Selinexor Active in Heavily Pretreated Myeloma

Author(s):

Selinexor, in combination with dexamethasone, induced a response rate of 20.5% (n = 16) among 78 heavily pretreated patients with relapsed/refractory multiple myeloma, according to results from the phase IIb STORM trial presented at the 2016 ASH Annual Meeting.

Dan T. Vogl, MD

In 48 patients with “quad-refractory” disease, the overall response rate (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.

“The combination of selinexor with low-dose dexamethasone has encouraging activity in patients with quad- and penta-refractory multiple myeloma. We also saw similar results in patients with high-risk cytogenetic abnormalities,” said lead study author Dan T. Vogl, MD, Abramson Cancer Center of the University of Pennsylvania.

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 proteasome inhibitors (PIs) bortezomib (Velcade) and carfilzomib (Kyprolis), as well as the immunomodulatory agents (IMiDs) lenalidomide (Revlimid) and pomalidomide (Pomalyst). Thirty-nine percent of patients (n = 31) were penta-refractory, meaning they were also refractory to an anti-CD38 agent, such as daratumumab (Darzalex) 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 very good partial response [VGPR] + partial response [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 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 his concluding remarks, Vogl said, “We are currently continuing enrollment in another expansion cohort of 122 patients with penta-refractory myeloma treated with 8 doses of selinexor and dexamethasone in each 4-week cycle to confirm these results.”

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.

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