Karyopharm Therapeutics Inc. (KPTI) Earnings Call Transcript & Summary

Good morning. I'm Eric Joseph, one of the senior biotech analysts at JPMorgan. And our next presenting company is Karyopharm Pharmaceuticals -- or Karyopharm Therapeutics, rather. It's my pleasure to welcome CEO, Michael Kauffman, to tell us a little bit about the company. Just as a reminder, the Q&A breakout session will be held in the Sussex Room. With that, Michael?

Thanks, Eric, and welcome, everybody today. It's great to be here. It's been a heck of a year for us and dive right in. As you all know, I'll make forward-looking statements. Please do review this slide and all the information in it. Now you're done reviewing. . Karyopharm's vision is to become a leading oncology company. We are the first company that has received approval for an oral Exportin 1 inhibitor, XPOVIO, and we have a few direct competitors in development. XPOVIO, U.S. accelerated approval occurred on January -- sorry, on July 2019, and we've had very nice launch metrics going in with the product sales in the first 6 months since launching this drug. We expect top line data in our confirmatory Phase III BOSTON study, which evaluates XPOVIO in combination with Velcade in second-line myeloma, which could potentially allow for the use of this agent in earlier lines of therapy in this difficult-to-treat disease. This mechanism of action, the inhibition of Exportin 1 is likely to be applicable across many, if not most, different kinds of cancers. And we've actually submitted our second NDA in diffuse large B-cell lymphoma in December of last year, with expected potential approval mid this year. We have 2 ongoing Phase III studies in solid tumors, in liposarcoma and endometrial cancer, and we've 2 additional homegrown drug candidates in early clinical development called eltanexor and KPT-9274. We have additional clinical development in other areas of unmet need, which I won't discuss today. As a commercial update, as I mentioned, on July 3, we received accelerated approval. This is the first approval in multiple myeloma in the penta-refractory setting, and our full year XPOVIO sales will come in unaudited, $30 million to $31 million. Over 550 physicians and accounts have prescribed XPOVIO in the first 6 months, and there have been approximately 1,400 XPOVIO prescriptions now fulfilled through the end of last year. BOSTON, as I mentioned, is on track for top line data expected in the next several months. The DLBCL submission occurred last year. The data that led to the approval were published in the New England Journal of Medicine last year, and this was followed up with 22 presentations at ASH. In addition, we filed for approval in Europe, and although things have been slowed down a little bit, we believe, because of Brexit, we are expecting a European decision in early 2020. Balance sheet is strong. We entered into a royalty agreement with HealthCare Royalty Partners. We ended Q3 with $270 million in cash, and that runway should get us into the middle of 2021. The accelerated approval, XPOVIO was very exciting. Now there are a number of very good agents for the treatment of myeloma. But unfortunately, it remains almost a universally fatal disease with over 13,000 deaths per year. We estimate that approximately 6,000 patients every year develop disease that is refractory to the 5 major drugs that are used to treat it. This is so-called penta-refractory disease, and XPOVIO in combination with low-dose dexamethasone was approved in penta-refractory disease. It was the first drug to be approved in this indication. The approval, we will -- expect will be supported by, hopefully, a successful BOSTON Phase III study in patients after only 1 line of therapy, allowing potentially for the use of XPOVIO in over 30,000 patients with second-line or further myeloma. While XPOVIO has the activity that I described, we've studied it intensely, and we understand the side effects of the disease -- of the drug, and we understand how to prevent, manage and support these side effects. Most of the side effects are reversible with dose modifications. And there are no black box warnings. There are no contraindications. And there are no known drug-drug interactions, making this a drug that can be used with straightforward applications in patients that are very complicated and very frail. The XPOVIO sales have been good since the initial launch, and we're excited about this because this is really a population that has no other options. $12.8 million in sales in Q3, followed by $17 million to $18 million in unaudited sales in Q4 with, as I mentioned, approximately 1,400 prescriptions already in this disease. Amongst -- looking at some of the launch metrics. There have been at least 550 prescribers and prescribing accounts. Most of the accounts are covered by Medicare as expected. About 40% of them approximately are covered by commercial payers. We prescribe this agent for 28 days, 28-day cycles and the refills are coming in nicely with an average of 29 to 33 days between refills, suggesting the drug is being used properly. And the most frequently prescribed dose is the indicated dose of 160 milligrams per week, taken as 80 milligrams twice a week. Although the other uses of this drug, 100 milligrams per week, 80 once a week and 60 once a week are also available as separate packages, which are priced the same as the 160 milligrams per week pricing. Just a couple of quick things. Within 4 months of launch, we're a small company. We're the first small company actually to enter into the multiple myeloma landscape, which is dominated by Celgene, BMS, Takeda, Janssen, Amgen and so forth. And we think our team has done an amazing job, frankly, of helping doctors to be educated about XPOVIO. This new mechanism of action XPO1 inhibition and so on. 90% of people that we talk to, recalled one or more branded XPO messages -- XPOVIO messages. And as another really important point, 60% of doctors -- this was within 4 months so we hope these numbers are going up with further education. 