What changed in Karyopharm Therapeutics Inc.'s 10-K — 2023 vs 2024

In January 2024, we announced that further clinical development of our eltanexor program is on hold in an effort to focus our resources on our prioritized late-stage programs. Our Strategy At Karyopharm we are passionate about our mission to positively impact patient lives and defeat cancer. With our first-in-class SINE technology, our foundation is in our science.

Our vision is to be a leading innovator that develops and commercializes transformative medicines for patients and society. There are four key pillars that we believe will drive our underlying value and provide significant market opportunities for us. • Maximize the Commercial Value of XPOVIO in Multiple Myeloma.

We are 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 focus on growing sales in our approved U.S. indications by establishing XPOVIO as a novel effective modality 5 Table of Contents that can become a standard of care in the second to fourth-line treatment setting following treatment with anti-CD38 therapy.

With our global partners, we plan to maximize the global opportunity to bring XPOVIO to patients worldwide. • Focus on our Prioritized Clinical Pipeline. Our science enables us to potentially make a big difference in the lives of patients and we are focused on three priority clinical programs: multiple myeloma, endometrial cancer, and MF.

Our clinical pipeline has been consciously and strategically focused to target cancers with high unmet need and a high probability of success based on the potential to provide meaningful clinical benefit to patients, potential regulatory approval, and supportive data.

We will also continue to expand our understanding of the role nuclear transport plays in the underlying biology of cancer through focused signal seeking activities to identify future opportunities in other oncology indications for our SINE technology that may provide support for additional clinical investigation. • Provide Strong Leadership.

We believe we have the right people in place and a strong leadership team with the ability to help position us to achieve scientific, clinical and commercial goals and to execute on our key corporate objectives.

We strive to be a top-talent destination for those who desire to make a difference in patients’ lives. • Maintain a Well-capitalized Business to Execute our Core Objectives. We are focused on maintaining a well-capitalized business that will enable the advancement of our clinical development opportunities.

Our Programs to Treat Cancer Overview Cancer cells develop when there is dysregulation of genes that regulate critical cellular behaviors, such as cell growth and survival. The abnormal control over gene function is most often due to damage to DNA.

Proteins called tumor suppressor proteins can monitor genes encoded in DNA for damage, and if damage is detected, the tumor suppressor proteins will direct the cell to attempt to repair it, or if the DNA damage is too severe, the tumor suppressor proteins will direct the cell to die in a process called apoptosis.

In this way tumor suppressor proteins can prevent healthy cells that acquire DNA damage from turning into cancer cells, and thus cancer cells need to functionally inactivate tumor suppressor proteins in order to survive. Many tumor suppressor proteins can only function properly when they are located inside of a cell’s nucleus.

Proteins, however, are not made inside the nucleus but rather are made outside of the nucleus in an area called the cytoplasm. A membrane, called the nuclear membrane, separates the nucleus from the cytoplasm. Larger nuclear proteins, including many tumor suppressor proteins, must be transported from the cytoplasm into the nucleus to perform their functions in keeping a cell healthy.

Similarly, these proteins can also be exported back into the cytoplasm. Proteins move from the nucleus to the cytoplasm through a protein complex embedded in the nuclear membrane called the nuclear pore. The nuclear pore works like a gate through which large molecules, including many proteins and ribonucleic acids, enter and exit the nucleus.

When molecules enter the nucleus from the cytoplasm, the process is called import, and when molecules exit from the nucleus to the cytoplasm, the process is called export. The import and export of most proteins and other large molecules between the nucleus and cytoplasm require specific carrier proteins to chaperone their cargo molecules through the nuclear pore complex.

Carrier proteins, which mediate the import of macromolecules into the nucleus, are called importins, and those which mediate the export of macromolecules out of the nucleus are called exportins. Therefore, the processes of import and export are carried out separately and are typically regulated independently.

One way that cancers functionally inactivate tumor suppressor proteins is via overproduction of a specific chaperone protein called XPO1.

