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

Hello. My name is Keith, and I will be your conference operator today. At this time, I would like to welcome everyone to the Karyopharm Therapeutics ASH 2020 Investor Conference Call. There will be a question-and-answer session to follow. 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 Senior Vice President, Investor and Public Relations.

Great. Thanks so much, and thank you all for joining us on today's conference call to discuss important clinical data presented at the American Society of Hematology 2020 Annual Meeting. This is Ian Karp, and I'm joined today by Dr. Michael Kauffman, Chief Executive Officer; Dr. Jatin Shah, Chief Medical Officer; as well as my 2 guests on today's call, who will join us a bit later: Dr. James Berenson, Founder, President and Medical and Scientific Director of the Institute for Myeloma and Bone Cancer Research; and Dr. Timothy Pardee, Director of Leukemia Program at the Wake Forest School of Medicine. On the call today, Dr. Kauffman will provide a brief summary of the role XPO1 plays in the development and proliferation of many types of cancer, and we'll also provide a short overview of the current treatment landscape in multiple myeloma. Dr. Shah will then provide a summary of the key presentations at ASH this year that highlighted data from our BOSTON and STOMP studies in multiple myeloma. He will then provide a brief overview of the treatment landscape in DLBCL, along with the data from the SIENDO study, which was also presented at ASH. We are very fortunate, as I mentioned, to have 2 well-recognized experts in the fields of multiple myeloma and leukemia joining us on today's call. Doctors Berenson and Pardee will offer some of their own insights on the data presented at ASH as well as will join us for the Q&A portion of the call. Additionally, Dr. Pardee will review data from an investigator-sponsored study he is leading at Wake Forest Baptist Health in the frontline setting for patients with acute myeloid leukemia, or AML, which were also presented yesterday at the ASH meeting. Please note that Doctors Berenson and Pardee are not employees of Karyopharm and have been invited to participate on today's call as they are experts in the field of hematological malignancies. Their comments and opinions shared today are completely their own and do not reflect official statements from Karyopharm or their institutions. Yesterday, we issued 2 press releases detailing XPOVIO data presented at this year's annual ASH meeting. These releases as well as a PDF copy of this presentation will be -- are available on the Investors section of our website at karyopharm.com. Before we begin our formal comments, I'll remind you that various remarks we will make today constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. These include statements about our future expectations, clinical developments and regulatory matters and time lines, the potential success of our products and product candidates, including our expectations related to the commercialization of XPOVIO; financial projections and our 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 filings we may make with the SEC in the future. Any forward-looking statements represent our views as of today only, but 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. I'll now turn the call over to Dr. Michael Kauffman, Chief Executive Officer of Karyopharm. [Technical Difficulty]

Please, can you hold the line? Dr. Kauffman has just disconnected. I will reconnect him.

If there's technical difficulties, we can proceed. Let me know. This is Dr. Shah.

Okay. One moment, please.

You know what? For the sake of time, why don't I start with the first 3 slides? And then we'll transition over to Dr. Shah shortly as Dr. Kauffman is dialing back in. So first, let me begin really with a bit of background as we're delighted to discuss some of the key XPOVIO clinical data presented at the ASH 2020 meeting today. We were particularly fortunate this year to be able to present a large and diverse set of data, which span across disease states, including multiple myeloma, lymphoma and leukemia. This was in part due to the growing recognition within the oncology research community that XPOVIO was playing a fundamental role in the proliferation of many cancers. And this is where we'd like to begin and before we actually move to the clinical data at which Dr. Shah will present for us. Now as many of you may know, there are 5 foundational pillars of cancer drug therapy, which are used across tumors and patients, often in combination to provide each patient the best chance at beating their disease. XPOVIO, which specifically targets a protein called XPO1, is the first anticancer drug whose primary activity is the activation of tumor suppressor proteins. There are about 20 of these proteins, including p53, BRCA1 and 2, Army and the inhibitor of NF-kB called IkB, which are critical parts of each cell's own natural defense mechanism to detect cancerous DNA changes and prevent the generation of moving cell. In short, XPOVIO could direct the cell, which has become cancerous, to commit suicide and potentially improve outcomes for a large variety of cancer. With that, I want to just check to see if Michael -- Dr. Kauffman has made it back on the line. And if so, we can move to Slide 6.

Yes. Thank you. Thank you. I apologize. I was kicked out. Somebody obviously did not like me. So let me find Slide 6, and we will move ahead. And I appreciate everybody's patience here while we dig into there. My apologies, Ian. I don't know where to pick up. I apologize.

Sure, Michael. We're just on the slide now that has the 4 graphs of XPO levels correlated with 4 cancer prognosis for patients.

Yes. So as you can see from these 4 separate graphs, which highlight previously published clinical data, higher XPO1 levels are correlated independently with overall survival in patients with myeloma, diffuse large B-cell lymphoma, soft tissue sarcoma, glioblastoma and many others where we didn't have a room to present. The main point here is that over the past 5 years, it has become increasingly evident that the over-expression of XPO1 plays a critical role in oncogenesis, largely by removing tumor suppressor proteins from the cell nucleus where they normally function. XPOVIO forces the retention of these proteins in the nucleus and keeps them there, restoring their tumor suppressor function. And that's why we've developed such a broad clinical program for XPOVIO across many different tumor types. XPOVIO is an oral selective XPO1 inhibitor that, first, reactivates multiple tumor suppressor proteins relevant to many cancer types; second, inhibits nuclear factor kappa B signaling; third, reduces c-Myc and other oncoprotein levels; and fourth, reactivates glucocorticoid receptor signaling in the presence of steroids, such as dexamethasone. Based on these important mechanisms, XPOVIO demonstrates synergistic activity in combination with bortezomib, pomalidomide and lenalidomide and other anticancer drugs in vitro and in vivo. And due to the broad applicability of XPOVIO across different tumor types, you can see that on the next 2 slides just how diverse our clinical development approach is. Here, you see our current and planned clinical trials in multiple myeloma, DLBCL and myelofibrosis. I'll also highlight a new Phase III trial in multiple myeloma that we plan to start in 2021, which will evaluate the combination of XPOVIO with Pomalyst and dexamethasone compared to Pomalyst and dexamethasone alone, which, if successful, could offer a very compelling all-oral regimen for multiple myeloma patients in the future. Next, while we won't spend much time today talking about our plans and aspirations in solid tumors, it's important to see the broader plans for XPOVIO where we're currently studying it across a number of solid tumor indications, including the Phase III SIENDO study as frontline maintenance therapy in endometrial cancer. Further, we're exploring a number of new trials, which could start in 2021, including in lung cancer, melanoma and colorectal cancer. As we move now to the next few slides, I'll briefly provide an overview of the multiple myeloma treatment landscape before I hand things over to Jatin to discuss our myeloma data presented at ASH. There are currently 4 main classes of drugs commonly used to treat patients with myeloma, which include proteasome inhibitors, immunomodulatory agents, monoclonal antibodies and now, a nuclear export inhibitor where, of course, XPOVIO is the only drug in this class. Patients typically receive 1 or 2 of these highly active agents in combination with a steroid such as dexamethasone in each line of therapy, and they're usually treated until their disease progresses. Physicians will then typically prescribe another combination, including steroids, in each of the subsequent lines of therapy. Our experience is that physicians generally prefer to combine at least 2 drugs with distinct mechanisms and proven single-agent clinical activity, typically with the additional steroids. And furthermore, there are a number of key features that can help predict the usefulness and ultimately, the success of a new multiple myeloma drug, which include demonstrating the following: significant single-agent activity, efficacy in heavily pretreated disease, compatibility to pair with drugs from other classes, tolerable and manageable side effects with minimal overlap in toxicity with other myeloma drugs that could be used in combination, robust Phase III data to support earlier line use, the ability to continue the agent indefinitely until relapse and finally, the potential to use in a frontline regimen. We believe that XPOVIO satisfies all of these features that may help predict the ultimate usefulness of a new myeloma drug, and much of the data presented at this year's ASH will help support a number of these dynamics. And the fact that XPOVIO is typically given orally only once per week make it particularly interesting partner with other agents. Finally, we eagerly awaited decision from the FDA regarding our sNDA for previously treated myeloma patients based on the BOSTON study. As a reminder, in BOSTON, we evaluated weekly XPOVIO in combination with weekly Velcade and low-dose dexamethasone. The BOSTON regimen exploits a completely novel synergy by combining an XPO1 inhibitor with a proteasome inhibitor. And based on the BOSTON results, we believe that treating patients with such a combination as early as possible may be vital for successful patient outcomes. If approved, I want to highlight the potential for XPOVIO as part of the BOSTON regimen to be, first, the first new mechanism approved since 2016 for patients following their first relapse, the only approved once-weekly Velcade combination regimen and third, a regimen with demonstrated rapid and sustained response despite the large percentage of patients with high-risk cytogenetics in the pivotal Phase III BOSTON study. With that, I'll now like to hand over the presentation over to Jatin, who will walk us through some of the key XPOVIO data presented this year at ASH. Jatin?

