Hello, my name is Keith. 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 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 two 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 & Bone Cancer Research, and Dr. Timothy Pardee, Director of the 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 will 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 SADAL study, which was also presented at ASH. We are very fortunate, as I mentioned, to have two well-recognized experts in the fields of multiple myeloma and leukemia joining us on today's call. Dr. 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 two press releases detailing XPOVIO data presented at this year's annual ASH meeting. These releases, as well as a PDF copy of this presentation, 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 timelines, 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. 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. I'll now turn the call over to Dr. Michael Kauffman, Chief Executive Officer of Karyopharm.
Please can you hold the line. Dr. Kauffman has just disconnected. I will reconnect him.
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 three slides, and then we'll transition over to Dr. Shah shortly as Dr. Kauffman is dialing back in. 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 spanned 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 is playing a fundamental role in the proliferation of many cancers. This is where we'd like to begin, and before we actually move to the clinical data, which Dr. Shah will present for us.
Now, as many of you may know, there are five 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 anti-cancer drug whose primary activity is the activation of tumor suppressor proteins. There are about 20 of these proteins, including p53, BRCA1 and BRCA2, Rb, and the inhibitor of NF-κB called IκB, which are critical parts of each cell's own natural defense mechanism to detect cancerous DNA changes and prevent the generation of malignant cells.
In short, XPOVIO could direct a 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 six.
Yes. Thank you. I apologize. I was kicked out. Somebody obviously did not like me. Let me find slide six, 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 four graphs of XPO levels correlated with poor cancer prognosis for patients.
Yeah. As you can see from these four 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 room to present. The main point here is that over the past five years, it has become increasingly evident that the overexpression 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. 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 NF-κB signaling. Third, reduces c-Myc and other oncoprotein levels. 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. Due to the broad applicability of XPOVIO across different tumor types, you can see that on the next two 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 pomalidomide and dexamethasone compared to pomalidomide and dexamethasone alone, which, if successful, could offer a very compelling all-oral regimen for multiple myeloma patients in the future.
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. We're exploring a number of new trials which could start in 2021, including in lung cancer, melanoma, and colorectal cancer. 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 four 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 one or two of these highly active agents in combination with a steroid, such as dexamethasone, in each line of therapy. They're usually treated until their disease progresses. Physicians will 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 two drugs with distinct mechanisms and proven single-agent clinical activity, typically with the additional steroids.
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.
The fact that XPOVIO is typically given orally only once per week make it particularly interesting partner with other agents. Finally, we eagerly await a 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. 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?
Thank you, Michael. 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 investigated the 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 that have received one to three prior therapies. Throughout the remainder of today's presentation, I will refer to these two treatment regimens as SVd and VD, respectively. As you may recall, the top-line results from the 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. A number of post-hoc subgroup analyses were conducted on the BOSTON data and presented at ASH, which we'll review today.
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 was 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 have 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 to 77% in the SVd arm, and an improvement in the depth of response.
There was an increase in the complete and stringent complete response rate from 9.4% in the VD arm to 14.8% in the SVd arm. Furthermore, the use of bortezomib-based regimens is common in newly diagnosed multiple myeloma, especially in patients who go on to receive a stem cell transplant. We specifically looked at patients that received a bortezomib-based therapy prior to stem cell transplant and a long bortezomib treatment free 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 - 13.1 months in SVd with a hazard ratio of 0.58. Non-peripheral neuropathy AEs were higher within the SVd arms than the VD arms, but most of the AEs were reversible and treatable.