60% believe XPOVIO is good option for patients with penta-refractory disease. We believe these numbers are consistent with the kind of good uptake we've seen already in this difficult last-line myeloma population. Let me switch over a little bit and talk briefly about the clinical data that led to support for the approval of selinexor in multiple myeloma. The plan's going forward in multiple myeloma and then in diffuse large B-cell lymphoma for our submitted NDA. Since the mechanism is novel, and I know the slide is complicated. I'll spend a couple of minutes on the mechanism. This drug, selinexor, is a selective inhibitor of nuclear export. It's the first-in-class of a new class of apoptosis-inducing compounds that is highly selective for blocking a single protein, namely Exportin 1. Exportin 1 levels are elevated in essentially all cancer studied to date. And the patients with the highest levels of XPO1 tend to have the worst prognosis. This is oncogenic. And the reason it's oncogenic is because XPO1 removes tumor suppressors from the cell nucleus where they work. And it leads to their deactivation. Selinexor really has 3 major mechanisms. The first is to block the export of tumor suppressor proteins and restore their activity in the cell nucleus. The second one is it traps oncoprotein messenger RNAS, and it leads to reduction in levels of many oncoproteins, including c-myc, bcl-2 and others. And the third one is it can retain activated glucocorticoid receptor in the nucleus, which can lead to restoration of sensitivity to glucocorticoids, which is very important in the treatment of multiple myeloma. This drug hits one protein, but it has many, many effects, making it applicable potentially across multiple cancers. The development strategy in myeloma is one that's been tried and true and tested successfully over the many years for drugs that have single-agent activity. And most doctors who treat myeloma want agents that have single-agent activity in this disease. And we proved that selinexor with low-dose dex has activity by itself, in patients with heavily pretreated refractory multiple myeloma. That led to the approval based on the STORM data. We have the pivotal Phase III BOSTON study, the combination with Velcade ongoing with data coming in the next several months. And we also have developed a STOMP protocol for patients who have -- are being treated with selinexor in combination with the available major myeloma agents. Quickly on the STORM study. The approval was based on a subset of patients who had documented penta-refractory multiple myeloma in -- within these 122 patients who entered the study. And we had very broad enrollment criteria, actually much broader than most clinical trials would allow. So these are sort of real-world patients, if you will. We had a 25.3% overall response rate adjudicated by an independent review committee and by FDA. And the full STORM results were published in the New England Journal and included 2 patients who had molecularly negative, that is MRD-negative, complete remissions on this single-agent oral therapy. Additional important data, particularly relevant to the practice of using now selinexor dex in the community and all is that although all the patients come into the study with rapidly progressing multiple myeloma, 71% of the patients treated with XPOVIO or selinexor dexamethasone had reductions in their M protein. This is clinically very important because it means we can take patients who've run out of options, and we can stop their disease in approximately 2/3 of them. And the survival of our patients who had at least a 25% reduction in their disease in this study was 15 months as compared to 1.7 months for patients who had no response to the therapy. That tells you, there aren't any good rescue medicines out there, and it does tell you that for the 40% of patients who had at least a minimal response to disease, they could expect potentially a longer survival. The safety data in STORM were very similar to what I already presented. The most common adverse reactions are low platelets, fatigue, nausea, anemia and low appetite, decreased weight and so on. Most of the patients do need a modification of their dose. When you're coming in with rapidly progressive disease, we need to get the disease under control or you will succumb to it. And we already saw that in the patients with no response. But the dose will then be reduced, and that's done easily with this oral medication. The BOSTON study uses once a week selinexor in combination with very commonly used agent Velcade. Velcade is given