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

Good afternoon. My name is Dilem, and I'll be your conference operator today. At this time, I would like to welcome everyone to the Karyopharm Therapeutics Phase III BOSTON Study Results Conference Call. [Operator Instructions] Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Mr. Ian Karp, Karyopharm's Vice President, Investor and Public Relations. Please go ahead.

Great. Thanks. And thank you all for joining us on today's conference call to discuss the results from the Phase III BOSTON study presented this morning at ASCO 2020. This is Ian Karp, and I'm joined today by Dr. Michael Kauffman, Chief Executive Officer; Dr. Jatin Shah, Chief Medical Officer; and Mr. John Demaree, Chief Commercial Officer. On the call today, Dr. Kauffman will provide some general thoughts about the Phase III BOSTON trial results, and then Dr. Shah will review the key findings from the study, which were presented for the very first time this morning at the ASCO 2020 Virtual Scientific Program. We will then ask our distinguished guest and myeloma expert, Dr. Paul Richardson, the Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center at the Dana Farber Cancer Institute and the R.J. Corman Professor of Medicine at Harvard Medical School, to provide his thoughts regarding the clinical significance of these study results. We will then open up the call to answer some of your questions. Yesterday afternoon, we issued a press release detailing the results from the BOSTON Phase III study. This release as well as an accompanying slide presentation are available on our website at karyopharm.com. Before we begin our formal comments, I'll remind those following along in the slide presentation, which is on Slide 3, that the various remarks we will make today constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. These include statements about our future expectations, clinical development and regulatory matters and time lines, potential success for our products and product candidates, including our expectations relating to the commercialization of XPOVIO, financial projections and plans and prospects. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our most recent quarterly report on Form 10-Q, which is on file with the SEC and in other filings that we may make with the SEC in the future. Any forward-looking statements represent our views as of today. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so even if our views change. Therefore, you should not rely on these forward-looking statements as representing our views as of any date subsequent to today. With that, I'll now turn the call over to Dr. Michael Kauffman, Chief Executive Officer.

Thank you, Ian, and good afternoon, everyone. I'm really thrilled to discuss the positive results from the Phase III BOSTON study. This is the first randomized Phase III trial to demonstrate clinically-significant activity of once-weekly XPOVIO in combination with the current standard of care anti-myeloma treatment in patients who'd previously received at least 1 prior therapy. We are tremendously excited about the results presented this morning at the ASCO annual meeting, and we believe that they could lead to a significant advancement in the second-line treatment of patients with multiple myeloma as well as offer patients increased convenience relative to other commonly used, currently used multiple myeloma treatment regimens. While XPOVIO in combination with dexamethasone received accelerated approval from the FDA in July 2019 for patients with heavily-pretreated myeloma, the results from the BOSTON study demonstrate the benefit XPOVIO may offer to patients earlier in their disease course and in combination with Velcade, one of the most commonly used anti-myeloma drugs available, subject to obtaining future regulatory approvals based on these and other clinical data. And I'm pleased that just last week, ahead of schedule, we submitted a supplemental New Drug Application to the FDA based on these data, requesting an expansion of XPOVIO's currently approved indication. For those following along in the slide presentation, please now turn to Slide 4. Unfortunately, despite all the progress that's been made over the past 5 to 10 years, multiple myeloma remains an incurable disease where patients and physicians are in need of new therapeutic options. Myeloma is the second most common form of blood cancer. Approximately 32,000 new patients diagnosed each year and nearly 130,000 U.S. patients living with and battling the disease. And despite a number of highly active drugs available to patients, approximately 13,000 people will die from this disease in 2020. I'd now like to ask you to move to Slide #5, where Dr. Jatin Shah will detail the results from the BOSTON study. Jatin?