Thrombocytopenia was more frequent in patients in the SVd arm, as was anemia, fatigue, and decreased appetite, among others. Peripheral neuropathy, which is the most common and important cause of discontinuation of bortezomib and can cause chronic, even lifelong pain, was observed less frequently on the XPOVIO arm than the control arm. On a pre-specified endpoint 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-containing regimen had lower rates of neuropathy than the bortezomib comparator regimen. Once-weekly SVd is an active and convenient regimen, and if approved, may become an important treatment option for patients with relapsed or refractory myeloma who've 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 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 one prior treatment as well as patients with two or more prior treatments, the overall response rate was significantly higher in patients with SVd compared to the VD arm. In addition, the durability 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 were more frequent for both patient populations when treated with SVd as compared to VD. Grade 2 or peripheral higher neuropathy occurred significantly less frequently across all SVd subgroups compared to the VD groups. Consistent with previous subgroups, adverse events of Grade 3 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 supportive 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. This is particularly compelling with the ability to incorporate two new classes of therapies in patients progressing on lenalidomide, and therefore leveraging the common practice of class switching in myeloma. Regardless of prior treatment, SVd treatment led to significantly improved overall response rates and progression-free survival, with the highest PFS of 16.6 months seen in patients following first relapse. The next subgroup analysis from 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 subgroups except translocation 14;16, which was in the smallest subgroup.
Notably in patients with both one cytogenetic abnormality or patients with two 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 the 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 reported by the progression-free survival in a different subgroup of patients with high-risk cytogenetics. Patients with high-risk cytogenetics, including deletion 17p, need new options with a novel mechanism of action. XPOVIO's novel mechanism, reactivating tumor-suppressive proteins and reducing levels of oncoproteins, may be particularly suited for patients with high-risk multiple myeloma. In non-peripheral neuropathy, adverse events were higher with SVd, most of these adverse events were reversible. The final subgroup analysis in the BOSTON study presented at ASH evaluated patients by both age and frailty. Similar to younger patients, the overall response rate was significantly higher with SVd treatment in patients who were 65 and older. SVd was also associated with 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. Regardless of whether the patients were 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 is 0.69 was the same for both fit and frail patients. A progression-free survival for 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 incidence 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 incidence 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 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. With my review of the data from the BOSTON study now complete, I will review the key data from the three 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 in patients with relapsed myeloma. The first arm of the study I'll discuss is from the combination arm with pomalidomide, otherwise known as pom, and low-dose dexamethasone, or SPd. Which is highlighted in the oral presentation today. Out of the 65 patients enrolled, 60 were deemed evaluable for efficacy. Among the 46 patients who were POM-naive or not refractory to pomalidomide, the response rate was 54%. Among the patients whose disease is pomalidomide refractory, the overall response rate was 36%. Note that with using the recommended phase II dose of selinexor 60 mg once weekly and pom 4 mg, the response rate was 60%. The waterfall plots that are seen below highlight the 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 were POM-naive or who did 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. Common non-hematologic side effects included nausea, fatigue, decreased appetite, weight loss, and diarrhea. Most of the non-hematologic side effects were low-grade, and all of 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 pre-treated myeloma.
The recommended phase II dose of selinexor 60 mg, pomalidomide 4 mg, and dexamethasone 40 mg, all given once weekly, with pomalidomide given days one through 21. The all-oral SPd combination was very active and produced responses which were durable, with a response rate of 60% at the recommended phase II dose. 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, IMiD, and 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. 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 evaluating XPOVIO in combination with carfilzomib and dexamethasone, or SKd. SKd treatment resulted in deep responses in heavily pre-treated patients, including 24 efficacy-evaluable patients. Among these 24 efficacy-evaluable patients, five patients achieved a complete response, eight patients achieved a very good partial response, and five achieved a partial response. The overall response rate was 75%. 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 five out of the 18 responders were still on treatment as of the data cutoff, with the longest patient staying on the treatment for 25 months. Common treatment-related hematologic adverse events included thrombocytopenia and anemia.
Common non-hematologic adverse events included nausea, fatigue, decreased appetite, and weight loss, with the vast majority of these being either Grade 1 or 2. No deaths due to adverse events were reported, and all of the adverse events, including 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 is once-weekly selinexor 80 mg, once-weekly carfilzomib 56 mg per meter squared, and dexamethasone 40 mg. This combination is active and durable with a response rate of 75%, with deep responses and a greater than VGPR rate of 54% in patients with a median of three 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 refractory myeloma. For the 12 evaluable patients with relapsed or refractory disease who were lenalidomide- naive, one patient achieved a complete response, four achieved a very good partial response, and six additional patients achieved a partial response for an overall response rate of 91.7% among the 12 lenalidomide- naive patients.