XPO1 is one of eight exportins that have been identified in human cells, and it exports over 220 proteins referred to as its “cargo proteins.” In particular, XPO1 appears to be the sole exporter for many critical tumor suppressor proteins that function in the cell nucleus, including p53, p73, p21, p27, APC, FOXO, pRB and survivin.

In addition to exporting tumor suppressor proteins out of the nucleus, XPO1 mediates the nuclear export of a protein called eukaryotic initiation factor 4E, which itself binds to the messenger ribonucleic acids (“mRNAs”) that encode many growth-regulating proteins, including c-myc, bcl-2, bcl-6 and cyclin D.

XPO1 carries these growth-promoting mRNAs from the nucleus into the cytoplasm where they are translated into proteins that promote cancer cell growth. XPO1 also exports the anti-inflammatory (and anti-tumor) protein IκB, which inhibits a protein called NF-κB.

NF-κB is found in the nucleus of most cancer cells and plays a role in cancer metastasis and chemotherapy resistance, as well as in many inflammatory and autoimmune diseases. In certain cancer cells, XPO1 levels are reported to be elevated when compared to their healthy cell counterparts.

Therefore, these elevated levels of XPO1 in cancer cells mediate the rapid export of tumor suppressor proteins as well as IκB and eIF4E out of the nucleus and can lead to reduced monitoring for DNA damage, the normal triggering of apoptosis and increased inflammation activity.

Higher levels of XPO1 expression in cancer cells has also been correlated with resistance to chemotherapy and poor prognosis in patients. 6 Table of Contents Mechanism of Action of Our SINE Compounds - Inhibition of XPO1 Selinexor and eltanexor are novel therapies that are oral SINE compounds specifically designed to force nuclear accumulation of multiple tumor suppressor proteins that function in the nucleus.

Selinexor and eltanexor also force nuclear accumulation of growth promoting mRNAs by similarly preventing their export, which prevents the translation of these mRNAs into proteins and thereby lowers expression of the growth promoting proteins that these mRNAs encode.

The forced nuclear retention of these proteins can counteract a multitude of the cancer-promoting pathways that allow cancer cells with gene dysregulation to continue to grow and divide in an unrestrained fashion. Because normal cells have little or no DNA damage to cause gene dysregulation, accumulation of tumor suppressor proteins in their nucleus generally does not lead to apoptosis.

The figure below depicts the process by which our SINE compounds inhibit the XPO1-mediated nuclear export of tumor suppressor proteins and oncoprotein mRNAs.

We believe that the novel mechanism of action, oral administration and low levels of major organ toxicities observed to date in patients treated with our SINE compounds, along with encouraging efficacy data, support the potential for their broad use across many cancer types, including both hematological and solid tumor malignancies.

Unlike many other targeted therapeutic approaches that only work for a specific set of cancers or in a specific subgroup of patients, we believe that by restoring tumor suppressor proteins to the nucleus where they can access a cell’s DNA, our SINE compounds may provide therapeutic benefits across a broad range of cancer types and can potentially benefit a wider range of patients.

Additionally, and as supported by their unique mechanism of action, and preclinical, clinical and post-approval data, we believe that our SINE compounds have shown additive or synergistic benefit with approved and experimental therapies in treating cancer patients and, therefore, have the potential to serve as a backbone therapy across multiple hematological and solid tumor malignancies as part of a variety of combination therapies.

Our Pipeline and Key Clinical Trials Oral selinexor is being evaluated in multiple early, mid and late-stage clinical trials in patients with hematological and solid tumor malignancies, including both in the first line and in the relapsed and/or refractory setting.

In general, relapsed disease refers to disease that progresses following the expiration of a specified period of time after discontinuation of therapy and refractory disease refers to disease that progresses while the patient is on therapy or within a specified period of time after discontinuation of therapy. Key clinical trials of selinexor and eltanexor are summarized in the chart below.

In addition to these studies, there are multiple ongoing investigator-sponsored clinical trials being conducted in a variety of hematological and solid tumor malignancies, post-marketing requirements, and potential signal seeking studies to further expand our development program in the future. 7 Table of Contents OUR SELINEXOR PROGRAM We are currently evaluating selinexor in certain hematological and solid tumor malignancies, including multiple myeloma, endometrial cancer, MF and DLBCL.

