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Therefore, you should not rely on these forward-looking statements as representing our views as of any later date. I'll now turn the call over to Richard. Please turn to Slide 4.

Richard Paulson -- Chief Executive Officer

Good morning. Thank you, Brendan, and thank you all for joining us today for Karyopharm's Q4 2024 earnings call. In 2024, we delivered solid financial results, delivering on our range of guidance with a profitable U.S. commercial organization and growing global demand in multiple myeloma.

We continue to execute well on our cost-reduction initiatives, reduced total expenses, particularly SG&A, while focusing resources on our Phase 3 clinical trials. Turning to Slide 5. In 2025, we expect to grow Xpovio's net product revenue, further reduce expenses, and advance our transformative programs in myelofibrosis and endometrial cancer, unlocking our innovation and growth strategy. Importantly, for 2025, we remain on track to complete enrollment in our Phase 3 SENTRY trial in the first half of this year and announce top-line data in the second half of this year.

Today, we are announcing modifications to our Phase 3 trial in endometrial cancer following discussions with the FDA in recent months. Our endometrial cancer data could become a key catalyst for us in 2026. First, let's focus on the transformational opportunity in 2025 to redefine the standard of care in myelofibrosis. As we think about our potential in myelofibrosis, it is worth remembering how we got here, which is outlined on Slide 6.

We've been taking deliberate steps over many years to put us in the position we are in today. This started with preclinical activity in myelofibrosis, followed by demonstrating a clear monotherapy signal in the essential investigator-sponsored trial that was presented at ASH in 2021. Following this, we initiated a Phase 1 study of selinexor in combination with ruxolitinib in JAK inhibitor naive patients. We presented data from this trial at ASH in both 2022 and 2023.

This data demonstrated a strong signal of benefit for the combination of selinexor and ruxolitinib. Based on this signal, we received both Fast Track designation and Orphan Drug designation from the FDA and rapidly initiated our Phase 3 SENTRY trial. We also watched and learned as other clinical trials evolved and aligned with the FDA last year on a change in our co-primary endpoint to absolute TSS. This was a very favorable change that we believe increases the probability of success of our Phase 3 SENTRY trial and a change that is strongly supported by leading KOLs and patient advocacy organizations.

We continue to progress our Phase 3 SENTRY trial faster than historical benchmarks while remaining incredibly focused on high-quality clinical trial execution. As I noted earlier, we remain on track to complete enrollment in the first half of this year, with top-line data expected in the second half of 2025. As outlined on Slide 7, leading KOLs in myelofibrosis, including Dr. Rampal from Memorial Sloan Kettering and Dr.

Mascarenhas from Mount Sinai, continue to highlight the need for new treatment options for patients with myelofibrosis and are encouraged by the strength of our data. Finally, I cannot overstate how transformational this opportunity could be for our organization. As shown on Slide 8, we believe the peak revenue potential for selinexor in myelofibrosis, if approved, is approximately $1 billion in the U.S. alone.

We are eager to see the outcome of our Phase 3 trial and the potential opportunity ahead. Now, I'd like to turn the call over to Reshma to discuss our programs in myelofibrosis, endometrial cancer, and multiple myeloma. Reshma?

Reshma Rangwala -- Chief Medical Officer and Head of Research

Turning to Slide 10. As Richard mentioned, we are focused on delivering top-line data from our Phase 3 SENTRY trial in myelofibrosis in the second half of this year. Let's start by reviewing the unmet need in JAK naive myelofibrosis on Slide 12, selinexor's potential to help patients with myelofibrosis, and our opportunity to redefine the standard of care as the first combination therapy. First, I think it is a helpful reminder that only approximately one-third of patients achieve a spleen volume reduction of greater than 35% with ruxolitinib alone.

As we have shared before, our Phase 1 data show that selinexor plus ruxolitinib more than doubles that SVR35 rate. Second, there has been a lack of new treatment options given that JAK inhibitors are the only approved class of therapies. Ruxolitinib has been the standard of care for over 13 years. As the potential first combination therapy in myelofibrosis, selinexor plus ruxolitinib would be a convenient all-oral therapy that the myelofibrosis community has clearly indicated interest in adopting given the rapid, deep, and durable spleen reductions and symptom improvement observed from the Phase 1 study.

Third, there is minimal evidence of disease modification with JAK inhibitors. As we have discussed in the past, along with the additive, it's not potentially synergistic clinical efficacy observed with selinexor and ruxolitinib. The combination also has the potential to enable disease modification. Let's now discuss why we believe selinexor as an XPO1 inhibitor is a rational mechanism to evaluate in patients with myelofibrosis, starting on Slide 13.