All seven efficacy-evaluable patients with newly diagnosed myeloma achieved a response, with an overall response rate of 100%, including deep remissions with one patient with a CR, four patients with a VGPR, and two patients with a PR. The waterfall plot shows reductions of M protein from baseline levels by more than 50% in 15 patients with relapsed refractory disease, and all patients with newly diagnosed multiple myeloma. Importantly, the SRd regimen results in durable responses. The swimmers plot here shows among the 12 responders with a linked PR with relapsed myeloma, and four were still on treatment as of the data cutoff, a PFS greater than 35 months, with the longest patient staying on treatment for greater than 50 months. Correction, for approximately 50 months.
The median PFS was assessed at 9.6 months, with two patients with newly diagnosed multiple myeloma are still on treatment as of the data cutoff, both having time on therapy greater than 24 months. Common treatment-related adverse events in patients with relapsed myeloma were thrombocytopenia, neutropenia, nausea, fatigue, and decreased appetite. 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 two to three years. Therefore, the all-oral combination of selinexor, 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 the three STOMP presentations, I'd like to ask Dr. Berenson to take a few minutes to provide his thoughts and implications from this combination data.
Yeah. Good morning or afternoon. I think the results of this have been very impressive, particularly the kind of response rates that we're seeing with selinexor, with len/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 selinexor/len. We're doing a len-resistant trial just to make sure that selinexor can overcome len resistance, we're enrolling several others in the next two weeks. We've been very encouraged by this. We've been doing this off trial in the clinic for the last year, off-label of course, with good results as well.
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. 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 a reduction in the neuropathy that in terms of tolerability. In this trial, of course, the dose that was used was higher with the selinexor at 100 mg once a week.
Again, we've seen a very good ability in this randomized phase III of selinexor to boost the activity of the proteasome inhibitor bortezomib and dexamethasone, with at the same time a reduction nicely in the peripheral neuropathy. This is certainly the biggest conundrum of using bortezomib, and I've been a firm proponent for now 20 years of using only four doses a month and actually using a little less drug. They use 1.3, which is the label dose in this study. Again, the durability here has been very good. 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've certainly used it with multiple proteasome inhibitors, and we've used this now with multiple immunomodulatory agents.
I think that we're learning more how to use this. We are certainly interested in perhaps alternative lower dose schedules that may be more frequently dosed. We don't have any data on that clinically. We're just doing pre-clinical work with the support now of Karyopharm to look at that possibility. 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. We certainly, again, have seen that in the clinic now. People who've seen Revlimid and been refractory, and I mean really refractory, progressing right through it. You add selinexor and you can overcome the refractoriness without. I would chime in that the toxicity in terms of GI is one that we're seeing early, and we tend to see it get reduced over the first couple of cycles.
It seems to be much better tolerated. Again, the lower dose in general has been well-tolerated, too, even when combined with other agents that may have toxicities. 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. 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 the perspective. I'd now like to switch gears a bit and talk about DLBCL and the 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%-50% of patients not cured by their initial treatment with chemotherapy and rituximab, who 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 to receive CAR T-cell therapy if they're appropriate candidates following progression after second-line treatment.
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 received FDA approval in June 2020. This approval was based on a SADAL study, which included 134 patients who had been previously treated with at least two prior multi-agent chemotherapies, and 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 mg 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 six months. The final data for the SADAL study was published in June of this year in The Lancet Haematology, and two important subpopulation analyses for the study were just presented at ASH 2020. The first analysis looked at the effect of 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. The complete response rates were 17.3% and 11%, respectively.
