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UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

SCHEDULE 14A

Proxy Statement Pursuant to Section 14(a) of the

Securities Exchange Act of 1934

(Amendment No. )

Filed by the Registrant ☒ Filed by a party other than the Registrant ☐

Check the appropriate box:

Karyopharm Therapeutics Inc.

(Name of Registrant as Specified In Its Charter)

(Name of Person(s) Filing Proxy Statement, if other than the Registrant)

Payment of Filing Fee (Check the appropriate box):

85 Wells Avenue, Newton, Massachusetts 02459 

PRELIMINARY PROXY STATEMENT - SUBJECT TO COMPLETION, DATED MARCH 31, 2023

NOTICE OF ANNUAL MEETING OF STOCKHOLDERS

TO BE HELD ON THURSDAY, JUNE 6, 2019WEDNESDAY, MAY 24, 2023

Dear Stockholder:

You are cordially invited to our 20192023 Annual Meeting of Stockholders (the “Annual Meeting”) to be held on Thursday, June 6, 2019,Wednesday, May 24, 2023, beginning at 8:9:00 a.m., Eastern time,Time, exclusively online via the Internet as a virtual web conference at our headquarters, 85 Wells Avenue, Newton, Massachusetts 02459, forwww.virtualshareholdermeeting.com/KPTI2023to consider and act upon the following purposes:matters:

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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 of our stockholders, we provideare 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 [    ], 2019,●], 2023, we will begin mailing a Notice of Internet Availability of Proxy Materials or Notice,(“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.

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

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 forto vote your shares to be voted.shares.

Our BoardOnly stockholders of Directors has fixedrecord at the close of business on April 12, 2019 asMarch 29, 2023, the record date for the determination of stockholdersAnnual Meeting, are entitled to notice of, and will be entitled to vote at, the Annual Meeting, andor any adjournmentadjournments or postponementpostponements thereof.

Whether or not you plan to attend the Annual Meeting in person,online, we urge you to take the time 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,

Michael G. Kauffman, M.D., Ph.D.

Richard Paulson

President, Chief Executive Officer and Director

Newton, Massachusetts

April [    ], 2019

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85 Wells Avenue, Newton, Massachusetts 02459

PROXY STATEMENT FOR THE 20192023 ANNUAL MEETING OF STOCKHOLDERS

TO BE HELD ON THURSDAY, JUNE 6, 2019WEDNESDAY, MAY 24, 2023

The boardBoard of directorsDirectors (the “Board”) of Karyopharm Therapeutics Inc. (which we also refer to as “Karyopharm”“Karyopharm,” “the Company,” “we,” “us,” or “the company”“our”) is soliciting proxies for use at the 2019 annual meeting2023 Annual Meeting of stockholders, orStockholders (the “Annual Meeting”), to be held exclusively online via the Internet as a virtual web conference at www.virtualshareholdermeeting.com/KPTI2023on Wednesday, May 24, 2023 at 9:00 a.m. Eastern Time. We have determined that the Annual Meeting towill be held atin a virtual meeting format only, via the Internet, with no physical in-person meeting. At our headquarters, 85 Wells Avenue, Newton, Massachusetts 02459, on Thursday, June 6, 2019 at 8:00 a.m., Eastern time.virtual Annual Meeting, stockholders will be able to attend, vote and submit questions by visiting www.virtualshareholdermeeting.com/KPTI2023. 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 Thursday, June 6, 2019:Wednesday, May 24, 2023:

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

On or about April [    ], 2019,●], 2023, we beganwill begin mailing a Notice of Internet Availability of Proxy Materials or Notice,(“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 Form10-K for the year ended December 31, 2022, which we filed with the Securities and Exchange Commission (the “SEC”) on February 17, 2023 (the “2022 Annual Report”) and view instructions on how to vote 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 viae-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/KPTI2023. 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 24, 2023. You will need the control number included on your proxy card or in the instructions from your broker in order to be able to enter 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 24, 2023, 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 governed by our Rules of Conduct and Procedures, which will be posted on the virtual meeting platform on the date of the

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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 of directorsBoard 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 in person.online. However, you do not need to attend the meeting virtually to vote your shares. Instead, you may 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 2022 Annual Report, on Form10-K for the year ended December 31, 2018, will be made available to each stockholder entitled to vote starting on or about April [    ], 2019.●], 2023. These materials are available for viewing, printing and downloading on the Internet at www.proxyvote.com.www.proxyvote.com.

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

Only stockholders who owned our common stockof record at the close of business on April 12, 2019March 29, 2023 (the “Record Date”) are entitled to vote at the Annual Meeting. On this record date,the Record Date, there were [                ]113,956,134 shares of our common stock outstanding and entitled to vote (each of whichshare entitles its holder to one vote per share)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?

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What is the purpose of the Annual Meeting?

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

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How many votes do I have?

Each stockholder is entitled to one vote for each share of our common stock that you own as of April 12, 2019 entitles you to one vote.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 vote:

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If your shares are held in“street name,” meaning they are held for your account by a bank, brokerage firm, or other nominee,Nominee, you may vote:

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

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:

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If your shares are held in “street name,” you may submit new voting instructions with a later date by contacting your bank, brokerage firm, or other nominee.Nominee. You may also vote in person atyour shares online while virtually attending the Annual Meeting, which will have the effect of revoking any previously submitted voting instructions, if you obtain a legal proxy as described in the answer to the question “How do I vote?” above.instructions.

Will my shares be voted if I do not return my proxy or do not provide specific voting instructions inon 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 vote over the Internet or by telephone prior to the Annual Meeting, by returning your proxy by mail, or by ballotonline 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 for the Annual Meeting,Notice, your shares will be voted as recommended by our board of directorsBoard on such matters, and as the proxyholders may determine in their discretion how to vote with respect to any other matters properly presented for a vote at the Annual Meeting.

If your shares are held in “street name,” your brokerage firm may, under certain circumstances, vote your shares if you do not timely return your voting instructions.Brokers canStock exchange rules permit a broker to vote their customers’ unvoted shares held in a brokerage account on discretionary matters but cannot vote such shares onnon-discretionary matters. If you docertain proposals if the broker does not timely returnreceive voting instructions to your brokerage firm to vote yourfrom you. Stock exchange rules, however, prohibit brokers from voting uninstructed shares your brokerage firm may, on discretionaryin the case of election of directors, executive compensation matters either vote your shares or leave your shares unvoted.

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Proposal 1 (election of directors), Proposal 2 (thenon-binding advisory vote onand certain other matters. Of the compensation of our named executive officers) and Proposal 3 (thenon-binding advisory vote on the frequency of future votes on the compensation of our named executive officers) arenon-discretionarymatters.If you do not instruct your brokerage firm how to vote with respect to any of these proposals, your brokerage firm may not vote with respect to such proposal or proposals, and those shares that would have otherwise been entitled to be voted on at the Annual Meeting, we expect the only proposals on which brokers will be counted as“brokernon-votes.” “Brokernon-votes”have discretionary voting authority are the approval of an amendment to our Restated Certificate of Incorporation to increase the number of authorized shares that are held in “street name” by a brokerage firm that indicates on its proxy that it does not have or did not exercise discretionary authorityof our common stock from 200,000,000 to vote on a particular matter. Proposal 4 (ratification400,000,000 (Proposal 4) and the ratification of the selectionappointment of our independent registered public accounting firm) and Proposal 5 (amendment to our Restated Certificate of Incorporation) are consideredfirm (Proposal 7).

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 matters, and your brokerage firm will be ableauthority to vote on these proposals even if it doesthat proposal and has not timely receivereceived voting instructions from you, so long as it holds your shares in its name. you.

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

How many shares must be representedWhat constitutes a quorum at the Annual Meeting?

A quorum is needed to hold a valid meeting. A quorum will be present if the Annual Meeting?

Aholders of at least a majority in voting power of ourthe shares of common stock issued and outstanding and entitled to vote on the Record Date are present at the record date must be present in personvirtual Annual Meeting either “in person” virtually or as represented by proxy to hold the Annual Meeting and conduct business. This is called a quorum.proxy. For purposes of determining whether a quorum exists, we count as present any shares that are voted over the Internet, by telephone, by completing and submitting a proxy by mail, or that are represented in person at the meeting. Further, for purposes of establishing a quorum, we will countabstentions and broker non-votes are counted as present shares that a stockholder holds even if the stockholder votes to abstain or only votes on one of the proposals. In addition, we will count as present shares held in “street name” by banks, brokerage firms, or nominees who indicate on their proxies that they do not have discretionary authority to vote those shares on Proposals 1, 2 and 3, or brokernon-votes.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 of our outstanding common stock as of April 12, 2019,the Record Date, or [                ]56,978,068 shares, 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 represented in person at the meeting.

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

Proposal 1—1 - Election of Directors

The three nominees for director to receive the highest number of votes FOR election will be elected as Class IIII directors. This is called a plurality.Proposal 1 is anon-discretionary matter. Therefore, if your shares are held by your brokerage firm in “street name” and you do not timely provide voting instructions with respect to your shares, your brokerage firm cannot vote your shares on Proposal 1. Shares held in “street name”street name by banks, brokerage firms, or nomineesNominees 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 the nominee. As a result, such “brokerany 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:

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

Proposal 2 - Approval of an Amendment to our 2022 Plan to Increase the vote.Number of Shares of our Common Stock Available for Issuance Thereunder by 5,000,000 Shares

Proposal2—Non-binding Advisory Vote on the Compensation of Our Named Executive Officers

To approve Proposal 2, stockholders holding a majority of the votes cast on the matter must vote FOR the approval of the compensation of our named executive officers, as describedproposal. Shares held in the “Compensation Discussion

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and Analysis,” executive compensation tables and accompanying narrative disclosures in this proxy statement.Proposal 2 is anon-discretionary matter. Therefore, if your shares are heldstreet name by your bank, broker or other nominee in “street name” and youNominees who indicate on their proxies that they do not have authority to vote your shares, your bank, broker or other nominee cannot vote yourthe shares on Proposal 2 will not be counted as votes FOR or AGAINST Proposal 2 and yournon-votewill be treated as broker non-votes. Broker non-votes will have no effect on the outcome of this proposal.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.

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 of directors (or any committee thereof). However, our compensation committee and our board of directors value the opinions expressed by our stockholders in their vote on this proposal and will consider the outcomeProposal 3 - Approval of the vote when making future compensation decisions forAmendment and Restatement of our named executive officers.ESPP

To approve Proposal3—Non-binding Advisory Vote 3, stockholders holding a majority of the votes cast on the Frequency of Future Advisory Votesmatter must vote FOR the proposal.Shares held in street name by Nominees who indicate on the Compensation of Our Named Executive Officers

To recommend the frequency of future advisory votes on the compensation of our named executive officers, you may:

The frequency choicetheir proxies that receives the highest numbers of votes cast will be considered to be the preferred frequency of our stockholders with which we are to hold futurenon-binding stockholder advisory“say-on-pay” votes on the compensation of our named executive officers.Proposal 3 is anon-discretionary matter. Therefore, if your shares are held by your bank, broker or other nominee in “street name” and youthey do not have authority to vote your shares, your bank, broker or other nominee cannot vote yourthe shares on Proposal 3 will not be counted as votes FOR or AGAINST Proposal 3 and yournon-votewill be treated as broker non-votes. Broker non-votes will have no effect on the outcome of this proposal.voting on Proposal 3. If you vote to ABSTAIN on Proposal 3, your shares will not be voted FOR any ofor AGAINST the frequency choicesproposal 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.