Selinexor prevents the nuclear export of various proteins and messenger RNA molecules. By doing so, it promotes the nuclear localization and activation of P53, an important tumor suppressor in MF given that approximately 95% of myelofibrosis patients are P53 wild-type. We'll review our data in myelofibrosis momentarily. But before we do, I think it is worth remembering that in long-term follow-up analysis from SIENDO, as shown on Slide 14, a median progression free survival of 28.4 months was observed in those patients with P53 wild-type endometrial cancer.

These clinical data further demonstrate the benefit that selinexor can achieve in tumors that are P53 wild-type. Moving to the data from our Phase 1 trial evaluating selinexor and ruxolitinib in JAK naive myelofibrosis patients, as outlined on Slide 15. Amongst the 14 patients who received selinexor 60 milligrams plus ruxolitinib, all evaluable patients achieved an SVR35 at any time, and 79% of patients in the ITT population achieved an SVR35 at week 24. Clean volume reduction is viewed as one of the most important factors by treating physicians given its correlation to overall survival.

Turning to Slide 16. Durability of response is also a key efficacy measure relevant to JAK naive patients. Our Phase 1 data demonstrate a 100% probability of continuing response for both SVR35 and TSS50 over a median duration of follow-up of 32 weeks and 51 weeks, respectively. This is particularly meaningful as it suggests that once patients achieve a response, they remain in response.

This is a reason why leading physicians have indicated that the combination of selinexor plus ruxolitinib should be initiated in all JAK naive myelofibrosis patients pending the outcome of our Phase 3 SENTRY trial. On Slide 17, the shift to Absolute Total Symptom Score as a co-primary endpoint increases our overall confidence in the Phase 3 trial. Using Absolute TSS to assess the average improvement in symptoms over 24 weeks has gained support from the FDA, investigators, and patient advocacy groups and is a more sensitive method to assess symptom improvement in myelofibrosis. On Slide 18, the depth of symptom improvement was 60 milligrams of selinexor plus ruxolitinib in our Phase 1 trial can be seen in comparison to historical data from ruxolitinib monotherapy.

The average reduction, which signifies improvement in Absolute TSS of 18.5 points with our combination, compares favorably to the average of 11- to 14-point reduction that have been observed with ruxolitinib alone in prior Phase 3 clinical trials conducted by others. The rapid, deep, and durable findings observed with SVR35 is also observed with average TSS, as seen on Slide 19. This was seen as early as week 4 despite any side effects that the patients may have experienced from the treatments. These symptom improvements continued through week 24, demonstrating meaningful sustained symptom improvement for the entire six-month duration evaluated.

For the adverse events experienced, the most common were nausea, anemia, thrombocytopenia, and fatigue. Even with this, you see very meaningful improvements in symptom scores over time. Turning to Slide 20. We continue to make strong progress toward our goal of enrolling 350 patients into the SENTRY trial and remain on track to complete enrollment in the first half of this year.

In summary, on Slide 21, I am eagerly anticipating the data from the SENTRY trial in the second half of 2025. Our clinical data thus far has shown deep spleen volume reduction over two times what has been seen with ruxolitinib monotherapy, robust symptom improvement, durable responses, a well-established safety profile with approximately 30,000 patients treated across multiple indications, and the potential for patient convenience with an all-oral combination. Now, let's shift our focus to endometrial cancer where we are providing an important update on our plans for our Phase 3 trial following dialog with the FDA over the past few months on the evolving treatment landscape. The key highlights are on Slide 23.

As you may recall, our original design for this trial involved enrolling 220 patients with P53 wild-type endometrial cancer regardless of MMR status. In late 2024 and early 2025, we had productive discussions with the FDA, during which the FDA recommended we take into account the evolving standard of care, specifically checkpoint inhibitors that were approved in combination with chemotherapy followed by checkpoint inhibitor maintenance for patients with advanced recurrent endometrial cancer. In addition, the FDA acknowledged that the efficacy observed in the PMMR tumors is less than in DMMR tumors, consistent with the biology and mechanism of this class of therapies and suggested that we focus our trial population on patients with PMMR tumors. In light of this suggestion, we are introducing a new modified intent to treat population that will consist of approximately 220 patients with PMMR tumors or patients who have DMMR tumors but are medically ineligible to receive checkpoint inhibitors.

Although this latter group may be small, we are including them given that this patient population has no other treatment options as well as the encouraging data from the SIENDO subgroup indicating that patients with P53 wild-type tumors may benefit from selinexor regardless of MMR status. Given that roughly approximately 80% of patients enrolled to date meet the new eligibility definition, the ITT population will now enroll approximately 276 patients, which will enable us to maintain approximately 220 patients in the MITT population, which are, again, P53 wild-type PMMR or DMMR medically ineligible to receive a checkpoint inhibitor. As a result of the increased trial size, we now expect to have top-line data in mid-2026. We believe that the changes that we plan on implementing may provide us with the data we need to seek regulatory approvals in the United States and globally.

