Good morning. My name is Thea, and I will be the conference operator today. At this time, I would like to welcome everyone to the Karyopharm Therapeutics Virtual Investor Day. If you would like to ask a question during today's conference call, please press star and the number One. If you would like to withdraw the question, press the pound key. As a reminder, today's call is being recorded. I would now like to turn the call over to Jason Finkelstein of Argot Partners. Jason?
Good morning, everyone, and thank you all for joining us today for Karyopharm Therapeutics Investor Day. My name is Jason Finkelstein, and my firm, Argot Partners, handles investor relations for Karyopharm. Immediately following our call today, the slides that are being presented will be made available on the investor relations section of Karyopharm's website. Before we begin, I'd like to remind you that various remarks we will make today constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995, as outlined on slide two. 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 relating to the commercialization of XPOVIO and eltanexor, our 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 other filings that 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. It is now my pleasure to introduce Richard Paulson, President and CEO of Karyopharm. Richard?
Thank you, Jason, and good morning, everyone. We are delighted that you're able to join us today for Karyopharm Therapeutics Investor Day. On behalf of all the panelists here today, I would like to thank you for taking the time to join us, to hear about our strategic priorities, our scientific capabilities, our prioritized pipeline, our views on the treatment landscape, and the commercial opportunities for our company over the near term. As you all know, today is the first Investor Day that we are hosting since I was named CEO in May. I've had the opportunity to speak with many of you. I've enjoyed hearing your perspectives on the company, and these discussions have helped inform some of the topics that we'll be presenting today. I'm joined today by six recognized thought leaders in the areas of multiple myeloma, endometrial cancer, myelodysplastic syndromes, and myelofibrosis.
Please join me in welcoming Dr. Rafael Fonseca from the Mayo Clinic in Phoenix, Arizona. Dr. Cristina Gasparetto from Duke University Medical Center, Dr. Vicky Makker from Memorial Sloan Kettering Cancer Center, Dr. Robert Coleman from US Oncology Research, Dr. Guillermo Garcia-Manero from MD Anderson Cancer Center, and Dr. Srinivas Tantravahi from the University of Utah. I am also joined today by several members of the Karyopharm management team, including Dr. Sharon Shacham, our Chief Scientific Officer and Co-founder, Dr. Jatin Shah, our Chief Medical Officer, Sohanya Cheng, our Senior Vice President of Sales and Commercial Operations, Stephen Mitchener, our Chief Business Officer, and Mike Mason, our Chief Financial Officer. Before we get started, let me provide you with a brief outline of what we'll be covering today. First, I'm gonna spend a few minutes discussing our strategic priorities and corporate vision.
Sharon will provide some background on our two lead assets, selinexor and eltanexor. We will then move into in-depth discussions around each of our four core development programs, including the treatment landscape and commercial opportunities. These sections will be led by Jatin and Sohanya, who will be accompanied by the guest speaking physicians that specialize in caring for patients with these four types of cancer. Each of these discussions will be immediately followed by a dedicated Q&A session, where you are welcome to address questions to our management team and the physicians that have joined us today. Stephen will discuss our global partnerships, and Mike will discuss our financial highlights. I will then provide an overview of our upcoming milestones and some closing remarks and open the call for a final Q&A session. Our goal is to wrap up by 12:30 P.M.
With that introduction, let's discuss our strategy and vision. Since joining, my aim has been on execution to ensure we are providing the highest quality customer engagement and are operating effectively to achieve our milestones and create value for both patients and shareholders. At Karyopharm, we are passionately driven in our mission to positively impact patient lives and defeat cancer. Our foundation is in our science. We are the global leader with our first-in-class science technology. As we look ahead to 2022 and over the near term, there are five key pillars that will be driving our underlying value, providing opportunity for what we believe will be substantial future growth. First, we are successfully building upon our existing U.S. multiple myeloma foundation as we continue to expand the breadth and depth of XPOVIO's use with earlier line patients.
We expect to continue to grow sales in our approved U.S. indications, establishing XPOVIO as a new effective modality that can become the standard of care in second-line plus post anti-CD38. We will continue to expand, working toward approvals in additional multiple myeloma settings where we have achieved clinical proof of concept and where we believe patients are most in need of new treatment options. With our global partners, we will increasingly bring XPOVIO to patients worldwide. In the near term, we are expecting the European CHMP to complete its review of the selinexor MAA in second-line plus and issue an opinion during the first half of 2022. Second, we are focused and working tirelessly for the potential to bring selinexor to patients with endometrial cancer, as there are no approved treatments for maintenance therapy following chemotherapy in any line of treatment.
We are looking forward to reporting top-line results from the phase III SIENDO study now in early 2022. Assuming the data are positive, endometrial cancer, which is the most common form of gynecological cancer, could be Karyopharm's first marketed solid tumor indication. Third, we are excited to unveil today our newly focused clinical pipeline that is being consciously and strategically focused on target cancers with high unmet need. Our science enables us to make a big difference in the lives of patients and with a high probability of success. To that end, we have rapidly initiated new phase II trials in myelodysplastic syndromes and myelofibrosis, where we believe we have the potential to achieve approvals over the next three to four years.
Fourth, we believe we have the right people in place and a strong leadership team with an exceptional ability to achieve both scientific and commercial excellence to execute on our key corporate objectives. Fifth, and finally, to support our strategic and focused growth plan, we are well capitalized to fund our operations with a cash runway into the middle of 2023. In order to achieve success, our strategic imperatives are centered around three core tenets. Patients, science, and people. As I mentioned earlier, we direct our resources toward cancers with high unmet need, a high probability of success, and where we can achieve commercial excellence. We do this by being a global leader with our first-in-class science technology that has now been approved in multiple types of hematological cancers, and we look forward to expanding these achievements soon into solid tumors.
Of course, it's our dedicated and passionate people who foster our high-performing entrepreneurial culture. They bring unparalleled scientific creativity to help multitudes of patients across the globe. We strive to be a top talent destination, and we have attracted world-class partners that we believe will help us achieve our goal of maximizing the global opportunity for all Karyopharm assets. It is with these product profiles, our breadth of data, along with our strategic vision and imperatives that has led us to the four core programs which we're here to discuss with you today, multiple myeloma, endometrial cancer, myelodysplastic syndromes, and myelofibrosis. That brings us to our newly focused pipeline, where we are targeting these four core areas of high unmet need. You will see here that we are building on our three approved XPOVIO indications through targeted research in four core areas.
The nearest term of these programs is our phase III SIENDO study, evaluating selinexor in the maintenance setting in patients with endometrial cancer, where top-line results are now expected early next year. We are also advancing four additional clinical studies for myelodysplastic syndromes and myelofibrosis. Finally, we continue to expand in multiple myeloma. The rest of the team will provide more detail around these programs in just a few minutes. Now I'd like to turn it over to Sharon, our co-founder, to provide some background on our SINE compounds. Sharon?
Thank you, Richard. Since its founding in 2008, Karyopharm has been the scientific leader in selective inhibition of nuclear export or SINE technology, which was designed to address the fundamental mechanism of oncogenesis, nuclear export dysregulation. One way cancers evade detection from the body's own defense mechanism is by removing tumor suppressor protein from the individual nucleus via an overproduction of a specific chaperone protein called exportin 1 or XPO1. Karyopharm's novel SINE compound, selinexor and eltanexor, have been designed to inhibit XPO1, which may restore the cell's core natural anticancer defenses. As the first and only approved nuclear export inhibitor, selinexor attacks the foundation of cancer. Our SINE compounds are designed to reactivate the tumor suppressor protein and have the potential for activity across a wide range of cancers.
We have studied them in multiple types of cancers to enable us to now utilize our breadth of data to focus on four key areas over the near term. We will also continue focused signal-seeking activities to identify future opportunities for our SINE technology to benefit patients over the mid and longer term. Selinexor and eltanexor are both promising SINE compounds that offer different advantages. Let's talk a bit about the differentiation between the two. Selinexor is the only approved protein class SINE compound that can be dosed once or twice a week. Selinexor is now approved in the U.S. and many other countries for multiple myeloma and diffuse large B-cell lymphoma. Last week, we announced the completion of enrollment in SIENDO, our phase III study of selinexor in patients with endometrial cancer.
Looking ahead, we are exploring the potential to use selinexor in other solid tumors and hematologic cancers, and believe there is a strong rationale for combining selinexor with immuno-oncology agents. eltanexor, on the right side of the slide, is our second novel SINE compound. eltanexor has shown minimal central nervous system penetration that allows for more frequent dosing, five times per week versus once or twice weekly with selinexor. We have now observed single-agent clinical activity in patients with HMA refractory MDS. Similar to selinexor, we believe there is a strong rationale to explore the use of eltanexor in other solid tumors and hematologic cancers. Here is the easiest way to think about the difference. We plan to focus our efforts for selinexor in areas where a high peak XPO1 inhibition impact is needed.
For eltanexor, since it can be administered more frequently and with better tolerability, it is better positioned in situations where continuous XPO1 inhibition is needed. With that, it is my pleasure to introduce Dr. Jatin Shah to lead the discussions around our four core programs. Jatin?
Thank you, Sharon. The first of the four core programs we'll review is multiple myeloma. We received our first indication in myeloma in 2019, and a label expansion one year ago in December 2020. We are actively generating new data in various combinations. We are fully committed to bringing new treatment options to patients battling multiple myeloma, and we're very excited to be joined today by Doctors Rafael Fonseca and Cristina Gasparetto to provide their insights and perspectives on the evolving treatment landscape and thoughts on XPOVIO. I will provide a brief overview of the multiple myeloma landscape and opportunity. Myeloma is the second most common blood cancer, and the incidence and prevalence continues to increase. It is an incurable cancer, even with the many advancements over the past decade, which underscores the increasing need for active combinations.
One key principle in myeloma that is well accepted is the concept of class switching. We're switching classes of drugs between lines of therapy, and Dr. Fonseca will provide much more detail on this approach. Now, despite the many advances, there are still several key areas of unmet need in myeloma and where XPOVIO can meet those needs, which we'll be providing additional clarity on today, including, number one, patients whose disease progresses following an anti-CD38-based therapy, and number two, patients with high-risk myeloma, both of which Dr. Fonseca and Dr. Gasparetto will discuss. XPOVIO has evolved in three key ways very rapidly over the past two years. Number one, from high-dose XPOVIO administered at 160 mg per week to lower doses of 60 mg-100 mg. Number two, from twice-weekly to once-weekly dosing.
Number three, we've moved from doublets in later lines of therapy to triplets in early lines of therapy. This evolution is common and happens with other myeloma treatments, and this evolution is important. We will elaborate on how we have moved into early lines on the next slide. Here, we provide extreme clarity on where there's a clear unmet need. There is an increasing use, at least 80% and growing, in the first two lines of an anti-CD38-based regimen. At this time, there's limited data in one to four lines of therapy from trials on how to manage patients whose disease progresses after an anti-CD38-based regimen. This data gap is significant, and the impact is seen in clinics every day where there is no clarity and where there's a clear opportunity for XPOVIO.
We have generated data with XPOVIO-based combinations, including in combination with pomalidomide, carfilzomib, and bortezomib, in this specific setting with the aim of filling that data gap. The beauty of this is it builds upon that well-established principle of class switching. With that, it is now my pleasure to introduce Dr. Fonseca and Dr. Gasparetto, who go into further details on this evolving landscape and the data. First, I'll turn it over to you, Dr. Fonseca.
Thank you very much, Dr. Shah. It's a pleasure to be with you all here today. As he mentioned, I'm gonna try to portray what we see for the treatment landscape as it relates to relapsing and refractory myeloma. Next slide, please. Through my slides, I'm gonna walk you through a few concepts that Dr. Shah has already alluded to. One is the fact of clear evidence of anti-myeloma activity of XPOVIO. Also, how we're thinking about patients that have some aggressive features that tend to respond better, and also how this can be used in the elderly, as well as the importance of the class switching that Dr. Shah mentioned. In front of you, I depict a graphic that shows the various lines of treatments that are often faced by patients with myeloma.
The field has converged in using the best there is for frontline therapy, where patients are now routinely getting four-drug combinations, and in some cases, with the addition of a stem cell transplant. Maintenance has been proven to be highly effective, and therefore, most patients have prolonged exposure to lenalidomide, which leads us to that first relapse, whereas in the past, regimens that contained IMiDs were widely used, and as I will show you next, seem to not have the punch that we need. We're moving forward towards carfilzomib-based combinations with monoclonal antibodies for that first relapse because of the possibility of this IMiD resistance.
That leads to the second relapse, where we really have a difficult spot, and we think there's a significant opportunity for new drugs such as selinexor that will cover the need for those patients who have been previously exposed to all other regimens. Of course, we remain with a theme of class switching for third relapse and so forth. Of course, as part of our horizon, we have the development of both CAR T-cells as well as bispecific antibodies. Next slide. This is a table that summarizes some of the key clinical trials that have been presented for myeloma that is recurring. On the left side, you see those that involve daratumumab, on the right side, those that involve isatuximab.