Multiple Myeloma Overview Multiple myeloma is a hematological malignancy characterized by the accumulation of monoclonal plasma cells in the bone marrow, the presence of monoclonal immunoglobulin, also known as M protein, in the serum or urine, bone destruction, kidney disease and immunodeficiency. Multiple myeloma is the second most common blood cancer in the world and there is currently no cure.

The American Cancer Society (the “ACS”) estimates that nearly 36,000 new cases of multiple myeloma will be diagnosed in the U.S. in 2024. Myeloma occurs most commonly in people over age 65 and the risk of developing multiple myeloma increases with age.

The treatment of multiple myeloma has improved over the last 20 years due to the use of high-dose chemotherapy and autologous stem cell transplantation, which is restricted to healthier, often younger patients.

Treatment decisions are based on physician and patient choice rather than clear treatment guidelines, with the current standard of care being to switch drug classes once a regimen stops working.

In addition to our XPO1 inhibitor, a number of non-chemotherapy drugs such as PIs, IMiDs, mAbs, bispecific antibodies, and CAR-T therapy, have also emerged as treatment options within the last two decades. The introduction of these non-chemotherapeutic novel agents has led to a significant increase in the survival of patients with multiple myeloma.

However, despite the wide variety of newly approved or experimental therapies that are being used to treat patients with relapsed and/or refractory disease either alone or in combination, nearly all patients will eventually succumb to their disease.

With nearly 12,500 deaths from multiple myeloma in the U.S. alone estimated for 2024 according to the ACS, we believe that there remains a need for therapies for patients whose disease has relapsed after, or is refractory to, available therapy or for whom current therapy is not suitable.

XPOVIO is currently approved to treat multiple myeloma in adult patients who have received at least one prior therapy based on data from the BOSTON Study and in adult patients with penta-refractory multiple myeloma based on data from the STORM Study.

In September 2023, the National Comprehensive Cancer Network Clinical Practice Guidelines (the “NCCN Guidelines”) elevated XPOVIO in combination with Velcade ® (bortezomib) and dexamethasone (“XVd”) to a preferred and category 1 regimen for lenalidomide- refractory patients with RRMM who have received one-to-three prior lines of therapy in its Clinical Practice Guidelines in Oncology.

The NCCN Guidelines are a comprehensive set of guidelines detailing the sequential management decisions and interventions that currently apply to 97% of cancers affecting patients in the U.S. and are intended to ensure that all patients receive preventive, diagnostic, treatment and supportive services that will most likely lead to optimal outcomes. 8 Table of Contents The BOSTON Study The December 2020 FDA approval of XPOVIO in combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy was based on the results of the BOSTON Study, a multi-center, Phase 3, randomized study conducted at over 150 clinical sites internationally.

The BOSTON Study evaluated 402 adult patients with RRMM who had received one to three prior lines of therapy.

The study was designed to compare the efficacy, safety and certain health-related quality of life parameters of once-weekly oral selinexor in combination with once-weekly administration of Velcade ® plus low-dose dexamethasone (the “XVd Arm”) versus twice-weekly administration of Velcade ® plus dexamethasone (the “Vd Arm”).

The primary endpoint of the study was progression-free survival (“PFS”) and key secondary endpoints included overall response rate (“ORR”) and the rate of peripheral neuropathy (“PN”), among others. Additionally, the BOSTON Study allowed for patients on the Vd Arm to crossover to the XVd Arm following objective (quantitative) progression of disease verified by an Independent Review Committee (“IRC”).

Despite the study having a high proportion of patients with high-risk cytogenetics (approximately 50%), the median PFS in the XVd Arm was 13.9 months compared to 9.5 months in the Vd Arm, representing a 4.4 month (47%) increase in median PFS (hazard ratio (“HR”) of 0.70; p=0.0075).

