A nalyst here at RBC Capital Markets. Our next presenting company is Karyopharm Therapeutics, and we're really pleased to have their President and CEO, Richard Paulson, and their CMO and Head of Research, Reshma Rangwala. Richard and Reshma, thanks so much for joining us. Thanks for having us, Brian. I know there's a lot to talk about on both the commercial and pipeline front, but maybe we can start with commercial and XPOVIO. Can you talk about some of the quarter-over-quarter dynamics you're expecting for XPOVIO this year that's going to enable you to get to your guidance and sort of what's gone into your guidance, what's shaped that in terms of your expectations for overall commercial penetration and dynamics? Sure. I think, as we just shared on our Q1 call, in Q1, year- over- year, we delivered 5% demand growth. Our Q1 was impacted in our returns reserve by about $5 million. It is kind of atypical returns of high dose, 80 and 100 mg selinexor. That was really related to a large batch which was produced to support the BOSTON trial and the label, which came to fruition in the end of 2020. As we have seen selinexor in the real world, we are seeing selinexor being used much more at the lower dose of 60 and 40. The return window opened, and we had a return, kind of atypical return of about $5 million. That is really a one-time impact, Brian. I think our focus, we know moving forward, real-world purchases, real-world utilization, the production that we do is really targeted towards that 60 and 40. We do not see that occurring moving forward. I think our focus moving forward is to continue working to deliver demand growth. I think, again, in Q1, the 5% year-over-year demand growth, we saw growth in both the academic setting and in the community setting. It is important because there are very different types of care that are utilized in the two settings. You have the majority of multiple myeloma patients which are being treated in the community. In the community, selinexor is positioned in that second to fourth line, really post anti-CD38, which are used increasingly in the first or second line. I think what the community physicians like a lot about selinexor is it is flexible. It can be used an oral, and it's enabled across kind of the treatment paradigm. From that mechanism, we're working to make sure we continue driving that utilization in the community setting. Community physicians are very comfortable having to use the dual antiemetics for a couple of months, enabling patients to really benefit from selinexor, depending on where they are in their treatment journey. In the academic setting, we've returned back to growth last year. That's really around all the engagement for T-cell engaging therapies. You're seeing, obviously, bispecifics, CAR-Ts, et cetera. In those settings, we generated a lot of data over the last couple of years to show that selinexor doesn't negatively impact the T-cell environment. International Myeloma Working Group put a lot of work together and issued some guidelines towards the beginning part of this year, really, again, stressing the importance of sequencing, kind of strategic sequencing before you're using the T-cell engaging therapies. And in there, selinexor comes out as an agent that they're recommending to be used pre-post T-cell. I think, again, we're going to continue to see that utilization grow. That's our focus within those two paradigms. As we know, kind of moving through the year, Q1, typically in oncology, is kind of your lowest quarter, kind of continues to evolve nicely during the year. We expect to see that moving forward. Great. Your outlook from the myeloma indication longer term, and you kind of alluded to some of the growth drivers. Can you maybe elaborate a little bit more on sort of where you see the most potential for growth to pick up? Yeah, I think really continuing in those areas. As we said, we have nice data and continuing to do data with regards to the academic and community setting around T-cell engaging therapies as those will continue to be used broadly in those areas. They're starting to move up into some earlier lines. Again, what's that sequencing pre? What's it post? That's going to be critically important, and we're going to continue to be used in those areas. We have some nice data being generated with mezigdomide, which we know is working and coming to market over the next couple of years. Again, in that area of T-cell engaging therapies, looking at that being used potentially post some T-cell engaging therapies. We have our SPD trial at the low dose of 40 mg, which we'll be reading out in the first half of 2026. Again, generating more data showing, as we showed initially last year from that trial, 40 mg, much improved toxicity profile. Patients were able to really get a nice benefit. I think, again, that's going to continue to drive our utilization in the community setting in the earlier lines. Okay. Great. Maybe we can move to some of the next indications for selinexor, maybe starting with myelofibrosis, because I know we're going to be coming up on some data fairly soon. You've shown some really promising data in a phase I study for the drug in combination with ruxolitinib in frontline myelofibrosis. Can you talk a little bit about those data sets? What