subcutaneously. Although, it's approved for twice a week dosing and requires 2 office visits per week with physicians, we chose to study it in combination with XPOVIO once a week only, which is how it's actually used in real life. So the approvals are twice a week Velcade, but the actual use of Velcade in medicine is typically once a week. selinexor, Vel, dex or XPOVIO, Vel, dex versus standard Vel, dex is the BOSTON study. And if this study is successful, this will be the first and so far the only study that will evaluate a once-weekly Velcade regimen, making it potentially one of the most simple regimens to give for patients with relapsed myeloma. In addition to the combination with Velcade, we've explored selinexor/XPOVIO with many other agents, including Pomalyst, DARZALEX, Kyprolis, Revlimid and even additional combos that are not on here. That's the STOMP study, and it informs physicians on how to use the combinations safely and potentially to achieve better clinical outcomes. In all cases -- and I won't go into the details here, in all cases, the combinations show superior response rates and when available progression-free survival rates as compared to historical controls for each of the different drugs. So here for proteasome inhibitors for the oral IMiDs, Revlimid and Pomalyst, in an all-oral regimen, and finally, for the anti-CD38 monoclonal DARZALEX. So selinexor once-weekly in combination with essentially any of the major 5 myeloma drugs appears to deliver higher response rates. And when it's available, progression-free survival than any of the single agents, making it a potentially ideal partner for use with any of these big myeloma drugs. Switching now to diffuse large B-cell lymphoma. We conducted the SADAL study in patients who've, again, run out of options. This is a single-arm study of selinexor XPOVIO, given 60 milligrams twice a week, a lower dose than used in myeloma, no dexamethasone here in patients whose disease has relapsed or is refractory to at least 2 prior therapies. There are no known treatment options of clinical benefit for this population, except for patients who are eligible for CAR-T, and our patients are not eligible for CAR-T, nor are they eligible for autologous transplant. The single agent oral response to this drug was 28.3%. It occurred in both -- responses occurred in both the germinal center B and the nongerminal center B type of disease, and we had over a 10% response rate, complete remission rate, with some of those patients over 2 years in complete remission on an oral therapy, which as far as we're aware is not been reported for most oral agents in this disease. This safety data, again, from this study were very similar to what we saw before, typically at lower rates and lower intensities, given that this was a lower dose. We presented 22 abstracts at ASH, and I won't go through them, except to highlight one of them, which received a lot of attention is that XPOVIO, Pomalyst, dexamethasone for myeloma, it's an all-oral combination. It's one of the few all-oral combinations with Pom that showed a striking 55% response rate, about twice as high as Pom alone, and it showed a progression-free survival close to a year, several times higher than Pomalyst alone, suggesting that this all-oral combination might be available option for patients if the doctors so choose. We also presented real-world data sets to try to figure out if selinexor could confer real clinical benefit as assessed by overall survival. We compared the real-world data sets from both the community and this Flatiron data set on your left and from academia, in the MAMMOTH data set on the right with patients with penta-refractory multiple myeloma, who could receive selinexor XPOVIO in the STORM study versus those who -- where -- it was not available. And in both cases, XPOVIO treatment performed better on survival than did retreatment with available agents. Moving now to the commercial opportunity in the first 2 potential indications, first in myeloma. There are 6,000 patients with penta-refractory myeloma, we estimate, which is the current label. And there are approximately 30,000 patients with second and further line myeloma that could open up with the BOSTON study. This is the second most blood cancer, 32,000 new cases per year, 130,000 patients living with the disease, but unfortunately, incurable to date with 130,000 deaths expected this year. This shows you the breakdown across the different lines of therapy, first-line therapy, which is typically a multiple combination therapy in about 31,000 patients can be effective for several years. But eventually, all patients essentially will relapse, leading into the second, third and fourth-line of therapy, and new therapies are badly needed in all of these lines. The successful XPOVIO commercial launch had 4 basic pillars: one was to establish nuclear transport inhibition and our sales force really was able to do that. Through the first half of last year prior to the approval because this is an entirely new mechanism and many physicians were not aware of it. We position XPOVIO as an oral agent of choice with a clinically meaningful efficacy, really on its own, with low-dose dex, which most drugs in myeloma are given in a patient population who've blown through some of the best drugs that we have in oncology. We