Trial Combines Selinexor With Standard Therapy in Multiple Myeloma

Selinexor (KPT-330), a promising drug that retards cell malignancy by blocking the transport of tumor-suppressor proteins out of the cell nucleus, is under investigation as combination therapy in heavily pretreated patients with relapsed/refractory multiple myeloma (MM). The phase III BOSTON trial is enrolling patients in over 100 clinical sites across 14 countries globally and expects to complete enrollment in 2018, with top-line data anticipated in 2019.

Further boosting confidence in the drug’s development, the FDA and the European Medicines Agency agreed that the BOSTON trial design was acceptable to support an application for approval, should the results prove positive.

Under investigation in both solid and hematological malignancies, selinexor previously received orphan drug designation from the FDA in both MM and diffuse large B-cell lymphoma. The designation promotes the development of treatments for rare disorders.

RATIONALE

Selinexor inhibits chromosomal maintenance protein exportin-1 (XPO1), levels of which cancer cells increase in order to transfer tumor-suppressor proteins out of the nucleus, and thus, inactivate cancer-fighting proteins.^1,2 High levels of XPO1 also promote production of oncoproteins that fuel the growth of the tumor. Blocking XPO1, limiting oncprotein production, and preventing the transfer of tumor-suppressor proteins out of the nucleus have emerged as promising new therapy.

Additionally, selinexor inhibits XPO1 from exporting the glucocorticoid receptors to which corticosteroids bind. Keeping those receptors in the nucleus strengthens the effects of steroids in the cell. In MM, corticosteroids can induce their own clinical antitumor response, and selinexor improves other agents’ efficacy.

The selinexor-containing triplet regimen has demonstrated positive responses in heavily pretreated patients with MM in the ongoing phase Ib/II STOMP trial, according to findings presented at the 2017 American Society of Hematology Annual Meeting.

TRIAL DESIGN

The multicenter interventional trial will randomize 364 adult participants to receive the triplet or bortezomib (Velcade) and dexamethasone. The primary endpoints are progression- free survival and overall response rate. Notably, patients who have progressive disease while on bortezomib and dexamethasone will have the option to cross over to the experimental arm to be treated with selinexor.

WHO IS ELIGIBLE?

Eligible patients will have documented evidence of relapsed/refractory MM after at least 1 but no more than 3 prior treatment regimens, which may include bortezomib or another proteasome inhibitor. Participants also must have no central nervous system involvement.

REFERENCES

• Overview. Karyopharm Therapeutics website. karyopharm. com/about/. Accessed April 24, 2018.
• Oral selinexor (KPT-330). Karyopharm Therapeutics website. karyopharm.com/pipeline/oral-selinexorkpt- 330. Accessed April 26, 2018.