Now, I will call your attention to the second column, the one with the label APOLLO, and the second to last, the one labeled ICARIA, where we see that the combination of monoclonal antibodies with IMiDs, in both of these cases, pomalidomide, seems to have a PFS, which is a third line of 12.4 months and 11.5, which is really subpar with what we would like to see. On the other hand, you see CANDOR and IKEMA regimens that are the combination of carfilzomib plus antibodies in the third and the last column that show superiority. This is really cementing what we're doing for that first relapse. Next slide, please. Now, a key concept that we have developed and published last year, as well as others, is this concept of attrition.
With every line of therapy, there's a significant loss of patients. In this particular slide, I show you a study we did with a large database, close to 22,000 patients, where we asked ourselves, if patients that finish one line of therapy, how many of them complete the next one? That's the percentage you see on the right side. The point here is that we want to use the best regimens up front, and the bigger opportunities are for moving agents that are active against myeloma towards the earlier lines of treatment. Next slide, please. Now, a key concept that builds on this class switching is that myeloma is a heterogeneous disease.
I won't walk you through all the details of the study, but just, know that each one of those pie charts represents a different time point at which we did genomic studies of the patient's plasma cells, their myeloma cells. The different colors represent the sub-clones that emerge and sometimes go away with the various treatments in what has been described as the clonal tides. Now, this is an important concept because it supports the notion that you cannot continue with the same, treatments that have been used before, and furthermore, also, I think, supports the notion of using combinatorial approaches, as was just described by Dr. Shah. Next slide, please. You're aware of the BOSTON trial, which was a well-designed phase III clinical trial that compared the doublet of bortezomib, dexamethasone versus selinexor, bortezomib, and dexamethasone.
This trial, despite having the odds stacked against selinexor, in particular because of a lower dose density for bortezomib and dexamethasone, showed the important contribution for disease control that selinexor provides. Next slide, please. This is best depicted by this graph that shows a very significant improvement in the progression-free survival for this patient. Given this data, it's incontrovertible that this important clinical activity against the neoplastic plasma cells in myeloma with combinations that include selinexor, and in this case, showing a 30% reduction in the risk of progression or death with a triplet combination. Next slide, please. Now, one of the things that Dr. Shah alluded to and that we have seen for essentially every single drug that has been approved for myeloma is that we learn better how to use these drugs as they are available in the market.
This is an analysis of the BOSTON trial that looks at the dose adjustment. What you can see there, where it says patients with dose reductions, is that the outcomes are similar, if not better. In fact, when you look at the PFS, it seems to be superior for those patients that have a dose adjustment at 16.6 months versus 13.9, which really denotes the importance of knowing how to use this regimen. You've heard from Dr. Shah the importance of getting the right dose, using lower doses, the schedule, the once per week, and also building on his comments regarding the combination strategies.
Next slide, please. Now we do the subset analysis for the various subgroups, and this is in particular, showing us that in the BOSTON trial, if you look under high-risk cytogenetics, there is a group that is marked as del(17p). Those are patients with high-risk multiple myeloma, which in this graph, by the fact that they have the dot most to the left, we see a significant impact for the subset of patients. These are patients that we consider high-risk myeloma patients and for whom better treatments are needed. This is a story that continues to evolve and positions XPOVIO as a particularly interesting agent for the treatment of high-risk cytogenetic patients. Next slide. Now, a story that is not told enough is that XPOVIO can also be used in patients of advanced age.
Myeloma often affects patients in their seventies and eighties, and this is an analysis looking at overall survival in patients over the age of 65 years, where you still see that benefit. If you know how to use the drugs and can provide the triplet as is shown here in the graph, the outcomes can be improved for this patient population. Next slide. Now, we will soon see at our professional meeting, the ASH Meeting coming up this week, data regarding preclinical analysis of XPOVIO, particularly as it relates to sequencing. This is an interesting study by Dr. Reddy, which will be presented, which suggests that in myeloma patients, those that are treated previously with daratumumab, perhaps are more sensitive to selinexor. This may be a function of expression of certain genes and proteins such as MYC.
Interestingly, there's glimpses of this and can be clinically validated by data from selinexor clinical trials, which show a deeper response in patients with prior exposure to CD38 monoclonal therapy. It really builds on the notion of the benefit of sequencing of the various therapies. Next slide. Now, this is one such analysis. If you can see on the gray box, we have the PFS in patients previously treated with daratumumab and where you still see the benefit of patients who have XPOVIO. Indirectly, it's interesting because you would think patients with this prior exposure perhaps are, in general, more advanced or more heavily pretreated. Despite that, we see the benefits of the three-drug combination. Next slide.
Lastly, as we look at the empirical validation of this, we see that the combinations with carfilzomib, SKD, and pomalidomide, SPd, appear also to be active in the post-daratumumab setting. As I mentioned before, this includes patients with high-risk cytogenetics. With this, I will conclude. Next slide, please. Thank you for your attention, and I will pass it on to Dr. Gasparetto.
Thank you. Good morning. Thank you, Rafael. Thank you, Jatin and Dr. Shah. My pleasure to share my experience today with selinexor for patients with multiple myeloma. Next slide. Myeloma, despite the introduction of many new agents over the last two decades, as it remains an incurable disease, and it's very difficult to choose the appropriate treatment, as Dr. Fonseca mentioned, particularly in the relapsed setting. Just to show an example, we are able to achieve deeper responses in a newly diagnosed setting. Generally these responses are durable for the majority of patients.
Unfortunately, at time of relapse, we start to lose control of the disease, or we are unable to achieve the deeper responses that we achieve in a newly diagnosed setting. Some of the responses are becoming, with time, less durable, until, unfortunately, patients will develop refractory disease. Next slide. These are the agent, the drugs that have been introduced for treatment of myeloma over the last two decades. Very important, the fact that we had the introduction more recently of a drug with different mechanism of actions. We're going from the proteasome inhibitor to the IMiD, to the monoclonal antibodies, particularly the anti-CD38 monoclonal antibody, daratumumab and isatuximab.
More recently, of course, the introduction of selinexor with unique mechanism of action, and then the anti-BCMA, B-cell maturation antigen, recently approved, targeted therapy, the belantamab and the, first CAR T-cell for myeloma. Next slide. when we choose a therapy, particularly in the relapsed setting, for patients with myeloma, we spend a fair amount of time to take in consideration many factors related to the patient per se, the age, frailty, other comorbidities, particularly patient with renal insufficiency, very difficult to treat, and very often excluded from clinical trials. having data on these particular populations of patients is becoming very important.
We take in account the disease, the tumor burden, how aggressive the disease, the presence of extramedullary disease, we need to achieve a deeper, better tissue penetration, and of course, the high-risk genetics. We take in account the prior treatment that the patient has received, so we can make a proper class switching, as we mentioned earlier. Of course, the toxicity that the patient has experienced in the past. Next slide. I'm not gonna spend a lot of time in these slides, but it's clear that at time of relapse when a patient becomes resistant to a particular combination, we need to change or go with the different mechanism of action and perform what we call the class switching.
Very important, as my colleagues have mentioned, particularly patients, they need to meet their unmet need of determining a new and powerful combination in patients progressing after an anti-CD38 monoclonal antibody-based therapy. Next slide. Patients with renal insufficiency, as I mentioned earlier, they have a difficult time with some of the regimen, difficult with increased toxicity and a worse outcome. It was clear from the BOSTON study that the addition of selinexor to the bortezomib-dexamethasone combination impacted favorably also in this population of patients. Here is the progression-free survival of patients with a moderate renal insufficiency with the addition of selinexor, which was almost double, more than double 16 months versus 7.3 months. Next slide. Also a positive impact, the addition of selinexor on patients with high-risk cytogenetics.
This is the progression-free survival on the right of patient with two, or at least two or more cytogenetic abnormalities. We recognize that these are the double-hit myeloma, the more difficult patients that we can treat with very aggressive disease. So again, the prolongation of the progression-free survival with the selinexor impacting these population of patients versus six months, 5.9 months without the addition of selinexor. The next slide. We are always focusing on this particular abnormality, the deletion seventeen, which is performing poorly, unfortunately correlates with very aggressive outcome. Again, we see the benefit of the addition of selinexor for these subpopulation of patients. Next slide.
As I mentioned earlier, we also take into account the toxicity and, you know, when we sit with the patient, we counsel the patient about the initiation of new therapy or new combination, we focus on the probability of developing toxicity. Selinexor, and these are some of the toxicity associated with some of the newer drugs approved recently over the last couple of years for treatment of myeloma, selinexor, ixazomib, belantamab and carfilzomib. The toxicity and we've learned these with the initial approval of selinexor with the data of the STORM study. Selinexor is associated with what we call the GI toxicity, nausea, diarrhea, general toxicity, constitutional, decreased appetite and some myelosuppression.
What is unique of this drug, and I've now been using selinexor for several years, that the toxicity associated with selinexor is not cumulative. It doesn't continue, it doesn't persist. If anything, it dissipate with time, and that is unique of this drug, is different from other anti-myeloma drugs that we use for our patients. Next slide. In fact, in the BOSTON study, this was just to prove the observation. Nausea is one of the most prevalent toxicity that we see when we start the selinexor, when we use selinexor for our patient. As you see, the nausea dissipates with time. In fact, the majority of patient had the improvement, resolution of their nausea after three to six months of treatment.
When I counsel a patient, I always discuss these concepts. I always tell patients we need to initiate antiemetic supportive care, particularly for the first few months. Then there is another patient and patient are capable of continuing therapy for a prolonged period of time without the aggressive supportive care. There is a mitigation of the toxicity. I have patient on selinexor now for a few years. Next slide. Jatin, Dr. Shah mentioned the concept of the evolution. The selinexor is a new drug. Of course, when it was first approved in 2019, based on the data of the STORM study, selinexor was given biweekly with a fair amount of GI toxicity, constitutional toxicity, the fatigue and myelosuppression.
It was clear when we started to combine selinexor as part of the STORM study with different anti-myeloma agent. It was clear from the very beginning that we didn't need the biweekly administration. The selinexor was effective at even weekly with less toxicity, with a very high level of tolerability. The evolution, I think the weekly administration is definitely a new drug, the new selinexor. Next slide. This is going back to one of the unmet need. This study, the MAMMOTH study and retrospective study that was published a couple of years ago, following the outcome of patients who become refractory to anti-CD38 monoclonal antibody. It's very important study for us because it becomes a benchmark. We use this study for comparison for design of clinical trials, comparison.
If you see for patients, for all patients, for the entire population of patients refractory to anti-CD38 monoclonal antibody, the median overall survival of 8.6 months. Of course, the patient who developed refractoriness to the penta-refractory patient to the two IMiDs, two proteasome inhibitors, the anti-CD38 antibody, the projected survival of less than six months. Next slide. As part of the STORM study, we combine selinexor given weekly to minimize toxicity, very effective in different combination. To give you an example, this is an all-oral combination of selinexor, pomalidomide, dexamethasone in patients in the relapsed setting. The overall response is 65%.
If we take into account only patients who have received prior anti-CD38 antibody, monoclonal antibody, and as I mentioned earlier, a very difficult population of patients to treat, a very respectable response rate of almost 58%. Next slide. We've seen also similar outcome in a different combination. It's probably very powerful, one of the most powerful combination, selinexor, carfilzomib, dexamethasone, also given weekly. The overall response on patients who have failed one to two prior lines of therapy was close to 90% with some deeper responses, and very high also in patients who had an exposure to anti-CD38 monoclonal antibody refractory disease with an overall response of about 60% and a progression-free survival of 15 months. Next slide.
To conclude, clearly, a selinexor-based regimen are showing high activity, even in patients prior exposed to anti-CD38 treatment. Also, we have seen now data, generating data on the benefit of the addition of selinexor in important subpopulations, particularly the older, the frail population, the patients with renal insufficiency and, as I mentioned, patients with high-risk cytogenetics. Of course, the toxicity, the evolution of this drug, understanding that weekly administration is sufficient, and patients are able to sustain therapy. The toxicity is definitely more manageable, and patients are able to remain on therapy for several months to a few years, in my experience. I conclude here, happy to take any question with Dr. Fonseca.
Thank you, Cristina. As we look at the opportunity in multiple myeloma, about 40,000 patients are treated in the second-line-plus setting in the U.S. every year, and this number continues to grow. We believe that XPOVIO will become a standard of care as we evolve from the original penta-refractory indication into earlier lines. We have a tremendous opportunity in front of us to continue expanding XPOVIO's breadth and depth of use through continued execution in the approved indications and through the advancement of key late-stage trials, including the all-oral triplet regimen study evaluating selinexor in combination with pomalidomide and dexamethasone in patients as early as the first relapse. We believe that the combinability with other approved agents and being a new class of therapy allow us to drive sustainable and long-term growth in the multiple myeloma marketplace. I will now recap our strong third quarter sales performance.