educate the physicians and focused a lot on the side effects. And many of the side effects you saw are bread and butter oncology side effects. We know how to prevent them. We know how to treat them. And I think the team has done a great job, and the doctors have done a great job helping their patients really get away without much nausea or none at all, minimal anorexia and so on, and make sure that the drug will be reimbursed, where we've not seen problems to date. We have a highly experienced team, educating the market about XPOVIO, about 70 sales representatives overall and an additional 8-Karyopharm nurse liaisons, who've all been practicing oncology nurses and also have industry experience. And they've been very helpful in making sure doctors, from patient number one, know how to prevent and manage side effects from selinexor. We know that there are 400 accounts that generate over half of the prescriptions for myeloma drugs, and we've hit all of those accounts. And we know that 1,300 accounts generate about 80%, and we're pretty close to hitting 90% of those accounts as well already with this team. So our team has done a great job, I think, even as a small company in this large commercial opportunity. For DLBCL, this is a relatively new opportunity. CAR-Ts have made it on. We just had the recent approval of Polivy, 32,000 new cases a year, but 40% to 50% or even higher percentage of patients are not cured with currently available therapy. And the patients whose disease is refractory or relapsed after 2 lines of therapy, unfortunately, will die of their disease. We estimate that there are about 9,000 patients in the third and fourth line of DLBCL every year. We also have, as I mentioned earlier, ongoing studies in 2 solid tumors. The first one is liposarcoma. This is dedifferentiated liposarcoma, several thousand patients each year in the U.S. who have dedifferentiated lipo. And if you're not cured by surgery with this disease, unfortunately, you will pass away from it. Current therapies are chemotherapies and various cocktails. And we've done a study in third-line liposarcoma which is now in Phase III, following a successful Phase II. We'll have data from this Phase III of XPOVIO versus placebo in mid-2000 -- this year, mid-2020. And hopefully, this'll lead to an approval for third-line liposarcoma, which currently has no oral options at all. And finally, selinexor in endometrial cancer. We're conducting a Phase III SIENDO study, which is the use of XPOVIO versus placebo in front-line endometrial cancer following initial induction chemotherapy. Current practices, platinum-taxol, induction chemotherapy, followed by waiting for relapse and eventually, second line. There is no maintenance therapy approved yet in endometrial cancer, and that is the area we are focused. We've updated our pipeline a little bit. We're a small company, but we're doing an awful lot. You can see the myeloma program at the top, following the approval of STORM. We'll be -- having the BOSTON data this year and hopefully a submission to the FDA and EMA later this year based on the BOSTON study. Additional data coming from the combination study STOMP. The SADAL study, I mentioned, we are going to be starting 2 new studies in DLBCL. One is called export DLBCL 30, which is a backbone of rituximab, gemcitabine, dexamethasone, platinum, so our RGDP plus or minus XPOVIO as a Phase III -- II/III study for confirmation of the SADAL's SNDA. And finally, on the solid tumor malignancies, you'll note here, a new study, Phase I/II in patients with colorectal cancer based on some investigator-sponsored trial data of XPOVIO plus pembrolizumab, Keytruda, in colorectal cancer and in combination -- XPOVIO in combination with docetaxel in patients with non-small cell lung cancer following relapse from initial chemotherapy. We have ongoing data from our glioblastoma program, and we'll be starting a combination study in frontline disease there. As well as in relapse and additional programs with our second-generation eltanexor XPO1 inhibitor and with 9274. We have financial strength with $270 million in cash, cash equivalents at the end of the Q3, we'll be updating our end-of-year cash at our earnings call in February. And this current runway is expected to run us into the middle of 2021 with 63 million shares fully diluted. Lots of milestones coming up and closing, early 2020, which we defined early as January through April. Top line Phase III data from BOSTON. This I would remind everyone, this is an event-driven study. It's based on progression-free survival events. So we are just waiting for events to come in. We can't give you better numbers on that and timing. We expect a regulatory decision in Europe based on the STORM study in penta-refractory myeloma, triple-class refractory disease. And in midyear this year, we'll have regulatory filings based on BOSTON, top line Phase III data in the SEAL study in liposarcoma, regulatory filings based on SEAL. Regulatory decisions of FDA and DLBCL, the U.S. commercial launch in DLBCL and the start of a confirmatory Phase III study in DLBCL in support of potential accelerated approval. And of course, hopefully, by the end of the year, launch in second line myeloma. With that, I'll thank you very much and happy to see you all in the breakout room. Thank you.