AsProposal 4 - Approval of an advisory vote, this proposal is not binding. Our boardAmendment to our Restated Certificate of directors will take into considerationIncorporation to Increase the outcomeNumber of this vote in determining the frequency of futurenon-binding advisory votes on the compensationAuthorized Shares of our named executive officers. However, because this vote is advisory andnon-binding, our board of directors may decide that it is in our best interests and those of our stockholdersCommon Stock from 200,000,000 to hold the advisory vote to approve the compensation of our named executive officers more or less frequently.400,000,000

Proposal 4—Ratification of Selection of Independent Registered Public Accounting Firm

To approve Proposal 4, stockholders holding a majority of the votes cast on the matteroutstanding shares of our common stock entitled to vote thereon must vote FOR the proposal.Proposal 4 is considered a discretionary matter. If your shares are held by your bank, broker or other nomineeNominee in “street name” and you do not timely provide voting instructions with respect to your shares, we expect that your bank, broker or other nominee firm mayNominee will have the authority to vote your unvoted shares on Proposal 4. If you vote to ABSTAIN from voting 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. Because Proposal 4 requires the proposal. Asaffirmative vote of stockholders holding a result,majority of the outstanding shares of our common stock entitled to vote thereon, voting to ABSTAIN will have nothe same effect on the outcome ofas a vote AGAINST Proposal 4.

Although stockholder ratification of our audit committee’s selection of Ernst & Young LLP as our independent registered public accounting firm for the year ending December 31, 2019 is not required, we believe

-Proposal 5 -

that it is advisable to give stockholders an opportunity to ratify this selection. If this proposal is not approved at the Annual Meeting, our audit committee will reconsider its selection of Ernst & Young LLP as our independent registered public accounting firm for the year ending December 31, 2019.

Proposal 5—Approval of an Amendment to our Restated Certificate of Incorporation to Increase the Number of Authorized Shares of Common StockReflect New Delaware Law Provisions Regarding Officer Exculpation

To approve Proposal 5, stockholders holding a majority of the outstanding shares of our common stock issued and outstanding and entitled to vote at the Annual Meetingthereon must vote FOR the approval of the amendment to our restated certificate of incorporation to increase the number of authorized shares of common stock.Proposal 5 is a discretionary matter. Therefore, if your shares areproposal. Shares held in street name by your bank, broker or other nominee in “street name” and youNominees who indicate on their proxies that they do not have authority to vote your shares, your bank, broker or other nominee may vote yourthe shares on Proposal 5.5 will not be counted as votes FOR or AGAINST Proposal 5 and will be treated as broker non-votes. If you vote to ABSTAIN from voting on Proposal 5, 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 5. Because Proposal 5 requires the affirmative vote of the holders ofstockholders holding a majority of the outstanding shares of our common stock issued and outstanding and entitled to vote at the Annual Meeting, a votethereon, broker non-votes and voting to ABSTAIN will have the same effect as a vote AGAINSTagainst Proposal 5.

How does the board

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Proposal 6 - Advisory Vote on the proposals?Compensation of Our Named Executive Officers

Our board of directors recommends that you vote:

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

Our Board recommends that you vote:

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, 6 and 5.7. 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.

Who

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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/KPTI2023, proceed to the “Ask A Question” area on the lower right 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 Procedures, which will be posted at www.virtualshareholdermeeting.com/KPTI2023during the Annual Meeting. The Rules of Conduct and Procedures will address the ability of stockholders to ask questions during the meeting, including rules on permissible topics, and rules for how questions and comments will be recognized. We will answer appropriate questions that are pertinent to the Company and the matters to be voted on by the stockholders at the Annual Meeting. Because time is payinglimited at the costs ofAnnual Meeting, we may not be able to answer all questions that are submitted. To promote fairness, efficiently use the Company’s resources and address all stockholder questions, we will limit each stockholder to one question, which should be succinct and should cover only one topic. Questions from multiple stockholders on the same topic or that are otherwise related may be grouped, summarized and answered together.

How are we soliciting these proxies?proxies and tabulating votes?

We will pay all of the costs of soliciting proxies. OurIn addition to these proxy materials, our directors, officers, and other employees may also solicit proxies in person or by mail, telephone, fax or email. email without additional compensation. We have retained Alliance Advisors, LLC, a proxy solicitation firm, to assist in the solicitation of proxies for a fee of approximately $25,000, plus expenses. We will pay our directors, officers,also reimburse brokerage firms, banks and other employees no additional compensationagents for these services. We do not currently plan to hire a proxy solicitor to help us solicit proxies, although we reserve the right to do so. We will ask banks, brokerage firms, and other nominees to forward thesecost of forwarding proxy materials to their principals and to obtain authority to execute proxies. Webeneficial owners. Votes will then reimburse them for their expenses. Our costs for forwarding proxy materials will not be significant.tabulated by Broadridge. If you have any questions or need assistance with voting please contact Alliance Advisors.

Alliance Advisors

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877-495-1344

KPTI@AllianceAdvisors.com

How do I obtain an Annual Report on Form10-K?

If you would like a copy of our 2022 Annual Report, on Form10-K for the year ended December 31, 2018 that we filed with the Securities and Exchange Commission, or SEC, we will send you one without charge. Please write to:

Karyopharm Therapeutics Inc.

85 Wells Avenue

Newton, Massachusetts 02459

Attn: Investor Relations

All of our SEC filings are also available free of charge under the heading “Financials & Filings—“Financial Information – SEC Filings”Filings” in the “Investors”“Investors” section of our website at www.karyopharm.com.www.karyopharm.com.

How can I find out the results of the voting at the virtual Annual Meeting?

Preliminary voting results will be announced at the Annual Meeting. Final voting results will be tallied by the inspector of election and published in a current report on Form8-K that we expect to be filedfile with the SEC within four business days after the Annual Meeting. If final voting results are not available to us in time to file a Form 8-K within four business days after the Annual Meeting, we intend to file a Form 8-K to publish preliminary results and, within four business days after the final results are known to us, file an amended Form 8-K to publish the final results.

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PROPOSAL 1:

ELECTION OF DIRECTORS

Our board of directorsBoard is divided into three classes, with one class of our directors standing for election each year to serve for a three-year term. Directors for each class are elected at the annual meeting of stockholders held in the year in which the term for their class expires and hold office until their resignation or removal or until their successors are duly elected and qualified. In accordance with our certificate of incorporation and bylaws, our board of directorsBoard may fill existing vacancies on the board of directorsBoard by appointment.

The term of office of our Class IIII directors, Garen G. Bohlin, Mikael Dolsten,Barry E. Greene, Mansoor Raza Mirza, M.D., Ph.D. and Michael G. Kauffman, M.D., Ph.D.,Christy J. Oliger, will expire at the Annual Meeting. Accordingly, the nominees for Class IIII director for election at the Annual Meeting are Mr. BohlinGreene, Dr. Mirza and Drs. Dolsten and Kauffman.Ms. Oliger. If Mr. BohlinGreene, Dr. Mirza and Drs. Dolsten and KauffmanMs. Oliger are elected at the Annual Meeting, each such individual will be elected to serve for a three-year term that will expire at our 20222026 annual meeting of stockholders and until such individual’s successor is duly elected and qualified.

If no contrary indication is made, proxies are to be voted for Mr. BohlinGreene, Dr. Mirza and Drs. Dolsten and Kauffman,Ms. Oliger, or in the event that any ofeither Mr. Bohlin and Drs. Dolsten and KauffmanGreene, Dr. Mirza or Ms. Oliger is not a candidate or is unable to serve as a director at the time of the election (which is not currently expected), for any nominee who is designated by our board of directorsBoard to fill the vacancy.

Our board of directorsBoard currently consists of seveneight members. We have no formal policy regarding board diversity, but our Corporate Governance Guidelines provide that the background and qualifications of the members of our board of directorsBoard considered as a group should provide a significant breadth of experience, knowledge, and ability to assist our board of directorsBoard in fulfilling its responsibilities. Our priority in the selection of board members isis: (a) identification of members who will further the interests of our stockholders through his or her established record of professional accomplishment, theaccomplishment; (b) ability to contribute positively to the collaborative culture among board members,members; (c) knowledge of our business,business; (d) understanding of the competitive landscapelandscape; and (e) adherence to high ethical standards. Our Board believes that personal diversity, including gender, ethnic and racial diversity, is an added benefit to the Board and its ability to function effectively. Therefore, the Board has committed to strengthening its consideration of diversity factors when evaluating potential director nominees in both the charter of the Nominating, Corporate Governance & Compliance Committee and the Company’s Corporate Governance Guidelines to include diversity among the factors it considers when evaluating potential candidates to the extent consistent with applicable legal requirements and the Board’s fiduciary duties. Certain individual qualifications and skills of our directors, including director diversity, that contribute to our board of directors’Board’s effectiveness as a whole are summarized and described below.

Board Diversity Matrix

The following Board Diversity Matrix sets forth gender and demographic information of our current Board members in the following paragraphs.accordance with Nasdaq Listing Rule 5606, as self-reported by our Board members.

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Information Regarding Directors

The information set forth below as to the directors and nomineenominees for directordirectors has been furnished to us by the directors and nomineenominees for director:directors:

NomineeNominees for Election to the Board of Directors

For a Three-Year Term Expiring at the

20222026 Annual Meeting of Stockholders (Class III)

I)

Garen G. Bohlin.Mr. Bohlin has served as a member of our board of directors since October 2013. Since April 2012, Mr. Bohlin has focused exclusively on service on boards of directors and consulting. From January2010 until his retirement in April 2012, he served as Executive Vice President of Constellation Pharmaceuticals, Inc., a biopharmaceutical company, where he served as a part-time business partner with the Chief Executive Officer. Prior to Constellation Pharmaceuticals, Mr. Bohlin served as Chief Operating Officer of Sirtris Pharmaceuticals, Inc., a biotechnology company, from January 2006 to December 2009, where he played key roles in the overall management of Sirtris, its initial public offering and the sale of the company to GlaxoSmithKline. Mr. Bohlin was the founding Chief Executive Officer of Syntonix Pharmaceuticals, Inc., a biopharmaceutical company, from 1999 through December 2008, where heplayed a key role in the overall management of Syntonix, positioning it for an eventual sale to Biogen Idec. Priorto Syntonix, Mr. Bohlin was Executive Vice President of Genetics Institute, Inc., a biotechnology company, where he played a key role in overall management, its initial public offering and its sale to American Home Products/Wyeth, and a partner at Arthur Andersen & Co., a public accounting and consulting organization. Mr. Bohlin serves on the boards of directors and audit committees of Collegium Pharmaceutical, Inc., Tetraphase Pharmaceuticals, Inc. and Proteon Therapeutics, Inc., each a public biopharmaceutical company. He previously served as a director of several private and public biotechnology companies. Mr. Bohlin holds a B.S. in Accounting from the University of Illinois. We believe Mr. Bohlin’s qualifications to serve on our board of directors include his extensive industry and board experience, including his audit committee experience, with publicly traded and privately held biotechnology companies.