We accelerated growth and continue to make steady progress across key indicators since our second-line-plus launch at the beginning of this year. Total XPOVIO net product sales for Q3 2021 were $26.7 million, a 32% increase quarter-over-quarter and a 25% increase year-over-year. We continue to see a positive shift from the penta-refractory setting towards earlier lines, with the most rapid growth this year in the third line, as we continue to focus our messaging on the white space of second to fourth line in the myeloma treatment journey. We are expanding in the breadth and depth of use of XPOVIO with strong growth in the community setting. We continue to add more accounts every quarter and increase penetration at top myeloma accounts.
In addition, our intent to prescribe data continues to show sustained improvement in the efficacy and safety perception of the product and growing confidence in utilization in earlier lines. Physicians are having an increasingly positive experience with the lower dose once weekly XPOVIO-based triplet regimen with over 90% of patients starting on 100 mg or lower dose. As we look to the future, we continue to prioritize expanding into earlier lines with our approved indication and with the upcoming planned initiation of the phase III registration-enabling study evaluating selinexor in combination with pomalidomide and dexamethasone. There are four key differentiators with SPD that we believe position it well in the second-line plus. Firstly, with the majority of multiple myeloma patients being exposed to an anti-CD38 monoclonal antibody, there is an unmet need for a new class of therapy.
Second, SPd will be an all-oral regimen, which is highly desirable with this patient population, with over half of the patients in second line being on an oral-containing regimen. Third, as Cristina reviewed earlier, our STOMP data showed robust efficacy and good tolerability. Fourth, we chose to combine with a well-established backbone pomalidomide, which is widely used in earlier lines with about 20% of patients on a pomalidomide-based regimen in second line. In summary, with XPOVIO, we look to continue to expand our breadth and depth of data in a growing patient population, where there is a clear unmet need for a product that is a new class of therapy with proven efficacy in the post-anti-CD38 setting, is able to combine with multiple backbones and a manageable safety profile.
As we look to critical success factors for growth in 2022, I'd like to reemphasize the following four key areas. First, strong execution of our messaging in the second line plus with focus on live physician engagements with a nimble and patient-centric team through the current COVID environment. Second, continue to shift into earlier line use. Third, increase breadth and depth of account adoption. That is, we add new accounts and increase the depth of experience with existing users. Finally, continue to build physician confidence through optimal patient management. With that, I will now turn things back to Jatin to outline the details of the SPd study and global expansion plans for multiple myeloma.
Thank you, Sohanya. To elaborate on Sohanya's comments, as part of our long-term commitment to myeloma patients and the continued shift to earlier lines of therapy, I will review our next phase III study, which is designed to investigate selinexor, pomalidomide, and dexamethasone, or SPD, versus elotuzumab, pomalidomide, and dexamethasone, or EPD. This is a randomized phase III study in patients who have received one to four prior lines of therapy, including an anti-CD38-based regimen. Patients will be randomized to SPD versus EPD in a one-to-one fashion, and this will be a global study that is expected to recruit up to 280 patients. We expect to dose the first patients in this study during the first quarter of 2022, and top-line data is anticipated in 2024. Now turning to our global expansion. We continue to increase access to selinexor worldwide, including with our strategic partners.
Our marketing authorization application based on clinical data from the phase III BOSTON study has been validated and is currently under review by the CHMP. We expect this review to be completed during the first half of 2022. There are also new drug submissions or applications for SPd submitted or on file in Canada and multiple Asia Pacific markets through our strategic partners, and we look forward to keeping you updated on those as approvals happen. Finally, I wanna close with several key messages on myeloma. First, we believe we're addressing a significant unmet need for patients with multiple myeloma following at least one prior line of therapy where an effective new class of therapies is needed.
Second, we have a long-term commitment in myeloma, and to that end, we have generated data and will continue developing additional data to establish XPOVIO-based combinations as the standard of care post an anti-CD38 and also in high-risk cytogenetics. Third, as Dr. Fonseca and Sohanya commented on, and Dr. Gasparetto's experience with several patients on for more than several years, physicians have learned how to use XPOVIO, and there is a growing confidence in the community with evolving once-weekly low-dose XPOVIO in combination with multiple partner drugs. Finally, we are evolving and expanding XPOVIO into earlier lines of therapy with a broader myeloma opportunity, including the all-oral SPd combination. With that, now we'll open the line for questions from the audience on the multiple myeloma program.
If you would like to ask a question, please press star one. Again, that's star one for any questions. We'll pause for just a moment. The first question will come from Maury Raycroft with Jefferies. Please go ahead.
Hi, this is Kevin Strang on the line for Maury. Just a couple quick questions from us. Seems like the strategy is to simplify the selinexor story myeloma to post-
CD38 around the third line. As you accumulate more data, do you have any plans for adding something to the label or maybe submitting to NCCN guidelines?
Yeah, great question. I think, yeah, we wanna be very clear. We are agreed we're simplifying the strategy to be post-CD38, not necessarily third line. As the CD38s move in the first line, we anticipate this moving in the post-CD38 setting. Number two, yes, with the SPd regimen, the plan is to expand the label based on that pending a positive study.
Great. Thank you. Just on something from earlier in the presentation, could you elaborate on why you think the side effects for selinexor are more transient than other medications in myeloma? Is that something where the doctors are managing the dose, or do you think it has something to do with the mechanism? Do you see a similar pattern across different dose regimens for selinexor?
Yeah, I'll start, and then I'll have Dr. Gasparetto and Dr. Fonseca comment. Yes, we have had patients now with many thousands of patients that we've dosed over many years. We have a really solid understanding of the side effect profile of selinexor. We have not seen long-term side effects or cumulative side effects, and that's been clearly established in our safety profile. Regarding really how to manage the side effects and the physician's learning curve, I'll have Dr. Gasparetto and Dr. Fonseca comment on their experience as they've learned how to use XPOVIO in managing the side effects and the transient nature of those. Dr. Gasparetto, maybe you can start.
Yeah, sure. Yes, initially, it was just an observation, being part of the STORM study now for a few years and had the opportunity to treat many patients with different combinations. It was clear from the very beginning we were going very aggressive out of the gate with the antiemetics, the fluids, nutritional support based on the experience of the STORM study. But it was clear that with weekly administration, we were seeing the same type of toxicity, but really mitigated, mainly grade one and two. Also there is an adaptation. For some reason, with time and as you see with nausea, the nausea almost dissipates after a few months.
There is an adaptation sometimes, so you know, we go down, we adjust the dosage based on the side effect. Eventually the patients are able to sustain therapy. I have patients on therapy for a few years, doing phenomenally very well with minimal toxicity. I'm not sure why, but that was an observation from the very beginning. When I counsel a patient, I always prepare them and say, "During the first couple of months, we have to monitor you more often, with blood work, sometimes some fluids." We used to see the low sodium, the hyponatremia with biweekly administration. We see that less commonly with weekly administration, but we provide patients with fluid with nutrition counseling. Really, we don't, these symptoms don't linger.
There is no accumulation or cumulative toxicity that we have seen with other agents. We are familiar with the myelosuppression of the IMiDs, the peripheral neuropathy of the bortezomib. It's almost, you know, the beginning, the induction, the first few months, and then that's only an adaptation for the patient and has to do with us sometimes adjusting the dosage, or just the patient becoming more used to the drug.
Thank you, Dr. Gasparetto. Dr. Fonseca, any comments?
Yeah. No, not much to add. I think that was a good summary. I would just particularly highlight the endurance, for instance, of the neuropathy you get with Velcade bortezomib. So this symptom suppressant is well on treatment, so that's one of the very attractive aspects. I mean, there's a number of other things, but I think Dr. Gasparetto had already made a good summary.
Perfect. Thank you.
The next question will be from Peter Lawson with Barclays. Please go ahead.
Great. Thanks for the call today. Just on the, I guess going back to the refocused pipeline, if you could kinda talk through the rationale that helped there, if there was any new data to kind of de-emphasize the solid tumor franchise.
Yeah. Thanks, Peter. You know, I can talk to that at a high level, and we can come back to that at the end because I wanna make sure that we're able to hear from our guests today. You know, I think overall, we've really evolved our strategy to ensure its greater emphasis and rigor on our portfolio prioritization. You know, we have the benefit of over a decade of amazing science and research, which has allowed us to find where can we have a big impact for patients and where is our high unmet need. Based on it being able to have, you know, a big impact for patients and with high unmet need, that's why we focused on those four core programs right now.
I think as you heard Sharon talk to, you know, we're continuing to engage in our solid tumor and heme signal-seeking activities in a number of areas. As we see the data evolve, you know, we're gonna look at, again, high unmet need. We can have a big impact for patients, and then move forward with those programs.
Perfect. Thank you. Just your thoughts around the post-Darzalex setting of that kind of white space and how that potentially changes with bispecifics and I assume kind of multiple BCMA lines of therapy with different approaches, how that could potentially morph over time.
Dr. Fonseca?
Thank you, Dr. Shah. I think.
Yeah.
That's a very important question. We see this currently being utilized primarily in the more advanced stages. We are currently in a phase, unfortunate phase, where actually the production capability for that has been an issue, so there's limited penetration. Right now, the CAR T, even centers like ours, have a very, very limited accessibility to those compounds. In the future, of course, you know, we're looking forward to these products being a part of our toolkit, but not everyone will be a candidate for that. But even if they are, there still is a significant gap when, you know, as patients plan for this or the patients need to engage in other activities that may not be ready or suitable candidates for that.
I think there is no question those will play a role, but as of now, as of today, it's mostly something that is in the more advanced stages of the disease.
Gotcha. Just maybe a final question around the SPD regimen. Just your thoughts around that SPD regimen if pomalidomide is being used in earlier lines, and whether that kind of prevents you from using an SPD regimen if they've had prior POM exposure.
Yeah, maybe I'll start. Yeah, I think when you look at the treatment landscape, and Dr. Fonseca and Dr. Gasparetto to comment, but when you look at the current treatment landscape, what's used in front line is, you know, lenalidomide or Revlimid plus bortezomib or carfilzomib in that setting. Pomalidomide is not used in newly diagnosed setting. It's used as a standard of care in the relapse setting. Building upon that foundation, it's not gonna move in the first line. I think that's gonna be fundamentally an unchanged principle moving forward, regardless of the change in treatment paradigms that may happen.
Dr. Fonseca?
You know, another comment to add is that in particular for the IMiDs and it would apply for proteasome inhibitors, which is relevant, of course, to selinexor, is that this drug don't necessarily go into a sort of black and white category as far as responding or not. In other words, it's not binary. For both of them, there seems to be a gradient upon which then they start killing cells. And that can happen, of course, if you pair one of those drugs with an effective agent. So the thought is there, you know, it's not gonna be used early, as Dr. Shah mentioned. And there is a possibility of the combination actually creating some synergies.
That's why, you know, it's being explored primarily as was represented with carfilzomib and pomalidomide, but I wouldn't say it's completely inevitable that you're gonna see that resistance.
Great. Thank you.
Thank you. I think we have time for one more question.
Yes, sir. The final question will come from Eric Joseph with JPMorgan. Please go ahead.
Hi. Thanks for taking the questions. I'm just curious from your panelists to get a sense of how they are using XPOVIO or the types of patients in which they're using XPOVIO currently, by age or other baseline comorbidities, given some of the subgroup analyses that were sort of walked through coming out of BOSTON. Also whether the tolerability profile is impacted at all in their experience, depending on whether XPOVIO is used as a combination agent or as monotherapy.
Yeah, perfect. I'll have Dr. Gasparetto comment on her experience with increasing use in the early lines of therapy. We'll talk about the tolerability profile specifically that evolved to the once-weekly low dose, and then triplet. Dr. Gasparetto?
Yes. You know, the STOMP study was designed to use selinexor in combination with different anti-myeloma therapies. We were stratifying the patients based on the prior exposure. We tested several combinations, and the patients were treated based on their prior therapies. When we were testing the combination for safety, we were enrolling patients that also received therapy before. For example, the SPd combination, at the beginning of enrollment, we had some patients that were previously exposed to pomalidomide. We were determining efficacy in different populations of patients. It was clear from the very beginning, as I mentioned earlier, that we didn't need the high dosage of the bi-weekly administration.
We were able to sustain the therapy longer, for a longer period of time with less toxicity and very effective combination. That's, you know, how we choose generally a therapy based on the prior therapy, and as I mentioned at the very beginning, based on the patient. The patient age is very important because with the older, more frail patients, we tend to treat them suboptimally. We tend to decrease to not use very aggressive combination.