The XVd Arm also demonstrated a significantly greater ORR compared to the Vd Arm (76.4% vs. 62.3%, p=0.0012). Further, XVd therapy demonstrated a significantly higher rate of deep responses, defined as ≥ Very Good Partial Response (“VGPRs”) compared to Vd therapy (44.6% vs. 32.4%) as well as a longer median duration of response (“DOR”) (20.3 months vs. 12.9 months).

Additionally, 17% of patients on the XVd arm achieved a Complete Response (“CR”) or a Stringent Complete Response (“sCR”) as compared to 10% of patients receiving Vd therapy. All responses were confirmed by an IRC. Rates of PN were significantly lower for patients receiving XVd therapy compared to those receiving Vd therapy (32% vs. 47%).

In addition, PN rates ≥ grade 2 were also significantly lower in the XVd Arm compared to the Vd Arm (21% vs. 34%). The most common adverse reactions (≥20%) in patients who received XVd were fatigue (59%), nausea (50%), decreased appetite (35%), diarrhea (32%), peripheral neuropathy (32%), upper respiratory tract infection (29%), decreased weight (26%), cataract (22%) and vomiting (21%).

Grade 3-4 laboratory abnormalities (≥10%) were thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia and neutropenia. In the BOSTON Study, fatal adverse reactions occurred in 6% of patients within 30 days of last treatment. Serious adverse reactions occurred in 52% of patients who received XVd. Treatment discontinuation rate due to adverse reactions was 19%.

In June 2023, we presented data from an unplanned subgroup analysis of BOSTON patients without prior PI exposure (XVd: n = 47; Vd: n= 48) at the 2023 European Hematology Association Hybrid Congress, which analysis demonstrated an approximate tripling of median PFS for XVd compared to Vd at 29.5 vs 9.7 months; HR for PFS favored XVd at 0.29 (95% Confidence Interval (“CI”) 0.14 - 0.63, nominal p= The STORM Study The July 2019 FDA approval of XPOVIO in combination with dexamethasone for the treatment of adult patients with RRMM who have received at least four prior therapies and whose disease is refractory to at least two PIs, at least two IMiDs, and an anti-CD38 mAb was based on the results of the STORM Study.

This indication was approved under accelerated approval. As the BOSTON Study served as the confirmatory trial for accelerated approval for the STORM Study, the BOSTON supplemental New Drug Application (“sNDA”) approval in December 2020 fulfilled the requirement of an accelerated approval.

The STORM Study was a global, multi-center, single-arm Phase 2b clinical trial evaluating oral selinexor in combination with standard, low-dose dexamethasone (“Xd”) in patients with heavily pretreated, RRMM. These heavily pretreated patients had a median of seven prior therapeutic regimens, including a median of 10 unique anti-myeloma agents.

Specifically, the myeloma patients who were eligible for the study had prior treatment with the two PIs, Velcade ® and Kyprolis ® (carfilzomib), the two IMiDs, Revlimid ® (lenalidomide) and Pomalyst ® (pomalidomide), and the anti-CD38 mAb Darzalex ® (daratumumab), as well as alkylating agents, and their disease was refractory to glucocorticoids, at least one PI, at least one IMiD, Darzalex ® , and their most recent therapy.

In all patients, this myeloma was considered “triple-class refractory.” The FDA’s accelerated approval of XPOVIO was based upon the efficacy and safety in a pre-specified subgroup analysis of the 83 patients in the STORM Study with documented penta-refractory myeloma, as the benefit-risk ratio appeared to be greater in this more heavily pre-treated population than in the overall trial population.

In addition to multiple-refractory disease, patients in the STORM Study had rapidly progressing myeloma, with a median 22% increase in disease burden in the 12 days from screening to initial therapy.

The ORR in this patient population was 25.3%. 9 Table of Contents For the STORM Study’s primary endpoint, selinexor achieved an ORR of 26%, including two (2%) sCRs, six (5%) VGPRs, and 24 (20%) partial responses (“PRs”) and the trial therefore met its primary endpoint. Both patients who had relapsed after CAR-T therapy achieved PRs.