Perfect. Thank you, Michael. So I'd like to first begin with the data from the Phase III BOSTON study, now published in The Lancet, which enrolled 402 patients and invest in a combination of once-weekly oral selinexor, once-weekly bortezomib, otherwise known as Velcade, and low-dose dexamethasone compared to standard twice-weekly bortezomib and moderate-dose dexamethasone in patients who have received 1 to 3 prior therapies. Throughout the remainder of today's presentation, we will refer to these 2 treatment regimens as SVd and Vd, respectively. Now as you may recall, the top line results for BOSTON trial showed a significant reduction of 30% in the risk of progression or death in patients receiving SVd as compared with standard Vd with a p value of 0.0075. Our number of post hoc subgroup analyses were conducted on the BOSTON data we presented at ASH, which we will review today. Now the first BOSTON subgroup analysis that I'll highlight evaluated the effect of prior treatment with proteasome inhibitors on the efficacy and safety of XPOVIO. The median progression-free survival is improved with SVd treatment compared with Vd treatment for patients who had prior proteasome inhibitor therapy as well as those who are PI naive. For patients who are PI naive, there was a significant benefit in progression-free survival with SVd treatment as the PFS was not reached yet in that group with a hazard ratio of 0.26. These results support the idea of using XPOVIO with bortezomib as a patient's first PI combination therapy. For patients that had prior PI therapy, the combination of SVd also led to a significant improvement in the overall response rate from 59.7% in the Vd arm, 77% in the SVd arm and an improvement in the depth of response. There's an increase in complete and stringent complete response rate from 9.4% in the Vd arm to 14.8% in the SVd arm. Now furthermore, the use of bortezomib-based regimen is common in newly diagnosed multiple myeloma, especially in patients who go on to receive a stem cell transplant. Therefore, we specifically looked at patients that received a bortezomib-based therapy prior to stem cell transplant in a long bortezomib treatment interval prior to entering the study. This is a common treatment paradigm here in the U.S. In these patients who received a prior PI therapy before receiving a stem cell transplant, SVd treatment led to an improvement in progression-free survival from 9.4 to 13.1 months with SVd with a hazard ratio of 0.58. Non-peripheral neuropathy were higher within the SVd arms than the Vd arms while most of the AEs are reversible and treatable. Thrombocytopenia was more frequent in patients in the SVd arm as was anemia, fatigue and decreased appetite among others. In contrast, peripheral neuropathy, which is the most common and important cause of discontinuation of bortezomib and can cause chronic and even lifelong pain, was observed less frequently on the XPOVIO arm than the control arm. Thus, on a prespecified end point of peripheral neuropathy of grade 2 or higher, there was less peripheral neuropathy in the SVd arm compared to the Vd arm. To our knowledge, this is the first study where a triplet bortezomib continuing regimen had lower rates of neuropathy than the bortezomib comparator regimen. Overall, once-weekly SVd is an active and convenient regimen, and if approved, may become an important treatment option for patients who had relapsed or refractory myeloma who had prior PI treatment such as bortezomib-based induction therapy or those who are PI naive. The next subgroup analysis in the BOSTON study looked at the impact of prior therapies and not just prior proteasome inhibitor therapy on the safety and efficacy of XPOVIO. Of particular importance in this analysis were the data for patients who had received prior lenalidomide or IMiD-based therapy. Similar to lenalidomide-naive patients, patients treated previously with lenalidomide showed a significant improvement in the response rate with SVd treatment compared to Vd treatment. The durability of the response and progression-free survival was significantly longer following SVd treatment compared to Vd regardless of prior lenalidomide treatment. The hazard ratio for the progression-free survival was 0.63 in patients with prior lenalidomide, which is very similar to the hazard ratio of 0.66 in patients who are lenalidomide naive. The longer PFS seen in lenalidomide-naive patients appears to be driven by the fact that these patients were in first relapse. For patients with 1 prior treatment as well as patients with 2 or more prior treatments, the overall response was significantly higher in patients with SVd compared to the Vd arm. In addition, the durability of response was also higher in the SVd-treated patients as evidenced by the significantly longer progression-free survival and hazard ratio of 0.63 and 0.69. Notably, the VGPR are more frequent for both patient populations when treated with SVd as compared to Vd. Grade 2 of peripheral higher neuropathy occurred significantly less frequently across all SVd subgroups compared to the Vd groups. Consistent with previous subgroups, adverse events of grade 2 or higher, notably thrombocytopenia, anemia and fatigue, were more commonly reported in the SVd treatment arm than the Vd arm and were mostly managed with dose modifications and/or support treatment. There were no differences between subgroups in grade 3 adverse events. In summary, regardless of prior lenalidomide treatment, the combination of SVd was active with a PFS hazard ratio of 0.63 among patients with prior lenalidomide treatment who received SVd compared to Vd. Now this is particularly compelling with the ability to incorporate 2 new class of therapies in patients progressing on lenalidomide, and therefore, leveraging the common practice of class switching in myeloma. In addition, regardless of prior treatment, SVd 2 had led to significantly improved overall response rates and progression-free survival with the highest PFS of 16.6 months seen in patients following the first relapse. Now the next subgroup analysis in the BOSTON study presented at ASH evaluated patients with high-risk disease versus standard-risk disease based on recognized cytogenetic factors. SVd treatment improved progression-free survival compared to Vd treatment across all 3 groups at sub-translocation 14;16, which was the smallest subgroup. Notably, in patients with both 1 cytogenetic abnormality or patients with 2 or more cytogenetic abnormalities, the PFS was improved in the SVd arm compared to the Vd arm. The time to next treatment was also significantly increased with SVd in the high-risk and standard-risk patients. Overall response rate was also significantly improved with SVd in the high-risk group and numerically improved in the standard-risk group with comparable rates between the high-risk and standard-risk groups in SVd arm. The safety profiles of SVd and Vd in the high-risk and standard-risk groups were consistent with the overall population, again, consistent with what we described: peripheral neuropathy adverse events of grade 2 or higher were lower with SVd compared to Vd in both the high-risk and standard-risk subgroups. In summary, SVd treatment was superior to Vd treatment, including in patients with high-risk disease as supported by the progression-free survival in a different subgroup of patients with high-risk cytogenics. Patients with high-risk cytogenics, including deletion of 17p, will need new options with a novel mechanism of action. XPOVIO's novel mechanism, reactivating tumor-suppressive proteins and reducing level of oncoproteins, will be particularly suited for patients with high-risk multiple myeloma. Again, non-peripheral neuropathy adverse events were higher with SVd, and mostly, the adverse events were reversible. The final subgroup analysis in the BOSTON study presented at ASH evaluated patients by both age and frailty. Now similar to younger patients, the overall response rate is significantly higher with SVd treatment in patients where they're 65 and older, and SVd is also associated with a longer progression-free survival with a hazard ratio of 0.55 in older patients. Overall, for both age categories, the VGPR rate was also higher with SVd-treated patients compared to those treated with Vd. Now regardless of whether the patients are fit or frail, the combination of SVd led to a higher response rate and a VGPR rate for patients treated with SVd. Importantly, the hazard ratio of 0.69 was the same for both fit and frail patients. And the progression-free survival with SVd-treated patients was 13.2 and 13.9 patients for both fit and frail patients. Similar to the overall population, the most common grade 3 or higher adverse events were thrombocytopenia, anemia, pneumonia and fatigue. In the SVd arm, the incidence of AE was comparable across all the subgroups except for a lower incidence of diarrhea and vomiting and a higher incident of nausea, fatigue and insomnia in patients 65 or older compared to those younger than 65. Among the frail patients, the AEs were comparable to fit patients with SVd, except for an increased influence of asthenia and pneumonia in the frail group. Overall, thrombocytopenia was more common in the SVd arm than the Vd arm. In summary, both elderly and frail patients had benefited from SVd treatment compared to Vd treatment. Activity of SVd was preserved in patients 65 or older with a PFS of 21 months compared to 9.4 months for patients treated with Vd and a hazard ratio of 0.55. SVd also had a similar progression-free survival in both fit and frail patients. Now with my review of the data from BOSTON study now complete, I will review the key data from the 3 presentations highlighting data from our STOMP study. As a reminder, STOMP was a multicenter, open-labeled, dose-escalation Phase I and dose-expansion Phase II study to assess the maximum tolerated dose efficacy and safety of selinexor in combination with other backbone myeloma treatments for patients with relapsed myeloma. The first arm in play I'll discuss is from a combination arm with pomalidomide, otherwise known as pom; and low-dose dexamethasone or SPd, which is highlighted in an oral presentation today. Out of the 65 patients enrolled, 60 were deemed evaluable for efficacy. Among the 46 patients who are pom naive or not refractory to pomalidomide, the response rate was 54%. And among the patients who are pomalidomide refractory -- whose disease is pomalidomide refractory, the overall response rate was 36%. Note that we've used the recommended Phase II dose of selinexor 60 milligrams once weekly and pom 4 milligrams, the response rate was 60%. The waterfall plots are seen below, highlight depth of response. The SPd regimen was highly active with durable responses and a prolonged PFS and duration of response. The median PFS was 12.3 months among patients who are pom naive or who do not have pom refractory disease. And the median DoR was 11.3 months. The progression-free survival and DoR have not been reached yet for the 20 patients dosed at the recommended Phase II dose. Common hematologic treatment-related adverse events included neutropenia, anemia and thrombocytopenia, and common non-hematologic side effects included nausea, fatigue, decreased appetite, weight loss and diarrhea. Move to the nonhematologic side effects were low grade, and all these side effects were expected and managed with supportive care and dose modifications. In summary, we believe XPOVIO given once weekly can be safely combined with pomalidomide and low-dose dexamethasone in patients with heavily pretreated myeloma. We recommended Phase II dose of selinexor, 60 milligrams; pomalidomide, 4 milligrams; and dexamethasone, 40 milligrams, all given once weekly, with pomalidomide given days 1 through 21. The all-oral SPd combination was very active and produced responses, which are durable with a response rate of 60% at the recommended Phase II dose. And this is in comparison to an expected overall response rate of less than 30% for pom-dex alone. These data support a planned Phase III study of the all-oral combination of SPd versus PD in patients with prior PI in the CD38 monoclonal antibody. Here, you can see the design for our planned Phase III study of selinexor plus pomalidomide and dexamethasone, which we expect to start in 2021. And we believe, if positive, could significantly add to the current myeloma treatment paradigm by offering patients a highly active and tolerable all-oral active regimen. The next arm from the STOMP study highlighted at ASH came from the arm [ evaluated ] XPOVIO in combination with carfilzomib and dexamethasone or SKd. SKd treatment resulted in deep responses in heavily pretreated patients, including 24 efficacy evaluable patients. Among these 24 efficacy evaluable patients, 5 patients achieved a complete response, 8 patients achieved a very good partial response and 5 achieved a partial response. The overall response rate was 75%, and the clinical benefit rate was 79.2%. The responses to the SKd regimen were also durable, and the median progression-free survival was 23.7 months for all patients and 12.7 months among the 17 patients dosed at the recommended Phase II dose. The swimmers' plot shows 5 out of 18 responders were still on treatment as of the data cutoff with the longest patients staying in the treatment for 25 months. Common treatment-related hematologic adverse events included thrombocytopenia and anemia. Common nonhematologic adverse events included nausea, fatigue, decreased appetite and weight loss with a vast majority with either grade 1 or 2. We believe that's where the adverse events were reported. And all of the adverse events, including the grade 3 and grade 4 thrombocytopenia, were successfully managed with supportive care and dose modifications. In summary, the recommended Phase II dose of SKd with continuous weekly selinexor as a once weekly; selinexor, 80 milligrams; once-weekly carfilzomib, 56 milligrams per meter squared; and dexamethasone, 40 milligrams. This combination is active and durable with a response rate of 75% and deep responses and a greater than VGPR rate of 54% in patients who had a median of 3 lines of prior therapy. Finally, the last arm of the STOMP study presented at ASH came from the lenalidomide arm of the study, which evaluated XPOVIO in combination with lenalidomide and low-dose dexamethasone in patients with both newly diagnosed and/or relapsed to refractory myeloma. For the 12 evaluable patients with relapsed or refractory disease who are lenalidomide naive, 1 patient achieved a complete response, 4 achieved a very good partial response and 6 additional patients achieved a partial response for an overall response rate of 92 -- 91.7% among the 12 lenalidomide-naive patients. All 7 efficacy evaluable patients with newly diagnosed myeloma achieved a response with an overall response rate of 100%, including deep remissions with 1 patient with a CR, 4 patients with a VGPR and 2 patients with a PR. The waterfall plot shows reductions of M-protein from baseline levels by more than 50% in the 15 patients with relapsed/refractory disease, and all patients were newly diagnosed with multiple myeloma. Importantly, the SRd regimen results in durable responses. And the swimmers' plot here shows among the 12 responders with the [ least ] PR with relapsed myeloma and 4 were still on treatment as of the date of cutoff, a PFS greater than 35 months with the longest patients staying on treatment for greater than 50 months -- correction, for approximately 50 months. The median PFS was assessed at 9.6 months, and 2 patients with newly diagnosed multiple myeloma are still on treatment as of the data cutoff, both having time on therapy greater than 24 months. [ Among ] the treatment-related adverse events in patients with relapsed myeloma were thrombocytopenia, neutropenia, nausea, fatigue and decreased appetite. In combination -- in summary, the combination is highly active with an overall response rate of 100% in newly diagnosed multiple myeloma and 92% in lenalidomide-naive patients with relapsed myeloma. These responses are durable with some patients staying on treatment greater than 2 to 3 years. Therefore, the all-oral combination of selinexor and lenalidomide and dexamethasone appear to be highly active, well tolerated and warrants further investigation. Having now reviewed the BOSTON subpopulation data analysis presented at ASH as well as our 3 STOMP presentations, I'd like to ask Dr. Berenson to take a few minutes to provide his thoughts and implications from this combination data.