In fact, if you look at the overall survival of patients with myeloma based on the age, the older patient, of course, have a more difficult and shorter survival, not because there is anything different in the biology of the disease, but is us not treating aggressively enough because they come with a lot of comorbidity and frailty. Having data on this particular population of patient was very important. It was clear with the usage of selinexor once a week that we could safely use a combination even in this particular population of patients. Then another important subpopulation of patients with renal insufficiency, about 50% of patients with myeloma will have renal compromise, mild, versus about more than 30% having a more severe compromise.
Unfortunately, some of these patients are excluded from clinical trials, and so having data in this particular population of patients are also very important. How I choose my combination is based on the prior exposure, based on some of the comorbidity, the factor, the patient's prior toxicity and you know, with great success, a lot of success stories of introducing selinexor earlier on in their as a treatment strategy for some of these patients, including the elderly coming out, for example, of the MAIA study, the dara, Revlimid, dexamethasone at the time of progression using a proteasome inhibitor, the Velcade with selinexor makes absolutely perfect sense.
Thank you so much, Dr. Gasparetto. I'd love to get Dr. Fonseca's kind of experience and thoughts on XPOVIO-based combinations in early lines as well.
Yes. Thank you, Dr. Shah. Actually, in my practice, I use it primarily in those earlier lines of therapy in combination with carfilzomib. We are very familiar with carfilzomib. We are familiar with the combination as well too. You know, but someone mentioned before, you know, what has been your experience? Like everything else, initially it was started down the line. Some of the patients that were being treated when we first had this become available were in fifth and sixth line of therapy. Especially since BOSTON was published, we have seen a significant shift towards the front line.
I in particular like to use carfilzomib as a proteasome inhibitor, because unlike bortezomib, again, doesn't have that enduring toxicity, which is a neuropathy, and have found it to be very well-tolerated in combination with selinexor and with the appropriate antiemetic regimen too. Our team has become very familiar with this. They know how to use the prophylactic medications. The nursing team has now, you know, they're fluent in how we do this. So our experience actually has been quite positive in this regard.
Okay. That makes both.
Thank you so much.
One more if I could, Jason, if that's all right.
Sure.
I just would also be interested in getting your panel's take on the use of EPd as a comparator arm in your phase III SPd trial. Also, you know-
Yeah.
from your perspective, how you arrived at that as the appropriate comparator? You know.
Yeah.
also, you know, does it reflect where Elo is currently being used in the overall treatment paradigm?
Yeah. Thanks so much for that question, Eric. Very quickly, I think when we're looking at designing randomized phase III studies for better registration enabling, the control arm has to be a regimen that is approved by the agency. That's an appropriate control arm. Two options in this setting really is gonna be a doublet of pomalidomide and dexamethasone, and the only other triplet that's approved in this setting is EPd. When we're designing the trial, we thought it was most appropriate for patients and physicians when we're designing a triplet versus a triplet with EPd. That's the rationale for that. Great question. I think we're gonna wrap up this myeloma section. I know lots of questions. Really appreciate Dr. Fonseca and Dr. Gasparetto for reviewing the treatment landscape, their perspective, and their experience with XPOVIO-based combinations.
We'll move on to our second core program next. Our second core program is endometrial cancer program, where we recently just completed enrollment and are expecting top-line data in early 2022 from the phase III SIENDO study, which is evaluating selinexor as a maintenance therapy following frontline chemotherapy. There are approximately 14,000 patients per year in the U.S. who are treated with frontline chemotherapy when they're diagnosed with an advanced or recurrent disease. We're excited about this program because selinexor has the potential to be the first and only therapy post-chemotherapy in the maintenance setting. We're joined in this section of the program by Doctors Robert Coleman and Vicky Makker. First, a little background. Endometrial cancer is the most common gynecologic cancer and arises in the lining of the uterus.
For patients with advanced or recurrent disease, the current standard of care is combination chemotherapy for four to six cycles. Unfortunately, this is not curative, and remission is typically short-lived for 4-6 months following chemotherapy. There are no strategies to prolong this short time in remission, and the current approach is typically close observation and watch and wait. Clearly, there's a need for new approaches that can prolong time in remission, which is a goal of our SIENDO study and also has the potential to be the first and only maintenance therapy following chemotherapy. With that, now I'd like to introduce Doctors Robert Coleman and Vicky Makker to review endometrial cancer, the treatment landscape, the data with selinexor, and their overall perspective. Dr. Coleman?
Yeah. Thank you. It's great to be with you guys today, and thanks for listening in. So I'm gonna just give you a brief overview of the therapeutic landscape for endometrial cancer. Over many years, you can see at the far left of this graphic, there's 1975, there was a higher rate of endometrial cancer new cases. Interestingly, this seemed to follow or parallel the increased use of endocrine therapy for hormonal replacement.
Postmenopausal women largely unopposed estrogen exposure, which led to this increase. Once that relationship was known and we added progestins to those, the incidence rates in endometrial cancer started to reduce and did so for many years. We've seen lately that there's been a slight increase in the overall incidence. What's more disturbing is that we're also seeing a slight increase in the overall mortality. When we look at this a little closer, we're seeing that it's not actually homogeneous across our population with certain subgroups of our U.S. population being disproportionately affected by not only the higher death rate that we're seeing with endometrial cancer, but also higher rates of aggressive subtypes.
We call them aggressive subtypes, which would be our uterine serous and clear cell tumors. Next slide. I think to put this in some context. Earlier this year, we heard a report from the NCI that said that we had made significant progress on the mortality in both men and women with respect to oncology. If you look at the midway through this graphic, you can see it says all sites. For men down 2% and women down 1.4%, which is tremendous success. As you know, this is a battle that has been waging since Richard Nixon signed the National Cancer Act to try to reduce mortality and suffering from cancer across the United States.
If you look at the top of that list in women, you can see that uterine cancer is distinguishing itself in a very bad way as being one of the few diseases that actually is showing reverse to this global trend and demonstrates a clear need for further drug development. Thanks. Next slide. Aligned with this kind of history, we have traditionally broken up endometrial cancer into two kind of general categories. These do represent kind of what patients actually that we see in the office. We have a cohort of women generally that are obese, have cancers that appear to be estrogen-driven, like as I mentioned with the when I opened up the comment here. They typically are Caucasian, early stage, well-differentiated.
In many cases, even without expert care, just a hysterectomy cures these patients. This has been where a lot of the kind of sense that endometrial cancer is a survivable tumor largely came from the experience that we had with this type of patient population. We know that there's another group out there. They make up a disproportionate segment of our recurrent patients and our metastatic patients, so we call them type two. They tended to be older patients, thin, multiple medical comorbidities, ethnic and racial imbalance, presented with advanced stage disease, and had a very poor overall prognosis. Next slide.
While that served us well for a lot of times, as we learned more about the biology of endometrial cancer and how diverse the tumor could be, we found out that that kind of general classification really did not serve us well, especially as we were looking into ways to expand the drug development landscape. What you're looking at here is a graphic that is outlining many, many features. You've probably seen this before. This is The Cancer Genome Atlas project, published about a decade ago in Nature that isolates several factors of this cancer, including the MSI, the copy number cluster, mutations in various genes, and how these all relate to each other.
You can see that there are these four categories now that seem to better represent a molecular characterization rather than just a phenotypic characterization of the patients that we see. We have these, POLE and hypermutated tumors. These are MSI-H patients. Then we have both copy number low and copy number high. You can see if you go over, all the way to the right, the copy number high is annotated by a large proportion of patients that have p53 mutation, and that is unique for that particular cohort of patients. Next slide. With the various tools that have been placed at our feet for years, that has really been around hormones.
You may remember that prior to the recent approvals of pembrolizumab and lenvatinib and pembro, Megace was approved in the fifties for endometrial cancer. That was our only drug that was actually formally FDA approved for decades. Outside of that, we had chemotherapy. Those two kind of modalities kind of served us well for a while. As we learn more about the molecular targeting and potential and the availability of biological agents, we were able to then start to match, as you can see on the right-hand side, the potential opportunity to engage patients with specific molecular alterations with drugs that are now being developed for that. This is kind of where the future started to spread.
You can see again, if the non-endometrial tumors, the kind of the second or third line from the bottom p53 mutation is seen in 50%-90% of those patients. Next slide. The kind of the first major win we had in this category was the identification of this hypermutable state being similar to what we see with other solid tumors that have high level of tumor-specific, you know, antigens and the incorporation of PARP inhibitors. Of course, the MSI-H, which represents about as much of a proportion of endometrial cancer as it does in colon cancer. It particularly, even with respect to the Lynch syndrome, endometrial cancer is the is tied with colon cancer for the index tumor for that specific syndrome.
This is a common event that we find easy to identify in our patient population. Next slide has led to a couple of early wins. You can see we have accelerated approval for pembrolizumab in 2017. Earlier this year, we had the approval of the dostarlimab, another immune checkpoint inhibitor for MSI-H, dMMR endometrial cancer, and then recently, the approval of lenvatinib, pembrolizumab in patients that are pMMR annotated endometrial cancer. Next slide. Just to kind of wrap this section up, right now for patients who's newly diagnosed metastatic disease, chemotherapy is still the treatment of choice. We really don't have much in this space.
You can see that our opportunities are to add immune checkpoint inhibitors for the tumors that are identified as microsatellite unstable or have MSI-H, assuming deficient MMR. We also have the opportunity to add agents such as anti-HER2-based therapies because of the availability. We have one trial that has shown efficacy of that combination in the setting. Of course, this is a great place to look at the opportunity for selinexor, particularly as a maintenance trial. That's as we already heard about it as part of the development program. In the recurrent setting with no prior treatment or adjuvant chemo, chemotherapy again is the staple, but this is a burgeoning area of new agents potential.
You can see one of them is to replace chemotherapy with lenvatinib or pembrolizumab or with just pembrolizumab in the MSI high patient cohorts. We have adjuvant immunotherapy and adjuvant immunotherapy combinations. Again, selinexor is a good fit here, as well as some of the other novel agents like PARP. Then in recurrent patients who've had prior chemotherapy, you can see the choices there. Our best choices are listed below single agent chemotherapy and endocrine therapy in this setting, but these will all be on the table. Of course, as we learn more about the disease, our ability to impact them with novel target therapies are an active area of ongoing investigation.
I think that's. Yeah, I kind of pass that on over to Vicky.
Thanks, Rob. Hello, everyone. It's a pleasure to join you today. I will continue to talk about endometrial cancer, and we'll focus on the current landscape regarding treatment for this disease. Then we'll discuss a key few studies of selinexor in advanced endometrial cancers. So here, you know, we're showing basically the current endometrial cancer treatment landscape, and I think a lot of this was discussed by Dr. Coleman. I, you know, just wanna punctuate a few of the points that he made, which is that endometrial cancer incidence and disease-related mortality are actually sharply on the rise by about 1.9% or so per year. This alarming trend is expected to continue well into the next decade. This is chiefly driven by obesity.
As you know, we're in the midst of an obesity pandemic. Obesity leads to a number of issues, including inflammatory vascular tumor microenvironment perturbations. As the obesity pandemic increases, we're gonna see a parallel increase in endometrial cancers, and I think that's a very important point, and this is in contrast to really any other solid tumor malignancy. Additionally, as he discussed, it's those aggressive uterine cancer subtypes that comprise the significantly greater proportion of deaths compared to their incidence. This is being seen more and more in underrepresented minorities and African American women who often are not even obese at time of diagnosis. Additionally, outcomes for women with endometrial cancers are drastically different based on race, as he pointed out.
When compared to White women, Black women, for example, have significantly higher mortality rates, even when controlling for high-risk factors such as stage and the more non-endometrioid histologies. This disease is and will continue to be a significant challenge for GYN oncologists. Hence, there really is a tremendous sense of urgency to develop improved therapeutics in this very heterogeneous and molecularly complex disease. With that, here I highlight the current treatment landscape for advanced recurrent endometrial cancers, and both the NCCN guidelines, as well as the European guidelines, are shown here. I think taking these guidelines together, the general approaches that we utilize are either hormonal therapy agents such as tamoxifen or megestrol acetate or aromatase inhibitors for low-grade, indolent, low-volume, hormone receptor-positive endometrioid adenocarcinomas, which comprise about a third of the recurrent disease cases.
We utilize platinum taxane-based combination therapy for patients with higher grade, large volume symptomatic disease. Palliative radiation, surgical resection of recurrent disease in very rare instances where it's technically feasible and cases of localized recurrent disease can also be utilized in addition to these systemic approaches. Following these upfront approaches in the second-line setting, the available approaches include clinical trials, which obviously is the thrust when we see patients, biomarker-directed therapy. For mismatch repair-deficient patients, as Dr. Coleman highlighted, we use immune checkpoint blockade therapy such as pembro, dostarlimab, nivo and PD-L1 agents such as avelumab. For TMB-high patients, we also have pembrolizumab that can be utilized.