Mikael Dolsten, M.D., Ph.D.Dr. Dolsten has served as a member of the board of directors since March 2015. Dr. Dolsten has served as President of Worldwide Research, Development and Medical and Executive Vice President of Pfizer Inc., which is one of the largest pharmaceutical companies in the world, since December 2010. Dr. Dolsten served as President of Worldwide Research and Development and Senior Vice President of Pfizer Inc. from May 2010 until December 2010 and President of Pfizer BioTherapeutics Research & Development Group and Senior Vice President of Pfizer Inc. from October 2009 until May 2010. From June 2008 to October 2009, Dr. Dolsten served as Senior Vice President of Wyeth, a biopharmaceutical company that was acquired by Pfizer Inc. in October 2009, and President, Wyeth Research from June 2008 to October 2009. Prior to joining Wyeth, Dr. Dolsten was a Private Equity Partner at Orbimed Advisors, LLC and Executive Vice President, Head of Pharma Research at Boehringer Ingelheim, a pharmaceutical company. Dr. Dolsten also previously held research leadership positions at AstraZeneca, Pharmacia and Upjohn. We believe Dr. Dolsten’s qualifications to serve on our board of directors include his depth of experience leading pharmaceutical research and development teams at large public companies. He is widely recognized as a leader within the medical research and drug development community and this level of expertise is significant to our board of directors as we continue to advance our clinical development pipeline and initiate additional clinical trials.

Michael G. Kauffman, M.D., Ph.D. Dr. Kauffman has served as Karyopharm’s Chief Executive Officer since January 2011 and has been one of our directors since 2008. Dr. Kauffmanco-founded Karyopharm with

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Dr. Sharon Shacham in 2008 and served as our President from January 2011 to December 2013 and as Chief Medical Officer from December 2012 to December 2013. Prior to joining Karyopharm, he was Chief Medical Officer of Onyx Pharmaceuticals Inc., a biopharmaceutical company, from November 2009 to December 2010. From November 2008 to November 2009, Dr. Kauffman was Chief Medical Officer of Proteolix Inc., which was acquired by Onyx Pharmaceuticals. At Proteolix, he led the development of Kyprolis^® (carfilzomib), a novel proteasome inhibitor approved in refractory myeloma by the Food and Drug Administration in July 2012. Dr. Kauffman was an operating partner at Bessemer Venture Partners from 2006 to 2008, where he led investments in biotechnology companies. From 2006 to 2008, he was President and Chief Executive Officer of Epix Pharmaceuticals, Inc., a biopharmaceutical company that underwent liquidation proceedings through an assignment for the benefit of creditors under Massachusetts law in 2009. Dr. Kauffman was President and Chief Executive Officer of Predix Pharmaceuticals, Inc., a private biopharmaceutical company focused on G protein-coupled receptors (GPCR), from 2002 until its merger into Epix Pharmaceuticals in 2006. In that role, he led the merger of Predix Pharmaceuticals and Epix Pharmaceuticals, oversaw the discovery and development of four new clinical candidates and led collaboration transactions with Amgen and GlaxoSmithKline. From March 2000 to September 2002, Dr. Kauffman was Vice President, Clinical at Millennium Pharmaceuticals, Inc., a biopharmaceutical company, where he led the Velcade^® development program. From September 1997 to March 2000, Dr. Kauffman held a number of senior positions at Millennium Predictive Medicine, Inc., a biopharmaceutical company and a subsidiary of Millennium Pharmaceuticals, where he led the discovery and development of novel molecular diagnostics for major cancers, including melanoma and led transactions with Becton-Dickenson and Bristol Myers Squibb. From August 1995 to September 1997, Dr. Kauffman held a number of senior positions at Biogen Idec, Inc., a biopharmaceutical company, where he led the clinical development of anti-CD40L antibodies in autoimmune and inflammatory diseases, and acted as the main medical advisor to the Biogen business development group. Dr. Kauffman currently serves on the board of directors, nominating and governance committee and research and development committee of Infinity Pharmaceuticals, Inc., a public biopharmaceutical company, on the board of directors and audit committee and as chairman of the compensation committee of Kezar Life Sciences, Inc., also a public biopharmaceutical company, and is the lead director and compensation committee member of Verastem Inc., also a public biopharmaceutical company. Dr. Kauffman previously served on the board of directors and compensation and audit committees of Zalicus Inc., a biotechnology company. Dr. Kauffman received his B.A. in Biochemistry from Amherst College and his M.D. and Ph.D. from Johns Hopkins Medical School, and he trained in internal medicine and rheumatology at Beth Israel Hospital (now Beth Israel Deaconess Medical Center) and Massachusetts General Hospital. He is board certified in internal medicine. We believe Dr. Kauffman’s qualifications to serve on our board of directors include his extensive experience in the healthcare industry as well his extensive knowledge of our company and its business since inception through service in multiple executive leadership positions and as a member of our board.

Members of the Board of Directors Continuing in Office

Term Expiring at the

2020 Annual Meeting of Stockholders (Class I)

J. Scott Garland. Mr. Garland has served as a member of our board of directors since November 2014. Mr. Garland has been the President and Chief Executive Officer of Portola Pharmaceuticals, Inc., a biopharmaceutical company, since October 2018. Mr. Garland was the President of Relypsa Inc., a biopharmaceutical company, from April 2017 to October 2018, and was Senior Vice President and Chief

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Commercial Officer from October 2014 to April 2017. Prior to Relypsa, Mr. Garland served as Executive Vice President and Chief Commercial Officer of Exelixis, Inc., a biopharmaceutical company focused on developing and commercializing cancer treatments, from October 2011 to October 2014. Prior to joining Exelixis, from April 2002 to October 2011, Mr. Garland held positions at Genentech, Inc., most recently serving as Vice President of Genentech’s Avastin^® franchise, where he led the U.S. sales and marketing efforts for the drug. Prior to that position, he served as Vice President, Hematology Marketing and Sales, overseeing the Rituxan^® franchise and as a Director on the Tarceva^® franchise. From July 1997 to April 2002, Mr. Garland held several positions within the sales and marketing division of Amgen, Inc. and from July 1991 to July 1995, he served as a professional sales representative at Merck & Co., Inc. Mr. Garland has an M.B.A. from Duke University’s Fuqua School of Business and a B.A. from California Polytechnic University (San Luis Obispo). We believe Mr. Garland’s qualifications to serve on our board of directors include his more than 20 years of sales, marketing and commercialization experience in the pharmaceutical and biopharmaceutical industry as well as his extensive management experience at publicly-traded biopharmaceutical companies.

Barry E. Greene.Mr. Greene has served as a member of our board of directorsBoard since January 2013 and as our Lead Independent Director since January 2015. Mr. Greene has served as Chief Executive Officer of Sage Therapeutics, Inc., a public biopharmaceutical company, since December 2020. Mr. Greene served as President of Alnylam Pharmaceuticals, Inc. (“Alnylam”), a public biopharmaceutical company, sincefrom 2007 to September 2020, and served as its Chief Operating Officer from 2003 to 2016. Mr. Greene joined Alnylam in 2003, bringing over 15 years of experience in the healthcare industry and in consulting. Prior to Alnylam, he was General Manager of Oncology at Millennium Pharmaceuticals, Inc. (“Millennium”), a public biopharmaceutical company, where he led the company’s global strategy and execution for its oncology business, including strategic business direction and execution, culminating in the successful Food and Drug Administration approval and launch of VELCADE^® (bortezomib) inmid-2003.company. Prior to joining Millennium in 2001, Mr. Greene served as Executive Vice President and Chief Business Officer for Mediconsult.com, a healthcare consulting company.Mediconsult.com. Prior to Mediconsult.com, Mr. Greene’s experience included serving as Vice President of Marketing and Customer Services for AstraZeneca (formerly AstraMerck), a public biopharmaceutical company; Vice President, Strategic Integration with responsibility for the AstraZeneca North American post-merger integration; and a partner of Andersen Consulting, a consulting company, where he was responsible for the pharmaceutical/biotechnology marketing and sales practice.Consulting. Mr. Greene currently ishas served as a member of the board of directors of Sage Therapeutics, Inc., a public biopharmaceutical company, since October 2020. Mr. Greene served as a member of the board of directors of BCLS Acquisition Corp., a special purpose acquisition company, from October 2020 to October 2022. From 2007 to September 2021, Mr. Greene served as a member of the board of directors of Acorda Therapeutics, Inc., a public biopharmaceutical company, where he servesalso served as a member of its compensation committee. Mr. Greene received his B.S. in Industrial Engineering from the University of Pittsburgh and served as a Senior Scholar at Duke University,University’s Fuqua School of Business. We believe Mr. Greene’s qualifications to serve on our board of directorsBoard and as our Lead Independent Director include his extensive experience in the healthcare and consulting industries as well as his practical experience with business and product aspects of the biopharmaceutical industry, including successfully guiding new drugs through research, development, and the commercialization process.