Excellent. Thank you, Michael. The BOSTON study was a randomized Phase III open-label multicenter study designed to compare the efficacy, safety and certain health-related quality of life parameters of once-weekly SVds, which refers to selinexor plus Velcade and dexamethasone versus twice-weekly Vd or a Velcade and dexamethasone alone, in adult patients with relapsed or refractory multiple myeloma who have received between 1 to 3 prior lines of therapy. Importantly, these dosing differences resulted in patients in the SVd arm receiving approximately 40% less Velcade and 25% less dexamethasone than in the Vd arm and having about 35% fewer clinic visits with the first 6 months of treatment. The BOSTON study enrolled 402 patients, and the primary endpoint of the study was progression-free survival. Key secondary endpoints included: overall survival -- correction, overall response rate; the rated-VGPR response or better; overall survival; and rates of peripheral neuropathy, among others, which I'll discuss momentarily. Additionally, the BOSTON study allowed for patients on the Vd control arm to cross over following objective progression of disease confirmed by an Independent Review Committee. The study was conducted at over 150 clinical sites internationally from the U.S., EU, India and Australia. As you can see on Slide 6, patient and disease characteristics were well balanced between the 2 treatment arms. Importantly, key patient characteristics that reflect what hematologists and oncologists see in the real world were well represented in the BOSTON study. For example, across both treatment arms, roughly 30% of patients had moderate renal impairment and approximately 50% had high-risk cytogenetics. And roughly -- correction, and approximately 50% had high -- and approximately 80% have previously been treated with Velcade or Kyprolis, and importantly, nearly 40% have been previously treated with lenalidomide. Turning now to Slide 7. You can see that the study met the primary endpoint, with a significant improvement in progression-free survival based on an Independent Review Committee assessments. In addition, I would like to highlight and bring your attention to a point that once-weekly SVd was associated with both an early and sustained PFS benefit as compared to twice-weekly Vd. You can see that the 2 lines in this PFS chart are separating the first few cycles of treatment and become wider over time. In fact, 10 patients on the Vd arm had immediate disease progression as compared with only 1 patient on the SVd arm. The median progression-free survival in the SVd arm was 13.9 months compared to 9.46 months in the Vd arm, representing a 4.47-month increase in progression-free survival and a 47% increase in median PFS with a hazard ratio of 0.7 and a p-value of 0.0075. Many patients in the study remained on SVd therapy for well over 1 year with some patients continuing on therapy for over 2 years. The average duration of treatment on SVd was 10 months at the time of the database log, and this number is increasing with the patients currently continuing on therapy. When you look at the PFS data across key subgroups, the data look equally, and in many cases, even more impressive, as can be seen on Slide 8. Now while the hazard ratio for the overall trial was 0.7, meaning SVd therapy resulted in a statistically significant 30% reduction in the risk of disease progression or death, the hazard ratio was even better across patient subgroups. This included the following: patients with 65 years or older; or those considered frail; patients with high-risk cytogenetics; and patients who have not been previously treated with a proteasome inhibitor; and patients who had been previously treated with lenalidomide. Now because we often get questions from investors about the tolerability profile of selinexor based on the previous STORM study in patients with penta-refractory disease, I want to emphasize that we think it's particularly noteworthy to see the specific PFS benefit achieved with SVd in patients over the age of 65 as well as in those patients who are considered frail. We believe these data further enforce the potential utility of selinexor in these vulnerable patient populations who are often prone to side effects from drug treatments as well as in patients with more standard risk. As we turn to Slide 9, you can also see that SVd is associated with a significantly higher overall response rate across both the overall population as well as across various patient subgroups. The overall response rate for SVd was 76.4% compared to 62.3% in the Vd treatment group. And when looking at the difference in response rates between the 2 groups, the benefit of SVd was even greater relative to Vd in some of the more difficult-to-treat patient subgroups, including those with moderate renal impairment and those with high-risk cytogenetics. Please now turn to Slide 10. While, of course, the overall response rate is an important measure of a therapy's clinical activity, the depth and duration of each response can often be an even more important feature for patients and physicians. In the BOSTON study, significantly more patients had a VGPR, or a very good partial response, or better on the SVd arm as compared to the patients on the Vd arm. A reminder, VGPR refers to at least a 90% reduction in a patient's myeloma markers, while a complete response refers to a 100% reduction. In the BOSTON study, 44.6% of patients on the SVd arm achieved a VGPR or better as compared to 32.4% of patients on the Vd arm. Similarly, 16.9% of patients on SVd achieved a CR or a stringent CR versus 10.6% of patients on the Vd arm. Additionally, the median duration of response were also significantly higher on the SVd arm as compared to the Vd arm. The median duration of response on SVd was 20.3 months as compared to 12.9 months on the Vd arm. Please now turn to Slide 11. Now while the survival data from the BOSTON study is still not final, the interim clinical data at the time of this analysis showed a trend toward an overall survival benefit associated with SVd. There were fewer deaths numerically reported on the SVd arm as compared to the Vd arm. The median overall survival for the SVd has not been reached as of the data cutoff of February 18, 2020. However, we find this interim data quite encouraging for 2 major reasons. First, approximately 50% of patients in the study had only received 1 prior line of therapy before entering the study and so were very early in their disease course. And secondly, the study included a crossover design allowing patients who progressed on the Vd arm to crossover following disease progression. Therefore, we see this trend towards an overall survival benefit in the context that most of the patients on the BOSTON trial did receive selinexor at some point in their treatment. Final data on overall survival will be reported as data matures and becomes available. Please now turn to Slide 12. Now as you may know, peripheral neuropathies are among the most common causes of treatment limitation and discontinuation of Vd and combination Vd regimens. I am pleased to report that in the BOSTON study, the rate of peripheral neuropathy on the SVd arm was significantly lower than the rate in the Vd control arm. Specifically, 32.3% as compared to 47.1%. Additionally, the rate of Grade 2 or higher peripheral neuropathy, which was a prespecified secondary endpoint on the BOSTON trial, was significantly lower in the SVd arm. This is a particularly important feature of SVd therapy and one in which we believe will be well received by both patients and physicians