Yes. Good morning or afternoon. So I think the results of this have been very impressive, particularly the kind of response rates that we're seeing with selinexor with 1 dex are incredibly impressive and the durability that we've seen with this. I really like the fact that we've learned how to use this drug; that the lower doses, which we're now using in clinic as well as a clinical trial, we're actually doing a trial with this triplet right now. We just got results, very nice results with seli-len on a -- we're doing a len-resistant trials to make sure that seli can overcome len resistance, and we're enrolling several others in the next 2 weeks. So we've been very encouraged by this. And we've been doing this off trial in the clinic for the last year, off label, of course, with good results as well. And I think the doses that we're using now, we're finding -- are highly effective without all the toxicity that we saw earlier with the 80 twice-weekly dosing. And we've been able to get in front of the GI and the nausea, the vomiting, toxicity, the anorexia with the antiemetics and then the olanzapine when we need it. In addition, I've been a big proponent in the BOSTON trial of giving less doses per month and less bortezomib per month, and we're seeing that reflected here with the reduction in the neuropathy than in terms of tolerability. In this trial, of course, the dose that was used was higher with the seli of 100 once a week. But again, we've seen a very good ability in this randomized Phase III of seli to boost the activity of the proteasome inhibitor, bortezomib and dexamethasone with, at the same time, a reduction nicely in the peripheral neuropathy. And this is certainly the biggest conundrum of using bortezomib, and I've been a firm proponent for now 20 years of using only 4 doses a month and actually using a little less drug. They use 1.3, which is the label dose in the study. But again, the durability here has been very good. And again, in the randomized Phase III, we saw the ability of this to be superior to bortezomib and dex alone. We are trying this drug in many other different applications off label. We certainly used it with multiple proteasome inhibitors, and we've used this now with multiple immunomodulatory agents. And I think that we're learning more how to use this. We are certainly interested in perhaps alternative lower dose schedule that may be more frequently dosed. We don't have any data on that clinically. We're just doing preclinical work with the support. Now Karyopharm will look at that possibility. But I think that as you get to learn more about this drug, you're more impressed with it and its ability to overcome resistance to a plethora of other drugs. And we certainly, again, have seen that in the clinic now, people who have seen Revlimid and been refractory. And I mean, really refractory, progressing right through it. You add seli and you can overcome the refractoriness without -- and I would chime in that the toxicity in terms of GI is one that we're seeing early, and we tend to get reduced over the first couple of cycles. It seems to be much better tolerated. But again, the lower dose, in general, has been well tolerated, too, even when combined with other agents that may have toxicities. So again, I think this is a drug that is a work in progress, that will have much use in combinations with lots of other drugs. I've also been impressed, of course, off label with the dara data. That certainly seems to boost dara activity quite a bit. We know that dara and dex alone has only a minority of patients respond. And yet in this early data, it looks promising. It's a much higher proportion than that here. So I think this will be another arrow in our quiver to knock out myeloma over the next few years.

