Karyopharm Therapeutics : April 19, 2024

NOTICE OF ANNUAL MEETING OF STOCKHOLDERS TO BE HELD ON MAY 29, 2024

Dear Stockholder:

You are cordially invited to our 2024 Annual Meeting of Stockholders (the "Annual Meeting") to be held on Wednesday, May 29, 2024, beginning at 9:00 a.m. Eastern Time, exclusively online via the Internet as a virtual web conference at www.virtualshareholdermeeting.com/KPTI2024 to consider and act upon the following matters:

1. To elect the following three Class II directors nominated by our Board of Directors to serve as directors, each to hold office for a three-year term to expire at the 2027 annual meeting of stockholders and until their resignation or removal or until their successors are duly elected and qualified: Deepika R. Pakianathan, Ph.D., Richard Paulson, M.B.A. and Chen Schor, M.B.A., C.P.A.;
2. To approve an amendment to the Karyopharm Therapeutics Inc. 2022 Equity Incentive Plan, as amended, to increase the number of shares of our common stock available for issuance thereunder by 6,000,000 shares;
3. To approve an amendment to the Karyopharm Therapeutics Inc. Amended & Restated 2013 Employee Stock Purchase Plan to increase the number of shares of our common stock available for issuance thereunder by 5,000,000 shares;
4. To approve a one-time stock option exchange program for non-executive officer employees;
5. To approve, on an advisory basis, the compensation of our named executive officers, as described in this proxy statement;
6. To ratify the appointment of Ernst & Young LLP as our independent registered public accounting firm for the year ending December 31, 2024; and
7. To consider and vote upon such other business as may be properly brought before the Annual Meeting or any adjournments or postponements thereof.

Our Annual Meeting will be a "virtual meeting" of stockholders, which will be conducted exclusively online via the Internet as a virtual web conference. There will not be a physical meeting location, and stockholders will not be able to attend the Annual Meeting in person. This means that you can attend the Annual Meeting online, vote your shares during the online meeting and submit questions during the online meeting by visiting the above-mentioned Internet site. We believe that hosting a virtual meeting will enable greater stockholder attendance and participation from any location around the world. We will continue to evaluate the format of our stockholder meetings on an annual basis.

Instead of mailing a printed copy of our proxy materials to all our stockholders, we are providing access to these materials via the Internet. This reduces the amount of paper necessary to produce these materials as well as the costs associated with mailing these materials to all stockholders. Accordingly, on or about April 19, 2024, we will begin mailing a Notice of Internet Availability of Proxy Materials ("Notice") to stockholders and will post our proxy materials on the website referenced in the Notice. As more fully described in the Notice, stockholders may choose to access our proxy materials on the website referred to in the Notice or may request to receive a printed set of our proxy materials. In addition, the Notice and website provide information regarding how you may request to receive proxy materials in printed form by mail, or electronically by email, on an ongoing basis.

Only stockholders of record at the close of business on April 4, 2024, the record date for the Annual Meeting, are entitled to notice of, and will be entitled to vote at, the Annual Meeting, or any adjournments or postponements thereof.

If you are a stockholder of record, you may vote in one of the following ways:

• Submit a proxy over the Internet prior to the virtual Annual Meeting, by visiting www.proxyvote.com (have your Notice or proxy card in hand to access the website);
• Submit a proxy by Telephone, by calling the toll-free number 1-800-690-6903 (have your Notice or proxy card in hand when you call);
• Submit a proxy by Mail, if you received a printed copy of the proxy materials, by returning the enclosed proxy card (signed and dated) in the envelope provided; or
• Vote online at the virtual Annual Meeting, by using the Notice or proxy card to access the Annual Meeting website, www.virtualshareholdermeeting.com/KPTI2024.

If your shares are held in "street name," meaning that they are held for your account by a broker or other nominee, you will receive instructions from the holder of record that you must follow to vote your shares.

Your vote is important to us. Whether or not you plan to attend the Annual Meeting online, we urge you to take the time to submit a proxy to vote your shares. Further information about how to attend the Annual Meeting online, vote your shares online during the Annual Meeting and submit your questions online during the Annual Meeting is included in the accompanying proxy statement.