Minimal response per International Myeloma Working Group criteria was observed in 16 (13%) patients and 48 (39%) patients had stable disease. Median time to PR or better was 4.1 weeks. The clinical benefit rate, meaning a minimal response or better, was 39%. All responses were adjudicated by an IRC consisting of four independent experts in the treatment of multiple myeloma.

Median DOR was 4.4 months. PFS was 3.7 months and overall survival (“OS”) was 8.6 months. In the 39% of patients who achieved a minimal response or better, median OS was 15.6 months, compared to a median OS of 1.7 months in patients whose disease progressed or where response was not evaluable.

The most common adverse reactions (≥20%) in patients who received Xd were thrombocytopenia (74%), fatigue (73%), nausea (72%), anemia (59%), decreased appetite (53%), decreased weight (47%), diarrhea (44%), vomiting (41%), hyponatremia (39%), neutropenia (34%), leukopenia (28%), constipation (25%), dyspnea (24%) and upper respiratory tract infection (21%). In the STORM Study, fatal adverse reactions occurred in 9% of patients.

Serious adverse reactions occurred in 58% of patients. Treatment discontinuation rate due to adverse reactions was 27%. The XPORT-MM-031/EMN29 Study The EMN29 study is an ongoing randomized global Phase 3 study sponsored by the European Myeloma Network evaluating selinexor in combination with pomalidomide and dexamethasone (“SPd”) versus elotuzumab, pomalidomide, and dexamethasone (“EloPd”) in patients with RRMM (the “EMN29 Study”; NCT05028348).

The EMN29 Study is expected to enroll up to 222 patients who will be randomized to either SPd or EloPd and is designed to evaluate a 40 mg once weekly dose of selinexor compared to standard dosing of elotuzumab in combination with pomalidomide and dexamethasone in RRMM as the immediate next line of therapy after treatment with anti-CD38 antibodies.

Patients enrolled in the EMN29 Study have received one to four prior lines of therapy, including a PI and lenalidomide, and have had an anti-CD38 mAb in their most recent prior line of therapy. The primary endpoint of the EMN29 Study is PFS, with ORR, OS and DOR, among others, as secondary endpoints.

Item 1C. Cyber security Cybersecurity Risk Management and Strategy Like all companies with an internet presence, we are regularly subject to cyberattacks and other cyber incidents, and, therefore, cybersecurity is an important element of our ongoing information technology operations.

We devote significant resources to protecting and enhancing the security of our computer systems, business information, software, networks and other technology assets, by applying our cybersecurity risk management processes, which consider physical, procedural and technical safeguards.

We have a multi-faceted program for assessing, identifying and managing cybersecurity risks, that is designed to help protect our information assets and operations from internal and external cyber threats by: • organizing our cybersecurity efforts based on the National Institute of Standards and Technology (“NIST”) Cybersecurity Framework by applying the framework’s rubric of Identify, Protect, Detect, Respond, and Recover; • seeking to understand, manage and mitigate risk while ensuring business resiliency and protecting business, employee and patient information from unauthorized access or attack; • identifying critical business information, the lifecycles of that information, and the systems where this information is stored, distributed, processed, and eventually destroyed.

For example, by managing important external parties and their operations, analyzing their cybersecurity risk to our business operations, and reviewing the residual risk with business leaders to accept and manage each external party appropriately; • protecting and securing our systems from attack with secure configuration standards and protective cybersecurity tools; • detecting potential attacks through appropriate tools, including cybersecurity-related data collection and analysis to help identify potential attacks; • responding to alerts from those tools with processes to verify whether there is a real incident and the severity of that incident using appropriate resources and team members, including establishing and exercising a Cybersecurity Incident Response Plan (“IRP”) based on recognized industry practices, including NIST guidance; and • establishing and exercising processes and procedures to recover from cybersecurity incidents. 94 Table of Contents Our IRP contains tools, and guidance related to cybersecurity events and is designed to help coordinate our response to, and recovery from, cybersecurity incidents, and includes processes to triage, assess the severity of, escalate, contain, investigate, and remediate incidents as well as comply with applicable legal obligations.