Awesome. Thank you, Dr. Berenson. Appreciate that insight and perspective. I'd now like to switch gears a bit and talk about DLBCL and a subpopulation data from our SADAL study, which was presented at ASH and begins on Slide 56. The treatment landscape in 2020 for DLBCL patients has evolved significantly over recent years with the approval of new agents, including XPOVIO as well as CAR-T therapies. However, unfortunately, for the approximately 40% to 50% of patients not cured by their initial treatment with chemotherapy and rituximab, you'll have progressive disease. If they're fit or healthy enough, they often will go on to get another course of combination chemotherapy followed by stem cell transplant. Some patients may also go on and receive CAR-T cell therapies of their appropriate candidates following progression after second-line treatment. However, for those patients who are not fit enough for a transplant or CAR T-cell or for those whose disease progresses after their second-line treatment, these patients will then require a third-line treatment option and for many additional treatment options in the fourth line or later. This is the patient population with the greatest level of unmet need and currently for which XPOVIO recently have received FDA approval in June 2020. This approval was based on a SADAL study, which included 134 patients who have been previously through at least 2 prior multi-agent chemotherapies. We included both patients with GCB and non-GCB subtypes of DLBCL. Importantly, patients with either de novo or transformed disease arising from follicular lymphoma were enrolled in the study, and patients received a starting dose of 60 milligrams of selinexor twice weekly. The study demonstrated an overall response rate of 29%, including 13% of patients achieving a complete response and 16% achieving a partial response. Importantly, the median duration of response was 9.3 months, with nearly 40% of responders remaining on therapy and in responses for at least 6 months. The final data for the SADAL study was published in June of this year in The Lancet Haematology, and 2 important subpopulation analyses for the study were just presented at ASH 2020. The first analysis looked at the effective age on the efficacy and safety of XPOVIO. In this sub-analysis, there was no statistical difference in the response rate in patients less than 65 years old versus greater than 65, and the complete responses are 17.3% and 11%, respectively. Importantly, the responses are durable, and the median duration of response was similar at 9.7 months in patients less than 65 and 9.2 months in patients above 65 -- correction, in patients at least 65 years old. The incidence of treatment-related adverse events were comparable between both groups. Older patients had less thrombocytopenia and anemia, however, as expected, had more nausea, vomiting, fatigue and asthenia. Overall, the common grade 3 or higher adverse events were thrombocytopenia, nausea and fatigue, which can be again managed with dose reduction and supportive care. In summary, patients with relapsed large cell lymphoma, who are 65 years or older, have similar clinical benefit to those younger patients when treated with selinexor with comparable response rates, CR, progression-free survival, duration of response and safety profile. The second subpopulation analysis from the SADAL studies presented at ASH looked at the impact of renal function on the efficacy and safety profile of XPOVIO. Treatment with XPOVIO demonstrated a similar overall response rate in patients with baseline reduced creatinine clearance versus those patients with a normal creatine clearance. A complete response was observed in 21.6% of patients with a reduced creatine clearance and 10.3% of patients with a normal creatinine clearance. The median overall survival in patients with a reduced creatinine clearance was 7.8 months compared to 9.1 months in patients with normal creatinine clearance. The incidence of treatment-related adverse events was comparable between both groups. The most common grade 3 or higher -- treatment-related adverse events for patients with reduced versus normal creatinine clearance again were thrombocytopenia, nausea and fatigue, which can be managed again with supportive care and dose modifications. The side effects were similar regardless of renal function, with an increase in anemia, vomiting and diarrhea in patients with renal dysfunction. There was no clinically significant increase in treatment-related serious adverse events or adverse events leading to discontinuation in patients with reduced or normal creatinine clearance. In summary, XPOVIO showed similar response rates and tolerability in patients in relapsed refractory large cell lymphoma regardless of the renal function. This is important because XPOVIO is not metabolized or cleared by the kidneys and is approved for use in the patients with severe renal dysfunction. No dose adjustments are required in patients with renal dysfunction. Patients with renal dysfunction and DLBCL were treated with XPOVIO. Now with my review of the SADAL data presented at ASH complete, I'd like now to ask Dr. Pardee to review the data from the investigator-sponsored study in [indiscernible] Wake Forest, which is evaluating frontline selinexor in combination with chemotherapy in patients with AML. Dr. Pardee?