By Order of the Board of Directors,

Richard Paulson

President, Chief Executive Officer and Director

Newton, Massachusetts

April 19, 2024

TABLE OF CONTENTS
GENERAL INFORMATION ABOUT THIS PROXY STATEMENT, THE ANNUAL MEETING AND
VOTING	1
PROPOSAL 1: ELECTION OF DIRECTORS	8
Board Diversity Matrix	8
Information Regarding Directors	9
CORPORATE GOVERNANCE	13
General	13
Director Independence	13
Board Leadership Structure	14
The Board's Role in Risk Oversight	14
Human Capital	15
Corporate Responsibility	16
Board of Directors Meetings	16
Committees of the Board of Directors	16
Compensation Committee Interlocks and Insider Participation	20
Code of Ethics and Business Conduct	20
Director Nomination Process	21
Limits on Director Service on Other Company Boards	22
Communications with Our Board of Directors	22
Director Compensation	23
Limitation of Liability and Indemnification	25
Report of the Audit Committee of the Board of Directors	26
PROPOSAL 2: APPROVAL OF AN AMENDMENT TO OUR 2022 EQUITY INCENTIVE PLAN, AS
AMENDED	27
Reasons Why Stockholders Should Approve the Amendment	27
Why We Are Requesting Stockholder Approval of an Amendment to the 2022 Plan	29
Sound Governance Features of the Amended 2022 Plan	30
Information Regarding Overhang and Burn Rate	32
Equity Compensation Plan Information	33
Description of the Amended 2022 Plan	33
PROPOSAL 3: APPROVAL OF AN AMENDMENT TO OUR AMENDED & RESTATED 2013 EMPLOYEE
STOCK PURCHASE PLAN	46
Description of the Amended 2013 ESPP	46
PROPOSAL 4: APPROVAL OF A ONE-TIME STOCK OPTION EXCHANGE PROGRAM	51
Introduction	51
Option Exchange Program Consideration	53
Reasons for the Option Exchange	54
Structure of the Option Exchange	55
Option Exchange Process	57
Impact of the Option Exchange	57
Material U.S. Federal Income Tax Consequences of the Option Exchange	58
PROPOSAL 5: ADVISORY VOTE ON THE COMPENSATION OF OUR NAMED EXECUTIVE OFFICERS ...	59
EXECUTIVE COMPENSATION	60
Compensation Discussion and Analysis	60
Tax and Accounting Considerations	72
Hedging and Pledging Policy	72
Compensation Recovery ("Clawback") Policy	72
Compensation Committee Report	72
2023 Summary Compensation Table	73
Grants of Plan-Based Awards in 2023	74
Outstanding Equity Awards at December 31, 2023	75

Option Exercises and Stock Vested in 2023	76
Employment, Severance and Change in Control Arrangements	76
Potential Payments Upon Termination or Change in Control	78
CEO Pay Ratio	80
Pay Versus Performance	81
2023 Performance Measures	83
Relationships Between Compensation Actually Paid to our NEOs and Performance Measures	83
SECURITIES AUTHORIZED FOR ISSUANCE UNDER EQUITY COMPENSATION PLANS	85
Equity Compensation Plan Information	85
CERTAIN RELATIONSHIPS AND RELATED PERSON TRANSACTIONS	86
Related Person Transactions	86
Policies and Procedures for Related Person Transactions	86
PROPOSAL 6: RATIFICATION OF THE APPOINTMENT OF INDEPENDENT REGISTERED PUBLIC
ACCOUNTING FIRM	88
Independent Registered Public Accountant Fees	88
Pre-Approval Policies and Procedures	89
SECURITY OWNERSHIP OF CERTAIN BENEFICIAL OWNERS AND MANAGEMENT	90
DELINQUENT SECTION 16(a) REPORTS	92
STOCKHOLDER PROPOSALS	92
STOCKHOLDERS SHARING THE SAME ADDRESS	93
INCORPORATION BY REFERENCE	93
OTHER MATTERS	93
APPENDIX A: Amendment to 2022 Equity Incentive Plan, As Amended	A-1
APPENDIX B: Amendment to Amended & Restated 2013 Employee Stock Purchase Plan	B-1