For the mismatch repair proficient patients, which again comprise 70% or more of the recurrent disease base, we now have the combination of pembrolizumab and VEGF-TKI lenvatinib and other VEGF-targeted therapies such as bevacizumab and cabozantinib based on small phase II studies. These are all associated with significant toxicity, which can make patient management challenging. Following this, we have palliative monotherapy chemotherapy options, hormonal therapy, palliative radiation, or best supportive care. Next slide, please. With regards to chemotherapy, which really has been the mainstay for management of the majority of advanced endometrial cancers, we clearly have to do better, and there remains a tremendous unmet need still in endometrial cancers, where response rates, as we can see here, to platinum taxane-based chemotherapy in the first line setting are really approximately about 50% only, with PFS in the 8- 1 4-month range.
This includes the interval of time that the patient was on chemotherapy. Overall survival is in the 32- 38 month range, and response to second-line therapy is even more sobering. Response rates are in the teens to 30%, but PFS is only on the range of about three months, and OS only 6-12 months. I also want to point out that with the exception of lenvatinib and pembrolizumab for mismatch repair-proficient endometrial cancers and checkpoint inhibitors for the deficient patients, this is also the range of efficacy that we see for hormonal agents and other targeted therapies that have been evaluated in endometrial cancers. I want to point out that a one-size-fits-all approach with chemotherapy or other therapeutic approaches really cannot be utilized in this extremely complex disease, and there really exists a tremendous need for improved therapeutics in endometrial cancers. Next slide.
With that, I'll shift to discuss the studies that have explored endometrial selinexor in advanced endometrial cancers. Preclinical studies in cell lines and rodent models have demonstrated that selinexor potentiates the effects of radiation therapy, DNA-damaging agents, PARP inhibitors, and even immunotherapies to enhance apoptosis and inhibit tumor growth. In tumors that are refractory to platinum-based therapy, selinexor treatment has been shown to promote nuclear localization of these tumor suppressor proteins and restore sensitivity to agents like cisplatin, platinum drugs, and hence induce apoptosis. Based on this, the Selinexor in Gynecologic Neoplasms or SIGN study was initiated, and this was a multicenter open-label study that enrolled 114 patients with advanced or metastatic gynecologic malignancies and included 23 endometrial cancer patients.
The primary endpoint was to determine the efficacy of selinexor as defined by disease control rate, which included a percent of patients with a CR, PR, or durable stable disease for 12 weeks or longer by RECIST 1.1. Secondary endpoints were to assess PFS, OS, and also quality of life. Eligible patients for this study had to be 18 or greater, had to be fit, and life expectancy of 12 weeks or more. For the ovarian cohort, patients had to have platinum refractory or resistant disease and had to have one or more prior lines of therapy. For the endometrial cancer and cervical cancer patients, they had to have one or more prior line of chemo and had to have relapsed or advanced disease. This important study was conducted in two parts.
In part one, they evaluated selinexor in patients with these advanced gynecologic malignancies that were treated at 50 mg per meter squared biweekly in a 28-day cycle. To optimize tolerability based on results from part one, the protocol was then amended to include a part two which tested additional dosing schedules in the more homogeneous ovarian cancer population. Next slide, please. The endometrial cancer cohort was very heavily pretreated with median prior regimens of two, but the range was 1-5, and nearly 50% of patients on this study received 4-5 prior lines of therapy. Among the cohorts, endometrial cancer had the highest disease control rate at 35%. The objective response rate in the endometrial cancer cohort was 13%.
The median PFS was 2.8 months, and median OS was seven months. These efficacy endpoints are very comparable to what we have seen with other monotherapy agents in advanced endometrial cancers. Again, it was encouraging to see this level of activity in such a heavily pretreated patient. As far as adverse events are concerned, the treatment-related adverse events that occurred in greater than 10% of patients, the most common, as expected, were nausea, fatigue, decreased appetite, vomiting, weight loss, but these were predominantly grade one and grade two. As my colleagues have stated before me, reproducible AE profile I think is really important to know about this agent. Very well controlled with supportive care, primarily anti-emetic therapy. In some instances, referral to nutrition therapy can help.
You know, frequent visits and when needed, dose adjustments. I think the weekly schedule really has been very important in helping to mitigate some of these more common and known toxicities related to selinexor. Next, please. In ovarian cancer and other malignancies, delayed DNA damage repair has been reported when selinexor is combined with DNA damage inducing chemotherapy and radiation therapy. With this background, a non-randomized open label phase I investigator-initiated study that used the standard three plus three dose escalation design was initiated, and this trial assessed selinexor plus the standard of care, which is carboplatin paclitaxel combination chemotherapy in advanced ovarian and endometrial cancers, including the more treatment recalcitrant subtypes such as carcinosarcomas.
In this study, patients had to have pathological confirmation of their disease, and patients with ovarian cancer had recurrent disease and had to have received one prior line of platinum-based chemotherapy. That could be in any standard form. They could have had prior bevacizumab or PARP inhibitors. In the endometrial cancer cohort, patients were either chemotherapy naive or received one prior line of platinum-based chemotherapy. Patients had to have measurable disease. The primary objective of this study was to evaluate the safety and tolerability of this combination approach and to determine the recommended phase II dose of selinexor in combination with platinum-based chemotherapy in this specific population. We also evaluated a secondary objective overall response rate, duration of response, PFS and OS.
Patients were enrolled regardless of disease type to one of four alternating dosing regimens, where we evaluated the Q3 week carboplatin paclitaxel and weekly paclitaxel plus Q3 week carbo, which are both standard dosing schedules in advanced gyn cancers and selinexor at 30 mg/m² bi-weekly versus 60 mg weekly. The combination of selinexor plus platinum-based chemotherapy was administered for six cycles but could be extended up to 10. If patients were doing well, they could continue to receive selinexor as maintenance therapy following chemotherapy at the same dose and schedule as administered during chemo, and treatment continued till PD, unacceptable toxicity or withdrawal of consent from patient.
We concluded at the completion of this study that combination selinexor plus carboplatin paclitaxel chemotherapy was A, safe, and B, well-tolerated in advanced ovarian and endometrial cancers. The recommended phase II dose was defined as 60 mg Q weekly in combination with chemotherapy. Next slide. This just breaks down the patients a little bit more and speaks to some of the efficacy that was seen. Twenty patients were included in the efficacy assessment. Eighteen endometrial cancer patients were included and were treated, and 10 of these had relapsed disease. Of these patients, 10 achieved a partial response as their best response. Again, these patients had really high-grade histology for the most part.
Four had serous cancer, two had carcinosarcomas, four had endometrioid adenocarcinomas, but of those two were high grade as well. Responses were noted in both newly diagnosed and platinum refractory patients. The longest median PFS of 11 months occurred on regimen three. OS was not reached for regimen three and was 34 months for regimen two. These efficacy parameters compare very favorably to frontline chemotherapy efficacy that was seen on GOG-0209, which really established carboplatin paclitaxel as the standard of care for patients with advanced or recurrent endometrial cancers. We concluded that selinexor at 60 mg Q weekly was the way to go, in combination with paclitaxel at the weekly dosing plus carboplatin, that this was really the most efficacious approach.
On this study, given the overlapping adverse events with chemotherapy and selinexor, the attribution of treatment-related adverse events were related to treatment regimens, not to individual drugs. But again, not surprisingly, the most common toxicities that we saw were the cytopenias, and the most common grade three, grade four treatment-related AEs were again, cytopenias and hypomagnesemia. We were encouraged that the AE profile in general was really easily managed with dose delays, reductions and supportive care. No new safety signals were identified, and no patients had death related to study treatment. Next slide, please. This leads us to the SIENDO trial, which is an international randomized double-blind phase III trial of maintenance therapy with selinexor versus placebo after combination chemotherapy for patients with advanced or recurrent endometrial cancer.
The rationale for this study was to obtain evidence of efficacy for maintenance selinexor in patients with advanced or recurrent endometrial cancers. We know that disease-free intervals become shorter and shorter in endometrial cancer in the relapsed setting. I think what's important to remember is that relapse doesn't just mean that it's time to initiate another type of palliative treatment, but it also means that patients are going to endure treatment-related toxicities and disease-related adverse events. It's important to keep in mind that endometrial cancer patients are often medically complex with multiple medical comorbidities such as metabolic syndrome, obesity, hypertension, diabetes, and these can make treatment of relapsed disease extremely challenging.
Endometrial cancer patients, I think, also desire maintenance therapy after you know, completion of chemotherapy, which for some can be difficult to tolerate, and there can be lingering side effects such as neuropathy, for example. I think oral therapies are in general, highly preferred by patients. I think it's tough for patients after they've completed their adjuvant therapy for advanced disease to just sort of now go to watchful waiting, and really improved therapeutics in that space are direly needed.
Given all of this and given what we know regarding the mechanism of action of this drug and prior data from studies in endometrial cancer, this phase III maintenance trial was devised. In this study, eligible patients included those who completed a single line of a taxane platinum-based combination therapy for primary stage 4 endometrial cancer and patients who received taxane platinum combination therapy for first relapse. This would be relapse after primary therapy, including surgery and/or some form of adjuvant treatment for stage 1 to 4 disease. Patients had to be in a complete or partial remission after completion of chemotherapy. Importantly, this study allowed for the more difficult to treat subtypes such as serous, undifferentiated, and carcinosarcomas of the uterus.
Stratification factors included stage four versus recurrent disease at time of taxane platinum chemotherapy and disease status after chemo, so PR versus CR. The primary endpoint is PFS from randomization until time of death or progression as determined by the treating investigator. In this event-driven study, the study has a hazard ratio of 0.6, which corresponds to 67% increase in median PFS, assuming median PFS of 4.5 months for placebo versus 7.5 months for selinexor. This would necessitate 248 eligible patients being randomized in a 2:1 fashion to selinexor once weekly, starting at 80 mg versus placebo once weekly. I think with this, I'll turn it back up to Jatin. Thank you for your time.
I appreciate being able to present.
Great. Thank you.
Thank you so much, Dr. Makker
Just to close on that last comment, again, the trial has completed enrollment, and we expect top-line data in the first quarter of 2022. Over to you, Sohanya. Sorry.
Thank you, Jatin. There will be over 66,000 cases of endometrial cancer in 2021, with approximately 14,000 frontline patients who will have advanced or metastatic disease and are treated with chemotherapy. This addressable patient population in the maintenance setting is expected to grow over time with new and more effective therapies. We believe that selinexor is well-positioned in this space with currently no approved drug therapies, post-chemotherapy in the maintenance setting to prolong response and remission. Single-agent selinexor has already shown robust results in a phase II study in patients with progressing endometrial cancer in second line and later. There are four key areas we're focused on in the near term that pave the way for a successful launch. First, deliver clinically significant results from SIENDO and rapidly engage the FDA and submit our supplemental NDA.
Second, similar to the ovarian cancer treatment space when PARP inhibitor is launched, we will provide disease state education to physicians on establishing endometrial cancer maintenance as a standard of care versus the current watch-and-wait approach. Third, we plan to utilize our current field medical and access capabilities and build upon this to ensure an efficient and effective launch. Finally, we will expand our relationships with opinion leaders and patient advocacy groups. From a commercial standpoint, we are excited about the opportunity ahead in this space to bring transformative value to patients with endometrial cancer. With that, I'll now turn things back to Jatin.
Thank you, Sohanya, Dr. Coleman, and Dr. Makker. To summarize, there's a significant unmet need for maintenance therapy in endometrial cancer. The SIENDO study attempts to address this unmet need and is well-positioned as an easy-to-administer once weekly oral therapy that can be taken at home. This is an important feature of long-term maintenance therapy. The trial has completed enrollment, and we're optimistic in the outcome of the trial. It is an event-driven endpoint. We expect the top-line data shortly. We're planning for success with a rapid sNDA submission. With that, now we'll open the line for questions from the audience on the endometrial cancer program.
If you would like to ask a question, please press star followed by the number one on your telephone keypad. Again, that's star one for any questions. As a friendly reminder, please limit yourself to one question. We'll pause for just a moment. The first question will come from Brian Abrahams with RBC Capital Markets. Please go ahead.
Hi. Thanks for that great overview, and I appreciate you taking my question. I guess for the physicians, I'm curious what you believe makes selinexor most optimal, either mechanistically and or based on the data, for use in maintenance in this setting versus in a combination. I'm also curious if you could maybe comment on the toxicity bar here, just given the significant tox you alluded to with the available therapies, how you guys will be thinking about the balance of safety versus efficacy, coming out of the SIENDO data as you determine whether or not you might use the drug in this setting. Thanks.
Thanks, Brian. I'll have Dr. Makker start, and I think she can comment on her experience so far, but also kind of her experience with managing selinexor on the trial, from a side effect profile perspective as well, and her thoughts about if the data is positive, what kind of uptake will there be in the community and the interest in something like this. Dr. Makker?
I'll speak to the first half of the question first, which was, you know, its applicability, as in this space but also in combination. First of all, I think that this drug has a really unique mechanism of action, and there is now really robust data that shows that it is synergistic with a broad class of therapies, whether they be chemotherapy, targeted therapies such as PARP inhibitors, for example, immunotherapies, that this agent, the selinexor, can really partner and be combined with a wide variety of classes that I think are absolutely relevant in endometrial cancer. I think there's a profound amount of growth and development that can take place in that arena.