Mansoor Raza Mirza,,M.D.Dr. Mirza has served as a member of our board of directorsBoard since October 2010. He has also served as a clinical consultant to us since 2010. Dr. Mirza ishas served as Chief Oncologist at the Department of Oncology, Rigshopitalet—Rigshopitalet - the Copenhagen University Hospital, Denmark since 2009 and as Medical Director of the Nordic Society of Gynaecological Oncology (NSGO).since 2012. Dr. Mirza is Chairman and Executive Founding Member of the European Network of Gynaecological Oncological Trial groups. Dr. Mirza is both a medical and radiation oncologist, with a primary focus innon-surgical treatment of gynecologic cancers. His key academic goals are to promote clinical research,He serves on several independent data safety monitoring committees of international trial collaborationstudies and education, and he has broad experience in clinical protocol development, trial conduct and clinical trial regulations. Dr. Mirza is the author of several phase 1, 2 and 3 studies, several of those leading to Food and Drug Administration and European Medicines Agency registration. He serves in several Independent Data Safety Monitoring Committees of international studies. He is an invited speaker at several international conferences, such as “Meet the Professor” at American Society of Clinical Oncology and “Presidential Symposium” at European Society for Medical Oncology. He is the senior author of national Danishglobal consensus guidelines for the management of endometrial, cervical, vulvarovarian cancer andnon-epithelial ovarian cancers as well as of the NSGO radiotherapyEuropean guidelines for cervical and vulvar cancers. He is authorthe management of European Guidelines in endometrial and vulvar cancers. Hisseveral gynecological malignancies. Dr. Mirza’s other current appointments include service as ESGO Council Member (EuropeanVice President of the European Society of Gynaecological Oncology),Oncology, Executive Director of GCIG (Gynecologicthe Gynecologic Cancer InterGroup), Vice-Chairman of the Danish Gynecological Cancer Society, Founding Executive Member of the

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European Network of Gynecologic Oncology Trials Group,InterGroup and faculty member of the European Society of Medical Oncology and of the International Gynecologic Cancer Society.Oncology. He also serveshas served on the board of directors of Sera Prognostics, Inc., a privatepublic biopharmaceutical company.company, where he also serves as a member of its compensation committee, since July 2021. He has multipleover 100 publications in high-impact journals, likeincluding several publications in the New England Journal of Medicine.Medicine and the Lancet. He holds aan M.D., Diploma in Surgery and Diploma in Clinical Oncology from the Pirogov Moscow State Medical Institute as well as post-graduate education and certification in radiation and medical oncology from the University of Southern Denmark. We believe Dr. Mirza’s qualifications to serve on our board of directorsBoard include his position as an expertexpertise in thenon-surgical treatment of cancer, and gynecologic cancers in particular, and his knowledge of our companythe Company and its business through service on our Board and as a consultant to the Company since 2010.

Christy J. Oliger. Ms. Oliger has served as a member of our Board since August 2020. Until August 2020, Ms. Oliger served in numerous leadership roles over twenty years at Genentech, Inc. (“Genentech”), a biotechnology

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company, including most recently as Senior Vice President of the Oncology Business Unit from 2017 to August 2020, and Senior Vice President, Neuroscience and Rare Disease Business Unit at Genentech from 2014 to 2017. During her tenure with Genentech, Ms. Oliger also held a number of senior leadership roles in both commercial and research and development across a variety of therapeutic areas, including oncology, neurology, rare disease, respiratory, dermatology and immunology. Prior to Genentech, Ms. Oliger held management positions at Schering-Plough. Ms. Oliger has served on the board of directors of Lava Therapeutics N.V., a public immuno-oncology company, since October 2010.March 2023, the board of directors of Reata Pharmaceuticals, Inc., a public biopharmaceutical company, since April 2021, where she also serves on the audit committee, nominating and corporate governance committee and the commercial and medical affairs committee, and the board of directors of Replimune Group Inc., a public biotechnology company, since December 2021, where she also serves on the audit committee and research and development committee. Ms. Oliger also served on the board of directors of Sierra Oncology, Inc., a public biopharmaceutical company, from June 2021 until July 2022, when it was acquired by GSK plc. Ms. Oliger holds a bachelor’s degree in Economics from the University of California at Santa Barbara. We believe Ms. Oliger’s qualifications to serve on our Board include her more than thirty years of strategic and operational experience in the biopharmaceutical industry with broad commercial, portfolio management and leadership expertise, including in the oncology field.

Members of the Board of Directors Continuing in Office

For a Three-Year Term Expiring at the

20212024 Annual Meeting of Stockholders (Class II)

Deepika R. Pakianathan, Ph.D.Dr. Pakianathan has served as a member of our board of directorsBoard since April 2013. Since 2001, Dr. Pakianathan has been a Managing Member at Delphi Ventures, a venture capital firm focused on biotechnology and medical device investments, andwhere she leads the firm’s biotechnology investment activities. From 1998 to 2001, Dr. Pakianathan was a senior biotechnology banker at JPMorgan, a global investment bank, from 1997 to 1998, she was a Researchresearch analyst covering biotechbiotechnology at Genesis Merchant Groupand from 1993 to 1997 she was a post-doctoral research scientist at Genentech. Dr. Pakianathan serveshas served on the boardsboard of directors of Alder Biopharmaceuticals,Theravance Biopharma, Inc., a public biopharmaceutical company, since July 2020, where she also serves as chair of the nominating and governance committee and a member of its compensationthe audit committee OncoMed Pharmaceuticals, Inc.,and scientific technology committee; Mereo Biopharma Group PLC, a public biopharmaceutical company, since February 2019, where she also serves as chair of its remuneration committee and a member of its audit and compensation committeesthe scientific technology committee; and Calithera Biosciences, Inc., a public biopharmaceutical company, since 2010, where she also serves as the lead independent director, chair of the nominating and is agovernance committee and member of itsthe compensation committee and scientific technology committee. In December 2020, Dr. Pakianathan was appointed to the board of directors of Palleon Pharmaceuticals, Inc., a biotechnology company, where she serves as lead director and chair of its nominatingthe audit committee and governancecompensation committee. From August 2020 to February 2021, Dr. Pakianathan served on the board of directors of Foresite Development Corp I, and from February 2021 to December 2021, Dr. Pakianathan served on the board of directors of Foresite Development Corp II, both public special purpose acquisition companies. From 2004 to 2016, Dr. Pakianathan served on the board of directors of Alexza Pharmaceuticals, Inc., from 2009 to February 2013, Dr. Pakianathan served on the board of directors of PTC Therapeutics, Inc., and from 2007 to 2012, Dr. Pakianathan served on the board of directors of Relypsa, Inc., each a public biopharmaceutical company. Dr. Pakianathan receivedholds a M.S. and Ph.D. from Wake Forest University, a B.Sc. from the University of Bombay, India and a M.Sc. from The Cancer Research Institute at the University of Bombay, India, and an M.S. and Ph.D. from Wake Forest University.India. We believe Dr. Pakianathan’s qualifications to serve on our board of directorsBoard include her experience as a venture capital investor in, and director of multiple biotechnology companies, as well as her experience as a biotechnology investment banker, research analyst and research scientist.

RecommendationRichard Paulson, M.B.A. Mr. Paulson has served as our President and Chief Executive Officer since May 2021 and as a member of our Board since February 2020. Prior to joining Karyopharm, Mr. Paulson was the Executive Vice President and Chief Executive Officer of Ipsen North America, a biopharmaceutical company, from February 2018 to May 2021. Mr. Paulson was Vice President and General Manager, U.S. Oncology Business Unit at Amgen Inc. (“Amgen”), a public biotechnology company, from 2015 to 2018 and prior to that was Vice President, Marketing for Amgen’s U.S. Oncology Business, General Manager, Amgen Germany and General Manager of Amgen Central &

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Eastern. Prior to Amgen, Mr. Paulson held a number of global leadership positions at Pfizer Inc. (“Pfizer”), including serving as General Manager of Pfizer South Africa and Pfizer Czech Republic. Mr. Paulson also previously held a variety of sales, marketing, and market access roles with increasing seniority at GlaxoWellcome plc, in Canada. Mr. Paulson has served on the board of directors of bluebird bio, Inc., a public biotechnology company, since April 2023. Mr. Paulson has an M.B.A. from the University of Toronto, Canada and an undergraduate degree in commerce from the University of Saskatchewan, Canada. We believe Mr. Paulson’s qualifications to serve on our Board include his more than 25 years of global biopharmaceutical industry experience, as well as his achievements in leading and growing businesses, both in the U.S. and internationally, as well as his extensive knowledge of, and leadership of, our Company as our President and Chief Executive Officer.

Chen Schor, M.B.A., C.P.A. Mr. Schor has served as a member of our Board since November 2020. Mr. Schor has served as the President, Chief Executive Officer and Director of Adicet Bio, Inc., a public biotechnology company, since September 2020. He held the role of President and Chief Executive Officer at resTORbio, Inc. (“resTORbio”) from 2016 until its merger with Adicet Bio, in September 2020. Prior to resTORbio, Mr. Schor served as President, Chief Executive Officer and Director of Synta Pharmaceuticals Corporation, from 2014 until 2016. Previously, he served as Vice President, Global Branded Business Development and Pipeline Management at Teva Pharmaceuticals Industries Ltd., and held leadership positions at several emerging private and public companies. Before that, Mr. Schor was a Partner at Yozma Venture Capital, where he led the foundation and growth of multiple therapeutic companies from inception to commercial success. Mr. Schor has served on the board of directors of resTORbio/Adicet Bio since 2016 and also served on the board of directors and audit committee of Brainstorm Cell Therapeutics Inc., a public biotechnology company, from 2011 until March 2020. Mr. Schor has led strategic transactions valued at over $8 billion with companies such as GlaxoSmithKline plc, Amgen Inc., Pfizer, Merck KGaA (co-led) and Cephalon, Inc. (co-led). Mr. Schor holds a B.A. in Biology and an M.B.A. from Tel Aviv University, a B.A. in Economics and Accounting from Haifa University and is a Certified Public Accountant. We believe Mr. Schor’s qualifications to serve on our Board include his substantial transactional and financial experience and extensive experience leading biotech companies across all stages, from formation and early stage discovery to publicly traded multi-product companies.

Members of the Board of Directors Continuing in Office

For a Three-Year Term Expiring at the

2025 Annual Meeting of Stockholders (Class III)

Garen G. Bohlin. Mr. Bohlin has served as a member of our Board since October 2013. Since 2012, Mr. Bohlin has focused exclusively on service on boards of directors and consulting. From 2010 until his retirement in 2012, he served as Executive Vice President of Constellation Pharmaceuticals, Inc. (“Constellation”), a biopharmaceutical company, which was private at that time. Prior to Constellation, Mr. Bohlin served as Chief Operating Officer of Sirtris Pharmaceuticals, Inc., from 2006 to 2009, which was acquired by GlaxoSmithKline plc. From 1999 through 2008, Mr. Bohlin served as President and Chief Executive Officer of Syntonix Pharmaceuticals, Inc. (“Syntonix”), which was acquired by Biogen Idec. Prior to Syntonix, Mr. Bohlin spent 14 years in executive management at Genetics Institute, Inc., which was acquired by Wyeth, and prior to that he was a partner at Arthur Andersen & Co., where he spent 13 years. Mr. Bohlin has served on the board of directors of Collegium Pharmaceutical, Inc., a public specialty pharmaceutical company, since 2015, where he also serves on the audit committee and compensation committee, and as Chairman of the board of directors of Curadel Surgical Innovations, Inc., a medical imaging company, since March 2020. Mr. Bohlin previously served on the board of directors of Proteon Therapeutics, Inc., a public biopharmaceutical company, from 2014 through January 2020, where he also served on the audit committee, compensation committee and nominating and corporate governance committee. He also previously served on the board of directors of Tetraphase Pharmaceuticals, Inc., a public biotechnology company, from 2010 through July 2020, where he also served on the audit committee. Mr. Bohlin holds a B.S. in Accounting from the University of Illinois. We believe Mr. Bohlin’s qualifications to serve on our Board include his extensive industry and board experience, including his audit committee experience, with publicly traded and privately held biotechnology companies.