alike. Turning now to Slide 13 and 14. I'd like to highlight the most common treatment-related adverse events in the SVd arm, which included cytopenias along with gastrointestinal and constitutional symptoms. And although higher in general than the Vd arm, these were consistent with the AEs previously reported from other selinexor studies. Most were manageable and reversible with dose modifications and standard supportive care. Additionally, when comparing the rate of adverse events in the BOSTON study to that in the STORM study, which evaluated a higher dose of selinexor in patients with more heavily-pretreated disease, it's important to keep in mind that patients in the BOSTON study remained on selinexor treatment for an average of 10 months compared to only approximately 3 months in the STORM study. In BOSTON, the most common nonhematologic treatment-related adverse events on the SVd arm were nausea, fatigue, decreased appetite, diarrhea and peripheral neuropathy, which are mostly Grade 1 and 2 events. The most common Grade 3 and Grade 4 treatment-related adverse events were thrombocytopenia, anemia and fatigue. Importantly, while thrombocytopenia was common across both treatment arms, the rate of bleeding, especially Grade 3 or higher, was very low in both treatment arms and seen in only 1% to 2% of patients. Peripheral neuropathy was the most common adverse event that led to treatment discontinuation across the entire study. However, as mentioned previously, the rate of peripheral neuropathy was significantly lower in the SVd group compared to the Vd group. Finally, the discontinuation rate due to adverse events was 17% on the SVd arm compared to 11% on the Vd arm. To put this in a broader perspective, in our STORM study, the discontinuation rate of selinexor due to adverse events was 27%. In addition, from other Phase III myeloma studies in second- and third-line settings, 3-drug combinations often have similar discontinuation rates. Furthermore, we have already seen from the commercial or the real-world setting, where XPOVIO is currently being prescribed, with increasing experience, XPOVIO can often be effectively managed with common supportive care measures and dose modifications, and we're already seeing much lower discontinuation rates in the real-world as compared to the STORM study. Turning now to Slide 15. I'll summarize the BOSTON data presented at ASCO earlier this morning. First, unlike most triplet therapies in myeloma, the SVd regimen represents a simplification of the Velcade-based triplets for relapsed myeloma. With SVd, weekly oral selinexor replaces one of the twice-weekly doses of Velcade. Ultimately, this means fewer clinic visits, less overall Velcade use and reduced dexamethasone use. Well, with this added convenience and simplified dosing, once-weekly SVd significantly prolonged PFS, demonstrating a median PFS improvement of 47% and significant increased overall response rates compared to twice-weekly Vd. This means that replacing the second dose of Velcade with 1 dose of oral selinexor led to significantly prolonged PFS. SVd was superior to Vd across key efficacy endpoints, including PFS, response rate, VGPR response rates and duration response; and across key subgroups, including in patients over the age of 65, frail patients, those with prior lenalidomide therapy and those with high-risk cytogenetics. Median OS has not been reached in patients with SVd versus a median overall survival of 25 months with Vd. In addition, once-weekly dosing used in the SVd arm was associated with significantly lower rates and severity of Velcade-induced peripheral neuropathy compared with the twice-weekly Vd. And finally, adverse events associated with SVd were manageable and reversible. In summary, we're able to conclude from the BOSTON study that in patients with myeloma who have received 1 to 3 prior therapies, including prior lenalidomide or a proteasome inhibitor, once-weekly SVd offers patients an effective, convenient triplet regimen requiring 35% fewer clinic visits and a reduced rate of peripheral neuropathy. Finally, as you know, the BOSTON study, in part, was conducted based on the encouraging earlier data we saw from Karyopharm's STOMP Phase IB/II trial evaluating XPOVIO and low-dose dexamethasone in combination with one of several standard approved myeloma therapies in patients with relapsed/refractory myeloma. We continue to be very encouraged by the data from the additional arms of the STOMP study, which indicate additive or synergistic activity with XPOVIO, especially when you view the data in context with historical benchmarks. The summary of this data can be seen on Slide 16. For example, in the XPOVIO plus Kyprolis and dexamethasone or SKd arm of the STOMP trial, we saw an overall response rate of 71%, which compares to an overall response rate of 23% in the benchmark study of Kyprolis and dexamethasone alone. Additionally, in the XPOVIO plus pomalidomide and dexamethasone or SPd arm, we saw a 56% overall response rate and a 12.2-month median PFS, which compares quite favorably to an overall response rate of 29% with PFS of 3.6 months in the benchmark pomalidomide plus dexamethasone Phase III study. While, of course, there are many limitations when trying to compare data across different clinical trials, the STOMP data provides strong rationale for further clinical investigation of selinexor in combination with standard approved therapies beyond just Velcade. Please now turn to Slide 17, where I'll highlight our key steps following today's exciting announcement. First, as we announced last week, we've already submitted an sNDA requesting an expansion of the current XPOVIO label. We'll continue to support the FDA's review of this application and hope to bring XPOVIO to an increasing number of patients as quickly as possible. Next, we'll continue to work with the EMA as we review our current MAA based largely on data from the STORM study, with a hope of receiving a decision later this year, and plan to submit the BOSTON data in a formal MAA later this year. And finally, depending on the FDA review time and outcome, we expect to commence the U.S. commercial launch of XPOVIO in the population studied in BOSTON, before the end of 2020 or early 2021 with our existing commercial infrastructure and the U.S.-based sales force. With that said, let me take this opportunity before Dr. Richardson says a few words to offer my very sincere appreciation to all the patients, their families, physicians, caregivers, advocacy organizations, our current Karyopharm employees and investors in our company who have helped us get to this monumental day. There's no way we could have gotten here without all of your dedication and persistence. And for that, we're immensely thankful. At this point, I'd like to ask Dr. Richardson, a world nonmyeloma expert who has been a leader in the clinical development of many of the myeloma drugs used today, including bortezomib, lenalidomide, pomalidomide and selinexor among others, to provide some of his thoughts about the current treatment paradigm and how the BOSTON data might impact future treatment options for patients. Dr. Richardson is the Clinical Program Leader and Director of Clinical Research at the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute. He is also the R.J. Corman Professor of Medicine at the Harvard Medical School. I'll also remind you that Dr. Richardson is not an employee of Karyopharm, and the views and statements he'll make on today's call are his own and specifically those -- not specifically those of Karyopharm. With that, Dr. Richardson.