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 at least 65 years old. The incidence of treatment-related adverse events were comparable between both groups. Older patients had less thrombocytopenia and anemia, 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 reductions and supportive care. 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 response, and safety profile.
The second subpopulation analysis from the SADAL study 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 normal creatinine clearance. A complete response was observed in 21.6% of patients with a reduced creatinine 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 event 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 a reduced or normal creatinine clearance. In summary, XPOVIO showed similar response rates and tolerability in patients in relapse/refractory large cell lymphoma, regardless of their renal function. This is important because XPOVIO is not metabolized or cleared by the kidneys and is approved for use in patients with severe renal dysfunction. No dose adjustments are required in patients with renal dysfunction and DLBCL who are treated with XPOVIO.
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 sponsor study he's leading at Wake Forest, which is evaluating frontline selinexor in combination with chemotherapy in patients with AML. Dr. Pardee?
Hey, good afternoon. Can everybody hear me okay?
Yes.
Great. 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, adults 60 years of age or older do quite poorly. They are very poorly responsive to chemotherapy. Some meta-analyses have shown five-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% five-year overall survival. 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 + 3 regimen, versus the same seven plus three regimen with the addition of a flat dose selinexor at 60 mg twice weekly for three 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. If patients required a second induction cycle, it's an abbreviated cycle, we call that 5 + 2. The control arm got the standard 5 + 2. The experimental arm got 5 + 2 with the addition, again, of selinexor at 60 mg twice a week for three weeks. On the next slide, responding patients could go on to get consolidation chemotherapy. Again, this is a standard practice.
Patients could get up to four 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-mg dose twice weekly for three weeks. 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 mg on days one and eight out of every 21 days. 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 seven patients enrolled in the standard of care arm and 21 patients enrolled in the selinexor arm.
There were slight differences in age, 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. There were also no male patients enrolled in the standard of care arm, so all seven patients were female. This was a statistical accident as opposed to 12 of 21 patients on the selinexor arm being male. There was also an imbalance in good risk karyotype. One of the most prognostic things about AML is the recurrent chromosomal and molecular abnormalities that come with it. The European LeukemiaNet has developed a cytogenetic risk score. 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. There was about 1/3 of patients in the selinexor arm who had prolonged thrombocytopenia that was transfusion dependent in one patient. In terms of the AE that most commonly resulted in either holding or dose modifications of the selinexor was diarrhea. On the next slide is the efficacy summary. 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%. In AML, as is also the case in myeloma, there's a lot of use of minimal residual disease testing. 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. 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. 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 one patient out of the seven.
In the selinexor arm, it was seven 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 nine months. That was statistically significant. The progression-free survival also favored the selinexor arm at 558 days compared to 108 days. However, this was not statistically significant. Finally, just to summarize, this combination of a fixed 60 mg dose of selinexor in combination with 7 + 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. I feel pretty strongly, actually, that the 60 mg 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. These cells typically are not dividing, which makes them much more difficult to kill with standard cytotoxic chemotherapies. Therefore, that may partly explain some of the excellent data that we're shown here. 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.
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. 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.
I'd now like to turn the call over to the operator so we can begin our Q&A session. Operator?
Yes. Thank you. We will now begin the question and answer session. To ask a question, you may press star, then one on your touchtone phone. If you are using a speakerphone, please pick up the handset before pressing the keys. To withdraw your question, please press star, then two. At this time, we will pause momentarily to assemble the roster. The first question comes from Brian Abrahams with RBC Capital Markets.
Hey, guys. Thank you so much for hosting this call, thanks for taking my questions. I guess first off, on the STOMP data, obviously selinexor is showing very nice activity across a variety of different combinations. 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 the next wave of studies, including the phase III STOMP study, in order to 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. In fact, in reality, they actually just ask that the patients have been treated with the major five drugs in myeloma before receiving XPOVIO, either with dexamethasone alone or in pretty much any combination. Right now, we are seeing reimbursement, and we do know that a substantial portion of patients currently receiving XPOVIO and with penta-refractory disease are receiving it and are having it reimbursed in triplet combinations.