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Peter Honig, M.D., M.P.H. Dr. Honig has served as a member of our Board since December 2021. Dr. Honig served as Senior Vice President and Head of Global Regulatory Affairs and Group Head of Development China and Japan at Pfizer, a public biopharmaceutical company, from January 2019 to July 2021 and as Senior Vice President, Worldwide Safety and Regulatory from 2014 to January 2019. Prior to joining Pfizer, he held senior leadership positions at AstraZeneca and Merck Research Laboratories and with the U.S. Food and Drug Administration (“FDA”), including as the first Director of the Office of Drug Safety in the FDA’s Center for Drug Evaluation and Research. Dr. Honig was also the PhRMA representative to the International Conference on Harmonisation steering committee from 2002 to 2021, is a past President of the American Society for Clinical Pharmacology and Therapeutics and was an associate editor of their flagship journal, Clinical Pharmacology and Therapeutics. Dr. Honig has been a member of the board of directors of Aerium Therapeutics, a biopharmaceutical company, since March 2022 and a member of the board of directors of Alopexx Enterprises, LLC, a biotechnology company, since October 2021. In addition, Dr. Honig is a member of the board of directors of the Drug Information Association, an executive advisor for Blackstone Life Sciences and an advisory board member of the Centre of Regulatory Excellence. Dr. Honig previously served on the board of directors of Orexigen Therapeutics, Inc., a public biopharmaceutical company, from 2010 to June 2018 and on the board of directors of Sesen Bio, Inc., a public biotechnology company, from July 2021 until its merger with Carisma Therapeutics Inc. in March 2023. Dr. Honig received his B.A., his M.D. and his M.P.H. from Columbia University. We believe Dr. Honig’s qualifications to serve on our Board include his substantial industry and board experience, including in drug development, life cycle management and regulatory sciences, with publicly traded and privately held biotechnology companies and his experience as a member of the FDA.

OUR BOARD OF DIRECTORS UNANIMOUSLY RECOMMENDS THAT THE STOCKHOLDERS VOTE FOR THE ELECTION OF EACH OF MR. GAREN G. BOHLIN,GREENE, DR. MIKAEL DOLSTENMIRZA AND DR. MICHAEL G. KAUFFMANMS. OLIGER AS A CLASS IIII DIRECTOR.

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CORPORATE GOVERNANCE

General

We believe that good corporate governance is important to ensure that Karyopharm Therapeutics Inc. is managed for the long-term benefit of our stockholders. This section describes key corporate governance practices that we have adopted. We have adopted, aincluding our Code of Ethics and Business Conduct, and Ethics, which applies to all of our officers, directors and employees, Corporate Governance Guidelines, and charters for our audit committee, our compensation committeeBoard of Directors’ Audit Committee, Compensation Committee, Nominating, Corporate Governance & Compliance Committee, and our nominatingCommercialization and corporate governance committee.Portfolio Committee. We have posted copies of our Code of Ethics and Business Conduct and Ethics andthe Corporate Governance Guidelines, as well as each of our committee charters, onunder the heading “Corporate Governance page of” in the “Investors” section of our website, www.karyopharm.com, which you can access free of charge. Information contained on the website is not incorporated by reference in, or considered part of, this proxy statement. We intend to disclose on our website any amendments to, or waivers from, our Code of Ethics and Business Conduct and Ethics that are required to be disclosed by law or the Listing Rules of the Nasdaq listing standards.Stock Market (“Nasdaq”). We will also provide copies of these documents as well as our other corporate governance documents, free of charge, to any stockholder upon written request to Karyopharm Therapeutics Inc., 85 Wells Avenue, Newton, Massachusetts 02459, Attn:Attention: Investor Relations.

Director Independence

Rule 5605 of the Nasdaq Listing Rules requires a majority of a listed company’s board of directors to be comprised of independent directors within one year of listing.directors. In addition, the Nasdaq Listing Rules require that, subject to specified exceptions, each member of a listed company’s audit, compensation and nominating and corporate governancenominations committees be independent and that audit and compensation committee members also satisfy independence criteria set forth in Rule10A-3 and Rule 10C-1, respectively, under the Securities Exchange Act.Act of 1934, as amended (the “Exchange Act”).

Under Rule 5605(a)(2) of the Nasdaq Listing Rules, a director will only qualify as an “independent director” if, in the opinion of our board of directors,Board, that person does not have a relationship that would interfere with the exercise of independent judgment in carrying out the responsibilities of a director. In order to be considered independent for purposes of Rule10A-3 of the Exchange Act, a member of an audit committee of a listed company may not, other than in his or her capacity as a member of the audit committee, the board of directors, or any other board committee, accept, directly or indirectly, any consulting, advisory, or other compensatory fee from the listed company or any of its subsidiaries or otherwise be an affiliated person of the listed company or any of its subsidiaries.

In addition, in affirmatively determining the independence of any director who will serve on a company’s compensation committee, Rule10C-1 under the Exchange Act requires that a company’s board of directors consider all factors specifically relevant to determining whether a director has a relationship to such company which is material to that director’s ability to be independent from management in connection with the duties of a compensation committee member, including, but not limited to: (i)(a) the source of compensation of the director, including any consulting, advisory or other compensatory fee paid by such company to the director; and (ii)(b) whether the director is affiliated with the company or any of its subsidiaries or affiliates.

Our board of directorsBoard has undertaken a review ofreviewed the composition of our board of directorsBoard and its committees and the independence of each director. Based upon information requested from and provided by each director concerning his or her background, employment and affiliations, including family relationships, our board of directorsBoard has determined that each of our directors, with the exception of Drs. Kauffman and Mirza,Mr. Paulson, is an “independent director” as defined under Rule 5605(a)(2) of the Nasdaq Listing Rules. In making this determination, our Board considered the consulting agreement we have in place with Dr. Mirza and concluded that this arrangement does not constitute a relationship that would interfere with such director’s exercise of independent judgment in carrying out his responsibilities as a director. Our board of directorsBoard also determined that Messrs. Bohlin and GarlandSchor and Dr. Pakianathan, who currently comprise our audit committee,Audit Committee; Dr. Pakianathan, and Mr. Greene and Ms. Oliger, who comprise our compensation committee,Compensation Committee; and Messrs. Greene, and Bohlin, and Schor and Dr. Dolsten,Honig, who currently comprise our nominating and corporate governance committee,Nominating, Corporate Governance & Compliance Committee, satisfy the independence standards for such committees established by the SEC and the Nasdaq Listing Rules, as applicable.

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In addition, our board of directors also determined that Kenneth E. Weg, who served as a member of our board of directors from February 2013 until the annual meeting of stockholders on June 19, 2018 and served as a member of the nominating and corporate governance committee and compensation committee during 2018 from January 1, 2018 until June 19, 2018, and F. Carsten Thiel, Ph.D., who served as a member of our board of directors from August 31, 2018 until his resignation on November 27, 2018, and served as a member of the compensation committee from October 11, 2018 until November 27, 2018, satisfied the independence standards for such committees established by the SEC and the Nasdaq Listing Rules, as applicable. In making such determinations, our board of directors considered the relationships that each suchnon-employee director has with our company and all other facts and circumstances our board of directors deemed relevant in determining independence, including the beneficial ownership of our capital stock by eachnon-employee director.

There are no family relationships among any of our directors or executive officers, except that Dr. Kauffman, our Chief Executive Officer and a director, is married to Dr. Shacham, our President and Chief Scientific Officer.officers.

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Board Leadership Structure

Our bylaws and Corporate Governance Guidelines provide our board of directorsBoard with flexibility to combine or separate the positions of Chairman of the Board and Chief Executive Officer and/or to implement the role of Lead Independent Director in accordance with its determination that utilizing one or the other structure would be in the best interests of our company.the Company.

At this time, we do not have a Chairman of the Board, though our board of directorsBoard appointed Mr. Greene to serve as Lead Independent Director in January 2015. While our board of directorsBoard believes that oversight of our companythe Company is the responsibility of our board of directorsBoard as a whole, and this responsibility can be properly discharged without a Chairman or Lead Independent Director, our board of directorsBoard determined that appointing Mr. Greene as Lead Independent Director would facilitate interactions between Dr. Kauffman, our Chief Executive Officer and the other independent directors and would enable the board of directorsBoard and the companyCompany to utilize Mr. Greene’s breadth of experience across many strategic and operational matters in development stage biotechnology companies.

Mr. Greene serves as a liaison between our Chief Executive Officer and our independent directors. Mr. GreeneHe meets regularly and communicates directly with the independent directors outside the presence of management and reports any comments and concerns of the independent directors to our Chief Executive Officer. He also meets regularly with our senior management to discuss operational and strategic matters. Mr. Greene presides over executive sessions of the board of directorsBoard and provides our Chief Executive Officer with an annual review, as well as regular feedback, based on the consensus views collected from members of our board of directors.Board.

While Dr. Kauffmanour Chief Executive Officer facilitates communications between members of our board of directorsBoard and works with management in the preparation of the agenda for each meeting of the board of directors,Board, Mr. Greene also has an important role in establishing the agenda, determining what information is provided to our board of directorsBoard and coordinating with management to ensure that sufficient meeting time is allocated to each agenda item. Additionally, all of our directors are encouraged to make suggestions for agenda items orpre-meeting materials for meetings of our board of directors.Board.

Our board of directorsBoard has concluded that the current leadership structure described above is appropriate at this time. However, our board of directorsBoard will continue to periodically review our leadership structure and may make such changes in the future, as it deems appropriate.

The Board’s Role in Risk Oversight

Our board of directorsBoard has responsibility for the oversight of the company’sCompany’s risk management processes and, either as a whole or through its committees, regularly discusses with management our major risk exposures, the

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potential impact of these risks on our business and the steps we take to manage them. The risk oversight process includes receiving regular reports from boardBoard committees and members of senior management to enable our board of directorsBoard to understand the company’sCompany’s risk identification, risk management and risk mitigation strategies with respect to areas of potential material risk, including operations, finance,the Company’s corporate strategy, business objectives, compliance, financial condition, legal, regulatory, strategiccommercial and reputational risk.

The audit committeecommittees of the Board execute their risk oversight responsibility for risk management as follows:

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While each committee is responsible for evaluating certain risks and overseeing the management of such risks, the entire boardBoard is regularly informed through committee reports about such risks. Matters of significant strategic risk are considered by our board of directorsBoard as a whole.

Human Capital

We believe that the success of our business is fundamentally dependent on our greatest asset, our employees. To that end, we have invested significant resources toward the attraction, retention and development of our people and the promotion of diversity in our workforce. To support these goals, our human resources programs and initiatives underscore our core values (Innovation, Courage, Alignment and Accountability, Resiliency, and Energy) and are designed to prioritize employees’ well-being, support their career development, offer competitive wages and benefits, and enhance our culture through efforts geared toward making the workplace more enriching, engaging, and inclusive.

