Selinexor Again Shows Promise in Heavily Pretreated Myeloma

Selinexor induced an overall response rate (ORR) of 25.4% in patients with penta-refractory multiple myeloma, according to top-line results from part 2 of the phase IIb STORM trial reported by Karyopharm Therapeutics.

The responses included 2 complete responses and 29 partial responses (PRs) or very good partial responses (VGPRs). The median duration of response was 4.4 months. Previously reported data from part I of the study showed that selinexor achieved an ORR of 20.5% in 78 patients with quad- or penta-refractory myeloma.

Full data from the study will be presented at an upcoming oncology conference, Karyopharm noted in its press release. The company also reported its intent to file an application with the FDA by the end of the year for an accelerated approval for selinexor as a treatment for patients with penta-refractory multiple myeloma.

“Despite numerous advances in myeloma treatment, currently available therapies are insufficient to address the increasing number of patients with highly resistant, penta-refractory myeloma, where the disease has ultimately become non-responsive to approved therapy,” Paul G. Richardson, MD, director of Clinical Research, Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute, said in a statement.

“There is, therefore, a real urgency for new therapies with novel mechanisms of action for these patients, who have a critical unmet medical need. Selinexor’s targeted inhibition of nuclear export could potentially expand the armamentarium of treatment options significantly in this important population for which no other established treatment is readily available,” added Richardson.

The 122 penta-refractory myeloma patients in part 2 of the STORM trial were treated with 80 mg of selinexor twice weekly combined with 20 mg of low-dose dexamethasone. According to Karyopharm, the study defined penta-refractory as “patients who have previously received at least one alkylating agent, glucocorticoids, two immunomodulatory drugs (IMiDs; lenalidomide [Revlimid] and pomalidomide [Pomalyst]), two proteasome inhibitors (PIs; bortezomib [Velcade] and carfilzomib [Kyprolis]), and daratumumab (Darzalex), and whose disease is refractory to glucocorticoids, at least one PI, at least one IMiD, and daratumumab, and whose disease has progressed following their most recent therapy.”

“The 25.4% response rate and 4.4-month duration of response observed in the STORM study are highly compelling,” Sundar Jagannath, MD, Director of the Multiple Myeloma Program and Professor of Medicine (Hematology and Medical Oncology) at Tisch Cancer Institute at Mount Sinai School of Medicine,” said in a statement.

“For an orally administered therapy, these new data underscore selinexor’s potential to be an exciting new treatment option for these difficult-to-treat patients who have exhausted approved therapies,” added Jagannath.

Results from part 1 of the STORM study were presented at the 2016 ASH Annual Meeting. 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). In the overall population, the median progression-free survival (PFS) and overall survival (OS) were 2.3 and 9.3 months, respectively.

In the multicenter, single-arm phase IIb STORM trial, 79 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 was ORR.

Sixty-one percent of patients (n = 48) were quad-refractory, meaning they had received the PIs bortezomib and carfilzomib, as well as the IMiDs lenalidomide and pomalidomide. Thirty-nine percent of patients (n = 31) were penta-refractory, meaning they were also refractory to an anti-CD38 agent, such as daratumumab or isatuximab.

In the quad-refractory group, the median age was 62 years (range, 41-78), the median number of prior regimens was 7 (range, 3-16), and the median duration from diagnosis was 4 years (range, 1-6). Eighty-three percent of patients received the 6-dose regimen and 17% of patients received the 8-dose regimen.

Among the penta-refractory cohort, the median age was 68 years (range, 34-78), the median number of prior regimens was 7 (range, 5-17), and the median duration from diagnosis was 4 years (range, <1-35). Thirty-five percent of patients received the 6-dose regimen and 65% of patients received the 8-dose regimen.

The clinical benefit rate (CBR; defined as VGPR + PR + minor response [MR]) was 33% in the overall population. The VGPR, PR, and MR rates were 5%, 15%, and 13%, respectively. The stable disease (SD) and progressive disease (PD) rates were 35% and 12%, respectively.

In quad-refractory patients the CBR was 29%, comprising VGPR, PR, and MR, rates of 4%, 17%, and 8%, respectively. The SD and PD rates were 44% and 8%, respectively. In penta-refractory patients, the CBR was 40%, comprising VGPR, PR, and MR rates of 7%, 13%, and 20%, respectively. The SD and PD rates were 20% and 17%, respectively.

Among patients receiving the 6-dose regimen, the ORR was 20%. The CBR was 29%, comprising VGPR, PR, and MR rates of 6%, 14%, and 10%, respectively. The SD and PD rates were 41% and 8%, respectively. In those receiving the 8-dose regimen, the ORR was 22%. The CBR was 41%, comprising VGPR, PR, and MR rates of 4%, 19%, and 19%, respectively. The SD and PD rates were 22% and 19%, respectively.

In patients with del(17p), the ORR 38%. The CBR was 63%, comprising VGPR, PR, and MR rates of 13%, 25%, and 25%, respectively. The SD and PD rates were 25% and 13%, respectively.

The median time to response was 1 month and the median duration of response was 5 months. Among patients who achieved at least an MR, the median OS was not reached and the median PFS was 5.5 months.

The most common all-grade adverse events (AEs) included nausea (73%), thrombocytopenia (73%), fatigue (63%), anorexia (49%), anemia (49%), vomiting (44%), diarrhea (43%), hyponatremia (42%), weight loss (33%), leukopenia (32%), neutropenia (24%), lymphopenia (14%), dehydration (11%), and dysgeusia (11%).

Grade 3 AEs occurring at the highest rates included anemia (27%), thrombocytopenia (25%), hyponatremia (22%), fatigue (15%), and leukopenia (13%). Grade 4 AEs included thrombocytopenia (34%), neutropenia (6%), anemia (1%), leukopenia (1%), and lymphopenia (1%).

Selinexor dose modifications included interruptions, reductions, and discontinuations in 52%, 37%, and 18% of patients, respectively.

On March 14, 2017, the FDA placed a partial clinical hold on trials of selinexor. Although the hold stopped additional enrollment in the trials, patients who had achieved SD or better could continue treatment.

“The FDA has indicated that the partial clinical hold is due to incomplete information in the existing version of the investigator's brochure (IB), including an incomplete list of serious adverse events associated with selinexor. At the FDA's request, Karyopharm has amended the IB and updated the informed consent documents accordingly and has submitted such documents to the FDA as requested,” Karyopharm reported in a statement at the time the hold was placed.

The company noted the hold was not related to any new safety concerns. On March 30, 2017, Karyopharm announced that the hold had been lifted and new patient enrollment and dosing recommenced for the selinexor clinical trial program.

Vogl DT, Dingli D, Cornell RF, et al. Selinexor and low dose dexamethasone (Sd) in patients with lenalidomide, pomalidomide, bortezomib, carfilzomib and anti-CD38 Ab refractory multiple myeloma (MM): STORM study. Presented at: 58th American Society of Hematology Annual Meeting; San Diego, CA; December 3-6, 2016. Abstract 491.