With regards to whether this, if the SIENDO trial is positive, whether there would be uptake, I can tell you that based on my experience, not only on study, but just in the real world, I think that there really is a tremendous need to develop efficacious maintenance therapies for these patients that often have, you know, a disease-free interval of a few months. When we need to restart them on therapy, they're still dealing with a lot of toxicity from their frontline therapy, fatigue, asthenia, weight loss in some cases, neuropathy in others, and really, you know, having a tough time, having the performance status to be able to do second and then, you know, further lines of therapy. I think there is a tremendous unmet need.
I think that our patients would absolutely want to partake in maintenance therapies that are effective. With regards to the toxicity profile, you know, I've worked with this compound for many years now, and I can tell you that compared to lenvatinib and pembrolizumab, for example, where AEs occurred in almost 90% of patients, dose reductions were necessitated in over 70% of patients, and that this agent does compare favorably with regards to the toxicity profile in a very significant way. I agree with the comments that were made by my colleagues previously. I do feel that the toxicity is not cumulative. I feel like the toxicities are really quite easy to manage.
We utilize a lot of prophylactic antiemetic, simple things that are readily available, such as ondansetron, drugs like, you know, olanzapine when needed, nutrition referral, hydration if needed. These are things we do for patients that are on chemotherapy also, by the way, routinely. I think, you know, that the drug has an AE profile that largely is easy to manage. We haven't seen a lot of issues with diarrhea and some of the other side effects that were noted in the myeloma population. I think compared to other therapies that are available in the second-line setting, compared to TKIs and targeted therapy, certainly the side effect profile, the AE profile of selinexor compares favorably to those agents.
Thank you so much. You know, Dr. Coleman, love to get your perspective as well. You know, thought about use of maintenance therapy and the uptake and the interest for this.
Sure. Thank you. Yeah. I think Vicky hit it right on target. What people have to remember is that most of the women, if you look at the advanced stage patient who is treated with just chemotherapy, that short PFS is representing the fact that tumor is not gone. It grows because those patients have finished therapy. I think we underappreciate the amount of disease is residual at the completion of chemotherapy, and this has actually driven the whole space of maintenance therapy because maintenance is not prevention. Maintenance is treatment. The reason we like to incorporate this is it's an alternate strategy that's based on tumor biology that is relevant to the tumors that have been studied, particularly those most aggressive types, as Dr.
Makker mentioned with p53 mutation that annotates the carcinosarcomas and the high-grade serous uterine serous carcinoma. If you think about it from that standpoint, maintenance if we could find the effect of maintenance, that's the key. That's why the PARP inhibitors have been so revolutionary in ovarian cancer. It's 'cause it's a treatment for small volume disease that's residual after chemotherapy, and it had a huge impact. We're very excited to have something here because we haven't had one. I think that with respect to uptake, something that works, even with a lot of toxicity, would be acceptable to patients, but this isn't that. We're hopeful that the maintenance strategy will work out in endometrial cancer.
Our previous attempts at this have not been all that successful. This, you know, aligns with the molecular biology that annotates the population, which we think is at most risk. We're very excited about the opportunity here.
Thanks so much.
Thank you, Dr. Coleman.
Yeah.
The next question will come from Jonathan Chang with SVB Leerink. Please go ahead.
Hi. Thanks for taking my questions. From the call for endometrial, how should we be thinking about what the benchmark or bar is in first and second-line endometrial maintenance, given that this isn't a part of the treatment paradigm today? For the management team, will you be providing preliminary Q4 and full year 2021 XPOVIO sales in January, as you have in the past? Thank you.
Yeah. Thanks so much, Jonathan. You know, I think when we think about the benchmark for how we design the trial, you know, there is really not a clear dataset. We've really compiled a number of different datasets for outcomes post first line as well as recurrent disease in this setting, including patients in the PR and the CR. We also have a number of different histologies that we've included to be all-encompassing to capture the entire endometrial patient population. Very heterogeneous patient population. As you look at that broadly, you know, the assumption that we have is a benchmark of 4-5 months. I think that's consistent with Dr.
Makker presented, where there's about an 8- 14 month PFS seen in other trials, but that includes all starting from including chemotherapy and the benchmark that we provide of 4- 5 months is after that chemotherapy. It adds up. Dr. Makker, your thoughts on the benchmark that we expect to see in this patient population.
No, thank you for that question. I think that the study's construct of this study very much, you know, have been very thoughtful, as you said, sort of keeping in mind the heterogeneity in this disease. I do think absolutely, you know, reflects what we see from other studies and I think very appropriate. You know, the median PFS certainly is, as I said, in the recurrent disease setting is on the order of three months and in the frontline setting is not much longer. I think that this absolutely is in line with how I would think about it.
Yeah. This is Rob. The one thing I would add to that is I think you guys just need to go look at GOG-0209's PFS curve to get an-
Yeah.
Appreciation about how terrible this disease is. If you look at that curve carefully, you'll see that within the first six months or so, we have lost, you know, nearly 50% of our patient population.
Correct.
That's those are patients who started chemotherapy, so they're progressing while on therapy. But also the patients that are getting the therapy, they're progressing at the same velocity, which is tragic.
Okay. Thank you.
Thanks. Jonathan, with regards to your other question, yeah, as we have in the past, we'll provide top line revenue at JPM. Also in Q1, we will be giving guidance for 2022.
The next question.
Got it. Thanks for taking my questions.
Mm-hmm.
The next question is from Colleen Kusy with Baird. Please go ahead.
Great. Good morning. Thanks for taking our questions. How many of the endometrial patients do you expect to be in the community setting, and how comfortable do you think community docs would be with the use of XPOVIO in the maintenance setting?
I think, yeah, thanks so much for that question, Colleen, regarding the number of patients in the community versus the academic center. I'll have, Sohanya, start with this.
Yep, absolutely. A couple of things. Many of these patients, the majority of them are treated in the community by a mix of gynecologic oncologists and medical oncologists. Just wanna note from a commercial standpoint, we have strong account overlaps in both medical oncology practices in the community as well as the large academic institutions building upon our current capabilities. As far as the experience in the maintenance setting, let's remember that the gynecologic oncologists and medical oncologists are building on the foundation of experience in terms of maintenance treatment that they have with ovarian cancer. On top of that, there's a high unmet need in advanced endometrial cancer setting, so they'll be building off of that experience that they already have.
Thanks so much. Yeah, Dr. Coleman, love to get your perspective on this, you know, as the leading US Oncology Research and all the community practice that you have a kind of a firm.
Yeah.
Sort of understanding and experience with this. Love to get your thoughts.
Yeah. Well, you know, it's interesting the question was made because I think our two biggest programs are myeloma and GYN oncology. It's actually a very nice mix of the two. I think we have. I can do a heat map of the United States and show you the density of both of those within the practices that are. We see a tremendous number of patients with that. Again, you know, I don't, you guys should stop thinking about this as something different than just treatment. Maintenance is treatment. Our experience with treatment in patients whether they have you know multiple different indications for which this drug is being explored and already approved, it's gonna be translatable completely to the maintenance setting.
It's about how to counsel patients as to what their treatment plan's gonna be. That's very easy to do because most patients are afraid that if they stop their treatment, the tumor's gonna come back, and they should have good reason for that, right? If you look at those survival PFS curves, as I mentioned, you'll see what the world we live in. The experience with administering this drug as a quote "maintenance" is basically the same as the experience we have with administering it as a treatment. It's just about preparing the patient for what the treatment package is gonna be if it involves an induction chemotherapy segment.
Perfect. Thanks so much, Dr. Coleman.
Very helpful.
The final question is from Ed White with...
Do we have time for one more question?
Yes, sir. The final question is from Ed White with H.C. Wainwright. Please go ahead.
Good morning. Thanks for taking my question. So you had mentioned several times about the PARP inhibitors in the ovarian market. You know, the three PARP inhibitor companies have only managed to penetrate less than 50% of the ovarian maintenance market, you know, versus watch and wait. What are your learnings from that? What do you see that they did perhaps wrong? You know, what can the company do to penetrate that market better in endometrial?
Yeah, great question, Ed. Maybe I'll start with just a few comments and then we'll have Dr. Coleman and Makker comment. I think fundamentally, when you look at options that are available to patients, either maintenance or relapse, that gives those patients an option, i.e., if I don't treat them with maintenance, I still have that option in relapse. That's fundamentally different in endometrial, where there are no maintenance options and limited to very few relapse options. You're going to use your best therapies early. You don't have that option of saving it for relapse like you do with PARPs in ovarian. Therefore, because of that rationale's position, they're gonna be more inclined to use their available options when they're available, which is it.
I think that that's a fundamental key difference, but I'd love to get Dr. Coleman and Dr. Makker's kind of perspectives on this space. Maybe start with Dr. Makker.
Yeah, I wholeheartedly agree with your comments. I think this comes up in clinic a lot, right? Which is, you know, do I use the PARP inhibitor upfront? Do I think this patient's gonna have a nice disease-free interval? Oh, but I have the option of using it later on. I think a lot of patients, you know, when they've had their upfront chemotherapy and are still recuperating from chemotherapy side effects, really don't wanna take on, you know, the weekly lab draws, the cytopenias that can develop, the pretty, you know, moderate nausea that can occur with PARP inhibitors. And just the constant sort of, you know, close follow-up that's required, at least in the first couple of months because they know they can receive it later. I wholeheartedly agree.
As you said, you know, those options don't exist for our patients. I think that's a really important point. We just have nothing. I think that this is a markedly different disease, markedly different response rates to chemotherapy, markedly shorter progression-free survival after frontline therapy, metabolically more complex patients. These are delicate patients. You know, the average endometrial cancer patient is not your average ovarian cancer patient. This is a very different disease. I think, you know, capitalizing on the gains made with chemotherapy, with maintenance therapy after frontline chemotherapy will be imperative in this particular disease.
Thanks so much, Dr. Makker. You know, I think great questions coming in this session. Appreciate that. Thank you so much, Dr. Co, Dr. Makker, for joining us today and providing your perspectives on endometrial cancer landscape and the opportunity and the need here for endometrial cancer patients. I think in lieu of where we're at with the great questions and the timing, we're gonna skip our 10-minute break and move on into our third core program. We'll be discussing MDS and myelofibrosis next, and then we'll present both of them and have a Q&A session at the end of the combination of MDS and the myelofibrosis sessions. Now we'll turn to our third core prioritized program, myelodysplastic syndrome or MDS. We'll be joined by international leader in MDS, Dr.
Guillermo Garcia-Manero, who's a professor of medicine at MD Anderson Cancer Center and chief of the section of MDS and the deputy chair of Translational Medicine. He'll review the treatment landscape, challenges and opportunity, and data with eltanexor in MDS. First, a little background. Approximately 15,000 patients each year are diagnosed with high-risk MDS that needs therapy. Currently, the only class of drugs that are approved are hypomethylating agents, also known as HMAs. HMAs are not curative, and once the disease progresses, there are no other approved therapies, and survival is very short, along the lines of 4-6 months. There's a clear high unmet need and a real opportunity to improve survival and outcomes for patients with MDS that is refractory to HMA. We believe we have the opportunity to do so with eltanexor based on the phase I data.
Now I'd like to turn over to Dr. Guillermo Garcia-Manero, who will discuss the MDS treatment landscape as well as the data from the phase I study evaluating eltanexor in patients with HMA-refractory MDS. Dr. Guillermo Garcia-Manero.
Thank you very much for this opportunity, Jatin, and for listening to the conversation. I'm gonna discuss a particularly difficult group of patients for which, unfortunately today there is no really standard of care or a good alternative. Let's start with some basics. This slide shows the kind of like five subsets of, or groups of patients that we think about myelodysplastic syndrome in a functional way. On the left, you see this kind of problem phase, including patients with idiopathic cytopenias, clonal hematopoiesis, this is CVS. Then we divide those patients with proper MDS that have enough criteria into a low risk and a high-risk situation based on percentage of blood, cytogenetics, and more recently, perhaps molecular alterations. As you see in the slide, there are two main subset of these patients.
You know, patients that are previously untreated and those that we refer to as HMA failure because the standard of care, as you heard a second ago, for a majority of our patients still today is a hypomethylating agent like azacitidine or decitabine. We're gonna focus on the bottom right, high-risk MDS HMA failure. This is a major problem for our patients worldwide. Next, please. The first question is: How is this defined? Because, again, majority of these patients are treated with hypomethylating agent, there is a clear definition that is followed by the U.S. FDA and the EMA in terms of, for instance, no response after four or six cycles of HMA-based therapy. Again, either azacitidine or decitabine. Patients that progress after these drugs after at least one cycle of therapy will also be considered as HMA failure. Next.
