Key Trial Data Supporting the Use of Selinexor in Patients with R/R MM


Two subject matter experts discuss keystone trials supporting the use of Selinexor in patients with R/R MM, each with unique dosing structures and different selinexor-based combinations.

Dr. Peter Forsberg: So, we do know that selinexor has been in the clinic now for a few years, first with approval in later relapsed patients following initial trials where it led to approval in 2019, in what describe as penta-refractory patients, essentially patients who have had two different proteasome inhibitors, two different immunomodulatory agents, and a CD38 monoclonal. So, that was based on the STORM trial, but subsequently with an expansion in its approval following the BOSTON trial which was a large phase III that compared selinexor, bortezomib, and dex, SVD, with bortezomib and dex. So, this led to an approval in 2020 in patients with one or more prior lines of therapy. So, not necessarily nearly as heavily pretreated, and also is pretty different in terms of the dosing structure. So, the initial approval that led to a lot of many of us who treat myelomas initial experience with selinexor was with a twice-weekly, 80 milligram dosing on days one and three each week. By the time that we were moving into the BOSTON trial, there was a shift towards once-weekly dosing with selinexor 100 milligrams each week along with, in this study, weekly bortezomib in combination with selinexor, and twice-weekly dexamethasone, compared to more dose-dense bortezomib or Velcade, dosed on twice-weekly, one, four, eight, and eleven, with dexamethasone. So, that was the comparison between selinexor bortezomib, and backed with a more dose dense bortezomib and dexamethasone, and led to a positive trial based around primary endpoint of progression-free survival with an improvement in PFS to 13.9 months in the selinexor-based arm, to 9.5 months in the bortezomib-dex control. And that did translate, so far, into an improvement in overall survival in that patient group as well, which is obviously an important consideration given some of the notable findings in phase II or phase III trials that have led to some drug approvals in myeloma recently. I think that gives us a baseline for the primary approvals with selinexor to date, but I do think that as this article gets into, there has been emerging data around several other combinations that has been able to impact at least my clinical practice. And I don't know if that's the same for you, Josh.

Dr. Joshua Richter: Yeah, couldn't agree more. I think you phrased it absolutely perfectly, everyone's journey through myeloma is unique, and you may end up in your third or fourth line having not been refractory to Velcade or you never got pomalidomide, and being able to mix and match this new MOA with another myeloma drug is great, and that led to this multi-arm trial of STOMP which used selinexor as a backbone and combined it with a lot of different myeloma therapies. And we can see here the three most matured data-sets, selinexor with pomalidomide, selinexor with daratumumab, and selinexor with carfilzomib. The STOMP study now has like 10 different arms, with Ninlaro, dara and Velcade, and a whole bunch of other arms. And what's really nice about this is exactly as you said, in the original STORM study, we gave selinexor twice weekly at 80 milligrams. It was more toxic that way, but it had to do all the heavy lifting. When we start combining with other agents that can share the load, we can get away with once-weekly dosing, and for the most part, the MTD of these studies, of these different arms, is based off of the myelotoxicity of the partner drug. So, daratumumab is not heavily myelotoxic so we got away with 100 milligrams once weekly with dara. Carfilzomib has a few more cytopenias, mostly thrombocytopenia, so we have to drop it down to 80. And when we mix it with IMiDs like Revlimid or Pomalyst, because they're more myelotoxic we have to give only 60 milligrams a week of selinexor. What we can see here in the data sets is that the response rates that we see when we combine selinexor with these other treatments of myeloma, we see response rates of 60-80% with progression-free survivals of over a year. What's really interesting in some of these arms, some of those patients were actually already refractory to the drug, so in the selinexor-Pom arm, some of those patients were already refractory to Pom, and the selinexor re-sensitized them. So, I think it's all about where can you squeeze a little more efficacy out of as your partner drug, because I agree with you, I don't just give selinexor, but I get it with a variety of them.