Thanks. Okay. We'll get started. I'm Eric Joseph, senior biotech analyst at JPMorgan, we're in the breakout session for Karyopharm. We just saw CEO, Michael Kauffman present. Maybe before we hop into the questions, Michael, just introduce who's at the dais with you, and we'll open it up.

Okay.

Sure, this Ian Karp, Head of Investor and Public Relations.

Perry Monaco, Senior Vice President of Sales.

Mike Mason, CFO.

And I'm Chris Primiano, Chief Business Officer.

And Michael Kauffman.

Maybe, I'll just kick things off with a couple of commercial questions related to XPOVIO. Now with 2 quarters under your belt, having preannounced fourth quarter, maybe just help us unpack the numbers a little bit, what you're seeing in terms of any bolus impact from, I guess, patients awaiting therapy. And also what you're seeing in terms of combination use? Any read on, sort of, real-world duration on therapy at this point, separate from what you've observed in the STORM study?

Yes. So I'll take that. The question was around just breaking down some of our early commercial success with regards to have we seen a bolus and duration of therapy and such. So with regards to the bolus, I mean, obviously, in a penta-refractory setting, there are no other options for these patients. So obviously, you're going to have a bench of patients that are waiting. We do believe that there may have been a bit of a slight bolus. But what we have been very pleased with is our refill rates. And we've seen several patients out quite a few months now. And then also with regards to duration of therapy, it's still too early to tell. We get visibility into some of this through our specialty pharmacy channel. We also -- about half of our accounts are going through the specialty distributor channel, which we don't get visibility into whether that is a new patient or a refill. What I can tell you is that we have been very, very pleased with our refill rates. And I believe Michael shared in his presentation, refills are coming in around 29 to 33 days, which would speak to patient being able to tolerate the therapy very well, too.

On the point of use, you noted in the presentation that most patients are on the twice-weekly, 160-milligram with the regimen. Anecdotally, we're hearing that there's actually a fair amount of combination use with Velcade as well. I was wondering if you can, kind of, elaborate on what kind of feedback that you're getting on combination use? And why is that, sort of, an attractive option?

Yes. So the question is around combination utilization. So obviously, the sales team is really only focused on what is our approved FDA label. What we have seen is a significant minority of patients are being used in combination, and it is across the board, probably what we hear anecdotally, the most is probably a Velcade-based regimen, but is a significant minority of patients that we're seeing that with.

And I'll just add, based on the STOMP study, which really focused on Velcade and Kyprolis, Pom, rev and dara, that we do -- we're also aware there was some data at ASH on combination -- patients getting combination with Kyprolis, particularly post CAR-T or patients that have severe extramedullary disease, which means myeloma that's escaped the bone marrow and is causing massive tumors actually as well as with DARZALEX in combination for those patients who maybe a little bit frailer and do better with an antibody.

And anything in the way of discontinuations that you're noticing from the commercial setting?

Yes, sure. I think what we've said, and clearly, what we're seeing is discontinuation rates that are -- from what we can tell and to Perry's earlier point, we have -- there's essentially 2 ways that patients can get XPOVIO through specialty pharmacy and through specialty distributors. Without going into the complexity of the distribution network, we do have -- we have higher visibility in some of those, some -- about half the business. And based on what we can tell, we're seeing discontinuation rates, certainly due to the side effects that are meaningfully lower than what we saw in the STORM study. In the STORM study, about 27% of patients dropped out of that study due to adverse events. And we're not seeing rates nearly that high in the real world. And a lot of that has to do -- and Perry can comment on, lot of that has to do with a lot of the work that Michael highlighted in his presentation, but the work that our sales force is doing, educating physicians about how to properly manage and support these patients. I don't know if you want to maybe just a couple of comments about that, Perry.

Sure. I think a couple of things that we made a very concerted effort to do with the launch was to be very proactive when it came to managing side effects. We believe that there is a formula to success. You have to aggressively manage these side effects, you can't wait for them to happen. So we've been very nimble. We try to educate prior to the patient actually starting therapy. We work with accounts to have the supportive care protocols loaded within their EMR before a patient starts so that there aren't any errors. And the feedback that we've been getting has been tremendous, a lot of success. And as Ian mentioned, the discontinuations due to side effects is significantly lower than what we experienced in the STORM study.

Do you have a sense of what dose docs are dropping down to, 160 to simply straight to 100? Or do they go...

Yes. So the question was around dose reductions, and what dose we're seeing as most common. So when we look at our refill analysis on the portion of the business that we have visibility into, the most commonly prescribed dose and refills is actually still our maximum dose, which a, speaks to tolerability. But when we do see dose reductions, it's mostly at the 100-milligram once per weekly, but we do see a decent mix between all of our SKUS.