In addition, as part of our overall risk mitigation strategy, we also maintain cyber insurance coverage; however, such insurance may not be sufficient in type or amount to cover us against claims related to security breaches, cyber-attacks and other related breaches.

We regularly engage external parties, inclusive of but not limited to, service vendors, consultants, independent privacy assessors, peer companies, industry groups, and governance experts to enhance our understanding and application of oversight of the cybersecurity landscape.

For example, we provide an annual assessment of our cybersecurity program, completed by our third-party Chief Information Security Officer (“CISO”), to our Audit Committee for review and feedback. These external parties provide an industry perspective on appropriate risk management and investment in our cybersecurity efforts that is reviewed and approved by company management and the Board of Directors.

We do not believe that there are currently any known risks from cybersecurity threats that are reasonably likely to materially affect the Company or its business strategy, results of operations or financial condition. Cybersecurity Governance and Oversight The Audit Committee of our Board of Directors provides direct oversight over cybersecurity risk.

The Audit Committee receives and provides feedback on quarterly updates from management regarding cybersecurity and is notified between such updates regarding significant new cybersecurity threats or incidents, if any.

As part of these quarterly updates to the Audit Committee, our Vice President of Information Technology presents any developments, emerging risks or key topics to the Audit Committee, including, among other things, the external threat environment, risk profile changes, training initiatives, the status of projects to strengthen cybersecurity, emerging global policies and regulations, cybersecurity technologies and industry practices, cyber readiness, results of third-party assessments, mitigation efforts and response plans.

The full Board of Directors receives regular reports from the Chair of the Audit Committee, as well as periodic updates highlighting recent incidents throughout the industry and the emerging threat landscape. Our Vice President of Information Technology leads an IT Security Team and has overall responsibility for the security program.

The IT Security Team is responsible for leading company-wide cybersecurity strategy, policy, standards and processes. The IT Security Team works across the enterprise to assess and prepare our employees and third parties to manage cybersecurity risks and detect, investigate and respond to cybersecurity incidents.

Our Vice President of Information Technology has 25 years of information technology experience, including 22 years of leadership responsibility, and has substantial operational experience with cybersecurity policy, protection, incident response, and governance. We also utilize a third-party cybersecurity advisor to act as our CISO, supporting the Vice President of Information Technology.

This fractional executive has extensive experience as a CISO and cybersecurity executive with over 25 years of expertise in designing, building, and operating transformational information security programs, is a Certified Information Systems Security Professional, and holds a Master of Science in Strategic Intelligence.

Further, our IRP establishes a Security Council, which is responsible for providing oversight, direction, and governance of incident response policies and processes and is composed of certain company stakeholders, including our Vice President of Information Technology and our third-party CISO.

In an effort to deter and detect cyber threats, we provide a monthly cybersecurity awareness newsletter to all employees, including part-time and temporary contractors, which covers timely and relevant topics, such as social engineering, phishing, password protection, confidential data protection, asset use and mobile security, and reminds employees of the importance of reporting all incidents quickly.

We run frequent phishing tests to raise awareness of spam emails, the primary attack vectors for cyber threats and to further raise awareness of cyber threats. We provide annual training on employee responsibilities for protecting company information and data along with our overall compliance responsibility.

Each October during cybersecurity awareness month in the U.S., we provide weekly updates on cybersecurity awareness and host a company-wide lunch and learn discussion of our cybersecurity program and the impact of cybersecurity on individuals as well as the company, with a data protection, cybersecurity and incident response and prevention training and compliance program. 95 Table of Contents

Stock Performance Graph The following graph shows a comparison from December 31, 2018 through December 31, 2023, of the cumulative total return on an assumed investment of $100.00 in cash in our common stock as compared to the same investment in the NASDAQ Composite Index and the NASDAQ Biotechnology Index.

Such returns are based on historical results and are not intended to suggest future performance.