Now, let's revisit why P53 wild-type is such an important biomarker that we believe can accurately identify patients who will benefit from selinexor therapy on Slide 24. Selinexor primarily functions by blocking the export of P53 from the nucleus to the cytoplasm. When P53 accumulates in the nucleus, it leads to disrupted DNA repair processes, cell cycle arrest, and increased apoptosis. This mechanism is underscored by the anti-tumor effects in P53-dependent tumors, specifically in endometrial cancer.

As seen on Slide 25, patients with both PMMR and P53 wild-type tumors make up approximately 50% of all advanced or recurrent endometrial cancer cases, representing a very sizable group of patients. On Slide 26, from the long-term follow-up of the SIENDO exploratory subgroup data, selinexor has the potential to provide promising outcomes for advanced recurrent endometrial cancer patients with P53 wild-type PMMR tumors with a median PFS benefit of 39.5 months observed with selinexor compared to the 4.9 months observed with placebo, corresponding to a hazard ratio of 0.36. Although we acknowledge the limitations of cross-trial comparisons, it's important to note that the PFS improvement with selinexor in this subgroup exceeds the median overall survival achieved by checkpoint inhibitors in PMMR patients, emphasizing selinexor's substantial efficacy for these individuals. The safety data in endometrial cancer patients from the SIENDO trial is displayed on Slide 27.

It's important to note that the adverse events associated with selinexor were generally manageable and well tolerated. Nausea, vomiting, and diarrhea were the most frequently observed adverse events regardless of grade. Notably, prophylactic dual antiemetics were not incorporated into the SIENDO trial, whereas dual antiemetics for the first two cycles are required in ECO-42 and all of our Phase 3 trials, including SENTRY. We anticipate the safety profile from our Phase 3 trials will be improved given the incorporation of these antiemetics as well as the lower starting doses of selinexor.

I remain encouraged with the potential of selinexor to achieve clinically meaningful outcomes in the maintenance setting for patients with P53 wild-type endometrial cancer. On Slide 28, we outline the updated study design for our XPORT-EC-042 trial, consistent with the key changes that I highlighted earlier. Given these changes and the increased number of patients we plan to recruit, we expect to report top-line data in mid-2026. Lastly, our Phase 3 EMN SPd trial is outlined on Slide 30.

This trial aims to address the unmet needs of patients with multiple myeloma by offering an all-oral triplet treatment option that could also benefit those undergoing pre and post T-cell engaging therapies. We have completed enrollment in this trial with approximately 120 patients and intend to provide an update once we have concluded our engagement with regulatory agencies on this trial. I will now turn the call to Sohanya.

Sohanya Cheng -- Senior Vice President of Sales and Commercial Operations

Thank you, Reshma, and good morning. On Slide 32, I will discuss our commercial highlights for 2024. Xpovio net product revenue was 29.3 million for the fourth quarter, similar to what we delivered in the third quarter and up 16% compared to the fourth quarter of last year. I am very pleased with how our organization responded to increased competition that pressured revenue last year.

For the year, we delivered within our guidance range for Xpovio, with net product revenue of 112.8 million, up from 112 million in 2023. This gain was achieved despite the introduction of new medications in the second half of 2023 into what was already a highly competitive multiple myeloma market and also a substantial increase in our gross-to-net. Even with the increased competition, demand for Xpovio was consistent in 2024 versus 2023 with 60% of our sales coming from the community setting. Community physicians continue to find value in Xpovio as an oral, convenient, flexible therapy in a landscape with several complex medicines that are potentially challenging for many patients and community-based physicians to access.

In the academic setting, we continue to see Xpovio being used pre and post T-cell therapy. And in January, the International Myeloma Working Group, a globally recognized myeloma expert committee, published a data recommendation for sequencing immunotherapies. This includes recommendations of Xpovio as a bridging option prior to CAR T and also as a treatment for patients who have disease progression following an anti-BCMA treatment. These recommendations are built upon a growing body of evidence we have generated exploring the potential role for Xpovio in promoting an anti-tumor immune microenvironment.

Moving now to Slide 33. We received a number of reimbursement approvals internationally throughout 2024 that triggered additional regulatory milestone payments. And with these increasing number of approvals, we are seeing our underlying royalty revenues on international sales becoming more meaningful and will continue to grow over time. As Richard and Reshma both mentioned, our organization's biggest area of focus in 2025 is our Phase 3 readout in myelofibrosis, and our commercial team is preparing for this opportunity.

As outlined on Slide 34, we continue to believe that our peak revenue opportunity in the U.S. alone is approximately a billion annually, if approved, with additional royalty and milestone revenue globally. On Slide 35, we outline why we believe we're so well-positioned for a rapid launch in myelofibrosis. As we've shared previously, 75% of the physicians that we surveyed say that they intend to adopt a combination therapy in myelofibrosis if one becomes available.

