Triplet Drug Combo Leads to Promising Response Rates in Relapsed/Refractory Multiple Myeloma

April 2020 Vol 11, No 4


Multiple Myeloma

In patients with multiple myeloma who were pomalidomide naive and refractory to lenalidomide, an alloral combination of selinexor, pomalidomide, and dexamethasone (SPd) led to a median progression-free survival (PFS) of 12.2 months and an overall response rate (ORR) of 56%, with 19% of patients achieving very good partial responses.

These data come from the phase 1/2b STOMP study, presented by Christine Chen, MD, at the 2019 ASH Annual Meeting. The investigators noted that the PFS rate observed in this study was significantly longer than the PFS of less than 4 months observed with pomalidomide/ dexamethasone in a similar patient population.

“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,” explained Dr Chen, from Princess Margaret Cancer Centre in Toronto, adding that “selinexor, once weekly, can be safely combined with pomalidomide and low-dose dexamethasone in patients with heavily pretreated multiple myeloma.”

The recent approval of selinexor in combination with low-dose dexamethasone was based on data from the STORM study, in which the drug combo led to an ORR of 26.2% in patients with triple-class refractory multiple myeloma. Additionally, previous research has demonstrated an ORR of 31% with a pomalidomide/dexamethasone combo in patients refractory to bortezomib and lenalidomide, contributing to the rationale for this study.

Dr Chen only discussed the data from a subset of 51 patients treated with SPd within the larger multicenter STOMP trial, a dose-escalation and expansion study evaluating selinexor in combination with other backbone antimyeloma therapies in patients with both newly diagnosed and relapsed/refractory multiple myeloma.

Twice-Weekly Selinexor Dose “Challenging”

In this subset, the safety, tolerability, and preliminary efficacy of SPd were evaluated in patients with relapsed/ refractory multiple myeloma. The primary objectives were determining the maximum tolerated dose and the recommended phase 2 dose.

Eligible patients had received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor, in combination or separately. Patients were progressing on or refractory to their previous regimen, and pomalidomide exposure was allowed only in the escalation phase. Enrolled patients had received a median of 4 prior treatment regimens, and 76% had a prior transplant.

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 phase 1 dose-escalation enrollment is now complete, and across all cohorts, 8 dose-limiting toxicities (DLTs) were observed (the researchers slightly modified the standard criteria for DLTs to account for expected side effects).

“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,” said Dr Chen.

Recommended Phase 2 Dose Confirmed

According to the investigators, SPd-related adverse events were comparable between the groups who received once-weekly selinexor 60 mg/pomalidomide 4 mg and those who received once-weekly selinexor 80 mg/ pomalidomide 2 mg, but the lower selinexor dose and higher pomalidomide dose led to higher response rates.

Therefore, 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 grade 3 or worse hematologic treatmentrelated side effects at this dose included neutropenia at 57%, thrombocytopenia at 27%, anemia at 27%, and leukopenia at 15%. Common nonhematologic adverse events included nausea, anorexia, and fatigue.

According to Dr Chen, these side effects can be managed with appropriate supportive care and/or dose modifications. Additionally, due to the study recommendations for aggressive antiemetic prophylactic therapy, gastrointestinal toxicities were minor (grade 1/2).

A phase 3 study with this novel combination of SPd is now in a planning stage, she added.

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Last modified: August 10, 2023

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