Good afternoon. Can everybody hear me okay?

Yes.

Great. So I'd like to just briefly take you through the data that I was able to present at ASH yesterday. We conducted a frontline trial of selinexor in addition to induction chemotherapy for patients with acute myeloid leukemia who are 60 years of age or older. It turns out that age is quite prognostic in AML. And adults, 60 years of age or older, do quite poorly. They are very poorly responsive to chemotherapy. And some meta-analyses have shown 5-year overall survivals for these patients of less than 10% with the study on the slide that's being displayed showing you a 6.6% of 5-year overall survival. So there's clearly a need for novel approaches. On the next slide, you'll see the schema for our study, which was a 1:3 randomization between the standard of care cytarabine and daunorubicin, the 7 plus 3 regimen versus the same 7 plus 3 regimen with the addition of a flat dose selinexor at 60 milligrams twice weekly for 3 weeks. As per the standard treatment for these patients, there is a day 14 bone marrow biopsy that's done to assess initial response to the chemotherapy. And if patients required a second induction cycle, it's an abbreviated cycle. We call that 5 plus 2. The control arm got the standard 5 plus 2. The treatment arm -- the experimental arm got 5 plus 2 with the addition again of selinexor at 60 milligrams twice a week for 3 weeks. On the next slide, responding patients could go on to get consolidation chemotherapy. Again, this is a standard practice. And so patients could get up to 4 cycles of high-dose cytarabine consolidation in the standard of care arm by itself and in the experimental arm in combination again with selinexor at a flat 60-milligram dose twice weekly for 3 weeks. And then finally, for patients on the experimental arm who had completed all planned consolidation therapy and were not moving on to an allogeneic stem cell transplant, there was an option for those patients to go on to maintenance therapy, which was a once-weekly dose of selinexor at 60 milligrams on days 1 and 8 out of every 21 days. And they would continue on that until relapse or unacceptable toxicity. The next slide shows you the demographics of the patients that we enrolled on our study. We had 7 patients enrolled in the standard of care arm and 21 patients enrolled in the selinexor arm. There were slight differences in age. So the median age of the standard of care arm was slightly older at 74 compared to the selinexor arm at 67. There was also an imbalance in gender. And so there were no male patients enrolled in the standard of care arm. So all 7 patients were female. This was a statistical accident as opposed to 21 -- excuse me, 12 of 21 patients on the selinexor arm being male. There was also an imbalance in good-risk karyotype. So one of the most prognostic things about AML is the recurrent chromosomal and molecular abnormalities that come with it. And the European Leukemia Network has developed a cytogenetic risk score. And so on the standard of care arm, almost half the patients, 43%, had good risk profile compared to only 19% on the selinexor arm. On the next slide is a brief review of the toxicities. Overall, the toxicities were quite comparable and were dominated by the standard of care chemotherapy. The 60-day mortality, which is a commonly used measure in AML for treatment -- acceptable toxicity of a regimen, was essentially the same, so 10% in the selinexor arm and 14% in the standard of care arm. However, there was about 1/3 of patients in the selinexor arm who had prolonged thrombocytopenia that was transfusion dependent in one patient. And then in terms of the AE that most commonly resulted in either holding or dose modifications of the selinexor was diarrhea. And then on the next slide is the efficacy summary. And so on that day 14 bone marrow that all patients underwent, half of the standard of care arm had residual disease demonstrable whereas only 10% of the selinexor arm did. In terms of the complete remission, 43% of patients on the standard of care arm achieved a complete remission compared to 76%. And then in AML, as is also the case in myeloma, there's a lot of use of minimal residual disease testing. And so for the 16 complete remissions in the selinexor arm, we were able to get minimal residual disease testing and 13 of 16 or 81% of those complete remissions were MRD negative. And then the overall response rate, which is complete remission plus complete remission with incomplete count recovery, 43% in the standard of care arm, 86% in the selinexor arm. And then another important readout for AML clinicians is the number of patients who are able to go on to get an allogeneic stem cell transplant. In the standard of care arm, that was only 1 patient out of the 7. In the selinexor arm, it was 7 patients out of the 21. The next slide is the overall survival analysis. Obviously, it's a small study. However, despite its small size, there was a statistically significant difference in median overall survival with the selinexor arm patients having a median survival of 839 days or about 27 months compared to the control arm, which had a median survival of 265 days or just about 9 months. And that was statistically significant. And then the progression-free survival also favored the selinexor arm at 558 days compared to 108 days. However, this was not statistically significant. And then finally, just to summarize -- so this combination of a fixed 60-milligram dose of selinexor in combination with 7 plus 3 was very active in our small study of fit elderly patients, and it provided a significant survival benefit despite the small size of the trial. toxicities were quite manageable with a similar 60-day mortality. And I feel pretty strongly actually that the 60-milligram dose is deserving of additional study in larger randomized trials. Thank you.