Data for the NASDAQ Composite Index and NASDAQ Biotechnology Index assume reinvestment of dividends. 97 Table of Contents Cumulative Total Return Comparison 12/31/18 12/31/19 12/31/20 12/31/21 12/31/22 12/31/23 Karyopharm Therapeutics Inc. 100.00 204.59 165.21 68.62 36.29 9.23 NASDAQ Composite 100.00 136.69 198.10 242.03 163.28 236.17 NASDAQ Biotechnology 100.00 125.11 158.17 158.20 142.19 148.72 The performance graph in this Item 5 is not deemed to be “soliciting material” or to be “filed” with the SEC for purposes of Section 18 of the Exchange Act, or otherwise subject to the liabilities under that Section, and shall not be deemed incorporated by reference into any filing of Karyopharm Therapeutics Inc. under the Securities Act or the Exchange Act, except to the extent we specifically incorporate it by reference into such a filing.

Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations The following discussion of our financial condition and results of operations should be read in conjunction with our consolidated financial statements and related notes included elsewhere in this report.

Some of the information contained in this discussion and analysis and set forth elsewhere in this report, including information with respect to our plans and strategy for our business, includes forward-looking statements that involve risks and uncertainties.

You should review the section entitled “ Risk Factors ” in Part I - Item 1A of this report for a discussion of important factors that could cause actual results to differ materially from the results described in or implied by the forward-looking statements contained in the following discussion and analysis.

Overview We are a commercial-stage pharmaceutical company pioneering novel cancer therapies and dedicated to the discovery, development and commercialization of first-in-class drugs directed against nuclear export for the treatment of cancer and other diseases. Our scientific expertise is based upon an understanding of the regulation of intracellular communication between the nucleus and the cytoplasm.

We have discovered and are developing and commercializing novel, small molecule Selective Inhibitor of Nuclear Export (“SINE”) compounds that inhibit the nuclear export protein exportin 1 (“XPO1”). These SINE compounds represent a new class of drug candidates with a novel mechanism of action that have the potential to treat a variety of diseases with high unmet medical need.

Our lead asset, XPOVIO ® (selinexor), was the first oral XPO1 inhibitor to receive marketing approval, receiving its initial U.S. approval from the U.S.

This indication was approved under accelerated approval based on response rate and was based on the results from the SADAL ( S elinexor A gainst D iffuse A ggressive L ymphoma) study. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

The commercialization of XPOVIO in the U.S. is currently supported by sales representatives, nurse liaisons, and a market access team, as well as KaryForward™, an extensive patient and healthcare provider support program. Our commercial efforts are also supplemented by patient support initiatives coordinated by our dedicated network of participating specialty pharmacy providers.

We plan to continue to educate physicians, other healthcare providers and patients about XPOVIO’s clinical profile and unique mechanism of action as we continue to expand XPOVIO use.

The commercialization of XPOVIO and NEXPOVIO ® (selinexor) (the brand name for selinexor in Europe and the United Kingdom (“UK”)) outside of the U.S. is managed by our partners in their respective territories.

XPOVIO/NEXPOVIO has received regulatory approval in various indications in over 40 countries outside the U.S. and is commercially available in a growing number of countries as our partners continue to secure reimbursement approvals.

Our primary focus is on marketing XPOVIO in its currently approved indications as well as developing and seeking the regulatory approval of selinexor as an oral agent targeting multiple high unmet need cancer indications, including our core programs in endometrial cancer, multiple myeloma, and myelofibrosis.

We plan to continue to conduct clinical trials and to seek additional approvals for the use of selinexor as a single agent or in combination with other oncology therapies to expand the patient populations that are eligible for treatment with selinexor.

We had net losses of $143.1 million, $165.3 million, and $124.1 million for the years ended December 31, 2023, 2022 and 2021, respectively. We recognized total revenue of $146.0 million in 2023, including $112.0 million of XPOVIO net product revenue and $34.0 million of license revenue.

License revenue included $15.0 million of revenue for the reimbursement of development related expenses from the Menarini Group (“Menarini”).

As of December 31, 2023, we had $191.4 million in cash, cash equivalents and investments. 99 Table of Contents Critical Accounting Estimates Our discussion and analysis of our financial condition and results of operations are based on our consolidated financial statements, which we have prepared in accordance with U.S. generally accepted accounting principles.