If that's the guide, 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. 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. 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 a hypothesis that there may continue to be complementary mechanisms and synergy with the PIs, or that complementary tox might enable fuller dosing versus with the IMiDs?
Yeah. I'll ask Dr. Berenson perhaps to comment on that, and then Dr. Shah also can follow up. Jim?
Yeah. 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've filled a number of priors. Not all of them have filled the five 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, that's what we observed. I think that combinations, you may unlock also different mechanisms of overcoming resistance, 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, there's some reasons that that may be a good combination.
Certainly, it seems across the board, kind of like the old days when I worked with Michael first on Velcade 20 years ago, that you're going to be able to combine this with about anything, it's going to show activity. In that regard, we've observed that with Venclexta, for example, a non-myeloma-approved drug, but we're using it at 20% of standard doses, and it's incredibly active when combined with Darzalex and/or Velcade. I think that's really good news for patients because they really want to get good quality. 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. 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.
Jatin-
Go ahead, sorry.
Sure, go ahead. Jatin, anything to add? Okay. I guess we may have had a technical problem. Brian, go ahead.
Oops, sorry. Sorry.
One more quick-
My apologies.
Go ahead, sorry.
I was going to say I agree with what Dr. Berenson said. I think we're seeing activity when we combine with both PIs and IMiDs. Even when you look in combination with pomalidomide or lenalidomide, you'll see that the response rates are we're seeing those other POM combinations or the IMiD lenalidomide-based combinations. We're seeing that synergistic activity or additive activity in combination with IMiD as well.
Got it. One more really quick one, if I could squeeze this in.
Yeah.
On DLBCL, it looks like you're seeing effects both in older and younger patients. 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? Thanks.
Jatin, can you take that, please?
Yeah, no, absolutely. I think when we look at the response rates, statistically, they're 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 the adverse events that we'd expect to see in these older patients are there, but we can still treat older patients with selinexor, and they just need that dose reduction or dose modification. When you provide those dose reductions or dose modifications for those patients, those side effects can be managed. I think it's still a very effective option, even in our older patients that are not going to be CAR T candidates or transplant candidates.
Great. Thanks again.
Thank you. The next question comes from Maury Raycroft with Jefferies.
Hi, everyone. Congrats on all the progress, thanks for taking my questions. First one is just based on the SPd data. You're seeing good activity at 60 mg, I think there was some dose-reducing to 40 mg in the study. In your phase III design, it seems like you might use a 40 mg seli. Can you talk more about what you see at 40 mg in patients, and talk more about the dosing strategy for the phase III?
Dr. Shah, can you take that, please?
Absolutely. The concept of dose reductions, yes, as part of our discussions with the agency, we are exploring 40 mg. That cohort of patients enrolling is ongoing at this point in time. I think even those patients who have dose reduced from 60 mg - 40 mg, that concept of dose reductions is very, very common across all of our myeloma therapies. We think we're in the right spot with the right dose and the right schedule. We're just doing a little bit of additional analysis of 40 mg, but I think that either 40 mg or 60 mg is what we'll be using at phase II trial. That concept of dose reductions is well-established, so that reduction is expected.
Got it. Maybe one follow-up for Dr. Berenson. We talked some about the safety profile of selinexor 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?
Yeah. I haven't used it really that early, so I can't specifically comment on earliest line therapy, but I can tell you that it's like the early days of a lot of these drugs. We've learned 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. The once-a-week 60-mg 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 ceased many years ago with good efficacy. These are patients that have multiply been multiply treated with multiple PIs and multiple IMiDs. They're not the usual suspects that we go up front with. They're very resistant, and that's impressive to me. I've always been the one is, if your drug can overcome resistance or add it 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 selinexor work with them.
I know it's being tried with even things that's disparate, not on label, obviously, is COVID now. In myeloma, I think the sky's the limit in terms of combining this thing now.
Got it. Thanks for taking my questions, and congrats again.
Sure.