Thank you very much, Dr. Pardee. That was a terrific summary of your very important study, and we're very excited about it as I know you are. I should also add that the early preclinical data with AML showed that selinexor could selectively kill leukemic stem cells, at least in mouse models. And these cells typically are not dividing, which makes them much more difficult to kill with standard cytotoxic chemotherapies. Therefore, we may -- that may partly explain some of the excellent data that we're showing here. But overall, this is a super exciting study and, hopefully, can replicate with more patients. Before we move to the question-and-answer portion of our call, let me just briefly summarize all that we've reviewed this afternoon. First, it's become quite evident that XPO1 overexpression plays a key role in cancer development and proliferation. And of course, XPOVIO is the only approved drug that specifically targets XPO1. Next, inhibiting XPO1 either alone or, more importantly, in combination with other anticancer drugs continues to show significant potential across numerous tumor types. We also shared updates from the ASH presentations highlighting the subpopulation analyses from the BOSTON, STOMP and SADAL studies, which provide key insights regarding patient types and combination approaches that may yield the greatest patient benefit. And finally, Dr. Pardee has just presented new data from a combination study of XPOVIO and chemotherapy in a randomized type of study in an older fit population of patients who have AML and further demonstrate the potential utility of XPOVIO as a partner for other anticancer drugs. The results that he showed do support the potential future clinical development of XPOVIO to treat patients with AML. With that, I'd now like to turn the call over to the operator so we can begin our Q&A session. Operator?

[Operator Instructions] And the first question comes from Brian Abrahams with RBC Capital Markets.

I guess first off, on the STOMP data, obviously, selinexor is showing very nice activity across a variety of different combinations. And I'm curious what your expectations are for access in terms of reimbursement for use of XPOVIO in the earlier line setting within these combinations. Is this something that you think will be accessible once NCCN guidelines potentially include the BOSTON data? Or do you think that you'll need to complete these -- the next wave of studies, including the Phase III pom study in order to have -- enable physicians to have access?

Certainly. Thanks very much, Brian, for that question. If our current experience is any indication, there seems to be little pushback across the country for the use of XPOVIO even in combination, provided it's in the labeled patient population. The main focus that payers seem to have is to ensure that the patients who are receiving it have met the criteria, that is that they have penta-refractory disease. And in fact, in reality, they actually just ask if the patients have been treated with the major 5 drugs in myeloma before receiving XPOVIO, either with dexamethasone alone or in pretty much any combination. So right now, we are seeing reimbursement, and we do know that a substantial portion of patients currently receiving XPOVIO with penta-refractory disease are receiving it and are having it reimbursed in triplet combinations. If that's the guide, and certainly historically with other myeloma drugs that has been the guide, we anticipate that, assuming we have the approval for BOSTON which would be for a second-line indication, that we could see the use of XPOVIO certainly with Velcade easily, but we do expect that will translate into the use of XPOVIO with other agents provided the patients have had at least one prior therapy.

Got it. That's really helpful. And then it looks like across the STOMP studies, you're seeing responses with all the different combinations, but perhaps the proteasome combos maybe have slightly higher response rates versus the IMiD combos. I was wondering if you could comment on that. Is this just a matter of differences in populations across the studies? Or do you think that there's -- is there a hypothesis that there may continue to be, I guess, complementary mechanisms and synergy with the PIs or that, I guess, complementary talks might enable fuller dosing versus with the IMiDs?

Yes. I'll ask Dr. Berenson perhaps to comment on that. And then Dr. Shah will also -- can follow up. Jim?

Yes. I mean I guess in answer to the first question, we've used this drug now in many combinations. We've had no pushback from the insurance companies when using it in previously treated patients who failed a number of priors. They -- not all of them have failed the 5 in the registration. That's obviously off-label use. I'm certainly really curious about whether we can use these drugs effectively at lower doses. And that's what we've observed. And I think the combinations, you may unlock also different mechanisms of overcoming resistance. And we need to learn more about that. We're doing some studies now with these guys that are supporting with JAK inhibitors that we hope to get going soon. We've had some really provocative data, and there are some reasons that, that may be a good combination. It certainly seems across the board kind of like the old days when I worked with Michael first on Velcade 20 years ago, you're going to be able to combine this with about anything, and it's going to show activity. And in that regard, we've observed that with VENCLEXTA, for example, a non-myeloma approved drug. We're using it at like 20% of standard doses, and it's incredibly active when combined with dara and/or Velcade. And I think that's really good news for patients because they really want to get good quality. And as we brought this dose down, we're seeing that now. And we're seeing also our ability to manage the side effects has markedly improved. And in addition, most importantly, those side effects seem to go away over a number of weeks to several months. They don't seem to maintain themselves, which certainly is not true of some of the other myeloma drugs, particularly the immunomodulatory agents, which seem to get only worse over time.

Got it. That's really helpful. One more -- go ahead, sorry.

Sure. Go ahead. Jatin, do you have anything to add? [Technical Difficulty] Okay, we'll just -- I guess we may have had a technical problem. Brian, go ahead.

Sorry, sorry, my apologies.

Go ahead, sorry.

No, I was just saying I agree with what Dr. Berenson said. I mean I think we're seeing activity when we combine with both PIs and IMiDs. And even when we look in combination of pomalidomide or lenalidomide, you'll see that the response rates are really -- we're seeing them with other pom combinations or IMiD lenalidomide-based combinations. So we're seeing that synergistic activity [indiscernible] in combination with IMiD as well.

Got it. One more really quick one, if I could squeeze this in. On DLBCL, it looks like you're seeing effects both in older and younger patients. But I'm just curious, the trend towards slightly lower response rates and higher AEs amongst the older patients, how might that impact the positioning relative to CAR-T or some of the other NHL options that younger patients may have these days?

Jatin, can you take that, please?

Yes. No, absolutely. So I think when we look at the response rate, statistically, they are very similar between the patients that are older -- above the age of 65 and younger than 65. I think what this really gets to the point is that there are adverse events that we expect to see in older patients are there, but we can still treat older patients with selinexor. And they just need that dose reduction or dose modification. And when you provide those dose reductions and dose modifications for those patients, those side effects can be managed. I think it's still a very effective option even in older patients that are not going to be CAR-T cell candidates or transplant candidates.

And the next question comes from Maury Raycroft with Jefferies.

Congrats on all the progress. First one is just based on the SPd data. There, you're seeing good activity at 60 mg, but I think there was some dose reducing to 40 mg in the study. And in your Phase III design, it seems like you might use 40 mg. So can you talk more about what you see at 40 mg in patients and talk about -- talk more about the dosing strategy for the Phase III?

Dr. Shah, can you take that, please?

Absolutely. So the concept of dose reductions -- so -- yes, so as part of our discussions with the agency, we are exploring 40 milligrams. And so that cohort of patients enrolling is ongoing at this point in time. But I think even those patients who were dosed reduced from 60 to 40 milligrams, that concept of dose reductions is very, very common across all of our myeloma therapies. And so we think we're in the right spot with the right dose and right schedule. We're just doing a little bit of additional analysis at 40 milligrams. But I think that we're -- either 40 or 60 milligrams is what we'll be using at Phase III trial. And that concept of dose reduction is well established. That reduction is expected.