You have been able to attain rather broad commercial reach, fairly broad commercial reach already. But I'm just curious to know whether you have an updated sense of the sizing of the addressable patient population with the current label, either penta-refractory, triple-class refractory, having now been in the commercial setting. I guess, maybe put it a little bit differently. Are there patients, I guess, that would fit the definition eligible for XPOVIO today that wouldn't necessarily be candidates based on performance status or for other reasons that you might not be reaching currently?

Yes. So the question is, are there patients based upon performance status or other factors that we might not be currently reaching. And as Michael shared in the presentation, a significant amount of the patients are -- and a significant amount of the myeloma drugs are prescribed by about 40% to 50% of the physicians that are within our target list. As we've done our analysis, we believe that we're sized properly. We believe that we're not missing the opportunity. Obviously, we're focusing on those accounts that see the most myeloma. And we actually believe that we have the right sized team for diffuse large B-cell lymphoma coming up later this year as well.

Just to add on to that, in terms of performance status and all, our protocol actually was very liberal in who we let in. And these were truly real-world patients. The good news is, now with this aggressive, but you could say, standard supportive care, which is definitively one, antinausea agent and the second one, if needed, and then olanzapine for any patient whose appetite is likely to be low or starting off with low appetite. Those 2 things together, antinausea and olanzapine can really mitigate the vast majority of side effects. The other thing to remember is these patients that triple-class refractory or penta-refractory disease, these are really sick people. They have months to live on the best of circumstances. And you have to manage them very aggressively. You have to be on top of that until the disease gets under control. And once the doctors understand it, just because this is an oral drug. This is an oral drug for patients whose disease is refractory to 5 of the best drugs we have in all of medicine, in cancer medicine. So you need to be on top of them. And I think once you get the disease under control, and many physicians have seen this, you can even take frail patients and give them some months and potentially longer to live and enjoy their life.

I guess, looking to the BOSTON study, and I'm not going to ask too many questions with the trial itself being so close to data. But I do want to dig in -- a little bit into the commercial data, I think, in the second-line plus setting, what that competitive landscape, sort of, looks like? What physicians are interested in seeing from BOSTON to be a commercially competitive product relative to other options available to them?

Sure. So the question is about the BOSTON population and how we think physicians will look at that data and view it in terms of the competitive landscape. So as many of you may know, the BOSTON Study is powered to show a 30% improvement in DFS, the primary endpoint is progression-free survival. And importantly, the BOSTON study is studying the traditional on-label, twice-weekly Velcade versus once-weekly regimen of Velcade with once-weekly selinexor, which -- that regimen in itself would be, if the data is positive, a sort of a tremendous success because again, patients don't want to come to the office, their physician's office for a subcu injection twice a week. Most actually can't or won't do it, particularly because of the side effects that are often seen, particularly peripheral neuropathy with twice-weekly Velcade. So we think that the Boston regimen, the once-weekly Velcade with once-weekly selinexor would be a particularly attractive regimen. It would be, again, a once-weekly regimen in this setting, XPOVIO or selinexor is used as just once per week. So we know that the side effect profile is markedly better. And so we think that is a particularly attractive combination. And as you look at the commercial landscape, there are many other regimens that are approved in the second line or later of multiple myeloma. And the way that multiple myeloma is generally treated, certainly in the U.S. is combinations of various mechanisms and various drugs, either as doublets or triplets and sometimes 4 drugs. And -- but none of these drugs are cures. And so the vast majority of patients will cycle through some combination of all these drugs and often see some of these drugs more than once during their full treatment paradigm. And so our goal and our aspiration is that the BOSTON regimen will be certainly, again, assuming the data is positive, then it would be the only once-weekly oral regimen with Velcade that would be quite competitive with many of the other approved combination study -- regimens. I don't know if Michael, you want to just maybe add.

I'll just add one other. The sort of straw man, if you will, would be that if someone's going to give DARZALEX, rev, dex in the front line, DARZALEX Revlimid, dexamethasone in frontline plus or minus, or they get a transplant, and they end up on a Revlimid as a maintenance therapy, you don't really want to go with another IMiD or another anti-CD38 in second-line. In general, the best way to treat almost all diseases in medicine is to switch class whenever you can. And eventually, we generate enough classes to really have chronic therapy. So you want to get away from an IMiD. If you start DARZALEX, rev, dex frontline, you don't want to use an IMiD again, and you don't want to use a CD-38. You probably want a proteasome inhibitor. And we're the fourth mechanism that's novel with stand-alone activity. And that's how we're painting this drug as being a really nice combination with Velcade, because this is a PI novel-novel, if you will, in terms of that patient in the second line. And obviously, if they get other stuff in second line, we can go in third line.