Thank you, Jatin. That's very kind of you. It's a pleasure to join you and Mike and the team on this afternoon's call. And it's wonderful to be part of the BOSTON study, and in particular, to see the success of BOSTON after the success, obviously, of STORM. But some of the questions that STORM left, I think, have been really addressed beautifully by the results from BOSTON, as you so nicely outlined. And I'm very happy to discuss some of those conclusions and the -- in my opinion, the very positive results, particularly regarding tolerability and some of the relevance of real-world data that this generates, in my view. But above all, the impressive results both in the population overall, but also in particular, in the high-risk patients, but we can certainly come back to that. What I wanted to do, first of all, for the audience was just to give some background on the treatment of multiple myeloma and recognize that, obviously, we've made tremendous progress in the last 2 decades against this still, unfortunately, here, the 2 incurable hematologic cancer. But having said that, with the advent of critical classes of drugs -- and I'm on Slide 19, just for everyone. You can see here that backbone agents such as bortezomib and carfilzomib have really provided important advances in this space. I do want to add to this ixazomib, which obviously has an improved role and has provided a very well-tolerated approach with proteasome inhibition. It's important to note, particularly given the oral approach, which, in my opinion, increasingly matters as we live in the post -- an ongoing COVID era. In terms of the immunomodulatory drugs, we've obviously got a host of opportunities there offered through, first, thalidomide, but now lenalidomide and pomalidomide. And obviously, there are some exciting new agents on the horizon in the form of the [ cell mods ] as well. We have monoclonal antibodies and specifically, of course, daratumumab and elotuzumab and the recent approval of isatuximab, I think, adds nicely to that platform, and we have some exciting new antibodies on the horizon. Now I think in the context of selinexor, what's so exciting to me personally is that it's an entirely novel mechanism of action. And this targeting of the nuclear export proteins, XPO1, which is so central to myeloma pathobiology. I think it's really important to appreciate. And this novel mechanism of action, in my mind, is in a central component of what we're trying to achieve in myeloma, which is to bring together a veritable sort of Army, Navy, Air Force, Marines, all the assets that we can to bring the disease under control. Now I think it's important to recognize that in the context of real-world practice, the ability to use backbone agents and combine them does actually generate some important concepts that we need to get our head around. And I think the point we're making here about drugs with proven single-agent clinical activity are generally preferred by clinicians is probably self-evident, I would suggest, to most people on the audience. But the critical thing to recognize is that by using these backbone approaches, typically with an immunomodulator and a proteasome inhibitor -- and we'll hear some very important data in that regard actually over the weekend at this meeting -- at the ASCO meeting I'm referring to, of course. But in that context, it's very important to recognize additional combination strategies that are incredibly relevant, obviously, with the introduction of the antibodies and now, of course, with the impact of selinexor and as so nicely illustrated with the results of BOSTON. Now when we think about the constructs of bortezomib, I think we will need to realize that this is a clearly well-established drug. It's really a first-in-class. And obviously, I'm biased. I was very fortunate and privileged, in fact, to be part of the development team on the clinical side for bortezomib, so bortezomib is very near and dear to my heart. But having said that, at a more practical level, especially in the real world of what we're facing now, it's a very good dance partner. It's a very cheap drug, relatively speaking now, with its generic status. And I think what's so exciting about weekly bortezomib, particularly combined with other strategies, is that it makes great sense in the context of the COVID era as we try to minimize visits from patients to the clinic, and at the same time, we want effective regimens that are practical, cost effective and useful. I want to use that last term carefully because that's obviously a complicated topic. But certainly, as a partner with other drugs, it makes great sense as a true backbone. Now we do know that bortezomib classically has dosed twice per week and subcutaneously now has made a big advance in terms of peripheral neuropathy. But what's also very important to recognize is that by going to a weekly schedule, and this has obviously not only improved tolerability dramatically but also has convenience as well underpinning it. And again, the results from BOSTON, I think, echo in that context. So as I move to Slide 20. I really wanted to sort of bring that out by comparing for you a variety of large Phase III trials. And of course, you've heard so nicely from Jatin about BOSTON, and obviously, Dr. Dimopoulos presented beautifully the results this morning. What you can see here, of course, is that its comparability to other regimens, certainly in terms of efficacy, is a natural partner in terms of what you see for BOSTON versus, for example, PANORAMA-1, and for that matter, for OPTIMISMM, which is a study that we published recently and has provided a very real-world platform. Clearly, the combination of daratumumab and bortezomib and dexamethasone in the CASTOR study stands out as being particularly active. But I think it's very important to realize in the real world as daratumumab is used increasingly upfront in the treatment of myeloma, the implications that, that has. I think also as we think about response rates across the respective studies, you can see here again that the BOSTON data actually are very comparable. And that also applies importantly to high-quality response. Now what I'm also particularly -- I think, is important as we translate these findings from a Phase III carefully controlled clinical trial to real-world practice. It's something that Jatin spent some time on and very appropriately, which is this whole construct around tolerability. And as you can see here, whilst we do see some magnification of hematologic toxicity, say, for example, for thrombocytopenia compared to OPTIMISMM, nonetheless, if you compare it to CASTOR, or for that matter, to the PANORAMA study from some years ago, you can see that the results are very comparable, particularly when it comes to thrombocytopenia. But also interestingly, it performs well in terms of neutropenia. Now what does stand out are some of the GI toxicities that Jatin talked about. I want to stress that these are manageable with appropriate supportive care. But no doubt, there's no question they are challenging, but they are manageable. And particularly in community practice, I've had many of my colleagues in the community stress that obviously, they're very comfortable managing antiemetic therapy in the context of other regimens for different malignancies such as colorectal disease. And so in this context, there's a matter of practical application with a proactive approach to antiemesis and GI management, and certainly, my own clinical experience in combination strategies. This is not an Achilles' heel, in my view, to the combination of bortezomib and selinexor. Far from it. And in fact, we're very pleased with how it's been performing in that context, particularly with the selinexor administered on a weekly basis. Now I think what's really attractive about the BOSTON data is the peripheral neuropathy signal, and that stands out. And as we compare, for example, BOSTON to CASTOR to PANORAMA, and indeed, to OPTIMISMM, you can see that in this context, peripheral neuropathy, obviously, is performing well compared to the comparators. And this, I think, is attractive. So in a nutshell, I think it's important to recognize that this twice-weekly dosing of this control arm in the BOSTON trial, as matched to these other studies, is very consistent. But what's also particularly striking is that in the 3-drug arm of the BOSTON study combined with selinexor, the tolerability profile is looking, I think, encouraging. And so with that in mind, I'd now like to focus on questions and answers because you've heard a lot from Jatin and hopefully, the information I've provided is also helpful to provide context. So Jatin, if I may, I'm going to move to Slide 21, which is to focus on questions and answers.