If selinexor is approved in combination with ruxolitinib, we could be the first combination therapy on the market. We would be an all-oral therapy which makes adoption much easier, especially in the community setting. On this point, we believe there is an 80% overlap between the physicians that we would target in myelofibrosis and the group of physicians that our organization is already calling on in multiple myeloma. And the same overlap applies to our patient support programs and medical affairs organization.

This means two things. First, we should be able to launch rapidly because we have already trusted relationships with many physicians. Second, the upfront investment required for us to launch in myelofibrosis would be minimal since we can launch with our existing organization. Finally, in endometrial cancer, as shown on Slide 36, we continue to believe that we have a significant opportunity in the P53 wild-type and PMMR patient population, which represents approximately 50% of advanced or recurrent endometrial cancer patients.

Similar to what I outlined for myelofibrosis, there is a large overlap between the potential community-based oncologists caring for endometrial cancer patients and those that we are already engaging with. Now, bringing it back to our commercial focus for 2025, it will remain strongly on driving Xpovio revenue growth in 2025, following the success we delivered in the second half of 2024, as well as planning for a successful launch in myelofibrosis if approved. Now, I'm delighted to turn the call over to Lori for the first time to give an update on our financial results and guidance.

Lori Macomber -- Executive Vice President, Chief Financial Officer and Treasurer

Good morning, everyone, and thank you, Sohanya. It is a pleasure to be participating in my first Karyopharm earnings call. I look forward to getting to know many of you personally. Turning to our financials.

Since we issued a press release earlier today with the full financial results, I will focus on the highlights and reviewing our guidance for 2025, starting on Slide 38. Total revenue for the fourth quarter of 2024 was 30.5 million compared to 33.7 million for the fourth quarter of 2023. This decrease was primarily due to lower milestone-related revenue from our licensing agreements. Total revenue for the year was 145.2 million compared to 146 million in 2023.

U.S. Xpovio net product revenue for the fourth quarter of 2024 was 29.3 million compared to 25.1 million for the fourth quarter of 2023. For the full year, U.S. Xpovio net product revenue was 112.8 million compared to 112 million in 2023.

The gross-to-net discount for Xpovio in the fourth quarter and full year 2024 was 33.3% and 30.9% compared to 23.5% and 22.3% in the same periods in 2023. The increase in both periods was primarily driven by 340B utilization and Medicare rebates. We expect the gross-to-net discount to be similar in 2025 to 2024, and as seen in previous years, it is expected to be higher in the first quarter than our average for 2025. R&D expenses for the fourth quarter of 2024 were 33.3 million compared to 39.4 million for the fourth quarter of 2023 and 143.2 million for the year ended December 31, 2024, compared to 138.8 million for the year ended December 31, 2023.

The increase in R&D expenditure in both periods was attributable to the advancement of our pivotal Phase 3 studies, partially offset by a reduction in head count and contractors related to ongoing cost optimization initiatives. SG&A expenses for the fourth quarter of 2024 were 27.2 million compared to 30.7 million for the fourth quarter of 2023. SG&A expenses for the year ended December 31, 2024, were 115.4 million compared to 131.9 million for the year ended December 31, 2023. The decrease in both periods was due to reductions in head count and contractors in connection with cost optimization efforts.

On a combined basis, R&D and SG&A were 258.7 million for the year, toward the lower end of our guidance of 255 million to 265 million. As a result, we delivered $12 million of annual savings compared to 2023 while advancing three Phase 3 clinical trials. We continue to be very diligent in allocating our resources and pipeline prioritization, delivering additional cost savings in 2025 while continuing to advance our Phase 3 clinical trials and driving our commercial performance. We exited the year with cash, cash equivalents, restricted cash, and investments of 109.1 million compared to 192.4 million as of December 31, 2023.

Based upon our current operating plans, we are introducing guidance for the full year of 2025 as follows: total revenue of 140 million to 155 million consisting of U.S. Xpovio net product revenue and license, royalty, and milestone revenue expected to be earned from our partners, primarily Menarini and Antengene. We are projecting U.S. Xpovio net product revenue to be in the range of 115 million to 130 million.

R&D and SG&A expenses will be in the range of 240 million to 255 million. And finally, our guidance for cash runway remains unchanged. We expect our existing cash, cash equivalents, and investments, the revenue we expect to generate from Xpovio net product sales and other license revenues, and ongoing disciplined expense management and cost saving measures will be sufficient to fund our planned operations into Q1 2026. This guidance does not include payment for the remaining 2025 convertible notes and our 25 million minimum liquidity covenant under our term loan.

Considering the repayment of the 2025 convertible notes and the minimum liquidity covenant, we expect cash, cash equivalents, and investments will be sufficient to fund our operations into the fourth quarter of 2025. In summary, we are focused on the advancement of our Phase 3 clinical trials and driving commercial performance while continuing to be very diligent when allocating our resources. We expect our 2025 operating expenses to be lower than 2024 as we recognize the full-year benefits of our ongoing cost-saving initiatives. We will actively engage in exploring various financing and business development activities to extend our cash runway to fund our operations into 2026 and beyond.