Dr. Peter Forsberg: And I think this update creates a great body of foundational data for us to understand doing the doses, giving us that dosing structure to begin with. And they're really sort of sketching out an efficacy and a safety profile. It's not a large phase III body of data, but it is enough to give us a sense of a pretty active combination strategy in the relapsed refractory, maybe a little bit heavier pre-treated than some of the other study scenarios. Even if comparing cross groups is always a little bit limiting in terms of saying, "Is there a best combo?" In three at least we get to say that there is good activity with each of these from what we can tell based on this, and that we do have some starting ground in terms of dosing and anticipated side effects. I guess this leads to a question, do you have any specific in mind that you think are suitable for each of those combinations, primary combinations that are more mature from the STOMP trial, these that have worked their way into the NCCN guidelines at this point in time as potential options, SPd, SDd, SKd?

Dr. Joshua Richter: Absolutely, and I think, to me the biggest determinant is what are they progressing on, and what have they seen? So, we’ll take SPd first, because I think to me, that's one of the easier ones. I think in early relapse, a lot of our patients have been getting CD38 and Pomalyst, it's been very common, dara/pom and isa/pom. But there's some more data now that the CD38 Kyprolis data may be even better for some patients. So, if you're getting dara/Kyprolis in your first relapse, then following that we need a pomalidomide-based regimen, I give XPd or SPd in that context. At the same token, if you've got carfilzomib/pom/dex as your second line, then I'll give selinexor/dara/dex. And if you've got dara/pom in your second line, I'd give selinexor/carfilzomib/dex. So, I think that helps drive it for me. I don't know if you would add anything.

Dr. Peter Forsberg: That's essentially the exact sort of same scenario that I come at it from, especially if we're thinking about it in that third-line setting, we're almost always looking for another partner for one of our core agents, whether that's they're pom naive, they're carfil naive, or they've had limited CD38 exposure. So, in that setting there's almost always somebody who needs a partner, and I think selinexor we have now have enough data to understand how to use it in that way, and to give us another really effective partner for that agent. Certainly, the question comes up, are there subgroups that we are less sure about, or less comfortable with? Older patients, patients with renal insufficiency. I don't necessarily think any of these are groups that would be excluded from selinexor-based therapy, I don't know if you have specific profiles in your practice that you consider to be better or less good selinexor candidates.

Dr. Joshua Richter: No, as it was, the patient I saw right before filming this, I'm not exaggerating, I'm starting on selinexor/Velcade/dex, and he's in his mid to late 70s, and he has a creatinine of three and a half. But he hasn't had Velcade since his initial diagnosis, and I'm giving him 60 once a week instead of the higher dose to offset any risk of toxicity, and I think for most of our regimens, and selinexor is included, we can dose it and support it in a way to get them through. To me, that's the big one. And I love this other question, and I have to steal it because I have a canned answer is, the role of selinexor in earlier lines, and to me, there is a very clear argument in early line for patients who get a MAIA approach upfront. So, if you get dara/rev/dex up front, and right now the MAIA data shows that most people are going to have greater than five year PFS. But if you get MAIA, and you underperform, you relapse in a year on dara/rev/dex, well, then your dara refractory, your IMiD refractory, your PI naive, and what's going to be the partner drug with a PI? To me, I don't want to give pomalidomide if you only did a short amount of time on rev, so to me, if you have an early relapse on DRd up front, I go to XVd as my next line, as a second line. I don't mean to steal them all, but I don't know if there's anyone else you would consider.

Dr. Peter Forsberg: No, I think that's a really interesting cohort of patients to think about it in. As we've talked about, I tend to think about it more in the third-line on, because my second-line in the post-rev relapse, younger, robust patients have been leaning towards the CD38 carfilzomib-based combinations currently. But I do think that's a unique cohort that needs an approach and it's probably emerging but not as well described as folks who have gotten that, our often used MAIA approach now in older folks but who need an option with maybe a suboptimal duration of response after open-ended CD38 and Revlimid therapy. So, I like that as a group, that's one where I'm going to certainly think about it in the future.

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