Great. So we can open -- operator, you can open the call up to questions, please.

[Operator Instructions] I show our first question comes from the line of Brian Abrahams from RBC Capital Markets.

Congratulations on the detailed data. First question for me, I guess, maybe more for Dr. Richardson. If you look at the overall survival curves, it looks like maybe there's some hints of a trend here for patients who start on the selinexor arm versus crossing over. And then the subgroup analysis suggests that this drug, this regimen may work better in patients in which this is the first -- their first PI exposure within this combo. So I'm just curious. Looking at those 2 pieces of data, how does this influence how you might think about how early to use selinexor within the treatment paradigm? And how do you sort of balance some of those efficacy attributes versus some of the tolerability characteristics that you mentioned? And then I had a follow-up for the company.

Yes. No, that's a great question, and thank you for it. It's a very important point because whilst we're making tremendous inroads against standard risk myeloma and we've got this wonderful median survivals that are now in figures that we could never have anticipated before, there is this real challenge of high-risk disease early. That's a real problem. It tends to be 17p-enriched and highly resistant. And I think that, that's why I personally, in this study, we're so pleased with the performance in the group with deletion 17p as one example. So clearly, in a high-risk disease, moving it earlier makes great sense. And I agree with you entirely when it's partnering for the first time with a proteasome inhibitor, the performance in that group is particularly impressive. So as you think through, it's logical to me that this would break its way up into the upfront setting, particularly in high-risk disease. I think, honestly, that would not be restrictive then. And I think, particularly now that some of the tolerability concerns that I think people legitimately had, based upon the STORM data, have been far more reassured by these data where you can show in the context of prospective randomized multicenter international trial, the fact that the side effect profile is manageable is particularly important. So I agree with you. I think moving earlier is going to become a next priority. And what is clear is that, in my opinion, is that waiting to use selinexor later in the disease may actually be entirely the wrong thing to do based upon some of these -- the information here. And I agree with you also that the fact that the overall survival signal is coming through so early, is actually -- that's particularly striking. As you may appreciate, that's obviously not what we all -- we see in necessarily other Phase IIIs in this setting.

Great. And then just a follow-up then maybe for the company on the safety side. I guess when you look at the differences in the overall adverse events, it looks like there's may be some imbalances in the GI tolerability and in cataracts as well. I guess for the latter, just wondering to what degree this might just represent the fact that patients are progressing or that the time to progression is longer, so they're on steroids for a longer period of time and maybe some of these adverse events -- imbalances might just be a function of how much time people are on -- patients are on each regimen prior to crossover? So curious if you've done any analyses sort of normalizing these AE rates for exposure to the arm that patients were randomized to and whether you might expect any ophthalmological requirements for patients going forward?

Jatin, do you want to take that?