Do you have a sense today of what share -- in that STORM, you set up in that post rev, DARZALEX patient cohort, do you have a sense of what share is between a Kyprolis or a Pomalyst, Velcade combination? And second to that, when it comes to Velcade combinations are -- do physicians kind of readily discount the activity in clinical trials, considering those are all done in -- with a twice-weekly regimen and practice, it's a once-weekly regimen that they are using?

Yes, maybe I'll take the first part of the question, and Michael can take the second about once-weekly versus twice-weekly Valcade. If you look at market share data from many of the companies that will put out market share data in multiple myeloma, it's quite interesting that as you look at second, third, fourth line plus, almost all of the major drugs used in myeloma have somewhere between a 10% and 30%, 35% market share in each of those lines of therapy. And ultimately, what happens is depending on what the patient got in the line or 2 earlier will dictate what they get in the next subsequent line. So there's really no dominant regimen in the second, third, fourth or fifth line or beyond that. And what you see is a pretty even distribution of all of these drugs being used in various combinations. And I think, ultimately, that's the way drugs are used in multiple myeloma. Now some of those percentages may change a little bit, plus or minus, depending on what -- again, what you got earlier and how DARZALEX is moving earlier into frontline, but that's certainly the way that we see this marketplace and where we would see selinexor or XPOVIO also coming in, in term -- I mean our ultimate goal was that virtually all patients that are ultimately eligible should receive selinexor at some part -- at some point during their treatment journey. And again, it will depend what other drugs and what sequence they've gotten before, and then certainly will dictate what they get after. I don't know, Michael, do you want to just comment?

Yes, just quickly on the Velcade issue. I mean it's, sort of, come to be accepted that you do your trial with twice-weekly Velcade on both arms, and you just add on. We took a different tact because we're late to the game, number one. And because, frankly, this is what patients want and what doctors want is to be as simple as possible. Velcade has the advantage that it's subcutaneous. So it could be a 1-hour office visit. It's not a 5-minute office visit, by the way. It's not a 5-hour office visit or 3-hour office visit with intravenous infusions and checking and everything else. Every doctor believes that Velcade has really good activity, and it does. And even once-a-week Velcade on its own has some activity. Potentially longer-term progression-free survival because you have less neuropathy. So patients tend to stay on it. It doesn't have the kind of disease control that twice-weekly Velcade has, for sure. On the contrary, selinexor, Velcade, dex, given once a week or XPOVIO, Vel, dex once a week has extraordinary disease control. We get -- we had, I think, one progression event out of 40 in our first trial and that one progression event was in a patient who was -- whose disease was refractory to Kyprolis, would never be on the BOSTON study. So this is a really nice once a week. It's one of the simplest regimens available for treatment of relapsed myeloma. Because it's a subcu injection with a couple of oral pills. And we think that'll carry a lot of weight. And we should be able to deliver the kinds of numbers that the twice-weekly Velcade add-on regimens have done in the past.

Some of the feedback from physicians is that the selinexor combination of VELCADE is actually synergistic in a sense from a mechanistic standpoint. Can you elaborate on that a little bit?

Sure. The question, you want to -- do you want to take that?

No, you go.

Have our CFO handle that one. Do it. So the question is whether there's real synergy we -- it's one of the few times in medicine that we might actually -- might actually understand the science of what's going on. Proteasome inhibitors kill myeloma cells from a variety of mechanisms that are thought to be true. But in a myeloma cell that's -- even a myeloma cell resistant to a proteasome inhibitor in terms of killing, the proteasome inhibitor still work. So let's forget a minute about killing the myeloma cell with the proteasome inhibitor and just know that it blocks the proteasome. What that allows is that good proteins like p53 and retinoblastoma and BRCA1 and FOXO and IkappaB, all the good guys levels build up in these cells. The problem in myeloma is that the XPO1 levels are very high. Exportin 1 levels are extraordinarily high, especially in refractory disease. And all of those good things are moved out of the nucleus. You can have as much P53 as you want in your cytoplasm, it isn't going to kill a tumor cell. It has to be in the nucleus to work. And I think that was the inspiration for this program, was to block the exit of these tumor suppressors, not just P53. But frankly, all the ones we know. Keep them in the nucleus, and when you add a proteasome inhibitor, the cell cannot degrade these proteins, these good proteins. And so the levels -- when you combine a proteasome inhibitor with XPOVIO, the levels of good proteins, that is the tumor suppressors go sky high, 5 to 10x higher than any drug alone, and they're in the right location, which is where they work in the nucleus. So there is true synergy. You get extraordinary disease control. We showed some of that with Velcade with the 80% response rate in the STOMP study, in the BOSTON-like population, but we also showed it with Kyprolis in patients whose disease is even Kyprolis refractory and even post CAR-T.

