And half of those patients had SVR35 response, even though the dose of ruxolitinib was very low. Perhaps the benefit of selinexor is being shown this way. We’ll see. But again, if we go back to ruxolitinib plus selinexor, if the study goes through and the drug is approved, will we give it to everyone? I think we have to emphasize the benefit for the spleen on patients with significant splenomegaly, patients who are interested, for whatever reason, to do spleen reduction before symptoms, for example, as a bridge to allogeneic stem cell transplant, the only curative treatment we currently have for this disease, they may benefit from this drug being used for this short period of time before the transplant. So again, we’ll see if Selinexor by itself has activity, right? You know, so you can envision how this can be used on its own. Again, you know, so this is a balance between the positive outcomes of the trial as well as side effects, which patients are willing to tolerate. And if it is survival, which has to be proven by long-term follow-up, then I suspect people will be able to tolerate more of side effects and just stay on the drug for survival benefit. Time will tell us about the survival. 

Raajit Rampal:

Along those lines, maybe the last question I’ll leave to, Pankit, is that, okay, we have these combinations. Does that give us, does it give us a reason to treat earlier? In other words, if we postulate that any cancer likely responds better to earlier intervention, and we have now data for multiple drugs that say they work better, at least if we look by SVR35, does that now empower us to say we should be treating patients earlier? 

Pankit Vachhani:

Great question. And actually, I think it’s a continuation of the question that you asked to Nikolai first, which is combination from day one or add the other drug at a later time point. And I think in general, when I think about this question, I would like to break it down into a couple of things. One is that in general, treating earlier leads to better responses across the field of oncology. Second is the fact that almost any treatment decision that we make in our field, going all the way back from vaccines for flu season, for example, all the way to treating cancers, any of our treatment decisions are based on risk-benefit analysis. So I think with any of these new drugs with different mechanisms of action, if we see an improvement of progression-free survival, quality of life in the long run, or durability of responses, as we are seeing with some of these drugs, and you had shown some data for pelabresib, we have seen data for other drugs as well, selinexor and navtemadlin and previously with other drugs too, you can make a case for treating early. But I don’t have a single answer. I would say let’s see the data and then follow it. And that may ultimately be the deciding principle for us to go down the philosophy of treating everyone with combination from day one, which may even include patients who don’t have massive splenomegaly. Who knows? Maybe if they benefit in the long run, we should be treating them or selectively treating some patients. I would say, you know, that’s one part of the answer. The other is we also have some other drugs coming up. We have drugs like the CALR antibodies that some of our colleagues touched upon. We have the more selective JAK2 inhibitors. They perhaps, and the preliminary data shows that some of these more targeted approaches have a better adverse event profile, at least let’s say the CALR antibodies. Yeah, one can make the case of starting treatment earlier rather than later. The good part is all the three drugs that we spoke about should still work even with these new backbone agents, be those calreticulin antibodies or bispecifics or the mutant-selective JAK inhibitors or type 2 JAK2 inhibitors. So exciting times for our field. We have also seen data from interferon where patients who are getting it for prefibrotic or lower-risk myelofibrosis, they are developing good outcomes, hematologic outcomes, spleen outcomes, also variant allele frequency reductions. We have seen similar data from RUX before, RUX monotherapy. So again, exciting times. Let’s wait for all the data to come out and then make our decisions. 

Nikolai Podoltsev:

So I just want to add that, you know, so if you’re considering treatment for low-risk disease, which perhaps doesn’t have any symptoms or significant risks immediately, you have to have a drug which is not only effective but is well-tolerated. And we have to remember financial toxicity as well, right? You know, so and finding this drug usually takes more severe disease, right? You know, so we are successful identifying those treatments for high-risk myelofibrosis, perhaps some of them will serve the role in earlier disease stages like prefibrotic myelofibrosis. 

Pankit Vachhani:

And this is also pushing the field and asking questions that we never asked before, which is what surrogate endpoints we should come up with? How are we going to validate it? And I think we had a fantastic discussion yesterday with members from the FDA with us and jointly talking about these things which will guide the field of MPN down and over the next couple of decades. 

Raajit Rampal:

All great points. And I think that we’re in an era, as you said, where we have promising new drugs, but I think we also have a lot of remaining questions to answer. So on behalf of my colleagues, I’d like to thank you for your attention.

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