PROXY STATEMENT FOR THE 2024 ANNUAL MEETING OF STOCKHOLDERS TO BE HELD ON

WEDNESDAY, MAY 29, 2024

The Board of Directors (the "Board") of Karyopharm Therapeutics Inc. (which we also refer to as "Karyopharm," "the Company," "we," "us," or "our") is soliciting proxies for use at the 2024 Annual Meeting of Stockholders (the "Annual Meeting"), to be held exclusively online via the Internet as a virtual web conference at www.virtualshareholdermeeting.com/KPTI2024 on Wednesday, May 29, 2024 at 9:00 a.m. Eastern Time. We have determined that the Annual Meeting will be held in a virtual meeting format only, via the Internet, with no physical in- person meeting. At our virtual Annual Meeting, stockholders will be able to attend, vote and submit questions by visiting www.virtualshareholdermeeting.com/KPTI2024. Further information about how to attend the Annual Meeting online, vote your shares online during the Annual Meeting and submit questions during the Annual Meeting is included in this proxy statement.

Important Notice Regarding the Availability of Proxy Materials for the Annual Meeting of

Stockholders to be Held on Wednesday, May 29, 2024:

This proxy statement and our annual report are available electronically at www.proxyvote.com.

On or about April 19, 2024, we will begin mailing a Notice of Internet Availability of Proxy Materials ("Notice") to our stockholders (other than those who previously requested electronic or paper delivery of proxy materials), directing stockholders to a website where they can access our proxy materials, including this proxy statement and our Annual Report on Form 10-K for the year ended December 31, 2023, which we filed with the Securities and Exchange Commission (the "SEC") on February 29, 2024 (the "2023 Annual Report") and view instructions on how to submit a proxy to vote your shares online or by telephone. If you would prefer to receive a paper copy of our proxy materials, please follow the instructions included in the Notice. If you have previously elected to receive our proxy materials electronically, you will continue to receive access to those materials via e-mail unless you elect otherwise.

GENERAL INFORMATION ABOUT THIS PROXY STATEMENT, THE ANNUAL MEETING AND VOTING

How do I attend the virtual Annual Meeting?

This year's Annual Meeting will be conducted as a virtual meeting of stockholders. We will host the Annual Meeting exclusively online via the Internet as a virtual web conference. You will be able to attend the Annual Meeting online, vote your shares online during the Annual Meeting and submit your questions online during the Annual Meeting by visiting www.virtualshareholdermeeting.com/KPTI2024. There will not be a physical meeting location, and you will not be able to attend the Annual Meeting in person. The webcast will start at 9:00 a.m. Eastern Time on Wednesday, May 29, 2024. You will need the control number included on your proxy card or in the instructions from your broker in order to be able to attend the Annual Meeting online. Information contained on this website is not incorporated by reference into this proxy statement or any other report we file with the SEC.

Online check-in will begin at 8:45 a.m. Eastern Time on Wednesday, May 29, 2024, and you should allow ample time for the online check-in proceedings. If you encounter any difficulties accessing the virtual Annual Meeting during the check-in or meeting time, please call the technical support number that will be posted on the virtual Annual Meeting log- in page. Technical support will be available starting at 8:45 a.m. on the day of the meeting.

Why is the Annual Meeting a virtual, online meeting?

We believe that hosting a virtual meeting will facilitate stockholder attendance and participation at the Annual Meeting by enabling stockholders to participate remotely from any location around the world. Our virtual meeting will be

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governed by our Rules of Conduct and Procedures, which will be posted on the virtual meeting platform on the date of the Annual Meeting. We have designed the virtual Annual Meeting to provide the same rights and opportunities to participate as stockholders would have at an in-person meeting, including the right to vote and ask questions through the virtual meeting platform. There will not be a physical meeting location, and stockholders will not be able to attend the Annual Meeting in person. We will continue to evaluate the format of our stockholder meetings on an annual basis.

Why did you send me these proxy materials?