I will now turn the call back to Richard for some final thoughts.

Richard Paulson -- Chief Executive Officer

Turning to Slide 40. In 2025, we expect to grow Xpovio net product revenue and advance our transformative programs in myelofibrosis and endometrial cancer, working hard to unlock our innovation and growth strategy. Myelofibrosis and endometrial cancer, depending on the outcome of the data, are both game-changing opportunities for patients, our organization, and our shareholders alike. As Lori just stated, as we deliver on 2025, we will also be working to explore various financing and business development activities to strengthen our financial resources and extend our cash runway.

In 2025, our No. 1 priority is to deliver on myelofibrosis. As seen on Slide 41, we are on track to complete enrollment in the first half of this year and eagerly await sharing the top-line data in the second half of the year. Pending positive data, we are excited by the opportunity to meaningfully improve clinical outcomes for myelofibrosis patients with the support of leading physicians and patient advocacy organizations and rapidly bringing the combination of selinexor plus ruxolitinib to patients.

Thank you again for joining us today, and I would now like to ask the operator to open the call up to the Q&A portion of today's call. Operator?

Questions & Answers:

Operator

Thank you. Ladies and gentlemen, we will now begin the question-and-answer session. [Operator instructions] One moment, please, for your first question. Your first question comes from Colleen Kusy with Baird.

Your line is now open.

Colleen Kusy -- Analyst

Great. Thanks. Good morning, and thanks for taking our questions. So, for the myelofibrosis Phase 3, I know you walked us through the data again that showed an 18.5-point reduction in TSS for the combo versus 11 to 14 for X alone.

So, what reduction in TSS in the Phase 3 would help -- would make you reach that sig? Just trying to figure out how much of a buffer your stats offer you in the Phase 3. And then I have a follow-up, please.

Richard Paulson -- Chief Executive Officer

Yeah, Colleen. Thank you. For the first part of that, I think I'll turn to Reshma to talk to that, and then let's follow up on your second question.

Reshma Rangwala -- Chief Medical Officer and Head of Research

Yeah. Thanks, Colleen. Great question. So, when we look at our data, we really have a lot of room to be able to demonstrate not only clinical and significant benefit, especially when we look at that Absolute TSS, the data suggests, right, and you alluded to that, with our 18.5 improvement relative to the 11- to 14-point improvement that we see with ruxolitinib in contemporary Phase 3 trials, we really could see a delta of three, four-plus points.

So, we feel very comfortable that we can see a very meaningful difference and improvement in that Absolute TSS. When we talk about the statistical aspect, we know from previous Phase 3 trials, and I'll allude to the MANIFEST trial, that stat sig was actually demonstrated with something far more -- I'm sorry, far more narrow. In fact, today, we saw stat sig with really only about a two-point difference. So, that gives you some context in terms of the data that we could provide from our Phase 3 as well as the delta that would need to be seen to show stat sig.

We haven't provided any of the details specifically from our Phase 3 trials. However, just note that we are using that information to really guide our powering assumptions as well as the delta that we can anticipate from this ongoing Phase 3 SENTRY trial.

Colleen Kusy -- Analyst

Super helpful. Thank you. And then can you give a little more color on the conversation that you had with the FDA around the endometrial study, kind of what drove the need for the meeting? And was there anything in the early PMMR data that made the FDA direct you toward just the DMMR population?

Reshma Rangwala -- Chief Medical Officer and Head of Research

Yeah, absolutely. So, as we announced back in December of 2024, we were engaged with the FDA, specifically evolving the treatment landscape in endometrial cancer. So, back when we had discussed with the FDA in 2022, prior to the start of the trial, there were really no new available therapies. These patients were treated with CarboTaxol for a fixed number of cycles followed by watch and wait.

Hence, the incorporation of that placebo in that control arm. Fast forward to '23, '24, we've now got introduction of multiple new therapies, including checkpoint inhibitors, whether it's pembrolizumab, dostarlimab, durvalumab, available in combination, followed by checkpoint inhibitor maintenance, really, for all patients with advanced recurrent endometrial cancer regardless of their MMR status. It was this evolving standard of care, i.e., the incorporation of the checkpoint inhibitors, that led the FDA to have a discussion with them about how this trial, right, fit into this evolving treatment landscape. We really had some very productive discussions with the FDA, and ultimately, what they recommended is to go after a patient population that, unfortunately, just doesn't benefit from the checkpoint inhibitors.

And this is that PMMR patient population. PMMR patients with PMMR tumors represent the vast majority of endometrial cancer patients at 80%. With that said, and this is very consistent with the biology of the checkpoint inhibitors, the efficacy or the benefit that those patients achieve with the checkpoint inhibitors is very, very modest. So, they recommended that we focus our patient population on that group of patients and conduct our Phase 3 as we currently are.

