As filed with the Securities and Exchange Commission on May 27, 2026

Registration No. 333-

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM S-8

REGISTRATION STATEMENT

UNDER

THE SECURITIES ACT OF 1933

Karyopharm Therapeutics Inc.

(Exact name of registrant as specified in its charter)

Karyopharm Therapeutics Inc. Amended & Restated 2013 Employee Stock Purchase Plan, as amended

(Full title of the plan)

Richard Paulson

President and Chief Executive Officer

Karyopharm Therapeutics Inc.

85 Wells Avenue, 2nd Floor

Newton, MA 02459

(Name and address of agent for service)

(617) 658-0600

(Telephone number, including area code, of agent for service)

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company, or an emerging growth company. See the definitions of "large accelerated filer," "accelerated filer," "smaller reporting company," and "emerging growth company" in Rule 12b-2 of the Exchange Act.

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 7(a)(2)(B) of the Securities Act. ☐

EXPLANATORY NOTE

This Registration Statement on Form S-8 is being filed to register an additional 1,400,000 shares of Common Stock, $0.0001 par value per share, of Karyopharm Therapeutics Inc., a Delaware corporation (the "Registrant"), issuable under the Registrant's Amended & Restated 2013 Employee Stock Purchase Plan, as amended (the "ESPP"). Pursuant to General Instruction E to Form S-8, except as otherwise set forth below, this Registration Statement on Form S-8 incorporates by reference the contents of (i) the Registration Statement on Form S-8, File No. 333-194746, filed by the Registrant with the Securities and Exchange Commission (the "SEC") on March 21, 2014 relating to the ESPP, (ii) the Registration Statement on Form S-8, File No. 333-210221, filed by the Registrant with the SEC on March 15, 2016 relating to the ESPP, (iii) the Registration Statement on Form S-8, File No. 333-229971, filed by the Registrant with the SEC on February 28, 2019 relating to the ESPP, (iv) the Registration Statement on Form S-8, File No. 333-237160, filed by the Registrant with the SEC on March 13, 2020 relating to the ESPP, (v) the Registration Statement on Form S-8, File No. 333-263075, filed by the Registrant with the SEC on February 28, 2022 relating to the ESPP, (vi) the Registration Statement on Form S-8, File No. 333-269845, filed by the Registrant with the SEC on February 17, 2023 relating to the ESPP, (vii) the Registration Statement on Form S-8, File No. 333-273593, filed by the Registrant with the SEC on August 2, 2023 relating to the ESPP, and (viii) the Registration Statement on Form S-8, File No. 333-279823, filed by the Registrant with the SEC on May 30, 2024 relating to the ESPP.

PART II

INFORMATION REQUIRED IN THE REGISTRATION STATEMENT

Item 8. Exhibits.

SIGNATURES

Pursuant to the requirements of the Securities Act of 1933, the Registrant certifies that it has reasonable grounds to believe that it meets all of the requirements for filing on Form S-8 and has duly caused this Registration Statement to be signed on its behalf by the undersigned, thereunto duly authorized, in the City of Newton, Commonwealth of Massachusetts, on this 27th day of May, 2026.

POWER OF ATTORNEY AND SIGNATURES

We, the undersigned officers and directors of Karyopharm Therapeutics Inc., hereby severally constitute and appoint Richard Paulson, Lori Macomber and Michael Mano, and each of them singly, our true and lawful attorneys with full power to them, and each of them singly, to sign for us and in our names in the capacities indicated below, the registration statement on Form S-8 filed herewith and any and all subsequent amendments to said registration statement, and generally to do all such things in our names and on our behalf in our capacities as officers and directors to enable Karyopharm Therapeutics Inc. to comply with the provisions of the Securities Act of 1933, as amended, and all requirements of the Securities and Exchange Commission, hereby ratifying and confirming our signatures as they may be signed by our said attorneys, or any of them, to said registration statement and any and all amendments thereto.

Pursuant to the requirements of the Securities Act of 1933, this registration statement has been signed by the following persons in the capacities and on the dates indicated.