Yes. Absolutely. So I think you make a good point there with the cataracts. I think what we've seen with the onset of cataracts, you're right, it's going to be multifactorial in terms of the reasons why our older patients get cataracts, and part of it's driven by the long-term steroid exposure. But there is the increased cataract risk that we see on the combination with SVd again. When we look at the time to onset of cataracts in the SVd arm, these patients is not an acute event. This occurs after about 7 months on therapy. And so it's after really prolonged therapy and exposure to this combination therapy. And in fact, these are very clinically manageable. So when patients have it, there's not any additional ophthalmological requirements or evaluations. This is really standard management. So if you have cataracts and seen by an ophthalmologist and then they worsen clinically, then you make the clinical judgment for when you need cataract surgery, these patients can go on, have cataract surgery and then get back on therapy independent with continued treatment. So I think there's -- to your question, it's typically seen on the delayed onset. Multiple factors can impact cataracts, and they can be managed with standard kind of cataract surgery with no additional ophthalmological evaluations or examinations or monitoring needed.

Thank you. A quick addendum to that -- there's a quick addendum to that. There were no discontinuations due to cataracts, which just reiterates what Jatin said, that this is very manageable. And actually, 2/3 of the patients across the trial came in with a history of cataracts and/or cataract surgery. So this was actually the most common medical history across the entire trial, which just stresses this is a very common event and essentially most of these patients, particularly with myeloma and the dexamethasone exposure, will develop them.

Yes. I agree, Mike. And if I may, I just want to add to that from a sort of a practice perspective. The whole -- to me, the other major advantage of the experimental arm in the BOSTON study was the fact you were relatively dex-sparing with the 3 drugs compared to the 2. So our impression from this was that was extremely helpful. So I agree with you entirely, Mike. It's a problem we face. We have an elderly population period -- patients have had a significant period on prior steroid exposure. And so they are set up for this issue. But the fact that this is actually a relatively steroid-sparing regimen is an important positive.

Our next question comes from the line of Peter Lawson from Barclays.

Dr. Richardson. Just on the change in landscape we're seeing for first-, second-, third-line treatment and also drugs move in earlier line. Do you think the current trial, it would make it clear where to use you selling in the treatment paradigm?

I think it definitely provides the highest level of evidence for using it earlier. And I think this Phase III trial -- let me speak, for example, to the NCCN. This will get a Category 1A designation based upon this. That's important from an insurer's point of view in the U.S. space, and I think it provides a great impetus to moving earlier in the European regulatory space well. So I think in first relapse, but as a fellow brit, you'll appreciate what that means perhaps in the United Kingdom will be an interesting one. But I hope, for example, it will provide the same sort of platform that was provided by panobinostat and bortezomib in the U.K. paradigm, for example, where the way in the United Kingdom, panobinostat and bortezomib is used -- is in early relapse based upon the PANORAMA data. I would argue that the justification for BOSTON moving seli and bortezomib earlier into a treatment paradigm, even in as difficult a space as the U.K. environment, is very much supported by the results of BOSTON.

Maybe you didn't pick up on my Brooklyn accent. And then just on PFS and hazard ratios, how should we think about that for the third-line patients? How do they -- or is there any color you can give in a sense of how they fared versus first-line and second-line patients?

Well, I think you have -- when you look at the forest plots, I find that slide that Jatin showed really informative. I think you've got, obviously, the striking benefit in first relapse. That's very typical of what we see actually in Phase III of this design. Obviously, the PI-naive patients did particularly well. Well, that's not surprising. But that's important in the groups of patients, for example, who are now receiving an image-based initial treatment with an antibody but are not necessarily exposed to a PI early. That's an increasingly large group with the success of the [ Myer ] trial and other such approaches. So an important positive for the study in that regard. And then as I mentioned before, the high-risk group are particularly impressive. But I think Jatin made a very important point that if you look at patients who are actually over the age of 65, that was a very important positive from the trial. I mean some cynics would have argued that's a surprise, and I would understand why they would say that. But that's actually a group in which we saw significant benefit. So I think, again, these forest plots are very helpful in making sense of that -- of your question.

And did we get any color around the third-line patients? I'm just trying to work out if it's kind of driven by first- and second-line patients and how those third-line patients may have done.

Well, the analysis that you saw on the forest plot is for 2, 3 for 204 folks. I would argue that the third-line group are probably -- and I'd want Jatin to give full numbers on this for you. But certainly, from my perspective, third-line patients to whom you would have equipoise exposing to bortezomib and dexamethasone as a doublet versus SVd as a triplet. That, I would imagine, is a minority of patients in this trial. Jatin, perhaps you can comment on that.

No. I mean I think you're absolutely right, Paul. What we see with the patients, 1 line versus 2 to 3 lines, we see a really preserved hazard ratio there. And so we see activity that we would expect to see if it's first or second or third. Obviously, when we look at patients, we've had prior PI therapies and really supports in the first relapse setting where we see those patients who are Velcade-naive have the most dramatic benefit that supports that.

Right. And I can add to that by giving you kind of real-world experience from since the approval of STORM. We've actually used, frankly, selinexor in combination as our approach. And typically, in that regard, we've either combined it with selinexor and carfilzomib, or combined it with selinexor and bortezomib. And our other approach has been with pomalidomide, actually. And that's kind of where in "the third line," you might be with seli. But that has, in fact, been an attractive approach in those settings because of the STOMP data supporting that. So that's kind of how we've approached it. This would now allow us to move earlier with the seli for sure.

Our next question comes from the line of Maury Raycroft from Jefferies.