To attract, retain and reward our employees, we provide competitive total compensation and benefits aimed at supporting the financial, physical and emotional health of our employees and their families. We currently offer equity to all new employees as well as to all current employees as an incentive in connection with our annual performance reviews. Our equity and cash incentive plans are designed to increase stockholder value and the success of our company by motivating our employees to perform to the best of their abilities and achieve our collective objectives. In addition, many of our employees are stockholders of our company through participation in our ESPP, which aligns the interests of our employees with our stockholders by providing stock ownership on a tax-deferred basis. We also provide up to a 4% match of components of employee compensation to our Section 401(k) retirement savings plan.

We strive to provide our employees with a safe and healthy work environment and believe that the overall health, safety and wellness of our employees is critical to our long-term success and our growth as a business. As such, we provide our employees and their families with access to a variety of innovative, flexible and convenient health and wellness programs, including benefits that provide protection and security so they can have peace of mind concerning events that may require time away from work or that impact their financial well-being. Our full-time employees are all eligible to participate in our health, vision, dental, life, and long-term disability insurance plans. To encourage employees to keep up with routine medical care and participate in our wellness program, we fund a Health Reimbursement Account for participating employees that partially covers employee deductibles. In addition, to help our employees cover medical expenses pre-tax, we offer employees a Flexible Spending Account as well as provide our employees with a monthly wellness fund designed to support broad well-being activities. In addition to the monthly wellness fund, our employees outside of the U.S. receive competitive compensation and benefits that are regularly benchmarked to ensure market norms and reflect our standards. All employees globally have access to complimentary virtual fitness programs, mental and emotional health support services, as well as support programs to assist working parents with childcare and tutoring. This benefit also extends to eldercare, pet care, and other needs facing our diverse global team.

We encourage and support the growth and development of our employees and, wherever possible, seek to fill positions internally, through lateral and promotional advancements and by leveraging our employee referral process. Continual learning and career development is encouraged through ongoing performance and development conversations with employees, a formal mentorship program, tuition assistance, employee and leadership training programs targeting both technical and soft skills, and customized corporate training engagements and seminars where employees are encouraged to attend in connection with current and future roles. Employees at all levels have an opportunity to develop and hone their skillsets, which provides a critically important growth path and continuity for our top performers.

Further, we strongly believe that diversity is a key driver of success. We strive to bring together employees with a wide variety of backgrounds, skills and culture and encourage all our employees to maintain a work environment in which our differences are respected. We have implemented company-wide diversity initiatives in order to support greater awareness and understanding of the behaviors we expect from our employees, such as our Dialogue on Diversity program, which provides a sense of belonging, psychological safety and a stronger sense of community to our employees. We have partnered with the biotech industry’s largest LGBTQ professional group, as well as other local organizations, to access diverse talent in the biotech industry and gain visibility in the community to build more diversity in the organization. We

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Board of Directors Meetings

Our board of directorsBoard met sevennine times during the fiscal year ended December 31, 2018, or fiscal year 2018,2022, including telephonic meetings. During that year,2022, each of our incumbent directors attended or participated telephonically in 75% or more of the aggregate of (i)(a) the total number of meetings of the board of directorsBoard held during the period for which he or she served as a director and (ii)(b) the total number of meetings of all committees on which the director served during the periods that he or she served. We do not have a formal policy regarding attendance by members of our Board at our annual meeting of stockholders. Four members of our Board serving at the time attended our 2022 annual meeting of stockholders held on May 19, 2022 by teleconference.

Committees of the Board of Directors

We haveOur Board currently has four standing committees: the audit committee,Audit Committee; the compensation committee,Compensation Committee; the nominating and corporate governance committeeNominating, Corporate Governance & Compliance Committee; and the compliance committee.Commercialization and Portfolio Committee. Each of these committees has a written charter approved by our board of directors.Board. A copy of each charter can be found under the

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heading “Corporate Governance”“Corporate Governance” in the “Investors”“Investors” section of our website at www.karyopharm.com.www.karyopharm.com. The following table provides membership information for the current composition of these committees:

* Committee Chair

Audit Committee

The members of our Audit Committee arecurrently include Messrs. Bohlin (Chair) and GarlandSchor and Dr. Pakianathan. Mr. Bohlin is the chair of the audit committee. Our board of directorsBoard has determined that each of Mr. Bohlin and Mr. Schor qualifies as an “audit committee financial expert” within the meaning of SEC regulations and the Nasdaq Listing Rules. In making this determination, our board hasBoard considered the formal education and nature and scope of Mr. Bohlin’sBohlin and Mr. Schor’s previous experience, coupled with past andor present service on various audit committees. Our audit committeeAudit Committee assists our board of directorsBoard in its oversight of the quality and integrity of our accounting, auditing and financial reporting process, and the audits of our financial statements.statements and our independent registered public accounting firm, including its appointment, compensation, and retention. The audit committeeAudit Committee met seveneight times during fiscal year 2018,2022, including telephonic meetings. The audit committee’sPursuant to its charter, the Audit Committee’s general responsibilities include:

currently include, among other things, the following:

assist in its evaluation of executive and director compensation, including the authority to approve the consultant’s reasonable fees and other retention terms.

In addition, under its charter, the compensation committeeCompensation Committee may form, and delegate authority to, subcommittees, consisting of independent directors, as it deems appropriate. The Compensation Committee can also delegate to one or more executive officers the authority to grant equity awards to certain employees, as further described in its charter and subject to the terms of our equity plans. The Compensation Committee has at times delegated to our Chief Executive Officer the authority to make equity awards under our 2022 Plan within approved guidelines to employees in connection with annual grant and promotional and recognition awards, other than grants to employees with a title of Senior Vice President or above (including our NEOs). The number of stock options or restricted stock units (“RSUs”) our Chief Executive Officer may grant under the 2022 Plan to any individual must be within the range set by our Compensation Committee for these awards.

Historically, the compensation committeeCompensation Committee has approved and, in the case of our Chief Executive Officer, the Compensation Committee has recommended to the Board and the Board has approved, significant adjustments to executives’ annual compensation, determined variable cash compensation and equity awards, and established new performance objectives at one or more meetings held during the last quarter of the year and the first quarter of the following year. However, the compensation committeeCompensation Committee also considers matters related to individual compensation, such as compensation for new executive hires, as well as high-level strategic issues, such as the efficacy of our compensation strategy, potential modifications to that strategy, and new trends, plans, or approaches to compensation, at various meetings throughout the year. The compensation committeeCompensation Committee is responsible for making determinations, or making recommendations to our board of directors,Board, regarding compensation of executive officers, making changes topre-approved salary ranges, salary increase budgets, equity award budgets, variable cash compensation targets, incentive payments, andpre-approved equity ranges for new hires and high performers, and making material changes to benefits offered to our employees. In determining compensation of executive officers other than our Chief Executive Officer, and President and Chief Scientific Officer, the Compensation Committee, with input from its compensation committeeconsultant, also considers the recommendations of our Chief Executive Officer and President and Chief Scientific

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Officer. In addition, the compensation committee,Compensation Committee, with input from its compensation consultant, makes recommendations to our board of directorsBoard regarding the compensation ofnon-employee directors. The compensation committeeCompensation Committee also administers our equity-based plans and determines whether to approve the maximum increases or smaller increases permitted to the number of shares reserved under our 2013 Stock Incentive Plan, or 2013 Plan, and 2013 Employee Stock Purchase Plan, or 2013 ESPP, that automatically occur each year pursuant to the “evergreen” provisions of such plans.compensation programs.

Nominating, and Corporate Governance & Compliance Committee

The members of our nominating and corporate governance committee areNominating, Corporate Governance & Compliance Committee currently include Messrs. Greene (Chair), Bohlin, and GreeneSchor and, as of September 2022, Dr. Dolsten. Mr. Greene, who joined the nominating and corporate governance committee in June 2018, is the chair of the committee.Honig. The committeeNominating, Corporate Governance & Compliance Committee met fourfive times during fiscal year 2018. The nominating and corporate governance committee’s2022. Pursuant to its charter, the Nominating, Corporate Governance & Compliance Committee’s general responsibilities include:

currently include, among other things, the following:

The nominating and corporate governance committeeNominating, Corporate Governance & Compliance Committee has not adopted a formal policy with respect to a fixed set of specific minimum qualifications for its candidates for membership on the board of directors.Board. The committee considers such factors, including those set forth above, as it may deem are in the best interests of our companythe Company and its stockholders. The committee further believes it is appropriate for at least one member of our board of directorsBoard to meet the criteria for an “audit committee financial expert” as that phrase is defined under the regulations promulgated by the SEC, and that a majority of the members of our board of directorsBoard be independent as required under the Nasdaq qualification standards. The committeeNominating, Corporate Governance & Compliance Committee believes it is appropriate for our Chief Executive Officer to serve as a member of our board of directors.Board. Our directors’ performance and qualification criteria are reviewed periodically by the nominating and corporate governance committee.Nominating, Corporate Governance & Compliance Committee.

Identification and Evaluation of Nominees for Directors

The nominating and corporate governance committeeNominating, Corporate Governance & Compliance Committee identifies nominees for director by first evaluating the current members of our board of directorsBoard willing to continue in service. Current members with qualifications and skills that are consistent with the nominating and corporate governance committee’sNominating, Corporate Governance & Compliance Committee’s criteria for board of directors’ service on the Board and who are willing to continue in service are considered forre-nomination, balancing the value of continuity of service by existing members of our board of directorsBoard with that of obtaining a new perspective or expertise. The Nominating, Corporate Governance & Compliance Committee reviews the overall service provided by these directors to the Company during their terms, including the number of meetings attended, level of participation, quality of performance and any other relationships and transactions that might impair the directors’ independence, as well as the results of the Board’s self-evaluation, which is generally conducted annually, to determine whether to recommend them to the Board for nomination for a new term.