We are providing these proxy materials because our Board is soliciting your proxy to vote at the Annual Meeting. This proxy statement summarizes information related to your vote at the Annual Meeting. All stockholders who find it convenient to do so are cordially invited to attend the Annual Meeting online. However, you do not need to attend the meeting virtually to vote your shares. Instead, you may submit a proxy to vote your shares as described in further detail in the answer to the question "How do I vote?" below.

The Notice of Annual Meeting, proxy statement, and voting instructions, together with our 2023 Annual Report, will be made available to each stockholder entitled to vote starting on or about April 19, 2024. These materials are available for viewing, printing and downloading on the Internet at www.proxyvote.com.

Who can vote at the Annual Meeting and what are the voting rights of such stockholders?

Only stockholders of record at the close of business on April 4, 2024 (the "Record Date") are entitled to vote at the Annual Meeting. On the Record Date, there were 116,465,736 shares of our common stock outstanding and entitled to vote (each share entitles its holder to one vote). Common stock is our only class of stock outstanding.

May I see a list of stockholders entitled to vote as of the Record Date?

A list of registered stockholders as of the close of business on the Record Date will be available for examination by any stockholder for any purpose germane to the Annual Meeting for a period of 10 days ending on the day before the Annual Meeting. If you wish to view this list, please contact our Corporate Secretary at Karyopharm Therapeutics Inc., 85 Wells Avenue, Newton, Massachusetts 02459, Attention: Corporate Secretary, [phone].

What is the purpose of the Annual Meeting?

At the Annual Meeting, stockholders will consider and vote on the following matters:

1. To elect the following three Class II directors nominated by our Board to serve as directors, each to hold office for a three-year term to expire at the 2027 annual meeting of stockholders and until their resignation or removal or until their successors are duly elected and qualified: Deepika R. Pakianathan, Ph.D., Richard Paulson, M.B.A. and Chen Schor, M.B.A., C.P.A.;
2. To approve an amendment to the Karyopharm Therapeutics Inc. 2022 Equity Incentive Plan, as amended (the "2022 Plan"), to increase the number of shares of our common stock available for issuance thereunder by 6,000,000 shares;
3. To approve an amendment to the Karyopharm Therapeutics Inc. Amended & Restated 2013 Employee Stock Purchase Plan (the "Amended & Restated ESPP") to increase the number of shares of our common stock available for issuance thereunder by 5,000,000 shares;
4. To approve a one-time stock option exchange program for non-executive officer employees (the "Option Exchange");
5. To approve, on an advisory basis, the compensation of our named executive officers ("NEOs"), as described in this proxy statement;
6. To ratify the appointment of Ernst & Young LLP as our independent registered public accounting firm for the year ending December 31, 2024; and

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1. To consider and vote upon such other business as may be properly brought before the Annual Meeting or any adjournments or postponements thereof.

How many votes do I have?

Each stockholder is entitled to one vote for each share of our common stock held by such stockholder on the Record

Date.

How do I vote?

If you are the "record holder" of your shares, meaning that you own your shares in your own name and not through a bank, brokerage firm or other nominee (each a "Nominee"), you may submit a proxy or vote your shares by any of the following methods:

• Over the Internet prior to the Annual Meeting: Go to the website of our tabulator at www.proxyvote.com. Use the vote control number printed on the Notice (or your proxy card) to access your account and submit a proxy to vote your shares. You must specify how you want your shares voted or your Internet proxy cannot be completed and you will receive an error message. Your shares will be voted according to your instructions. You must submit your Internet proxy before 11:59 p.m. Eastern Time on May 28, 2024, the day before the Annual Meeting, for your proxy to be validly submitted over the Internet and for your vote to count.
• By Telephone: Call 1-800-690-6903, toll free from the United States, Canada and Puerto Rico, and follow the recorded instructions to submit a proxy to vote your shares. You will need to have the Notice (or your proxy card) in hand when you call. You must specify how you want your shares voted and confirm your vote at the end of the call or your telephonic proxy cannot be completed. Your shares will be voted according to your instructions. You must submit your telephonic proxy before 11:59 p.m. Eastern Time on May 28, 2024, the day before the Annual Meeting, for your telephonic proxy to be valid and for your vote to count.
• By Mail: If you received a printed copy of the proxy materials, complete and sign the enclosed proxy card and mail it in the enclosed envelope, postage prepaid, to Vote Processing, c/o Broadridge, 51 Mercedes Way, Edgewood, NY 11717, where the proxy card must be received no later than May 28, 2024, the day before the Annual Meeting, for it to be valid and for your vote to count. Your shares will be voted according to your instructions. If you return your proxy card but do not specify how you want your shares voted on any particular matter, they will be voted in accordance with the recommendations of our Board.
• Online while virtually attending the Annual Meeting: You may vote your shares online while virtually attending the Annual Meeting by visiting www.virtualshareholdermeeting.com/KPTI2024. You will need your control number included on your Notice or proxy card in order to be able to vote during the Annual Meeting.

