Selinexor Shows Promise in Heavily Pretreated Myeloma

Keith Stewart, MB ChB

Selinexor (KPT-330) demonstrated promising clinical activity in patients with heavily pretreated multiple myeloma, according to Karyopharm Therapeutics, the manufacturer of the selective inhibitor of nuclear export.

In the phase IIb STORM trial, the overall response rate (ORR) with selinexor was 20.5% (n = 16) among 78 patients with relapsed/refractory multiple myeloma. In 48 patients with quad-refractory disease, the ORR was 20.8% (n = 10), and in 30 patients with penta-refractory disease, the ORR was 20% (n = 6).

The STORM trial is now being expanded to include an estimated 120 additional patients with penta-refractory multiple myeloma. If the subsequent findings (expected in early 2018) are consistent with the initial results, Karyopharm plans to submit the selinexor data to the FDA for consideration of an accelerated approval and to the EMA for a potential conditional approval.

“Although treatment of multiple myeloma has improved dramatically, eventually many patients will develop refractory disease, no longer responding to any of the immunomodulatory agents and proteasome inhibitors commonly used (quad-refractory). These patients will also eventually progress on anti-CD38 monoclonal antibodies, which we refer to as penta-refractory disease. These are clearly the patients with the highest unmet need, as they have no remaining viable treatment options,” lead investigator Keith Stewart, MB ChB, Anna Maria and Vasek Polack Professor of Cancer Research at the Mayo Clinic, said in a statement.

“The STORM data are compelling because they demonstrate that oral selinexor achieves a 20.8% response rate in the quad-refractory group, similar to recently reported intravenous anti-CD38 therapy results in the same patient population. Selinexor also achieves an equally notable 20% response rate in the penta-refractory group, with the significant advantage of oral administration. We are currently unaware of any other therapy, oral or intravenous, reporting such activity in these difficult-to-treat patients who have exhausted all available therapies,” added Stewart.

Selinexor links to and inhibits XPO1 (CRM1), a nuclear export protein. There is an accumulation of tumor suppressor proteins in the cell nucleus as a results of this activity, and, subsequently, the cell’s tumor suppressor function is regained and amplified, which investigators hypothesize induces apoptosis.

In the multicenter, single-arm phase IIb STORM trial, 78 patients with heavily pretreated relapsed/refractory multiple myeloma (median of 7 prior treatment regimens) received 80 mg of oral selinexor plus 20 mg of oral dexamethasone twice weekly. Over each 4-week cycle, patients were dosed continuously (8 doses/cycle), or 3 weeks on and 1 week off (6 doses/cycle). The primary endpoint of the STORM study is ORR.

Sixty-two percent of patients were quad-refractory, meaning they had received the proteasome inhibitors (PIs) bortezomib (Velcade) and carfilzomib (Kyprolis), as well as the immunomodulatory agents (IMiDs) lenalidomide (Revlimid) and pomalidomide (Pomalyst). Additionally, quad-refractory patients must have previously received an alkylating agent and a glucocorticoid, and be refractory to at least 1 PI, 1 IMiD, and their most recent therapy. Thirty-eight percent of patients were penta-refractory, meaning they were also refractory to an anti-CD38 agent, such as daratumumab (Darzalex) or isatuximab.

The responses to selinexor in the STORM trial included very good partial responses (VGPRs) and partial responses (PRs). Several patients are still receiving treatment. The safety profile for selinexor was similar to previously reported adverse-event data for the drug. Further data from the study will be reported later this year, according to Karyopharm.

Combination data for selinexor in relapsed/refractory multiple myeloma from the phase Ib/II STOMP trial (NCT02343042) were previously reported at the 2016 European Hematology Association Annual Meeting. In the 3-arm study, selinexor and low-dose dexamethasone were combined with bortezomib (SVd), pomalidomide (SPd), or lenalidomide (SRd).

As of June 8, 2016, the ORR in 16 patients who received SVd was 69% (n = 11), which included 1 complete response (CR), 3 VGPRs, and 7 PRs. Among the 10 patients in this arm who were refractory to bortezomib, carfilzomib, or both PIs, the ORR was 70%, including 1 CR, 1 VGPR, and 5 PRs.

Karyopharm plans to add 2 arms to the study, 1 that will combine selinexor with daratumumab (Darzalex) and 1 that will examine selinexor with both bortezomib and pomalidomide. The company also intends to submit updated STOMP data for presentation at an upcoming medical meeting this year.

"Myeloma continues to be an incurable blood cancer in most patients and our main goal in treating refractory disease is to induce responses and maintain them as long as possible. In addition to these new data with oral selinexor and low-dose dexamethasone, the emerging clinical data from selinexor in combination with bortezomib, including in proteasome-inhibitor refractory disease, suggests a synergistic effect and favorable safety profile. These data are quite exciting and will form the basis for future studies," Sagar Lonial, MD, professor and chair, Department of Hematology and Medical Oncology, Emory University School of Medicine, and Chief Medical Officer, Winship Cancer Institute of Emory University, said in a statement.

Karyopharm has also announced its plan to launch the multicenter, open-label, randomized phase III BOSTON trial, which will compare the SVd regimen with bortezomib and low-dose dexamethasone in patients with multiple myeloma following 1 to 3 prior lines of therapy. The study, which the company hopes to launch in early 2017, has a targeted enrollment of 360 patients. The primary endpoint will be progression-free survival, with secondary endpoints including duration of response, overall survival, and quality of life.

"Our updated clinical development plan for selinexor in myeloma reflects the strong foundation of clinical data from both the STORM and STOMP studies,” Michael G. Kauffman, MD, PhD, Chief Executive Officer of Karyopharm, said in a statement. "We believe this development plan provides a path to potential FDA and EMA filings for oral selinexor in multiple myeloma, with the potential to support accelerated or conditional approval if the FDA or EMA, respectively, agree. We look forward to sharing the additional data from both STORM and STOMP later this year. We believe selinexor has the potential to be a much-needed oral treatment option for patients suffering with this incurable disease."

In the SPd arm, the ORR was 57% (n = 4) among 7 patients, including 1 VGPR and 3 PRs. The 1 evaluable patient at the cutoff who received SRd had a PR. The safety profile for the 3 treatment arms was consistent with, or less toxic than, what has been previously reported with single-agent selinexor.