Congrats on the update. First one, I guess, for the management team or for Dr. Richardson, too. Just wondering if you could talk more about -- potentially quantify dose reductions and interruptions and how those influence SVd efficacy and how this influence real-world practice.

Jatin, maybe you can comment on that?

Yes, absolutely. So I think when we look at the dose reductions, there's going to be the anticipated dose reductions that we'll see with bortezomib. When it comes to selinexor, patients who do have a dose reduction typically will have 1 dose reduction. So when you look at the median dose intensity for those patients who have a dose reduction of 80 milligrams once a week, so we traditionally see that those patients who do need a dose reduction will go to 80 milligrams once a week from 100 milligrams. And that has been, I think, the dose of most of the patients who need a dose reduction will do. It's -- and they get all the side effects that we see are dosing schedule dependent. And so those can be eliminated, and we see that with just a single dose reduction. So it's not necessarily a difficult transition to identify the right dose for that patient.

Yes. And just to add, from best we can tell, there's very little effect of the dose reduction on the continued efficacy. All the patients, as Jatin said, started 100. And it's a little bit like Revlimid in that regard, where you started at 25 and you keep going down as you need to with neutropenia, usually. We go down and we maintain these responses for a very long time, as you saw with the DoR in the 20-month range.

Yes. Sorry, sorry, Jatin. No biggie. But I was just going to echo those 2 comments very quickly because I think we're very comfortable with that as a treatment approach. You'll find best dose and over time, less is more. But at the same time, that's a paradigm that's very, very practical and something we do frequently. So sorry, Jatin, please carry on.

No, that's exactly what I wanted to [indiscernible]

Got it. And then for the patients that progress and cross over to the SVd arm, can you say what the overall response rate or [ DCR ] rate was for those patients? And as OS matures, will you continue to send those updates to FDA?

Yes. I'll take that. We don't have the data completed yet for the crossover. We know those patients do stay on. We have had bona fide responses in them, even though they're patients who have disease that's immediately refractory to Velcade. And we will, to answer your second question, we will absolutely, and we always do, have periodic safety updates to the FDA, which includes overall survival.

Our next question comes from the line of Jonathan Chang from SVB Leerink.

First question, just in reference to something that Dr. Richardson mentioned earlier. In terms of the initial launch of XPOVIO, can you provide any color on how much of the utilization is already in the BOSTON or some other triplet setting versus the STORM setting?

Yes. Paul, you can start. And then John will take over.

Yes. I'm very happy to do that. I mean obviously, we've used it per label. I want to be careful about this because I certainly don't want to imply that we run around prescribing off-label all the time. But my point is that it has been prescribed per label, and we then have in our own practice and certainly speaking to my own, I've combined it. And I would say I've actually gone more in that direction than I have as truly on-label per the relapsed refractory approval. But I would stress that that's very much a practice pattern that most -- especially in the myeloma expert space, and I'm considered relatively experienced in that regard, that's what we kind of do. In community practice, it may be a little bit less so and then may be more literal to the label. But I think once the STOMP data became more widely appreciated, and in particular, after Christina Chen's presentation of pomalidomide and selinexor at ASH, with some very positive comments generated thereafter by thought leaders in the field such as my colleague, Vincent Rajkumar, who have been previously rather much more cautious with selinexor. Basically, I think the combination approaches have gathered -- garnered increasing popularity. But I want to be careful about that because that's just my impression, but I would hand to Jatin to comment further.

And maybe over to John, our Head of Commercial. Jatin, first.

Yes. Of course. Of course.

I think Dr. Richardson framed it very well. From what we've heard in ad boards, a number of the leading advisers, a number of the leading academics have tried the drug in the triplet setting or the multiple combination setting. So what we see for the most part is still -- the majority of usage is still on-label in STORM-based population as XPOVIO plus dexamethasone at this point.

Got it. And just second question, can you talk about next steps for XPOVIO multiple myeloma development in other combination settings, given the data that's been generated already in the STOMP study?

Yes. I'll take that quickly. We have a number of combinations ongoing that are continuing within STOMP, and then we are planning on a Phase II or III study of Selinexor/Pom/Dex versus pom-dex as a randomized study. This would be an all-oral triplet and versus an all-oral doublet. And we're working with regulators to design that study. We're hoping that, that study will be occurring in the upcoming -- within the -- by the end of the year or early next year, just given all the other things that we have going on. We have -- we're accumulating additional data in combination with daratumumab with Kyprolis. And with Kyprolis, I would emphasize, particularly in the very late-stage in patients with extramedullary disease, we've had some pretty intriguing results as well as after CAR-T relapses. So that's an area there. And then our intention is, as newer agents are approved, we believe that given the mechanism of action, which is as a tumor suppressor activator, but also given the fact that we can administer this drug orally once a week, that selinexor represents a really optimal or potentially optimal partner for these other drugs. And we intend to combine pretty much with any other agent available in myeloma.

Our next question comes from Eric Joseph from JPMorgan.

Just a couple from me. The first on peripheral neuropathy. I'm wondering whether there's any trend as to where the benefit was strongest, perhaps depending on whether a patient stopped prior [indiscernible] or any other kind of baseline characteristics? And then for Dr. Richardson, I'm curious to know sort of to what extent a patient's present rate [indiscernible] they might see in a cellular [indiscernible]

Eric, you're breaking up. Eric, maybe we'll give you a minute. Maybe we'll answer the first question, and then you'll answer -- ask the second one. Hopefully, your Internet comes back. Jatin, can you give any insight on the PN?