If your shares are held in "street name," meaning they are held for your account by a Nominee, you may submit voting instructions or vote your shares by any of the following methods:

• Over the Internet prior to the Annual Meeting or by Telephone: You will receive instructions from your Nominee if they permit you to submit voting instructions over the Internet or by telephone. You should follow those instructions.
• By Mail: You will receive instructions from your Nominee explaining how you can submit voting instructions by mail. You should follow those instructions.
• Online while virtually attending the Annual Meeting: You will receive instructions from your Nominee explaining how you can vote your shares online during the Annual Meeting. You will need your control number included on the Notice or voting instruction form in order to demonstrate proof of beneficial ownership and to be able to vote during the Annual Meeting.

If you hold your shares of our common stock in multiple accounts, you should vote your shares or submit a proxy as described above for each account.

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Can I revoke or change my vote?

If your shares are registered directly in your name, you may revoke your proxy and change your vote at any time before the Annual Meeting. To do so, you must do one of the following:

• Submit a proxy over the Internet or by telephone prior to the Annual Meeting as instructed above. Only your latest Internet or telephonic proxy submitted prior to the Annual Meeting will be counted. You may not revoke or change your proxy over the Internet or by telephone after 11:59 p.m. Eastern Time on May 28, 2024.
• Sign a new proxy card and submit it by mail to Vote Processing, c/o Broadridge, 51 Mercedes Way, Edgewood, NY 11717, where the proxy card must be received no later than May 28, 2024. Only your latest dated proxy will be counted.
• Attend the virtual Annual Meeting and vote online as instructed above. Attending the virtual Annual Meeting alone will not revoke your Internet proxy, telephonic proxy, or proxy submitted by mail, as the case may be.
• Provide our Corporate Secretary written notice before or at the Annual Meeting that you want to revoke your proxy.

If your shares are held in "street name," you may submit new voting instructions with a later date by contacting your Nominee. You may also vote your shares online while virtually attending the Annual Meeting, which will have the effect of revoking any previously submitted voting instructions.

Will my shares be voted if I do not return my proxy or do not provide specific voting instructions on the proxy card or voting instruction form that I submit?

If your shares are registered directly in your name, your shares will not be voted if you do not submit a proxy over the Internet, by telephonic vote or by returning your proxy by mail prior to the Annual Meeting, or attend and vote online at the virtual Annual Meeting. If you submit a proxy card without giving specific voting instructions on one or more matters listed in the Notice, your shares will be voted as recommended by our Board on such matters, and as the proxyholders may determine in their discretion how to vote with respect to the matters properly presented for a vote at the Annual Meeting.

If your shares are held in "street name," your Nominee may, under certain circumstances, vote your shares if you do not timely return your voting instructions. Stock exchange rules permit a broker to vote shares held in a brokerage account on certain proposals if the broker does not receive voting instructions from you. Stock exchange rules, however, prohibit brokers from voting uninstructed shares in the case of election of directors, executive compensation matters and certain other matters. Of the matters to be voted on at the Annual Meeting, we expect the only proposal on which brokers will have discretionary voting authority is the ratification of the appointment of our independent registered public accounting firm (Proposal 6).