They are very well of our data, right? So, they appreciate from the SIENDO subgroup, specifically on that PMMR P53 wild-type population, hazard ratios of approximately 0.36 can be achieved with selinexor. So, it really provides a potential new option for patients who are specifically P53 wild-type PMMR. That benefit can now rival what the checkpoint inhibitors are now specifically providing to the MMR patients.

Colleen Kusy -- Analyst

Great. Thank you. And does the inclusion of the MMR status, will that impact the rate of enrollment, you think, or will these patients already have kind of known their PMMR or DMMR status?

Reshma Rangwala -- Chief Medical Officer and Head of Research

Yeah, really the latter. They are -- it is very much standard of care to test that MMR status. So, this is really not an obstacle at all.

Colleen Kusy -- Analyst

Great. Thanks for taking our questions.

Richard Paulson -- Chief Executive Officer

Thanks, Colleen.

Operator

Your next question comes from Maury Raycroft with Jefferies. Your line is now open.

Maury Raycroft -- Analyst

Hi. Good morning, and thanks for taking my questions. I'm wondering, for the SENTRY study, can you talk more about whether patient baseline profiles are tracking with your expectations? And is there any perspective you can share on baseline TSS and SVR35 and what you're seeing for discontinuation rates and potentially dose reductions for rux or selinexor?

Reshma Rangwala -- Chief Medical Officer and Head of Research

Sure. Great question. So, it is very much tracking with not only our Phase 1 patient population but really the patient populations that have been enrolled as part of recent contemporary Phase 3 trials, including MANIFEST as well as TRANSFORM. So, again, right, these are all JAK naive patients.

Every single patient has to have a baseline platelet count of 100 or above. Again, this is very consistent with the enrollment criteria in our Phase 1. Beyond that, when we look at the breakdown between DPS status, intermediate 1, intermediate 2, high-risk driver mutations, baseline spleens, baseline hemoglobin, and even baseline platelet counts, they really are very, very much tracking to, again, those three trials that I alluded to before, i.e., the Phase 1 MANIFEST as well as TRANSFORM. In terms of your other questions in regards to discontinuations, both treatment as well as study as well as dose modifications, so this is a blinded study.

So, we're not privy to any of that information by treatment arm. We haven't provided any additional blinded data beyond the demographics that I've provided earlier.

Maury Raycroft -- Analyst

OK. I guess for the -- for those rates, though, are you seeing -- are they tracking with your expectations for discontinuations with what you would expect?

Reshma Rangwala -- Chief Medical Officer and Head of Research

Yes. Yes, they are.

Maury Raycroft -- Analyst

OK. And then maybe one other quick question just for Absolute TSS endpoint for the SENTRY study. I believe fatigue is not included, but you're still measuring it. Just wondering if you could talk more about that, how FDA will assess and weigh fatigue and factor this into the approval decision process.

Reshma Rangwala -- Chief Medical Officer and Head of Research

Yeah. So, you're correct. So, the MFSAF version 4 collects information on seven different domains, fatigue being one of those domains. So, we are collecting that information.

However, for the primary analysis of Absolute TSS, fatigue is going to be excluded. I'll note this is the same way that we evaluated the symptom improvement in our Phase 1 trial. We've had great conversations with the FDA regarding this. They are very much in alignment, and that's how we're going to proceed with the analysis again when the top-line data report out in the second half of 2025.

We'll always have that option, right, to incorporate fatigue at a later date if that's an analysis that we want to conduct. But again, the primary analysis will not include fatigue. Lastly, I'll just remind everybody that this is the same way that the original COMFORT trials were performed. So, when ruxolitinib was approved based upon COMFORT-I, COMFORT-II, fatigue was also excluded.

This was very similar to how fedratinib also evaluated their symptoms, too. So, there is multiple precedent in the domains included for overall symptom analysis.

Maury Raycroft -- Analyst

Got it. OK. Thanks for taking my questions.

Richard Paulson -- Chief Executive Officer

Thank you, Maury.

Operator

Your next question comes from Peter Lawson with Barclays. Your line is now open.

Unknown speaker -- -- Analyst

Hey, good morning. This is Alex on for Peter. Thank you for taking our questions. So, I have two questions.

One on endometrial. I guess you noted, depending on the strength of the data, you would pursue regulatory approval. Can you walk us through your thinking here with respect to the bar for success? What would be a scenario where you seek approval versus a scenario where maybe you don't seek approval? And then my second question is on the SENTRY-2 study in JAK naive patients with moderate thrombocytopenia. I guess, have you submitted an abstract already for medical meeting for this data? And then how much data could we expect to see? Thank you.