This is a very important area of investigation in multiple centers, including here at MD Anderson, trying to understand the pathogenesis, trying to develop new targets, and for sure have new clinical trials and interventions for our patients. Next slide, please. Today, or up to today, to my knowledge, there have only been two phase III registration trials specific for this patient population. One is called the ASTRAL-3 with decitabine. This data has not been presented, so I'm not gonna show you the data. I was the PI of that study, and from press release we know that this was a negative trial. The second study that actually indeed was the first, was published in Lancet Oncology a few years ago, and this was the so-called ONTIME trial with the rigosertib compound from Onconova, the ON01910.
This was a large multi-center trial that basically was open in many continents around the world. Patients were randomized to rigosertib versus best supportive care. As you see there, the median survival with this multikinase inhibitor, the Onconova compound, was around 8.2 months versus best supportive care with around 6 months. Next. This is the Kaplan-Meier plot. I have to also say that the best supportive care in this study actually could be some type of treatment, including low-dose cytarabine or some other intervention. As you see there, the P value for this curve was around 0.3, and the hazard ratio was around 0.87. Unfortunately, this was not deemed enough by the U.S. FDA to warrant an approval of this particular compound in our patients.
Why this was published in Lancet Oncology, that as you know, is one of the top journals in our field, is because this in a way served as a true prospective evaluation of the natural history of patients with a hypomethylating agent failure disease. This actually is the expected natural history of this disorder. Next, please. We tried to do some analysis in terms of different cytogenetic alterations. As you see here, some examples with monosomy seven, trisomy eight. There was also some differentiation in terms of what they call primary versus secondary HMA failure. This resulted on the INSPIRE trial that unfortunately also was not, quote-unquote, "a positive study." Next. As of today, there are actually not many interventions for our patients. Most of the clinical trials that are open right now actually focus on the frontline context.
There are some data that I'm gonna briefly review here, for instance, with venetoclax, the BCL-2 inhibitor that is actively being investigated in MDS, in combination with an HMA. This is gonna be updated this weekend at the ASH meeting. This is from last year, or actually I should say two years ago, ASH meeting by Dr. Seydan, with the center trial that I was part of. phase I of venetoclax in high-risk HMA failure. Next slide. As you can see in this graph here, is that as a single agent, this compound has basically no activity in high-risk myelodysplastic syndrome. Combined with a hypomethylating agent, you see there an overall response rate of around 40% or something like that. Next, please.
When we see the overall response of this compound, again, is around the lines that we saw with the rigosertib story by itself or in combination with a hypomethylating agent. Next. Indeed, there is no, as far as I know, phase III randomized study looking at this particular compound in patients with high-risk myelodysplastic syndromes. What we do right now in our community is some patients may be candidates for some form of intensive chemotherapy. They tend to be younger. Some of these patients may have some targeted alteration, like IDH1, IDH2, some of them FLT3, but these are sporadic, and they do not account for more than around 20% of the patients.
In the next slide, I'm gonna show you the data that we have with eltanexor in MDS and indeed actually why MD Anderson decided to be part of the ongoing trial. This was presented at EHA 2021, so you may be familiar with this data. Basically here again a small pilot exploratory trial in patients with high-risk MDS, 20 patients. There were different doses of the eltanexor, as you see there, 10 or 20, and you can see basically the schedule on a 28-day cycle. Next. These are the demographics of these patients. Median age 77 years. The median age of patients with MDS is around 72-74 years, so this is right on target. A majority of these patients were primary refractory.
This means that they never had a response. As you can see from the IPSS risk score, a majority of these individuals had a high-risk disease over 60%. A third of them had an intermediate disease. Based on MD Anderson score that we used, that is a little bit different than the IPSS risk score. Again, 80% of them will be in an intermediate to high risk situation. The most commonly used hypomethylating agent worldwide is azacitidine, and you see that there. Now, you see that also there's 55% of these patients with decitabine or the oral decitabine. This means actually that these patients got more than one line of therapy. Next.
One thing that is very important and that perhaps could differentiate some of the data I'm gonna show you from our experience with the Onconova compound, and here I'm not judging the Onconova compound, I'm using it as kind of like our first randomized phase III study. This is our kind of threshold to build in a way. The response rate with the rigosertib compound was very small. It was a low rate of responses that we saw with that particular compound. I think in this disease, in HMA failure MDS, having an equilibrium between the toxicity but some responses that then could translate into overall improvement in survival is really important.
Indeed, here we see that in the experience in this original study with eltanexor in high-risk MDS, the overall response rate was over 50%. You see there that these responses were basically what we call mCRs being around 60% with eltanexor at 10 and basically around 40% with the higher dose. You see the median time to response around 8-9 weeks. This is in line with other therapies. This suggests that this compound in this group of patients has activity. Next, please. This is the preliminary experience in terms of survival with this compound in this highly refractory poor risk group of patients.
The important thing, I'm going back to this issue of the response, is that those patients that achieved MCR, so this is basically an improvement in their blood and their bone marrows, had a median overall survival that was close to 12 months. For all patients, actually, it was close to, like, 10 months as you see there. Patients that had progressive disease, of course, did poorly. You see that around three months or so. In this small cohort exploratory trial, we see a survival that is starting to break from our prior experience with other compounds in this context. Next. With this, I'm gonna conclude here. I think it's obvious that HMA-refractory MDS is in need of new approaches.
This is something that we've been working for many years, and in a way we're kind of desperate. This is really a major unmet need because majority of patients with MDS are indeed treated with a hypomethylating agent. As you just heard, there is no good standard of care for our patients. The data that I just presented to you from the EHA meeting indicates that single-agent oral eltanexor was active in patients with high-risk MDS that is primary refractory to a hypomethylating agent. Those patients that had evidence of a response, in this case indicated by this MCR, had actually a survival that was significantly longer than expected and better than those without that kind of response.
Therefore, we strongly support the notion that we need further evaluation of eltanexor in MDS as a single agent, and actually also in combination with other agents in patients with myelodysplastic syndrome, both in relapse refractory setting, where I think the major need is right now, but also in a frontline setting. Next. With that, I want to thank you all for this opportunity.
Thank you, Dr. Garcia-Manero. As you mentioned, you know, further study is warranted. Based on that exactly, we've started a phase II expansion study evaluating single-agent eltanexor in HMA-refractory MDS, as seen here. This trial enrolled approximately 83 patients, with the first patient dosed in September of 2021, and we expect top-line data reporting in the first half of 2023. Again, this is looking at single-agent eltanexor based on the initial phase I experience in patients with high-risk primary refractory MDS. With that, now I'll turn it over to Sohanya to talk about the potential market opportunity.
Thank you, Jatin. We are excited for opportunity and unique value proposition of our novel compound, eltanexor, in the MDS space. It is estimated that approximately 15,000 new cases of intermediate to high-risk MDS occur in the U.S. annually, with a prevalence of between 60,000 and 170,000 at any given time. With an aging population and improving awareness of the disease and new options entering the treatment space, we expect the incidence and treatment rate to increase. We believe we are well-positioned to serve patients in the HMA refractory disease space. Since there is no class of drugs approved, the disease prognosis is poor, and there is a dire need for a class switch following HMA treatment. Ongoing agents in development externally are focused in newly diagnosed MDS, leaving a wide space in the HMA refractory setting for a novel efficacious agent.
We're focused on four key areas in 2022 as we prepare for a successful launch. First, continue with rapid trial enrollment to deliver clinically meaningful efficacy in HMA refractory MDS. Second, develop and deepen relationships with key MDS investigators educating on SINE technology. Third, educating on the benefit of a class switch following progression or intolerance to HMAs. Finally, leverage existing internal capabilities and infrastructure in the hematology setting. We remain committed to serving this growing population of high-risk MDS patients that face a significant need for a better outcome. Back to you, Jatin.
Thank you, Sohanya. In summary, there's a clear unmet need and an opportunity in HMA refractory MDS. We have robust single-agent data with a 53% response rate and overall survival greater than 10 months that is compelling. We're accelerating our development program in MDS and have the potential to be the first new approved class of therapy in HMA refractory MDS. We're also exploring, as Dr. Garcia-Manero mentioned, in combination with HMAs in frontline as part of our development program. We will save questions from MDS until the end of the myelofibrosis presentation by Dr. Tantravahi. With that now I'd like to pivot and review our fourth core program, myelofibrosis. In this section, we'll be joined by Dr. Srinivas Tantravahi, who's an assistant professor of Hematology and BMT at the University of Utah and the lead investigator of the Essential trial evaluating selinexor in myelofibrosis.
His work will be presented for the first time in an oral presentation at ASH 2021, and we're very excited to have him with us today. First, a little background. There are approximately 5,000 patients per year in the U.S. diagnosed with myelofibrosis. Myelofibrosis is a specific type of blood cancer affecting the bone marrow that leads to extensive scarring or fibrosis in the marrow and is associated with significant anemia, weakness, fatigue, and splenic enlargement. The only class of drugs approved in myelofibrosis are JAK inhibitors. Unfortunately, these are not curative, and 60% of patients do not respond. Even among the 40% of patients who do respond initially, the response lasts at most four years. There is no other class of drugs approved, and survival is short for these patients, typically less than 14 months.
In this setting, we have promising data with once-weekly low-dose selinexor that Dr. Tantravahi will review, along with information around the treatment landscape. Now it's my pleasure to introduce Dr. Tantravahi.
Thank you, Jatin. It's my privilege to be here to discuss selinexor as a potential novel non-JAK inhibitor treatment option for myelofibrosis. Next slide, please. Myelofibrosis, as already introduced by Jatin, is an advanced incurable form of blood cancer. The prevalence of the disease is estimated to be 4-6 cases per 100,000. The estimated five-year survival of myelofibrosis is only 5% per the data from U.S. Medicaid enrollees. Population-based studies done in countries like Sweden also showed that patients with MF have worse survival compared to other MPNs and also the general population. Next slide, please. Patients with myelofibrosis experience debilitating symptoms and a very poor quality of life.
Majority of the clinicians that treat MF can recognize these patients when they first present with constitutional symptoms, particularly weight loss and cachexia. In addition, they experience fatigue, night sweats, decreased appetite, and bone pain, and many of these symptoms are attributable to markedly increased circulating inflammatory cytokines. As detailed earlier, the disease disrupts normal blood cell production in the bone marrow, causing low blood count, such as anemia, low platelets, and infections. One of the characteristic features of this disease is markedly enlarged spleen, but the spleen doesn't contribute much towards blood cell production, but instead causes significant discomfort, early satiety, and a very poor quality of life. In addition, there are several disease-related complications such as blood clots, portal hypertension, pulmonary hypertension, although the latter two are somewhat rare.
The major event that contributes to the majority of the morbidity and mortality of the disease is progression to acute leukemia. Next slide, please. The discovery of JAK2 mutation in 2005 was a landmark event in both the diagnosis and therapeutic aspect of myeloproliferative neoplasms, particularly myelofibrosis. Subsequently, two different gene mutations are described in MPL and calreticulin. These mutations are mutually exclusive, and they lead to constitutive activation of JAK-STAT pathway, which is central to the pathogenesis of myelofibrosis. The discovery of these mutations led to the development of JAK inhibitors. There are currently two agents that are approved for treatment of myelofibrosis, ruxolitinib and fedratinib. Next slide, please.
This slide illustrates the drug development in myelofibrosis at this time, which is focused mostly in combination with JAK inhibitors both in the frontline and also in the relapse setting. Next slide, please. JAK inhibitors are effective in the treatment of myelofibrosis. They decrease the size of the spleen, improve constitutional symptoms by decreasing the inflammatory cytokine profile, and also overall improve the quality of life. There are many limitations to JAK inhibitors. The major limitations are worsening of preexisting blood counts. JAK pathway is also involved in the normal production of blood cells, so inhibition of JAK pathway will cause anemia and low platelets. As detailed, the responses are transient in many patients and suboptimal in some of the patients.
Moreover, we know that there was limited effect on the biology and natural history of this disease. Therefore, we need improved therapies that can significantly alter the course of the disease and also improve outcomes. Next slide, please. This slide illustrates the major unmet need in patients with myelofibrosis that become refractory or intolerant to JAK inhibitors. Approximately 70% of patients with newly diagnosed myelofibrosis are treated with JAK inhibitors. Only about 20% or less than 20% will receive allogeneic stem cell transplant, which is currently the only curative therapy.
The reason for this low number is the lack of suitable donor and also advanced age of the majority of these patients. Among patients that are treated with JAK inhibitors, it is estimated that 60% will require a salvage therapy, therefore, after a median duration of approximately 2-3 years. Therefore, there's a major unmet need for new agents after failure of JAK inhibitors, and at the moment there are no approved agents. Next slide, please. Our group has previously shown that nucleocytoplasmic transport inhibition is a novel therapeutic target in myelofibrosis. In summary, the JAK2 mutant cell lines such as HEL and SET-2 are exquisitely sensitive to selinexor.