A "broker non-vote" results on a matter when your broker returns a proxy but does not vote on a particular proposal because it does not have discretionary authority to vote on that proposal and has not received voting instructions from you.

We encourage you to timely provide voting instructions to your Nominee. This ensures that your shares will be voted at the Annual Meeting according to your instructions. You should receive directions from your Nominee about how to submit your voting instructions to them.

What constitutes a quorum at the Annual Meeting?

A quorum is needed to hold a valid meeting. A quorum will be present if the holders of at least a majority in voting power of the shares of common stock issued and outstanding and entitled to vote on the Record Date are present at the virtual Annual Meeting either "in person" virtually or as represented by proxy. For purposes of establishing a quorum, abstentions and broker non-votes are counted as present or represented. If a quorum is not present, we expect to adjourn the Annual Meeting until we obtain a quorum. The presence at the Annual Meeting, in person or by proxy, of holders representing a majority in voting power of our outstanding common stock as of the Record Date, or 58,232,869 shares,

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constitutes a quorum at the Annual Meeting, permitting us to conduct the business of the Annual Meeting. Shares present virtually during the Annual Meeting will be considered shares of common stock present in person at the meeting.

What vote is required to approve each matter and how are votes counted?

Proposal 1 - Election of Directors

The three nominees for director to receive the highest number of votes FOR election will be elected as Class II directors. This is called a plurality. Shares held in street name by Nominees who indicate on their proxies that they do not have authority to vote the shares on Proposal 1 will not be counted as votes FOR or WITHHELD from any director nominee and will be treated as broker non-votes. Broker non-votes will have no effect on the voting on Proposal 1.

You may:

• vote FOR all nominees;
• vote FOR one or more nominees and WITHHOLD your vote from the other nominee or nominees; or
• WITHHOLD your vote from all nominees.

Votes that are withheld will not be included in the vote tally for the election of directors and will not affect the vote results.

Proposal 2 - Approval of an Amendment to our 2022 Plan to Increase the Number of Shares of our Common Stock Available for Issuance Thereunder by 6,000,000 Shares

To approve Proposal 2, stockholders holding a majority of the votes cast on the matter must vote FOR the proposal. Shares held in street name by Nominees who indicate on their proxies that they do not have authority to vote the shares on Proposal 2 will not be counted as votes FOR or AGAINST Proposal 2 and will be treated as broker non-votes. Broker non-votes will have no effect on the voting on Proposal 2. If you vote to ABSTAIN on Proposal 2, your shares will not be voted FOR or AGAINST the proposal and will also not be counted as votes cast or shares voting on Proposal 2. As a result, voting to ABSTAIN will have no effect on the voting on Proposal 2.

Proposal 3 - Approval of an Amendment to our Amended & Restated ESPP to Increase the Number of Shares of our Common Stock Available for Issuance Thereunder by 5,000,000 Shares

To approve Proposal 3, stockholders holding a majority of the votes cast on the matter must vote FOR the proposal. Shares held in street name by Nominees who indicate on their proxies that they do not have authority to vote the shares on Proposal 3 will not be counted as votes FOR or AGAINST Proposal 3 and will be treated as broker non-votes. Broker non-votes will have no effect on the voting on Proposal 3. If you vote to ABSTAIN on Proposal 3, your shares will not be voted FOR or AGAINST the proposal and will also not be counted as votes cast or shares voting on Proposal 3. As a result, voting to ABSTAIN will have no effect on the voting on Proposal 3.

Proposal 4 - Approval of a One-Time Stock Option Exchange Program for Non-Executive Officer Employees

To approve Proposal 4, stockholders holding a majority of the votes cast on the matter must vote FOR the proposal. Shares held in street name by Nominees who indicate on their proxies that they do not have authority to vote the shares on Proposal 4 will not be counted as votes FOR or AGAINST Proposal 4 and will be treated as broker non-votes. Broker non-votes will have no effect on the voting on Proposal 4. If you vote to ABSTAIN on Proposal 4, your shares will not be voted FOR or AGAINST the proposal and will also not be counted as votes cast or shares voting on Proposal 4. As a result, voting to ABSTAIN will have no effect on the voting on Proposal 4.