Richard Paulson -- Chief Executive Officer

Yeah. Thanks for the question, Alex. I mean, I'll just address the second one first, and then I'll turn to Reshma to address the first one on EC. But overall, with regards to SENTRY-2 trial, as we've shared, we'll be sharing some data in the first half of this year on an initial set of patients.

And we don't comment on whether or not we've submitted that yet for an abstract, but we're looking to share that data here in the first half of the year. And maybe, Reshma, if you can answer the second question with regards to EC and the strength of the data and what we're looking to see.

Reshma Rangwala -- Chief Medical Officer and Head of Research

Yeah, absolutely. So, just stepping back to the SIENDO subgroup in which we evaluated the benefit and the risk of selinexor specifically in that P53 wild-type subgroup, we saw very, very meaningful benefit. At the time of the top-line results, we saw a more than 10-month delta -- an approximately 10-month delta when you compare the median PFS observed in the selinexor arm as compared to the placebo arm. That, in the context of a very safe and tolerable safety profile, really suggests that the overall benefit-risk of selinexor could be substantial for this patient population.

That was a robust subgroup, and we do expect that similar kind of profile to translate to our ongoing ECO-42. With that said, I will remind everybody that in ECO-42, the starting dose of selinexor is lower, and we've incorporated dual antiemetics for the first two cycles. So, what we could actually observe is very meaningful benefit, i.e., a median PFS delta of greater than six months, potentially even 10, as we saw before, in the context of now even a better safety profile. I think that, again, would be a very meaningful outcome for this patient population.

Richard Paulson -- Chief Executive Officer

Thank you, Alex.

Operator

Your next question comes from Jonathan Chang with Leerink Partners. Your line is now open.

Jonathan Chang -- Analyst

Hi, guys. Good morning, and thanks for taking my questions. First question, can you provide any color on how enrollment in the Phase 3 endometrial cancer study had progressed to date? And then second question, how should we be thinking about your cash runway guidance relative to the timelines of the Phase 3 studies and data readouts? Thank you.

Richard Paulson -- Chief Executive Officer

Sure. Thanks, Jonathan. Maybe for the first, I'll turn to Reshma, and then we'll come back with Lori on the second part.

Reshma Rangwala -- Chief Medical Officer and Head of Research

Sure, Jonathan, and thanks for the question. Enrollment is going well in our endometrial cancer trial. We are now tracking to approximately 276 patients. It is a global trial where there is a lot of interest in selinexor, specifically in this novel population defined by their P53 status.

So, that interest is translating to robust enrollment. And we're now looking at top-line results in the middle of 2026.

Richard Paulson -- Chief Executive Officer

Lori, do you want to answer the second part?

Lori Macomber -- Executive Vice President, Chief Financial Officer and Treasurer

Yes. Hi, Jonathan. Thank you for the question. And it's an important one that I know and understanding how we're going to extend our cash runway and to ensure that we can see the data readouts for these Phase 3 trials.

The first thing I just want to make sure that I emphasize is we do understand the importance of being well-capitalized. And the first thing that I want to make sure that I emphasize is we do have a profitable, revenue-generating business in multiple myeloma. So, that starts our foundation. And as you mentioned, we have these two big data readouts coming in front of us.

We have the one for myelofibrosis and then also for EC. So, we are very well thinking through how are we going to be well-capitalized going into these readouts. And as you know, there's a number of ways that we can look at financing and extending our cash runway, and these activities are similar to any other companies would explore. But we'll continue to look at business development, collaborations, or strategic alliances, particularly on our early stage programs.

For example, with verdinexor, we can look at -- for KPT-350 or KPT-9274, which has a rare pediatric disease and orphan drug designation. We can take a look at extending our near-term debt obligations, or we can take a look at equity capital raises. We'll continue to evaluate all these options. We just want to make sure that we maximize the value for our shareholders.

We take the proper path forward.

Jonathan Chang -- Analyst

Understood. Thanks for taking the questions.

Operator

Your next question comes from Brian Abrahams with RBC Capital Markets. Your line is now open.

Unknown speaker -- -- Analyst

Hi. This is Kevin on for Brian. Thanks for taking our questions. Can you maybe just tell us a bit more on any particular characteristics of the DMMR population that is not eligible for checkpoint inhibitors and any reason to expect any different efficacies there? And just to add on to that, did you have any such patients in the SIENDO study? And just curious how they did on that study.

Thank you.

Reshma Rangwala -- Chief Medical Officer and Head of Research

Sure. Great question. So, these DMMR patients who are medically ineligible, no, there are not any unique characteristics about this patient population. Again, is that patient population whose tumors are DMMR? Of course, they're going to be P53 wild-type.