If any member of our board of directorsBoard does not wish to continue in serviceto serve on the Board or if our board of directorsBoard decides not tore-nominate a member forre-election, and our boardBoard seeks to fill such vacancy, the nominating and corporate governance committeeNominating, Corporate Governance & Compliance Committee identifies a new nominee that meets the criteria above. The committeeNominating, Corporate Governance & Compliance Committee generally inquires of our board of directorsBoard and members of management for their recommendations. The committeerecommendations and may also review the composition and qualification of the boards of directors of our competitors and mayor seek input from industry experts or analysts. The nominating and corporate governance committeeNominating, Corporate Governance & Compliance Committee then reviews the qualifications, experience, and background of suggested candidates. Final candidates, if other than our current directors, would beare interviewed by the members of the nominating and corporate governance committeeNominating, Corporate Governance & Compliance Committee and by certain of our other independent directors and executive management. In making its determinations, the nominating and corporate governance committeeNominating, Corporate Governance & Compliance Committee evaluates each individual in the context of our board of directorsBoard as a whole, with the objective of assembling a group that can best contribute to the success of our companythe Company and represent stockholder interests through the exercise of sound judgment. After review and deliberation of all feedback and data, the nominating and corporate governance committeeNominating, Corporate Governance & Compliance Committee makes its recommendation to our boardBoard. The Nominating, Corporate Governance & Compliance

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Table of directors. The nominating and corporate governance committeeContents

Committee has previously engaged a search firm to conduct a search for additional directors with extensive development, regulatory or commercialization expertise to join our board of directors.Board. The nominating and corporate governance committeeNominating, Corporate Governance & Compliance Committee may in the future engage additional third-party search firms in those situations where particular qualifications are required or where existing contacts are not sufficient to identify an appropriate candidate.

We have not received director candidate recommendations from our stockholders and do not have a formal policy regarding consideration of such recommendations. However, any recommendations received from stockholders will be evaluated in the same manner that potential nominees suggested by board members, management, or other parties are evaluated. We do not intend to treat stockholder recommendations in any manner different from other recommendations.

Stockholders wishing to recommend a director candidate for consideration by our nominating and corporate governance committeeNominating, Corporate Governance & Compliance Committee must writesubmit such recommendation in writing to our principal executive offices at Karyopharm Therapeutics Inc., 85 Wells Avenue, Newton, Massachusetts 02459, Attention: Corporate Secretary. Recommendation of director candidatesSuch recommendation must be received by our Corporate Secretary at our principal executive offices.us no later than February 24, 2024. Such submissions must state the nominee’s name, together with appropriate biographical information and background materials, and information with respect to the stockholder or group of stockholders making the recommendation, including the number of shares of common stock owned by such stockholder or group of stockholders. We may require any proposed nominee to furnish such other information as we may reasonably require to determine the eligibility of suchthe proposed nominee to serve as an independent director or that could be material to a reasonable stockholder’s understanding of the independence, or lack thereof, of such proposed nominee.

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Stockholders also have the right under our bylaws to directly nominate director candidates, without any action or recommendation on the part of the nominating and corporate governance committeeour Nominating, Corporate Governance & Compliance Committee or the board of directors,Board, by following the procedures set forth below under “Stockholder Proposals.“Stockholder Proposals.” If our board of directorsBoard determines to nominate a stockholder-recommended candidate and recommends his or her election, then his or her name will be included in our proxy statement and proxy card for the next annual meeting of stockholders. Otherwise, candidates nominated by stockholders in accordance with the procedures set forth in the bylaws will not be included in our proxy statement and proxy card for the next annual meeting.

Limits on Director Attendance at Annual MeetingsService on Other Company Boards

We do not have a formal policy regarding attendance by membershighly effective and engaged Board, and we believe that our directors’ service on other companies’ boards enable them to contribute valuable knowledge and perspective to our Board activities. Nonetheless, the Board is sensitive to the external obligations of ourits directors and the potential for overboarding to compromise their ability to effectively serve the Company. Our Corporate Governance Guidelines limit each director’s service on other boards of public companies to a number that permits them, given their individual circumstances, to responsibly perform all director duties. Directors who serve as chief executive officers of a public company may not serve on more than two public company boards other than the board of the company of which he or she is chief executive officer. All other directors at our annual meeting of stockholders. Three members of our board of directors serving at the time attended our 2018 annual meeting of stockholders heldmay not serve on June 19, 2018 in person or by teleconference.more than five public company boards.

Communications with Our Board of Directors

Stockholders seeking to communicate with our board of directorsBoard must submit their written comments to our Corporate Secretary, Karyopharm Therapeutics Inc., 85 Wells Avenue, Newton, Massachusetts 02459.02459, Attention: Corporate Secretary. The Corporate Secretary will forward such communications to each member of our board of directors;Board; provided that, if in the opinion of our Corporate Secretary it would be inappropriate to send a particular stockholder communication to a specific director, such communication will only be sent to the remaining directors (subject to the remaining directors concurring with such opinion).

Director Compensation

We seek to attract exceptional people to serve on our Board and, therefore, our policy is to compensatenon-employee members of our Board competitively relative to members of the board of directors for their service usingof comparable companies. The Board believes that including equity as a combinationpart of our director compensation helps align the interest of directors with those of our stockholders. Accordingly, our director compensation is a mix of cash and equity compensation. Directors who areThe Board also employees do notbelieves that it is appropriate for the Chair of each standing committee of the Board to receive anyadditional compensation for service on the board of directorsadditional workload and time commitment required for Board members who serve in addition to compensation payable for their service as our employees.such capacities. Thenon-employee members of our board of directorsBoard are also reimbursed for travel, lodging, and other reasonable expenses incurred in attending board of directorsBoard or committee meetings. Directors who are also employees, such as Mr. Paulson and,

During 2018, we compensated

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until March 2022, Dr. Kauffman, do not receive any compensation for service on the Board in addition to compensation received for their service as our employees.

The following table reflects the cash and equity compensation that our directors were eligible to receive under the terms of our Non-Employee Director Compensation Policy in effect during 2022.

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The stock options granted to ournon-employee directors for service on our board of directors or its committeesBoard have an exercise price equal to the fair market value of our common stock on the date of grant, expire ten years after the date of grant, and are subject to the director’s continued service to the Company on the applicable vesting dates. In addition, our 2022 Plan includes limitations on director compensation, including, with respect to non-employee directors, a maximum aggregate amount of cash paid and value of awards granted (calculated based on grant date fair value for financial reporting purposes) equal to, in the case of any incumbent director, $750,000 in any calendar year, and, in the case of any newly elected or appointed director, $1,000,000 in such director’s initial year of election or appointment. Exceptions to these limitations may only be made by our Board in extraordinary circumstances provided that the non-employee director receiving any additional compensation does not participate in the decision to award such compensation. The foregoing limitations in non-employee director compensation do not apply to cash or equity awards granted to a non-employee director in his or her capacity as an advisor to the Company.

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The following table sets forth the compensation paid to or earned by our non-employee directors during the year ended December 31, 2022.

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2018 Director Compensation

Limitation of Liability and Indemnification

Our certificate of incorporation limits the personal liability of directors for breach of fiduciary duty to the maximum extent permitted by the Delaware General Corporation Law (the “DGCL”) and provides that no director will have personal liability to us or to our stockholders for monetary damages for any breach of fiduciary duty as a director. However, these provisions do not eliminate or limit the liability of any of our directors:

Report of the Audit Committee of the Board of Directors

The audit committeeAudit Committee oversees the company’sCompany’s financial reporting process on behalf of the boardBoard of directors.Directors. We have reviewed the company’sCompany’s audited consolidated financial statements for the fiscal year ended December 31, 20182022 and discussed them with Company management and Ernst & Young LLP, the company’sCompany’s independent registered public accounting firm for the fiscal year ended December 31, 2018.2022.

We have received from, and discussed with, Ernst & Young LLP, which is responsible for expressing an opinion on the conformity of the company’sCompany’s audited consolidated financial statements with accounting principles generally accepted in the United States, its judgments as to the quality, not just the acceptability, of the company’sCompany’s accounting principles and such other matters as are required to be discussed with the audit committeeAudit Committee under generally accepted auditing standards, including the matters required to be discussed as required by AS 1301: Communications with Audit Committees, as adopted bythe applicable requirements of the Public Company Accounting Oversight Board (the “PCAOB”“PCAOB”) and all other communications required under the standards of the PCAOB.SEC. In addition, we have discussed with Ernst & Young LLP its independence from management and the company,Company, have received from Ernst & Young LLP the written disclosures and the letter required by applicable requirements of the PCAOB regarding its communications with us concerning independence, and have considered the compatibility ofnon-audit services with the auditors’ independence.

Based on the review and discussions referred to above, we recommended to the boardBoard of directorsDirectors that the audited consolidated financial statements be included in the company’sCompany’s Annual Report on Form10-K for the year ended December 31, 2018.2022.

This report of the audit committeeAudit Committee is not “soliciting material,” shall not be deemed “filed” with the SEC and shall not be incorporated by reference by any general statement incorporating by reference this proxy statement into any filing under the Securities Act of 1933, as amended, or the Securities Exchange Act of 1934, as amended, whether made before or after the date hereof and irrespective of any general incorporation language in any such filing, except to the extent that we specifically incorporate this information by reference, and shall not otherwise be deemed filed under such acts.

The foregoing report has been furnished by the audit committee.Audit Committee.

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PROPOSAL 2:

APPROVAL OF AN AMENDMENT TO OUR 2022 EQUITY INCENTIVE PLAN TO INCREASE THE NUMBER OF SHARES OF OUR COMMON STOCK AVAILABLE FOR ISSUANCE THEREUNDER BY 5,000,000 SHARES

Why We Are Requesting Stockholder Approval of an Amendment to the 2022 Equity Incentive Plan

Background

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 lead asset, XPOVIO® (selinexor), was approved in the U.S. in mid-2019 and is currently approved and marketed in the U.S. in three oncology indications, most importantly multiple myeloma. XPOVIO and NEXPOVIO® (selinexor) (the brand name for selinexor in Europe and the United Kingdom) is also approved in various indications in approximately 40 countries outside of the U.S., including the European Union, United Kingdom, Singapore, Mainland China, South Korea, Australia, Canada, Taiwan and Israel, and is commercially available in a growing number of countries.

The 2022 Plan is our existing equity incentive plan and was originally approved by the Board on April 4, 2022 and by our stockholders on May 19, 2022 (the “2022 Plan Effective Date”). When the 2022 Plan was adopted, we expected that the share pool under the 2022 Plan would allow us to continue to grant equity awards (other than to newly hired employees who will receive grants under the Karyopharm Therapeutics Inc. 2022 Inducement Stock Incentive Plan, as amended (the “2022 Inducement Plan”), to the extent eligible) at our historic rates for approximately one year. Such year has expired and, as expected, the remaining share pool under the 2022 Plan is insufficient to meet our equity compensation needs. We have a practice of Directors

Garen G. Bohlin (chair)

J. Scott Garland

Deepika R. Pakianathan

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INFORMATION ABOUT EXECUTIVE OFFICER COMPENSATION

Compensation Discussion and Analysis

Our compensation committee is responsible for overseeing the total compensationgranting equity-based awards broadly throughout our organization. In order to support our ability to continue to grant equity awards to all of our senior management team,employees as part of our compensation program and to remain competitive in the challenging markets in which we compete for talent, and based on careful weighing of the considerations, as more fully described below, upon the recommendation of the Compensation Committee, in March 2023, our Board approved an amendment to the 2022 Plan to increase the share pool under the 2022 Plan by 5,000,000 shares of common stock, subject to stockholder approval (the “Amendment”). No other amendments are being made to the 2022 Plan. If approved, the new shares reserved under the 2022 Plan would represent approximately 4.4% of our 113,968,884 outstanding shares as of March 20, 2023. Our Board believes the proposed dilution to stockholders as a result of the Amendment is judicious and sustainable and, importantly, critical to meet our business goals.