gives you the most confidence in the phase III readout from those data? Maybe talk about what you're seeing as the study has continued, as patients continue to be dosed in terms of durability, and how we should contextualize that with what we would expect from ruxolitinib historically. I know we've seen some pretty recent follow-up data. I think it was right around your first quarter earnings press release. Maybe you could talk about that as well. Absolutely. Obviously, really, really excited about our myelofibrosis opportunity. We do have an ongoing phase III trial. It is known as the SENTRY trial that is evaluating in a double-blind setting the efficacy and safety of ruxolitinib and selinexor 60 mg versus ruxolitinib alone. That trial should be completing enrollment very soon in that June-July timeframe. Now, to your question, a lot of this trial was based upon an earlier data set, specifically a phase I/II study that evaluated the efficacy and safety of selinexor plus ruxolitinib in this JAK-naive population. Despite the fact that we have been studying myelofibrosis for over seven years, I think these were the data that really entrenched our belief of the benefit that selinexor can provide in arguably this hard-to-treat patient population that does not have a lot of options in which to get treated. When we looked at the efficacy, that SVR35 at week 24 was 79%. Now, compare this with ruxolitinib in a similar patient population. SVR35 rates for ruxolitinib less than half at maybe 30%-35%. So a really remarkable increase in those overall rates. Now, in parallel, we also saw very meaningful improvements in terms of symptoms. We've looked at symptoms two different ways. TSS50, which was the traditional endpoint in myelofibrosis, but also Absolute TSS, which is a more sensitive method of assessing that symptom improvement over the course of those 24 weeks. When we look at that Absolute TSS data, it really shows a very, I think, remarkable 18.5 improvement at week 24 relative to baseline. When we look at the SVR35, that TSS, again, that 18.5 compared to ruxolitinib, maybe 11-14 points based on recent data, it really suggests that we can maximize both SVR35 rates, which is spleen volume shrinkage, as well as very meaningful symptom improvement. Now, to your point, both of these endpoints are just assessed at week 24 or six months. What this patient population really wants to appreciate is that once they achieve benefit, they're going to stay in benefit. We looked at that durability of response. There, too, really, I think, encouraging data. When we looked at these data and presented it last year, what we found is that patients who achieved either an SVR35 or a TSS50, they remained in response. It was a 100% durability of response, again, for both SVR35 and TSS50 responders. We got the improvement. We've got the durability. Safety is also evolving very nicely. The low dose incorporation of the dual antiemetics, both from a heme as well as non-heme perspective, that safety, again, profile is evolving very nicely. The new data that we presented, and I just want to touch upon this very quickly, was from a completely different data set. So this data set was specifically evaluating selinexor monotherapy in a large patient population. This is selinexor monotherapy in this heavily pre-exposed, high-risk population. What we demonstrated is that selinexor is impacting all four hallmarks of disease. We see this very meaningful SVR reduction. We're seeing very meaningful symptom improvement. We're seeing really intriguing hematologic improvements as well, specifically anemia. Hemoglobin levels are stabilizing. We're seeing in this cohort that the transfusion burden is lower as compared to the physician's choice arm. Lastly, we're seeing really exciting disease modification. That disease modification in terms of lower cytokine levels that drive many aspects of this disease is occurring as fast as we recall. We are really seeing just remarkable data. These data are just the most recent data that demonstrates selinexor is active in this myelofibrosis population. Great. How has the phase III been going? What's the latest feedback you're getting from principal investigators, third-party CROs, and the overall study conduct? How are you feeling about the way enrollment's gone, conduct's gone? We're really excited here. I think we've got KOLs from all of our academic sites in the U.S., as well as ex-U.S. that are participating in this trial. They are clamoring for new therapies in myelofibrosis. Standard of care has been ruxolitinib for over a decade. Yes, it has provided some degree of spleen volume reduction, some degree of symptom improvement. I think everybody appreciates that benefit is still quite modest and is really only impacting a very small group of patients. We need new therapies to really provide benefit to a much larger group of patients. They're really excited. We see that translate to enrollment. I think the other aspect is that they're really pleased that we've been able to evolve this symptom endpoint from TSS50 to absolute TSS. It's just perceived as a more sensitive way of detecting that symptom improvement. Yeah, we're really excited about what the next six months holds for us. Can you talk a little bit more about that endpoint