Thank you. The next question comes from Jonathan Chang with SVB Leerink.
Hi, everyone. Thanks for taking my questions. This is John Barrett on for Jonathan. Just a couple from me. For Dr. Berenson to start, how do you view SVd as positioned in the second to fourth-line, multiple myeloma treatment landscape? 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. I'm certainly not using it second-line today. I guess we'll see how the future comes. I don't use a lot of IMiD up front. I think IMiDs are not well-tolerated. I tend to be an outlier. I tend to use not IMiD up front and then add IMiD second-line. Therefore, I'm more likely to bring this drug third or fourth-line because of tolerability issues. 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. We certainly know those guys don't do well. 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. 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 timelines associated with starting enrollment and potential readout of that trial.
Jatin, you want to take that?
Yeah, absolutely. We're just finishing enrollment to the 40-mg of selinexor combination with pomalidomide cohort. We'll meet with the agency to nail down exactly which dose we'll be moving forward and then report quickly from that. 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. As soon as we complete enrollment of the 40-mg arm, we should be able to rapidly move into the phase III study early 2021.
Got it. 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. 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. The pathophysiology involves the nuclear cytoplasmic shuttling of the mutant protein that's prevented by selinexor, at least in preclinical models. It's a natural potential biomarker for this approach. We did have four such patients in the selinexor arm, and all of them achieved a complete remission. I think that would be an obvious sort of low-hanging fruit one to go after.
Awesome. Thanks for the answers.
I think 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 non-mutated 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.
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. Therefore, we would look at that in other diseases.
Very exciting.
Next question.
Thanks, congrats on the data.
Yes.
Thank you.
Thank you. That comes from Peter Lawson with Barclays. Please go ahead, Mr. Lawson. Your line is live. I'll move on next to David Lebovitz with Morgan Stanley.
Thank you very much for taking my question. When you look forward to a potential BOSTON approval, given that the really hits the various lines 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 third-line usage?
Yeah, this is Michael. I'll start, then we can have Jatin and Dr. Berenson also comment. This will probably be fluid as it is for other disorders. One can imagine that if a patient received no Velcade in front line, for example, if they got a daratumumab Revlimid dex-based regimen in front line, 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 had limited Velcade exposure in front line. I could see that being used there. I think for other patients who get full course RVD in front line followed by, say, R 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.
We do agree that somewhere in the 2 line and 3 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?
Yeah, absolutely. I think in addition to that, as you mentioned, this is fluid. There's two other key areas where we see it being used in earlier lines of therapy, and that includes in patients with high-risk disease. I think those patients really need a different mechanism of action. Fundamentally, the way that XPOVIO works really gets to the root of high-risk disease. That's one area where we see this in combination with bortezomib, and we know that PIs are the go-to therapy in high-risk disease. It's a really nice combination in that setting. We can anticipate that being used in earlier lines of therapy for high-risk disease. The second is in patients with renal dysfunction as well. Again, recognizing that bortezomib is not renally cleared or metabolized either, it is also very much a go-to drug in this setting of renal dysfunction.
This combination is ideally suited for both high-risk patients as well as renal dysfunction. We see that being used outside of the typical treatment paradigm and can be used early or second-line. Dr. Berenson?
Thanks, Dr. Berenson. Thank you for taking my questions.
I guess I would say that my likelihood is to use it third-line or later given my way I do things, but that may change with time if we find this is highly effective in those high risks. The high risks, 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 gotten used to not coming with the COVID outbreak. 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. The ease of administration is a key as we have more chronicity to this disease.
These patients are living now decades, not just years. 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.
Thank you, Jim.
Thank you, Jim. That's great.
Thank you. The next question is another attempt from Peter Lawson with Barclays.
Hi. Thanks for taking my questions. Just I guess a follow-up for Dr. Pardee on the NPM1 mutants. If you suspect that seli could also work in the Menin-MLL rearrangements as well, and for the NPM1 mutations, would that be selinexor in combination with something else you'd have to pursue that?