Proposal 5 - Advisory Vote on the Compensation of Our Named Executive Officers

To approve Proposal 5, stockholders holding a majority of the votes cast on the matter must vote FOR the approval of the compensation of our NEOs, as described in this proxy statement. Shares held in street name by Nominees who indicate on their proxies that they do not have authority to vote the shares on Proposal 5 will not be counted as votes FOR or AGAINST Proposal 5 and will be treated as broker non-votes. Broker non-votes will have no effect on the voting on Proposal 5. If you vote to ABSTAIN on Proposal 5, your shares will not be voted FOR or AGAINST the proposal and

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will also not be counted as votes cast or shares voting on Proposal 5. As a result, voting to ABSTAIN will have no effect on the voting on Proposal 5. As an advisory vote, this proposal is not binding. The outcome of this advisory vote will not overrule any decision by us or our Board (or any committee thereof). However, our Compensation Committee and our Board value the opinions expressed by our stockholders in their vote on this proposal and will consider the outcome of the vote when making future compensation decisions for our NEOs.

Proposal 6 - Ratification of the Appointment of our Independent Registered Public Accounting Firm

To approve Proposal 6, stockholders holding a majority of the votes cast on the matter must vote FOR the proposal. If your shares are held by your Nominee in "street name" and you do not timely provide voting instructions with respect to your shares, we expect that your Nominee will have the authority to vote your shares on Proposal 6. If you vote to ABSTAIN on Proposal 6, your shares will not be voted FOR or AGAINST the proposal and will also not be counted as votes cast or shares voting on Proposal 6. As a result, voting to ABSTAIN will have no effect on the voting on Proposal 6. Although stockholder ratification of our Audit Committee's appointment of Ernst & Young LLP as our independent registered public accounting firm for the year ending December 31, 2024 is not required, we believe that it is advisable to give stockholders an opportunity to ratify this appointment. If this proposal is not approved at the Annual Meeting, our Audit Committee and Board will reconsider the appointment of Ernst & Young LLP as our independent registered public accounting firm for future service.

How does the Board recommend that I vote on the proposals?

Our Board recommends that you vote:

• FOR the election of the three nominees to serve as Class II directors on our Board for a three-year term to expire at the 2027 annual meeting of stockholders and until their resignation or removal or until their successors are duly elected and qualified;
• FOR the approval of an amendment to our 2022 Plan to increase the number of shares of our common stock available for issuance thereunder by 6,000,000 shares;
• FOR the approval of an amendment to our Amended & Restated ESPP to increase the number of shares of our common stock available for issuance thereunder by 5,000,000 shares;
• FOR the approval of a one-time stock option exchange program for non-executive officer employees;
• FOR the approval of the compensation of our NEOs; and
• FOR the ratification of the appointment of Ernst & Young LLP as our independent registered public accounting firm for the year ending December 31, 2024.

Are there other matters to be voted on at the Annual Meeting?

We do not know of any matters that may come before the Annual Meeting other than Proposals 1, 2, 3, 4, 5 and 6. If any other matters are properly presented at the Annual Meeting, the persons named in the accompanying proxy intend to vote, or otherwise act, in accordance with their judgment on the matter.

How do I submit a question at the virtual Annual Meeting?

We invite appropriate questions pertinent to the Company and the matters to be voted on at the Annual Meeting. We will not be providing a business update at the Annual Meeting or discussing matters related to our business or operations. If there are any matters of individual concern to a stockholder or not related to the matters to be voted on at the Annual Meeting, or if a question was not otherwise answered, such matters may be raised separately after the Annual Meeting by contacting Investor Relations at https://investors.karyopharm.com/contact-us.

If you wish to submit a question on the day of the Annual Meeting, beginning at 8:45 a.m. Eastern Time, you may log into the virtual meeting platform at www.virtualshareholdermeeting.com/KPTI2024, proceed to the "Ask A Question" area on the lower left side of the screen, select a "Question Topic" from the drop down menu, type your question where it states "Enter Question" and click the "Submit" tab. Our virtual meeting will be governed by our Rules of Conduct and

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