Yes. Your specific question, is there any subsets of patients that had less or more peripheral neuropathy? And so we have not done that analysis. And so broadly speaking, one of the key points around this whole peripheral neuropathy issue is that any time we have any triplets, we see increases in the rate of peripheral neuropathy compared to the control arm of Vd. And this is one of the first triplets -- this is the first and only triplet that actually shows reductions in peripheral neuropathy with better outcomes. And this is significantly important because these are patients getting earlier lines of therapy with these combinations, and neuropathy can be lifelong or cause significant long-term morbidity. And so this is, I think, an important issue for both patients and caregivers. But from, I think practically speaking, in context, when we look at other triplets, in fact, this is a lower peripheral neuropathy we see with other triplets when you add on to a Velcade-based regimen.

Right. And I would add to that with the following sort of scientific observation that we've been very struck that bortezomib neuropathy is a complicated entity. And there are multiple approaches to abrogating, which are particularly important now, given that there are different toxicities from different classes of proteasome inhibitor that are becoming much more important as we think about where we are now in terms of a real-world practice. And I'm speaking specifically in the COVID era and how we've got to be very careful about some toxicities that are vascular. So this makes it very, very important for us to think proactively about neuropathy and say, okay, neuropathy has been a big problem. And it's why, typically, I mean, personally, carfilzomib has been a fabulous PI. It's a great addition to the arm [indiscernible]. Personally, it tends to be my second choice. I think the reality is that in practice now, with some of these differential toxicities beginning to matter, managing peripheral neuropathy is going to be very important. So the fact that we're seeing a lower rate with this approach is in a value-add in my opinion. And the mechanism behind it's intriguing. I think an anti-inflammatory effect may be very relevant. We've made this observation previously with other approaches such as partnering steroids appropriately with bortezomib to minimize neurotoxicity, and I'm intrigued by the observation that we've seen from seli, that it's not just simply the weekly schedule. It may be more than that. And I think that's very important to remember.

Ray, I'm sorry. Unfortunately, we're coming up on the hour, and I'm cognizant of everyone's time. I think we have time for just one more question. And I apologize for those still in the queue. This has been a great, great discussion, and we're happy to follow-up separately. So I apologize in advance, and maybe we'll just take one final question.

Our last question comes from the line of Arlinda Lee from Canaccord.

I had a couple of questions on the GI toxicities. You -- I'm curious about how much of the proactive management of these went into the BOSTON trial. And then secondly, Dr. Richardson, I was -- you had mentioned that you see this going earlier in lines of therapy. And I was wondering, in particular, were there particular combinations that you were interested in? And if so, what would you like to see?

So Jatin, maybe you'll take the first one and then -- for the call and then over to Paul.

Yes. Absolutely. So on the GI side effects, there's a protocol mandated, Zofran or 5-HT antagonists. And so that was effective. We were finding in the real-world, as folks use it commercially, is oftentimes, they'll use 2 antiemetics, and that can be also affected as well. So the protocol mandate is single antiemetic. And I think you have to remember the side effects, again, were different than we see in STORM, where we use the 80 milligrams twice a week. And the GI side effects are -- we saw an increased number in severity at that dose. And so the dose and schedule changed to once weekly. That's also been significant in improving the tolerability.

Yes. Mike, with pleasure. I would simply add to that, that, obviously, in our practice, we're very comfortable using multiple antiemetics as needed to improve tolerability and being proactive about them rather than reacting to nausea, being proactive to head it off of at the pass. But building to the second question, which I thought was very good, and thank you, would be what platforms will we use? Well, I think one of the obvious ones is we're establishing the PIs and IMiDs, our backbone approaches, in combination. And you'll hear some very important data this weekend from the plenary session in that spirit. And I think, obviously, we'd be looking to how to best partner seli in that space. Frankly, we already know that seli partners very well with them as we know that from the STOMP data and Christina Chen's presentation at ASH in December. And obviously, now we have highest-level data that it partners well with bortezomib. So one could think about an IMiD PI platform upfront being a logical place for seli to move as a next step.

Okay. Thank you. Thank you, everybody. Again, apologies for the short notice. Just to summarize and close. BOSTON is the only Phase III study to our knowledge to evaluate a once-weekly Velcade-based regimen on the experimental arm. All the other Phase III studies utilize standard twice-weekly Velcade on both experimental and control arms. And looking across the studies, as Paul did in his discussion, provides an initial indication of once-weekly Velcade may provide a desirable dosing regimen in combination with selinexor and dex. The efficacy and safety characteristics of the SVd regimen with its simple once-weekly dosing schema, leading to lower cumulative Velcade and dexamethasone dose, may offer patients and physicians a novel and highly active approach to their recurrent myeloma, particularly compared with the additional Vd dosing regimens for twice weekly. And given the oral nature of selinexor and the once-weekly regimen, we think this is particularly relevant in today's treatment landscape. Thank you all very much, and we look forward to additional updates in the future. Have a great day.

Bye, now.

Thanks very much, everyone. Thank you.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating, you may now disconnect.