The NPM1 mutation is just sort of the lowest hanging fruit because the pathophysiology plays exactly into the mechanism of action of selinexor. 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. MLL rearranged disease is known to suppress p53 signaling, I think you can envision that interrupting the intra-organelle communication in that situation in the face of chemotherapy would be advantageous. 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 FLT3 inhibitors and also with BCL-2 inhibition with venetoclax. 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.
Gotcha. Thank you. Just a follow-up question for Michael, just around the next steps. I may have missed this, for SKd and SRd, what are the next steps there?
Yeah, I'll turn that actually over to Jatin, please.
Yeah, absolutely. You said SKd, and what's the second one? I'm sorry.
I guess SRd.
SRd. Okay, perfect. Thank you. I just wanted to make sure I got the right combination. With SKd, and I think you've seen the data with SKd, we think clearly that's an important combination that's highly active. 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 naive patients in a relapse setting as well as in patients with newly diagnosed myeloma. We're under discussions right now. There's two ways of leveraging that information and the data. One is really, I think it speaks to the long-term tolerability. You see a number of patients on for two and three years with Phelie and selinexor and lenalidomide.
That does then start to raise the question of 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. 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 Australasian Leukaemia & Lymphoma Group. The SRd data I think can be leveraged to really in the upfront setting exploring it in a maintenance strategy because I think 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. To be better ongoing at this point in time in this clinical development.
Gotcha. Thank you. Maybe if I could sneak in another question, a follow-up question for Dr. Pardee. The NPM1 mutant patients, if you'd characterize the additional mutations they may be harboring. Just again, I know there's often an association with additional mutations for the NPM1, just curious.
Yeah.
About the additional mutations.
Sure. They tend to co-occur with the FLT3 mutations or other signaling pathway mutations like RAS. 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. I would say off the top of my head, those are probably the two most common are FLT3 and DNMT3A.
Do you know the mutational status of the patients you saw responses with around the NPM1?
Yes. 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 four patients had.
Thank you. The next question comes from Edward White with H.C. Wainwright.
Good afternoon, thanks for taking my question. Michael, this question is for you just to stay on AML. What are the next steps for the company in AML, if anything, or due to the size of the market, are you prioritizing the other potential indications and continuing with perhaps ISTs looking forward in AML? Thanks.
Yeah. Let me start 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 that Dr. Pardee has figured out a way to appropriately dose selinexor, XPOVIO, in combination with 7 + 3 chemotherapy. 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 two things. First of all, the XPOVIO is used in consolidation, so it's not just the one or two cycles of induction therapy, but also in consolidation, and many of the patients receive consolidation therapy.
He's also exploring the use of maintenance therapy, which would substantially expand the duration of treatment for patients, particularly as MRD takes on more focus going forward. We are focused on this. As you say, though, we have a lot going on, Ed, and we do need to prioritize. In addition to expanding the size of his own trial, and we'll continue to do that, we are working closely with other groups. 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?
Yeah. Thanks so much, Michael. Appreciate it. Let me just highlight the one point here that we do have an executed CRADA with the NCI and the CTEP. One of the main keys or areas of view can be with myeloid malignancies, specifically AML and MDS. That's going to be a significant area of interest and focus working with the cooperative groups and the NCI with selinexor in both AML and MDS. I think that could be our primary focus as we develop and both understand and explore this data and explore the next steps.
Okay. Thank you.
Thank you. This concludes our question and answer session. I would like to turn the conference back over to Dr. Michael Kauffman for any closing remarks.
Yeah. Thanks very much, everybody. It was a lot of data to go through. We really appreciate your attention and interest in XPOVIO. We think this is just a continuation on what will become a bigger and bigger application of this unique oral therapy. Thanks very much. We look forward to speaking with you in the near future. Special thanks to Doctors Pardee and Berenson for joining us today. Bye-bye.
Thank you. The conference is now concluded. Thank you for attending today's presentation. You may disconnect your lines.