Any questions, any more questions on myeloma. I kind of want to give a couple of minutes for DLBCL with an anticipated accelerated approval decision this year. I guess, just how should we be thinking about the -- how the selinexor is likely to get sequenced relative to some of the other recently -- either recently approved or soon to be approved regimens -- combination regimens?

Yes, the selinexor's application for accelerated approval for DLBCL is a stand-alone single agent oral therapy. It's very different. Roche received a very nice approval for Polivy in combination with benda, Rituxan, that's a triplet IV combination. It requires extended infusion time and so on and so forth. It's an effective combination. It is chemotherapy, and it does have the toxin conjugate with various issues there. There are a set of patients that just don't want to get another intravenous therapy, especially their third- or fourth-line chemotherapy. So there will be a set of patients that don't want that. There will be other patients who will choose to get to triplet, which likely has a higher response rate in any given patient because it's a triplet. And then they can cycle on to XPOVIO. XPOVIO had the same response rate, basically, whether a patient had 3 priors, or 2 priors. So we're okay to be there. The eventual use as in myeloma, but in lymphoma, the eventual real use of this drug will be in combination with a variety of different things. And we'll be setting up a STOMP-like study. I've mentioned it briefly, that's our Study 25, a STOMP like combination study for lymphoma with all the available combos. The MorphoSys' Revlimid combination that's been submitted looks very interesting as well. But again, it's a parenteral therapy. So doctors and patients will figure out what they like to do. And hopefully, we'll be generating the combo data because none of these agents is curative. And the goal here is to give patients the best shot.

What's the breakdown of, I guess, distribution of treatment for refractory DLBCL, I guess, between academic and community centers, if you're relating that in comparison to myeloma -- how myeloma is treated?

Yes. I don't think it's too much different than what you typically see in myeloma. There are -- we do know that there are a handful of centers that have dedicated lymphoma centers. But for the most part, your mix is going to be very similar to what you see in myeloma.

And maybe just a final question on solid tumors. Maybe just the latest recruitment update for the SIENDO trial, and what that trial is designed to detect in terms of efficacy over -- sort of maintenance study, what would be clinically beneficial data in that study?

Right. The study has -- enrolls patients, as I mentioned, who've received their frontline chemo regimen, which is typically platinum-taxol 6 cycles. And then that stopped because it's not tolerated beyond that, and you're basically in a watch and wait. About 20% of the patients will have a complete remission on scan, but frankly, all of them will eventually relapse in months, many months. And then about 40% to 50% of patients will have a partial response on scans. And those partial responses are somewhat durable, but typically relapse within -- it can be 4 to 6 months of relapse for those. So overall, we're looking at a relapse at around 6 overall, about 6 months, 7 months for that population. And if we can extend that by 3 or 4 months, similar to before, around a 30% improvement, that would be clinically meaningful. And I think patients would really appreciate that. That study, by the way, utilizes once-weekly selinexor at 80 milligrams once a week. So again, a use of a lower dose in a setting where the tumor is under control. And the question about enrollment, so we'll -- we expect to have data by the end of next year, and we'll give more guidance on that as we get towards.

There's not a lot of work that goes on in the industry in sarcoma. I'm wondering if you partner with a group like from the Memorial Sloan Kettering, where they have a major sarcoma center.

This was not a plant. The question is, yes, the should I repeat the -- the question is whether we partner, yes. So we absolutely do partner in sarcoma. These -- some of you may know, because these are relatively rarer tumors. And they're difficult-to-treat and manage. They tend to be treated best at specialized sarcoma centers, Memorial Sloan has 1 of the best. They are our largest recruiting site, and our lead investigator, Mrinal Gounder, who's the head of their sarcoma center is our lead investigator for the SEAL study, but we work with a number of other great sites across the U.S. and Europe for this and because this is a concentrated area, it's a fairly easy one. The sarcoma group is aware of this study and hope for the best for the SEAL study.

We've gone out of time. Thanks very much.

Thank you all.

Thank you.