The all-oral combination of selinexor, pomalidomide, and dexamethasone (SPd) is durable and active in patients with multiple myeloma (MM) who are pomalidomide-naïve and refractory to lenalidomide, leading to an overall response rate (ORR) of 56% in this patient population, with 19% of patients achieving very good partial responses, according to data from the phase 1/2b STOMP study.
The 3-drug combination also led to a median progression-free survival (PFS) of 12.2 months in these patients. According to the investigators, this is significantly longer than the PFS observed with pomalidomide/dexamethasone in a similar patient population (<4 months).
Selinexor in combination with low-dose dexamethasone was recently approved based on data from the STORM study, wherein the drug combination induced an ORR of 26.2% in patients with triple-class refractory MM. The combination of pomalidomide and dexamethasone has previously demonstrated an ORR of 31% in a population of patients refractory to bortezomib and lenalidomide.
“We were interested in adding selinexor to the combination of pomalidomide and dexamethasone in a novel triplet, taking advantage of the known synergistic activity of pomalidomide and selinexor in vivo, and also appreciating that this is attractive as an all-oral regimen,” said the study’s presenting author Christine Chen, MD, from Princess Margaret Cancer Centre, Toronto, Canada.
Based on these rationale, the study was designed to assess the safety, tolerability, and preliminary efficacy of the combination of SPd in patients with relapsed/refractory (R/R) MM.
Dr Chen presented data from a subset of 51 patients treated with SPd within the larger STOMP trial, a multicenter, open-label, dose-escalation and expansion study evaluating selinexor in combination with other backbone anti-myeloma therapies in patients with newly diagnosed and R/R MM.
Patients who received ≥2 prior therapies, including lenalidomide and a proteasome inhibitor (in combination or separately), were eligible for enrollment in the SPd substudy. Patients had to be progressing or refractory to their previous regimen, and pomalidomide exposure was allowed only in the escalation phase.
Oral selinexor was evaluated in 2 different dosing schedules: once weekly or twice weekly at 60 mg or 80 mg, with escalating doses of pomalidomide at 2 mg, 3 mg, or 4 mg (days 1-21), and low-dose dexamethasone 20 mg twice weekly or 40 mg weekly. The primary objectives of the study were to determine the maximum tolerated dose and the recommended phase 2 dose of SPd in these patients.
As of October 1, 2019, 51 patients (27 male and 24 female) were enrolled; the median age was 64 years. Patients received a median of 4 prior treatment regimens, and the majority (76%) received prior transplant.
The investigators slightly modified the criteria for dose-limiting toxicities (DLTs) from the standard to account for expected side effects. Grade 3 nausea, vomiting, dehydration, diarrhea or fatigue lasting more than 3 days despite optimal supportive modifications, grade 4 neutropenia lasting more than a week and complicated by fever, or grade ≥3 thrombocytopenia with clinically significant bleeding, petechiae, or purpura were considered DLTs.
The phase 1 dose-escalation enrollment is now complete, and across all cohorts, 8 DLTs were observed.
“After cycle 1 it became clear that this twice-weekly selinexor dosing could be challenging to maintain at full dose, and many required dose reductions,” she said.
SPd-related adverse events were comparable between once-weekly selinexor 60 mg/pomalidomide 4 mg and once-weekly selinexor 80 mg/pomalidomide 2 mg, but the lower selinexor dose and higher pomalidomide dose led to higher response rates.
The recommended phase 2 dose was found to be selinexor 60 mg once weekly in combination with pomalidomide 4 mg/day and dexamethasone 40 mg weekly. Common hematologic treatment-related adverse events at this dose included (grades 1/2, grades ≥3) neutropenia (9%, 57%), thrombocytopenia (24%, 27%), anemia (18%, 27%), and leukopenia (21%, 15%). Common nonhematologic adverse events were nausea, anorexia, and fatigue. According to the investigators, these side effects can be managed with appropriate supportive care and/or dose modifications.
“With the recommendations for aggressive antiemetic prophylactic therapy, GI toxicities were minor (grade 1-2),” Dr Chen noted.
The clinical benefit response was 74% across all patients, and 78% in pomalidomide-naïve patients.
“Selinexor, once weekly, can be safely combined with pomalidomide and low-dose dexamethasone in patients with heavily pretreated multiple myeloma,” she concluded.
A phase 3 study with this novel combination of SPd, XPORT-MM-032, is in a planning phase.
Chen CI, et al. ASH Abstract 141. Session 653.
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