Our Board believes that equity compensation provides a meaningful and differentiating incentive for our employees, directors and other service providers, creates an essential link between our service providers and our stockholders and allows us to conserve cash resources to support our growth objectives. Our Board further believes that our success depends, in large part, on our ability to maintain a competitive position by attracting, retaining and motivating key employees with experience and ability. Central to these objectives is our equity compensation program, which is comprisedconsistent with our compensation philosophy and the compensatory practices of other pharmaceutical companies in our peer group and other companies that we compete with for talent. Therefore, we are asking our stockholders to approve the Amendment to ensure we can continue to retain and motivate all of our executive officersemployees, directors and certain other senior managers. In this capacity,service providers and provide them with compensation that is linked to our growth as well as the creation of stockholder value.

We utilize the 2022 Plan to grant equity awards to our existing employees, non-employee directors, consultants and advisors in order to retain and reward those who are critical to our success. If the Amendment is not approved by our stockholders, we will not be able to grant any meaningful equity awards to our existing employees and directors, which would force us to increase the cash component of our compensation committee designs, implements, reviewsprograms to retain and approves allmotivate our employees, directors and other service providers, putting us at a significant disadvantage compared to our competitors and adversely impacting our business.

Our Compensation Committee determined the requested number of shares provided for in the Amendment based on projected annual equity awards to employees and our non-employee directors, employee recognition and promotion awards, and an assessment of the magnitude of increase that our stockholders would likely find appropriate. We and our Board also understand that our equity-compensation needs must be balanced against the dilutive effect of such equity compensation program on our stockholders. If stockholders approve the Amendment, subject to adjustment in the event of

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stock splits and other similar events, awards may be made under the 2022 Plan, as amended by the Amendment (the “Amended 2022 Plan”), for named executive officers (NEOs)up to a number of shares of common stock equal to the sum of: (i) 9,100,000 shares of common stock; and (ii) such additional number of shares of common stock (up to 14,231,243) as is equal to the sum of (x) the number of shares of common stock that were reserved for issuance under our 2013 Stock Incentive Plan (the “2013 Plan”), exceptwhich remained available for grant immediately prior to the 2022 Plan Effective Date and (y) the number of shares of common stock subject to awards granted under our 2013 Plan that were outstanding as of such date which awards expire, terminate or are otherwise surrendered, cancelled, forfeited or repurchased by the Company at their original issuance price pursuant to a contractual repurchase right (subject, however, in the case of Michael G.incentive stock options to any limitations under the Internal Revenue Code of 1986, as amended, and any regulations thereunder (the “Code”)).

We have for the past five years relied on the inducement grant exception under Nasdaq Listing Rule 5635(c)(4) to grant nonstatutory stock options and/or RSUs (“Inducement Awards”) to all of our newly hired full-time employees who are eligible under the Nasdaq rules to receive such grants. In furtherance of this approach and because the shares available for issuance under the 2022 Plan have been (and will continue to be even if the Amendment is approved) insufficient to meet our equity grant needs, in February 2022, our Board approved the 2022 Inducement Plan. Our Board further approved an amendment to the 2022 Inducement Plan on each of May 31, 2022 and February 10, 2023 to increase the number of shares reserved for issuance thereunder for Inducement Awards to be granted to newly hired full-time employees, with the total number of shares remaining available for the grant of new awards under the 2022 Inducement Plan being 1,593,230 as of March 20, 2023. The 2022 Inducement Plan will remain in effect even if the Amendment is approved.

The following table includes information regarding all of our (i) outstanding equity awards under all of our equity compensation plans under which shares of common stock may be issued, other than our ESPP, (ii) outstanding Inducement Awards that were granted as stock options or RSUs outside of our equity compensation plans, and (iii) shares available for future awards under the 2022 Plan (prior to the Amendment) and the 2022 Inducement Plan, each as of March 20, 2023:

* Beginning in February 2023, our equity awards also took the form of performance-based RSUs (“PSUs”). These PSUs will vest only if challenging performance goals relating to revenue and relative total stockholder return are achieved over a three year performance period and challenging performance goals relating to clinical milestones are achieved over a four year performance period. The number of PSUs outstanding as of March 20, 2023 are reflected in the table above assuming maximum performance. The number of PSUs outstanding, assuming target performance for PSUs, is 1,418,255. For members of our executive leadership team, the PSU awards will vest between zero and 200% of the target number of shares awarded and for all other PSU recipients, the PSU awards will vest between 50% and 150% of the target number of shares awarded. Maximum performance reflects vesting at the 200% and 150% level, as applicable, for each of the three performance goals.

** The number of shares remaining available for issuance under the 2022 Plan as of March 20, 2023 assuming target performance for PSUs is 2,097,792.

*** The number of shares remaining available for issuance under all plans as of March 20, 2023 assuming approval of the Amendment and target performance for PSUs is 3,691,022.

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As of March 20, 2023, there were no outstanding shares of restricted stock, no stock appreciation rights (“SAR”), or any other stock-based awards.

We expect that the proposed share pool following the Amendment will allow us to continue to grant equity awards (other than to newly hired employees who will generally receive grants under the 2022 Inducement Plan to the extent eligible) at our historic rates for approximately one year, but the actual duration of the share pool may vary based on changes in participation, the Company’s stock price and market practice. If stockholders do not approve the Amendment, the 2022 Plan will remain in effect pursuant to its terms.

We believe that our stock-based compensation programs have been integral to our success in the past and are critical to our ability to succeed in the future. If the Amendment is not approved by our stockholders, we will not be able to make long-term equity awards that are sufficient to meet our needs. The inability to make competitive equity awards to retain talented employees in a highly competitive market would likely have an adverse impact on our business. Further, if the Amendment is not approved, we would be forced to increase cash compensation, which would reduce the resources we have allocated to meeting our business needs and objectives, which we do not believe would be as effective or in the best interests of our stockholders. Therefore, the approval of the Amendment is vital to our future success.

Accordingly, our Board believes approval of the Amendment is in the best interests of the Company and its stockholders and recommends a vote “FOR” the approval of the Amendment.

The remainder of this Proposal 2 includes:

•Highlights of the Amended 2022 Plan;

•Reasons Why Stockholders Should Approve the Amendment;

•Information Regarding Overhang and Burn Rate; and

•Description of the Amended 2022 Plan.

Highlights of the Amended 2022 Plan

The Amended 2022 Plan includes several features that are designed to protect the interests of our stockholders, align awards with such interests, and reflect sound corporate governance practices. Certain of these features are highlighted below, and these and other terms of the plan are more fully described in the summary of the Amended 2022 Plan further below as well as in the copy of the 2022 Plan and the Amendment in Appendix A to this proxy statement.

No Evergreen. The Amended 2022 Plan does not include an “evergreen” or other provision that provides for automatic increases in the number of shares available for grant under the plan and therefore any increase to the maximum share reserve in the Amended 2022 Plan is subject to approval by our stockholders, allowing our stockholders to have a say in our equity compensation programs.

Minimum Vesting Provisions. Minimum vesting provisions of one year generally apply to all awards to participants, with the exception of awards for up to 5% of the shares of stock reserved under the Amended 2022 Plan.

Clawback Policy. Awards to certain officers will be subject to clawback in the event that we are required to prepare an accounting restatement due to material noncompliance with financial statement requirements.

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No Automatic Vesting of Awards on a Change in Control Event; Double-trigger Acceleration of Vesting upon a Change in Control. The Amended 2022 Plan does not provide for the automatic vesting of awards in connection with a change in control event. Instead, the Amended 2022 Plan includes “double-trigger” acceleration, pursuant to which options, RSU awards and restricted stock awards will become fully vested and nonforfeitable if the holder of such award is terminated without cause or resigns for good reason within one year following a change in control event.

No liberal share recycling. The Amended 2022 Plan prohibits the re-granting of (i) shares withheld or delivered to satisfy the exercise price of an award or to satisfy tax withholding obligations, (ii) shares that were subject to a SAR, and were not issued upon the net settlement or net exercise of such award, or (iii) shares repurchased on the open market using proceeds from the exercise of an award.

No Repricing of Options or SARs. The Amended 2022 Plan prohibits the direct or indirect repricing of stock options or SARs without stockholder approval.

No Discounted Options or SARs. All options and SARs must have an exercise or measurement price that is at least equal to the fair market value of the underlying common stock on the date of grant.

No Reload Options or SARs. No options or SARs granted under the Amended 2022 Plan may contain a provision entitling the award holder to the automatic grant of additional options or SARs in connection with any exercise of the original option or SAR.

No Dividend Equivalents on Options or SARs. No options or SARs granted under the Amended 2022 Plan may provide for the payment or accrual of dividend equivalents.

Dividends and Dividend Equivalents on Restricted Stock, Restricted Stock Units and Other-Stock Based Awards Not Paid Until Award Vests. Any dividends or dividend equivalents paid with respect to restricted stock, RSUs or other stock-based awards will be subject to the same restrictions on transfer and forfeitability as the award with respect to which they are paid.

Limit on Non-Employee Director Compensation. The maximum aggregate amount of cash earned or paid and value of awards (calculated based on grant date fair value for financial reporting purposes) granted to any non-employee director in any calendar year may not exceed $750,000 in the case of an incumbent director. However, such maximum aggregate amount shall not exceed $1,000,000 in any calendar year for any individual non-employee director in such non-employee director’s initial year of election or appointment. Exceptions to these limitations may only be made by our Board in extraordinary circumstances provided that the non-employee director receiving any additional compensation does not participate in the decision to award such compensation.

Material Amendments Require Stockholder Approval. Stockholder approval is required prior to an amendment of the Amended 2022 Plan that would (i) materially increase the number of shares authorized (other than as provided under the Amended 2022 Plan with respect to certain corporate events or substitute awards), (ii) expand the types of awards that may be granted, or (iii) materially expand the class of participants eligible to participate.

Administered by an Independent Committee. The Amended 2022 Plan is administered by the Compensation Committee, as delegated by our Board. The Compensation Committee is made up entirely of independent directors.

Reasons Why Stockholders Should Approve the Amendment

Incentivizes, Retains and Motivates Talent. It is critical to our success that we incentivize, retain and motivate the best talent in what is a tremendously competitive labor market. Our equity compensation program has always been and will continue to be a key component in our ability to pay market-competitive compensation to our employees.

Broad-based Eligibility for Equity Awards. Our equity incentive program is broad-based, with all eligible employees in good standing receiving equity awards annually as part of our annual performance review based upon level, performance and contribution. Furthermore, since our Board typically grants awards to employees that generally vest over

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