Got it. And maybe one follow-up for Dr. Berenson. So we talked some about the safety profile of selinexor in myeloma and how you're getting ahead of managing patients. I guess can you provide some more perspective on how the AE profile and overall patient experience looks for earlier line patients versus later line patients?

Yes. I mean I haven't used it really that early, so I can't specifically comment on an [ earlier line ] therapy, but I can tell you that it's like the early days of a lot of these drugs. We wanted to kind of get our hands around it. And I think that responses that we're seeing have been durable, and patients are able to go about their lives. I think the higher doses were not well tolerated, and we certainly are not using those anymore. But the once-a-week 60-milligram dose, which is kind of our stable, has been able to be combined with a multitude of different drugs, even some of the antibiotics that we've used many years ago with good efficacy. And these are patients that are multiply -- that multiple -- we treated with multiple PIs and multiple IMiDs. So they're not the usual suspects that we go upfront with. So they're very resistant. And that's impressive to me. I've always been the one as -- if your drug can overcome resistance or added to something else, we've been kind of the king of that, doing that kind of study. You got a drug, and that's what we're seeing with selinexor. We're seeing that it can do that. It's a whole new mechanism, and I'm excited to combine it with other drugs that may get repurposed, and we may be able to make seli work with them. And I know it's being tried with even things that's disparate, not on label obviously, as COVID now. And -- but in myeloma, I think the sky is the limit in terms of combining this thing now.

Congrats again.

And the next question comes from Jonathan Chang with SVB Leerink.

This is John Barrett on for Jonathan. Just a couple for me. For Dr. Berenson, to start, how do you view SVd as positioned in the second to fourth line multiple myeloma treatment landscape? And specifically, what percentage of your patients do you expect to use the SVd regimen in the second line if BOSTON were to be approved?

I don't think we know quite yet, and I'm certainly not using it second line today. I guess we'll see how the future comes. But I don't use a lot of IMiD upfront. So I think IMiDs are not well tolerated. So I tend to be an outlier. So I tend to use non-IMiD upfront and then add IMiD in second line. So then therefore, I'm more likely to bring this drug third or fourth line because of tolerability issues. And I think as I see more data, we may bring this even further up if we see good data combining this with other agents to overcome high-risk features. And we certainly know those guys don't do well. But I'm likely to use it third and fourth line. I would probably not much use it second line yet. I would say yet.

Got it. That's helpful. And for the Karyopharm team, what are the expected benchmarks? I know you mentioned them slightly, but if you could expand on that for the SPd 031 study and its time lines associated with starting enrollment and potential readout of that trial.

Jatin, do you want to take that?

Yes, absolutely. And so we're just finishing enrollment to the 40-milligram of selinexor combination with pomalidomide cohort. We'll meet with the agency to nail down exactly which dose we'll be moving forward and to move forward quickly if not. Everything else is in place for the Phase III protocol in terms of discussions with the agency, the protocol design and much of the operational work. So it's -- as soon as we complete enrollment of 40-milligram arm, then we should go to rapidly move into the Phase III study in early 2021.

Got it. And one more, if you don't mind, for Dr. Pardee or for the team. Given selinexor's mechanism of action, are there any mutational profiles that would make more sense to pursue in AML populations, for example, like TP53 mutation or others?

Yes. I'm happy to answer that one initially. So one particular recurrent mutation that comes to mind, and that's been studied a little bit in the preclinical setting, is NPM1 or nucleophosmin 1. This is a recurring mutation that happens in about 45% or so of AML patients, one of the most common, if not the most common mutation. And the pathophysiology involves the nuclear-cytoplasmic shuttling of the mutant protein that's prevented by selinexor at least in preclinical models. And so it's a natural potential biomarker for this approach. We did have 4 such patients in the selinexor arm, and all of them achieved a complete remission. So I think that would be an obvious sort of low-hanging fruit one to go after.

Yes, the company absolutely supports that. I think it is important to remember though that one of the unique things about XPOVIO is that by blocking XPO1, given that there's approximately 20 major tumor suppressors, that even in patients who have mutant disease, we believe we can help overcome that because you can go over and reactivate some of the nonmutated tumor suppressors. We saw such an effect in the BOSTON study. Dr. Shah mentioned that the hazard ratio for patients with chromosomal abnormalities, that is high-risk chromosomal abnormalities, was quite striking in the BOSTON study despite the fact that we were using such a low dose of Velcade in the selinexor/XPOVIO/Velcade/dex arm. And in particular, the most striking effect was actually in those patients that had lost a copy of the p53 tumor suppressor protein, suggesting that this drug really could overcome p53 deficiency at least in myeloma. And therefore, we would look at that in other diseases.

Very exciting. Congrats on the data.

Next question. And that comes from Peter Lawson with Barclays. All right then. I'll move on next to David Lebowitz with Morgan Stanley.

When you look forward to a potential BOSTON approval, given that the --it really hits the various lines, has been fairly fluid. Where do you ultimately see the XPOVIO-Velcade combination being used mostly? Do you expect it to be primarily in second line or in the third line usage?

Yes. This is Michael, and I'll start and then we can have Jatin and Dr. Berenson also comment. So the -- this will probably be fluid as it is for other disorders. One can imagine that if a patient received no Velcade in frontline, for example, if they got a daratumumab/Revlimid/dex-based regimen in frontline, it would make a lot of mechanistic sense to completely switch out the major mechanisms, that is to say, to move away from a CD38 and move away from an IMiD, which would leave you with a proteasome inhibitor and XPOVIO to be used in second line. Similarly, if a patient -- as Jatin mentioned, if a patient received a short course of Velcade as part of an RVd induction followed by transplant, upon relapse, we show that we had a very potent effect in the second line with XPOVIO/Velcade/dex, even in the second line following patients who use -- who had limited Velcade exposure in frontline. So I could see that being used there. I think for other patients who get full course RVd in frontline followed by, say, our maintenance, one could imagine that you would want to switch out the proteasome inhibitor on second line and maybe use a different type of regimen, including daratumumab in second line and then easily come back in third line to an XPOVIO-based regimen. So we do agree that somewhere in the second and third-line setting, it would make sense from a mechanistic switch point of view that this would be an effective way to treat myeloma. Jatin, do you want to comment? And Jim?

Yes, absolutely. I think in addition to that, as you mentioned, this is fluid. There's 2 other key areas where we see it being used kind of in earlier lines of therapy, and that includes in patients with high-risk disease. And I think those patients really need a different mechanism of action. And fundamentally, the way that XPOVIO works really gets to the root of high-risk disease. And so that's one area where we see the combination of bortezomib, and we know that PIs are the go-to therapy in high-risk disease. So it's really a nice combination in that setting. We can anticipate that being used in earlier lines of therapy for high-risk disease. And the second is in patients with the renal dysfunction as well, again, recognizing that bortezomib is not renally cleared or metabolized either, [ even then ] it's also very much a go-to drug in the setting of renal dysfunction. This combination makes -- is ideally suited for both high-risk patients as well as renal dysfunction. So we see that being used outside of that typical treatment paradigm and can be used early or second line.