Selinexor also selectively decreased the proliferation and increased the apoptosis of patient-derived myelofibrosis cells in comparison to normal cord blood cells. In addition, we observed an additive effect of selinexor with ruxolitinib in killing the myelofibrosis cells, but also in alleviating the disease burden in a mouse model, which is not detailed here. Next slide, please. This preclinical data investigating selinexor actually originated from an initial library screen that I had performed. In that genetic library screen, the proteins involved in the nucleocytoplasmic transport, such as XPO1 and Ran, were in the top 10 targets. Therefore, we investigated selinexor since there is a pharmacological agent to inhibit this pathway. We found that selinexor decreases the proliferation and increases apoptosis of these JAK2 mutated cells.
More importantly, in our lab, we generated a cell line that is refractory to ruxolitinib. In the far right panel, you can see that selinexor and eltanexor, the SINE compound, is effective in killing these cells. Next slide, please. Based on that strong preclinical data, an investigator-initiated study was performed in our center at the Huntsman Cancer Institute. Patients with myelofibrosis who received at least three months of prior JAK inhibitor treatment and were considered resistant either due to the presence of persistent splenomegaly or intolerant to the drug were eligible to participate in this study. We treated these patients with a single-agent oral selinexor once a week at a dose of 60 mg-80 mg weekly and continued this until progression.
The primary endpoint is spleen response, which is defined as more than 35% reduction on MRI scan or CT scan after 24 weeks of selinexor. In addition, we also evaluated the bone marrow for any changes in the fibrosis and monitored patient symptoms on the study. Next slide, please. So far we have treated 12 patients with on this study, and median age was 68 years, and majority of these patients received JAK inhibitors for an extended period of time. The median duration of JAK inhibitor therapy was 22 months. There was only one patient who received JAK inhibitor for a short duration and was intolerant to it. 92% of the patients were considered resistant to prior JAK inhibitor therapy. In myelofibrosis field, we have now discovered certain mutations that carry a high risk prognosis profile.
87% of the patients that we treated had at least one high-risk molecular mutation. Next slide, please. This slide illustrates that the single-agent selinexor once a week resulted in a sustained spleen response in patients that are previously refractory to ruxolitinib. At 24 weeks, 33% of the patients showed more than 35% spleen volume response. We have a little bit more mature data that we'll be presenting at this weekend at the ASH conference. Next slide, please. In addition to the spleen response, more excitedly, we did not see any worsening of preexisting blood count. Moreover, we actually saw an improvement in hemoglobin in majority of the patients. We observed hemoglobin improvement in patients who had a baseline hemoglobin of less than 10 g, but not requiring transfusions.
We also observed transfusion independence in a patient who was requiring baseline packed red cell transfusions, and this occurred approximately 36 weeks after treatment with selinexor. The patient maintained transfusion independence for almost two years, which is a big deal in a disease such as myelofibrosis. Next slide, please. As talked quite a bit earlier in terms of side effects, nausea and some anorexia was quite common, and this was manageable with supportive care. We also observed weight loss in some patients, which was the most common treatment-related adverse event. Weight loss is a common symptom of myelofibrosis. Some of these patients gain weight on treatment with JAK inhibitors.
On this study we monitored the weight very closely, so we were capturing very every little change in their weight during the course of treatment. As of now, six patients are continued to be on treatment, and there were two patients that discontinued due to side effects. Next slide, please. I would like to illustrate the one case study to discuss the response of selinexor both on spleen and hemoglobin. This was a 76-year-old woman who was the first to be treated with selinexor with myelofibrosis. She had JAK2 positive myelofibrosis and previously treated with ruxolitinib and also a combination of ruxolitinib and azacitidine due to severe anemia requiring transfusions every 1- 2 weeks. She also had a baseline thrombocytopenia.
She was started on treatment with selinexor, initially 80 mg weekly and subsequently decreased to 60 mg weekly at week four. At week 24, the MRI scan showed almost 60% reduction in spleen volume compared to the baseline. This patient became transfusion independent after approximately 36 weeks of treatment and did not require transfusions for almost two years. The more exciting part is that we noticed a normalization of white blood cell count after 1 week of starting selinexor, and we also noted a decrease in LDH to the normal range, and it was also sustained. LDH elevation is almost near universal in myelofibrosis patients, and it reflects the advanced myeloproliferative state of this disease. This patient developed mild drop in platelet count, which didn't require any further dose reduction.
Also had weight loss, which was managed with supportive care and also dose reduction of selinexor. Next slide, please. My final remarks are that there's a huge unmet need for new treatment options for patients with myelofibrosis after failure of JAK inhibitors. In our study, in a single center, we showed single agent activity with spleen responses and also a potential for hemoglobin and anemia response in MF patients that are refractory to JAK inhibitors. The treatment was well tolerated with three out of 12 patients being on the study drug for up to two years. Based on this data, two registration studies are initiated, which we are also participating and enrolling patients. One is a phase I study in combination with ruxolitinib in JAK-naïve patients.
The other study is for patients that are previously treated with JAK inhibitors and became refractory. There's also potential for future combination studies with other agents that are currently being developed in this space, including BCL-2 inhibitors and BET inhibitors. Please tune in to my presentation on Saturday at this weekend's ASH conference. Thank you for having me. I think that is my last slide, and I would be happy to take any questions.
Thank you, Sri. Really appreciate it. Great data with a single-agent SVR rate of 33%, improvements in anemia, and the durability of response. Again, please note they'll have updated data because what we saw here is that these responses deepened with time, and so with more follow-up, we expect a new and updated data at ASH, so please stay tuned for that. As Sri mentioned, we're moving quickly into a global randomized phase II study. This trial is recruiting patients with at least six months of prior JAK inhibition and randomizes them to once-weekly low-dose selinexor or physician's choice. 112 patients are expected to be enrolled, and we're very excited as the first patient was just dosed earlier this week. I'll now turn it over to Sohanya to talk about the potential market opportunity.
Thank you, Jatin. I'll now highlight the opportunity surrounding our fourth core program in myelofibrosis, where selinexor has the potential to improve patient outcomes in JAK inhibitor-refractory disease. In the U.S., it is estimated that approximately 5,000 cases of myelofibrosis occur annually with a prevalence of 16,000-18,500. Selinexor is well-positioned in this space as no other class of drugs are approved in ruxolitinib-refractory myelofibrosis, and there is a high unmet need for a class switch post-ruxolitinib. Furthermore, anemia side effect is a major problem with JAK inhibitor agents and limits its use in combinations in the relapse setting. As Dr. Tantravahi pointed out, with selinexor, we saw hemoglobin improvement in transfusion-independent patients with hemoglobin less than 10 g per deciliter. As we prepare for a successful launch, we remain focused in the following key areas.
Firstly, continue with rapid enrollment to deliver clinically meaningful efficacy. Secondly, developing relationships with key myelofibrosis investigators and educating physicians on our science with SINE technology and the benefit of a class switch following JAK inhibitors. In summary, as a commercial team, while we remain laser-focused in 2022 on strong execution on multiple milestones, we are also leveraging all of our existing structure and capabilities to build, prepare for launch excellence in endometrial cancer, MDS, and myelofibrosis. Now back to Jatin.
Thank you, Sohanya. In summary, similar to our MDS experience, we're excited about the robust single agent activity with a 33% response rate that we see with once-weekly low-dose selinexor in JAK inhibitor-refractory myeloma. Again, this is a disease with a single class of drugs. No other drugs approved after JAK inhibitors. We have the potential to be the first approved new class with class of drugs with clear single agent activity. In addition, we're also exploring combinations in the frontline setting as part of our development program. We'll now open up the call to questions regarding the myelofibrosis or the MDS program for Dr. Tantravahi and Dr. Garcia-Manero.
Okay, we have a question from Maury Raycroft with Jefferies. Please go ahead.
Hi, thanks for taking my question. Just wondering if you could talk more about the unique rationale behind your decision to move forward with elotuzumab and MDS. Can you talk about the predictability of safety with elotuzumab and compare and contrast this with what you see with selinexor?
Yeah, great question. Thanks Maury for that question. I think when you look at the rationale for moving forward with elotuzumab in MDS, it's really two things. One, strong pre-clinical rationale when you look at both selinexor and elotuzumab in MDS. Number two, based on the strength of the data that we saw with elotuzumab, and the key there is that we have prolonged inhibition of XPO1, and that's critically important when you're talking about a low proliferative index disease like MDS, where they need constant inhibition of XPO1. The pre-clinical model support continuous XPO1 inhibition, as opposed to the peak XPO1 inhibition that we get with selinexor. The clinical data also strongly supports this as well.
When you look at the side effect profile, essentially we see a similar side effect profile, and we're still growing our body of data with elotuzumab in the setting, but what we've seen is that this has been well tolerated with the low dose elotuzumab dosing daily.
Great. Thank you.
There are no further questions at this time.
Perfect. Thank you so much. We'll wrap up the presentation of the four key presentations.
Can you move to the next slide?
Mm-hmm.
Stephen.
Great.
Karyopharm continues to focus on global R&D and U.S. commercialization, our business development activities continue to focus on leveraging strategic partners to support this commercialization outside the U.S. This global footprint helps us to bring XPOVIO to patients worldwide with existing partners Spore in Canada, Neopharm in Israel, and AntenGene in Asia Pacific. For Europe, in parallel with ongoing partnership discussions, we are focusing efforts in two key areas. The first, centered around regulatory activities to enable an EMA decision in that second line plus multiple myeloma population. The second are activities focused on value dossier preparation that will enable reimbursement. Building on what you've heard earlier, we see a large patient pool in second line multiple myeloma outside the US that could benefit from XPOVIO, with approximately 60,000 patients in the market shown on the slide.
In endometrial cancer, the number of ex-U.S. patients approaches 40,000, with a substantial portion coming from Europe. With the potential introduction of maintenance treatment therapies, we expect those XPOVIO to play a key role in this dynamic market. With that being said, we look forward to sharing future updates on both our existing alliances as well as any future partnerships when appropriate. I'll now hand it over to Mike Mason to share more on our financials.
Thanks, Stephen. With our newly focused pipeline in multiple myeloma, endometrial, MDS, and myelofibrosis, we are confident in developing this advancing pipeline while focusing in other areas, allowing us to reduce overall R&D expenses in 2022 by approximately 15% compared to 2021. We also expect for the first time to give annual product revenue guidance when we announce our full year results in February. Cash, cash equivalents, and restricted cash and investments as of September 30th, 2021, total $209.3 million, which in combination with the revenue we expect to generate from XPOVIO product sales and other licensed revenues will be sufficient to fund our planned operations through the middle of 2023. I will now turn the call back to Richard to outline the milestones and provide some closing remarks.
Thank you.
Thank you, Mike, and thank you to all our speakers here today. As we look ahead to 2022 and beyond, the following are the corporate milestones we will be working towards. For the first half of 2022, we expect to continue to enhance our commercial capabilities and increase U.S. XPOVIO sales. To dose the first patient in our phase III study evaluating selinexor, pomalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. To report top-line data from the phase III SIENDO study in endometrial cancer. Assuming a positive outcome from SIENDO, we plan to submit a new sNDA requesting approval for selinexor as a maintenance therapy in endometrial cancer. To receive a decision from the CHMP and EMA on our MAA requesting approval for selinexor, bortezomib, and dexamethasone in patients with multiple myeloma following at least one prior therapy.
Six, commence pre-launch activities for selinexor in endometrial cancer. As you can see on the right side of this slide, for the second half of 2022 and into 2023, key milestones for that timeframe that we're working diligently to deliver on. In closing, there are four key takeaways I would like everyone to walk away with today. First, we are continuing to successfully execute in multiple myeloma, establishing selinexor as a standard of care in second-line plus, while expanding in other combinations and settings. Second, we have strategically prioritized the pipeline into four core areas of high unmet patient need, where we believe we have strong science and a high probability of success.
Third, we are focused on the near-term launch in endometrial cancer, where there is a high unmet patient need in the maintenance setting following frontline chemotherapy, which could be our first marketed indication in solid tumors. Fourth, we have the people and capital that we need to continue advancing our science and delivering for both patients and shareholders. With that, we'll take some final questions. Sorry, we ran a little bit over, but some great questions, as we were able to hear from our guest speakers and our opinion leaders. Thank you very much, and open it up for Q&A.
Once again, ladies and gentlemen, if you'd like to ask a question, please press star one. Again, that's star one for any questions. We'll pause for just a moment. Okay, and at this time, I'm showing no responses.
Thank you everyone for joining us today and again, asking so many great questions. A special thank you once more to our guest speakers and all of our employees that have helped make today possible and are continuing with their passion and focus to develop our medicines for patients in the future. We look forward to seeing many of you in person at the J.P. Morgan conference in January. Have a great day, everyone.
Ladies and gentlemen, thank you for participating in today's conference call. You may all disconnect.