This is, again, one of the key criteria. That medical ineligibility really just goes to some baseline medical history. By and large, these are comorbidities, autoimmune in nature that may preclude them from receiving a checkpoint inhibitor, or a physician may have initiated treatment with a checkpoint inhibitor, and then they unfortunately develop some kind of toxicity that requires them to permanently discontinue that checkpoint inhibitor. So, it's really nothing about their underlying endometrial cancer or tumor type that would make them eligible for this trial.

It's really more about the comorbidities that, again, doesn't prevent them from receiving or continuing with that checkpoint inhibitor therapy. In terms of data from the SIENDO trial, no, I can't comment. We haven't gone back and taken a look at the SIENDO data. With that said, we don't expect there to be any difference to -- I go back to the SIENDO subgroup, which really suggested that P53 is the driving factor that determines efficacy with selinexor.

And the reason I highlight that is because when we look at the efficacy, specifically the hazard ratio by MMR status, both the PMMR as well as DMMR really demonstrated very robust improvement, with hazard ratios in that 0.45 to 0.35 range.

Richard Paulson -- Chief Executive Officer

Thanks, Kevin.

Operator

[Operator instructions] Your next question comes from Ed White with H.C. Wainwright. Your line is now open.

Edward White -- Analyst

Good morning. Thanks for taking my questions. I just wanted to dive in a little bit more on your revenue guidance for 2025. Can you break it down on how you're thinking about growth in volume versus growth in price?

Richard Paulson -- Chief Executive Officer

Yeah. Thanks, Ed. I'll turn to Sohanya to talk to that.

Sohanya Cheng -- Senior Vice President of Sales and Commercial Operations

Hey, Ed, thanks for the question. We feel confident about the guidance range we put out there, 115 million to 130 million, where the midpoint represents approximately 11% revenue growth year over year. As we think about the drivers and the headwinds, our plan is to grow demand as well as revenue in 2025 year over year. Now, our plan is to build upon the momentum that we've seen in the second half of 2024, where we grew demand in both the community and academic setting.

And our plan is to, again, grow in 2025 versus 2024. As we think about the key headwinds in the space, of course, it's the ongoing competitive environment that we're in, with two new potential entrants in 2025. Again, as we think about the role of Xpovio, it is distinctly positioned in the community setting in that second to fourth line as a flexible oral drug, as well as in the academic setting now that we have this growing body of evidence pre and post T cell therapy. The second key headwind really is gross-to-net.

We expect it to be similar in 2025 to 2024, as Lori mentioned, with Q1 having a higher gross-to-net than the average for 2025, consistent with our historical results. And in terms of sort of quarterly variability, we expect to see similar seasonal patterns that we have seen in the past. And so, all these components are captured in the revenue guidance that we put out, and we feel confident in delivering within that range.

Edward White -- Analyst

OK. Thank you. And just a question on your R&D and G&A guidance. Should we expect to see what we saw in 2024, as you are investing more in your Phase 3 studies, that R&D should move a bit higher while you're still seeing SG&A cuts?

Richard Paulson -- Chief Executive Officer

Yeah. Thanks, Ed, for that. I'll turn to Lori to talk to it broadly. Yeah.

Lori Macomber -- Executive Vice President, Chief Financial Officer and Treasurer

Hi, Ed. For R&D, to be honest, it's going to be fairly comparable to 2024. As you know, we have the Phase 3 clinical trials that we're heavily investing in. Where we are seeing the reductions is on the SG&A due to the cost optimization initiatives that we've put in place over the last two years, and that's where we're seeing this significant decline in our operating expenses.

Edward White -- Analyst

OK, great. Thank you for taking my questions.

Richard Paulson -- Chief Executive Officer

Thank you, Ed.

Operator

There are no further questions at this time. I will now turn the call over to Richard Paulson for closing remarks.

Richard Paulson -- Chief Executive Officer

Thank you, operator, and thank you, everyone, for joining us today. As I shared, we are focused, and in 2025, our No. 1 priority is to deliver on myelofibrosis. As we move through the year, pending positive data, we are excited about the opportunity to meaningfully improve clinical outcomes for myelofibrosis patients and look to move forward and potentially bring this combination of selinexor plus ruxolitinib to patients.

So, once again, thank you for joining us for today's call, and hope everyone has a great day.

Operator

[Operator signoff]

Duration: 0 minutes

Call participants:

Brendan Twohig Strong -- Senior Vice President, Investor Relations and Corporate Communications

Richard Paulson -- Chief Executive Officer

Reshma Rangwala -- Chief Medical Officer and Head of Research

Sohanya Cheng -- Senior Vice President of Sales and Commercial Operations

Lori Macomber -- Executive Vice President, Chief Financial Officer and Treasurer

Colleen Kusy -- Analyst

Maury Raycroft -- Analyst

Unknown speaker -- -- Analyst

Jonathan Chang -- Analyst

Edward White -- Analyst

Ed White -- Analyst

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Karyopharm Therapeutics (KPTI) Q4 2024 Earnings Call Transcript was originally published by The Motley Fool