Dr. Berenson?

Yes. I guess I would say that my likelihood it is used as third line or later, given my -- I do think that, that may change with time if we find this is highly effective in those high risk. So the high risk, we generally add Revlimid as the fourth drug and maybe we'll be adding seli. Maybe we'll be doing both. I would also chime in importantly that this drug is a pill, and that's a major advantage for patients today. They really don't want to come to clinic. And I think they've got used to not coming with the COVID outbreak. And I think that's a big home run that this drug can be taken orally unlike the PIs, except ixazomib, and certainly like the antibodies and certainly, the CAR-T cells. I mean ease of administration is a key as we have more chronicity to this disease. These patients are living now decades, not just years. So things have changed dramatically. They want to be able to go about their life. And taking this drug once a week makes that pretty easy.

And the next question is another attempt from Peter Lawson with Barclays.

Just, I guess, a follow-up for Dr. Pardee on the NPM1 mutants. If you kind of select -- if you suspect that seli could also work in the many MLL rearrangements as well. And for the NPM1 mutations, would that be selinexor in combination with something else if you'd have to pursue that?

So I -- the NPM1 mutation is just sort of the lowest-hanging fruit because the pathophysiology plays exactly into the administration of -- the mechanism of action, excuse me, of selinexor. But I would agree also with what was said right after that, which is that it is such a general mechanism. And my own research has shown that you need careful coordination between the nucleus and other various parts of the cell in order to optimally resist chemotherapy, and selinexor could interfere with that process in a wide variety of mutational backgrounds, including MLL-mutated disease. So MLL rearranged disease is known to suppress p53 signaling. And so I think you can envision that interrupting the intra-organelle communication in that situation in the face of chemotherapy would be advantageous. And I think that there's agents of many different mechanisms that would likely synergize with this mechanism of action. I know there's data out there with some 3 inhibitors and also with BCL-2 inhibition with venetoclax. So I think we're many years behind our myeloma colleagues in the use of this drug, but I have every reason to be just as excited about it.

Got you. And then just a follow-up question for Michael just around the next steps. I may have missed this, but for SKd and SK, what are the next steps there?

Yes. I'll turn that actually over to Jatin, please.

Yes, absolutely. So SKd and what's the second one, I'm sorry?

I guess SRd.

SRd. Okay. Perfect. Thank you. Just wanted to make sure I got the right combination. So with SKd, I mean I think you've seen the data with SKd. We think clearly that's an important combination that's highly active. So we're discussing various trials that are in exploration at this point in time with SKd. With SRd, I think that clearly, the data there shows high response rates both in len-naive patients in a relapse setting as well as in patients with newly diagnosed myeloma. And so we're under discussions right now. There's 2 ways of leveraging that information and the data. And one is, really, I think it speaks to the long-term tolerabilities that you see in a number of patients on for 2 and 3 years with selinexor and lenalidomide. And so that does then start to raise the question that can this combination be used as an all-oral therapy as a maintenance strategy, given the ability to have long-term durability and staying on therapy for long term really speaks to both the tolerability and effectiveness of that combination. So leveraging that strategy, we have an ongoing or just initiated IST, randomized Phase III study of lenalidomide versus lenalidomide plus selinexor as a maintenance strategy done by the Australian leukemia and lymphoma group. And so the SRd data, I think, you may leverage to really [ adopting ], exploring in the maintenance strategy, [ counting ] that's an ideal all-oral combination. We're also starting to explore other combinations in the upfront setting as well as IST studies looking to kind of build upon the SRd backbone. So to be -- that are ongoing at this point in time in this [ timing of ] development.

Got you. But maybe if I could sneak in another question -- a follow-up question for Dr. Pardee. For the NPM1 mutant patients, if you characterize the additional mutations that they may be harboring, just -- I know there's often an association with additional mutations of the NPM1s. So just curious about the additional mutations.

Yes, sure. So they tend to co-occur with the FLT3 mutations or other signaling pathway mutations like RAS. But then there are also associations with some of the chromatin-modifying mutations as well, like DNMT3A. It is, as I mentioned, one of the most commonly mutated genes in AML. So It has several other mutations that it pairs with. But I would say off the top of my head, those are probably the 2 most common, FLT3 and DNMT3A.

Do you know the mutational status of the patients you saw it responses with around the NPM1?

Yes. So we have a 42-gene panel that we got on all patients that were enrolled in that study. I don't have that -- I can't tell you off the top of my head what other mutations those 4 patients had.

And the next question comes from Ed White with H.C. Wainwright.

So Michael, this question is for you just to stay on AML. What are the next steps for the company in AML, if anything? Or are -- due to the size of the market, are you prioritizing the other potential indications and continuing with perhaps ISTs looking forward in AML?

Yes. Let me start, and I'll -- and then turn it over to Jatin. I think importantly, there's a huge unmet medical need as Dr. Pardee mentioned here, and we are really ecstatic about these results. It does look like we've -- that Dr. Pardee has figured out a way to appropriately dose selinexor/XPOVIO in combination with 7 and 3 chemotherapy. And if we could really make this kind of impact, we will find a way to move this forward. One of the other differences between this regimen and some of the others is it permits 2 things. First of all, the XPOVIO is used in consolidation, so it's not just the 1 or 2 cycles of induction therapy but also in consolidation. And many of the patients received consolidation therapy. And he's also exploring the use of maintenance therapy, which would substantially expand the duration of treatment for patients, particularly as MRD takes in more focus going forward. So we are focused on this. As you say, though, we have a lot going on, Ed, and we do need to prioritize. So in addition to expanding the size of his own trial, and we'll continue to do that, we are working closely with other groups. And I'll let Jatin talk a little bit about our CRADA with the NCI and some of the other plans we have to expand in AML. Dr. Shah?

Yes. Thank you so much, Michael. Appreciate it. Just to highlight the one point here that we do have an executed CRADA with the NCI and CTEP. One of the main areas of these can be with myeloid malignancies, specifically AML and MDS. And so that's going to be of significant interest and focus working with the cooperative groups and the NCI with selinexor in both AML and MDS. And so I think that's going to be our primary focus as we develop and both understand and explore this data and explore the next steps.

Thank you. And this concludes our question-and-answer session. I would like to turn the conference back over to Dr. Michael Kauffman for any closing remarks.

Yes. Thanks very much, everybody. It was a lot of data to go through. We really appreciate your attention and interest in XPOVIO, and we think this is just a continuation on what will become a more -- a bigger and bigger application of this unique oral therapy. Thanks very much, and we look forward to speaking with you in the near future. And special thanks to Doctors Pardee and Berenson for joining us today. Bye-bye.

Thank you. The conference has now concluded. Thank you for attending today's presentation. You may now disconnect your lines.