change and maybe a little bit of background on sort of what had catalyzed the change to Absolute TSS, the receptivity that you're getting both from regulators and from clinicians on that change? I think you're also, there's updates that exclude fatigue in the TSS calculation as well, sort of how that plays in. I think that's important because I know previously TSS50 has been a challenge for other developmental programs. Just kind of curious, kind of the engagement and buy-in of the community and regulators for this change. Yeah, yeah. To step back here, when we talk about TSS50, Absolute TSS, it's important to remember the raw data is absolutely the same. Everybody fills out, every patient fills out a form called the MFSAF form, and they fill it out daily. The endpoints, the TSS50 versus Absolute TSS, all it does is just analyze the data a little differently. TSS50 is just looking at that week 24 endpoint, that time point, comparing it to baseline. Absolute TSS is actually leveraging all of the data that has been collected over this point, six months, and then averaging the benefit relative to baseline. Because you can leverage that 24-week or six-month data, it's just perceived as a more sensitive way of detecting that improvement above and beyond ruxolitinib. That's the key point. To your point, Brian, TSS50 has dogged multiple trials. How many phase IIIs have we seen in which TSS50 has missed? Absolute TSS has gotten a little bit closer. I think we have a huge opportunity to now really be able to demonstrate that meaningful symptom improvement by using this Absolute TSS endpoint. There's been a lot of positivity around this. Investigators, I already talked about, advocacy groups are really excited about this evolution because it's just an easier way to explain this improvement to patients. What they want to be able to tell them is that, yes, you can experience some degree of improvement above and beyond ruxolitinib. It's just an easier way to explain it. FDA as well, regulators, I think they've also appreciated TSS50. While it served its purpose for the original trials, it's just not sufficient when you're going up against an active control. A lot of agreement. Including the new FDA, new administration leadership? Nothing's changed. Nothing's changed. Nothing's changed under the administration. Reshma, maybe just talk to the fatigue. Yeah. Yeah, the fatigue aspect. This isn't new for us. It's not new for myelofibrosis. The reason I say this is that going back to the original COMFORT and JAKARTA trials that led to ruxolitinib, fedratinib, they excluded fatigue from their TSS50 analyses. Largely, they did it in agreement with the FDA because it's such a challenging endpoint to really assess improvement. They excluded it. Something that we've done from the very beginning of our myelofibrosis program, something that's going to be done in our phase III as well. Got it. One of the biggest questions we get asked about with regards to selinexor is on the drug safety and tolerability. I know you've done a lot of work to optimize dosing and ancillary medications like antiemetics. Can you talk about how that's being incorporated into the phase III, what you guys are seeing in the study in terms of how much antiemetic use there's been? Is there any concern that the use of antiemetics across all patients may actually mitigate the ability to demonstrate a delta on symptoms if you're sort of helping alleviate some of the symptoms on the ruxolitinib placebo patients as well? Yeah. Great question. We have a lot of experience with selinexor going all the way back to our multiple myeloma days, nausea, vomiting, no side effects of selinexor. We know that there are two drivers to really mitigate against nausea and vomiting, lowering the dose and incorporation of dual antiemetics. All of the patients in our myelofibrosis phase III, as well as our other phase IIIs, including endometrial cancer, EC-042, as well as the multiple myeloma trial, must take dual antiemetics, so two antiemetics prior to each dose for the first two cycles. This is really easy for these patients. It is really easy. It is easy to prescribe. We see compliance extremely high in our phase III. It is greater than 85%. We also see that translating to an improved GI profile, lower rates and grades of nausea and vomiting. The reason I can say that is, again, going back to this data set, this new data set that we just presented a few weeks ago at our earnings call, nausea rates with patients treated with selinexor alone were as low as 33%. These patients were also treated with dual antiemetics. We see this really nice evolution in terms of lower rates and rates of nausea with antiemetics. Okay. You talk about the MF opportunity. Where do you see this potentially fitting in? Is this something you would imagine all frontline patients would take or patients maybe who have specific issues in terms of extremely large spleens or symptoms? How are you leveraging your existing infrastructure from a commercial standpoint as you think about anticipating the launch? Yeah, Brian, I mean, as Reshma just touched on and you mentioned, we are targeting all frontline patients, really all JAK-naive patients, very consistent with what ruxolitinib has been targeting, obviously, patients with greater