We believe that the estimates and assumptions involved in the accounting policies described below may have the greatest potential impact on our consolidated financial statements and, therefore, consider these to be our critical accounting estimates. We evaluate our estimates and assumptions on an ongoing basis. Actual results may differ from these estimates under different assumptions and conditions.

See Note 2 “ Summary of Significant Accounting Policies” to the consolidated financial statements included under Part II, Item 8 of this Annual Report on Form 10-K for information about our significant accounting policies.

Product Revenue Reserves We recognize product revenue, net of variable consideration related to certain allowances and accruals, when the customer takes control of the product, which is typically upon delivery to the customer. Revenue from product sales is recorded at the net sales price, which includes estimates of variable consideration for which reserves are reported.

These reserves are based on the amounts earned, or to be claimed on the related sales, and are generally classified as reductions of accounts receivable (if the amount is payable to the customer) or a current liability (if the amount is payable to a party other than a customer).

Certain amounts are known at the time of sale based on contractual terms and are recorded pursuant to the most likely amount method, which is the single most likely amount in a range of possible considerations. Other amounts are estimated pursuant to the expected value method, which is the sum of probability-weighted amounts in a range of possible considerations.

Relevant factors used in the expected value method include: current contractual and statutory requirements, specific known market events and trends, industry data, and forecasted customer buying and payment patterns. These reserves reflect our best estimates of the variable consideration based on the terms of the respective underlying contracts.

The estimates for our product revenue allowances and accruals are most significantly affected by chargebacks, which are contractual commitments to provide products to qualified healthcare entities at prices lower than the list prices charged to our customers who purchase XPOVIO directly from us, and rebates that represent discount obligations under government programs, including Medicaid, Medicare, the Department of Veterans Affairs, the Department of Defense, and others.

A 10% increase or decrease in these estimates would impact net product revenue by a corresponding increase or decrease of less than $3.0 million. License and Asset Purchase Agreements We generate revenue from license or similar agreements with pharmaceutical companies for the development and commercialization of certain of our products and product candidates.

At contract inception, we evaluate all goods or services in the agreement to determine if they are distinct. If they are not distinct, they are combined with other promised goods or services to create a bundle of promised goods or services that are distinct. Distinct goods or services and distinct bundles of goods or services are considered performance obligations.

Optional future services where any additional consideration paid to us reflects their standalone selling prices do not provide the customer with a material right and, therefore, are not considered performance obligations.

Optional future services that are priced in a manner which provides the customer with a significant or incremental discount are considered performance obligations because they provide the customer with a material right. We utilize judgment to estimate the transaction price at contract inception.

We evaluate contingent milestones to determine if they should be included in the transaction price using the most likely amount method. Milestone payments that are not within our control, such as regulatory approvals, are not considered likely of being achieved until those approvals are received and are excluded from the transaction price using the most likely amount method.

The transaction price is then allocated to each performance obligation on a relative standalone selling price basis, for which we recognize revenue as or when the performance obligations are satisfied.

At the end of each reporting period, we re-evaluate our estimate of the transaction price including the probability of achieving milestone payments that may not be subject to a material reversal and adjust the transaction price if necessary.

Any such adjustments are recorded on a cumulative catch-up basis, which would affect license and other revenue in the period of adjustment. 100 Table of Contents Accrued Research and Development Costs We estimate our accrued research and development costs by reviewing quotes and contracts, identifying services that have been performed on our behalf, and estimating the associated cost incurred for services performed when we have not yet been invoiced or otherwise notified of the actual cost.

Most of our service providers invoice us monthly in arrears for services performed or when contractual milestones are met. We make estimates of our accrued research and development costs at each balance sheet date in our financial statements based on facts and circumstances known to us at that time.

We periodically confirm the accuracy of our estimates with the service providers and make adjustments if necessary.

The significant estimates in our accrued research and development costs include fees to be paid to contract research organizations (“CROs”) and contract manufacturing organizations (“CMOs”) in connection with research and development activities as well as fees to be paid to investigative sites in connection with clinical studies, for which we have not yet been invoiced.