than 100,000. Within that population, there has not been any evolution in terms of frontline standard of care for 13 years. As Reshma just touched on, the opportunity to more than double the response when you look at SVR35, when you look at all four key hallmarks, SVR, symptoms, anemia, hemoglobin, and disease modification, I think it's an incredible opportunity to really add on to the standard of care, which has done wonderful things for patients. Adding on to the standard of care, I think, makes it a very easy and convenient opportunity for uptake with physicians. Our commercial infrastructure is strong. We already have strong commercialization capabilities from a medical affairs perspective, from an access and reimbursement perspective, and from a sales and marketing perspective. The majority of myelofibrosis patients are actually treated in the community. We have about an 80% overlap already with the majority of prescribers. We are able to commercialize rapidly with a lot of synergy. In some market research we've done with physicians, we see, again, there's a significant unmet need. Research shows that about 75% of physicians would be adopting doublet therapies that address all these key hallmarks of the disease really rapidly to help improve outcomes for patients. I think the other key area that we've seen in our data is that selinexor works across all subgroups of patient populations. The opportunity to really address a wide swath of kind of on-target patients and to build, I think, on the durability component that Rachel touched on. Right now, in the real world, I think when you're looking at ruxolitinib, you have about 12-13 months' worth of therapy in the real world. If we have good durability, I think we can build on that and, again, deliver benefits for patients and rapidly commercialize. Great. I know we've only got a few minutes left, but I definitely want to touch on the endometrial cancer program for selinexor. Can you talk about how that phase III is going, kind of your level of confidence in terms of potential timelines there and where you see this potentially fitting in an evolving landscape? I know it's a little bit more of a slightly more complicated landscape than MF, but just kind of where you see this ultimately fitting in, where the biggest pockets of unmet need are going to be. Yeah. Another really exciting program we have, an ongoing phase III, as mentioned, the phase III EC-042 trial. This is leveraging a biomarker, so specifically TP53 wild- type, which is observed in over half of all patients with advanced recurrent endometrial cancer. Based upon the data from an earlier phase III, we really demonstrated some really interesting efficacy with selinexor, specifically in that subgroup of patients whose, again, tumors are TP53 wild- type. This ongoing phase III is enrolling patients who are TP53 wild- type. To your point, though, I think the greatest opportunity is really going to be those patients whose tumors are TP53 wild- type and are proficient. That group of patients is also very sizable, of around 50% of all patients. They remain really that unmet need population. I say that because, yes, there has been introduction of new therapies, specifically the checkpoint inhibitors, pembrolizumab, dostarlimab, for all patients. What we see when we really interrogate the data is that the benefit with the checkpoint inhibitors, that MMR proficient subgroup, is really modest. EFS is only 10-13 months. This includes that induction chemotherapy. The benefit that we are seeing of 40 months actually exceeds the overall survival that they're seeing with the checkpoint inhibitors. Really driving that benefit in that, again, high at-need subgroup, enrollment is going really well. We anticipate being able to complete enrollment sort of over the course of the next few months and top-line results likely in the middle of 2026. Great. Good. Just before we wrap up, last question. Can you talk about how your kind of bigger picture is staying disciplined with your OpEx and some of the key steps that you're taking to support operations into the phase III MF readout? Sure. I mean, we're staying very disciplined. We're very focused and have put efforts in place over the last couple of years to really ensure our focus is on the phase III readouts. We don't have any other programs running. We've shut down all kind of previous programs and are supporting a profitable commercial multiple myeloma business and very targeted on delivering the phase III programs as we move forward. I think, as Reshma touched on, we're really focusing on how do we make sure we have great clinical trial execution, great quality in our work, helping to identify the right patients, making sure we're on top of having the dual antiemetics used through the execution. As we go through that and roll through, being able to read the data out quickly and hopefully positively is critically important. It's what the organization is focused on. It is a super exciting time with these major readouts right in front of us and being transformational when you look at myelofibrosis and endometrial cancer, kind of building on the foundation we have in multiple myeloma. Great. Thank you guys so much for being here. Thank you, everyone, for joining us. Thank you, Brian.