Selinexor Triplet Highly Active in Relapsed Myeloma

Darrell White, MD

The all-oral triplet regimen of 60 mg of weekly selinexor (Xpovio) plus lenalidomide (Revlimid) and dexamethasone appears to be highly active and well tolerated in patients with relapsed, refractory multiple myeloma, particularly in patients who did not receive prior lenalidomide, according to results of the multi-arm STOMP study that were presented during the 17th International Myeloma Workshop (IMW).¹

Data showed that the objective response rate (ORR) was 60% for all evaluable patients (n = 20), with 5% stringent complete response (sCR), 15% very good partial response (VGPR), 40% PR, and 10% minimal response (MR); the clinical benefit rate (CBR) was 70%, explained lead study author Darrell White, MD, Dalhousie University, Halifax, Nova Scotia, who presented the findings during the meeting. In lenalidomide-naïve patients, the ORR was 92%.

Selinexor is a first-in-class, oral selective inhibitor of nuclear export (SINE); the nuclear export protein Exportin 1 (XPO1) is overexpressed in a wide variety of cancers, including multiple myeloma. Selinexor inhibits XPO1, forcing tumor suppressor proteins to be retained in the cell nucleus where they are active, rather than be transported to the cytoplasm where they are ineffective.

In July 2019, the FDA approved selinexor in combination with dexamethasone for the treatment of patients with relapsed/refractory myeloma who have received ≥4 prior therapies and whose disease is refractory to ≥2 proteasome inhibitors (PI), ≥2 immunomodulatory (IMiD) agents, and an anti-CD38 monoclonal antibody. The approval was based on data from part 2 of the phase IIb STORM trial, in which selinexor in combination with dexamethasone resulted in an ORR of 26.2% in patients with myeloma that was refractory to 3 classes of agents in the STORM study.²

The combination of lenalidomide and dexamethasone, which is an approved regimen in relapsed/refractory myeloma, has an ORR in the range of 60% to 76%. In preclinical models, the combination of selinexor and lenalidomide showed at least additive activity in preclinical multiple myeloma models.

Therefore, investigators hypothesized that the all-oral combination of selinexor, lenalidomide, and dexamethasone (SRd) might result in improved response rates.

The phase I/II STOMP study (NCT02343042) is assessing selinexor in combination with several backbone therapies for both patients with newly diagnosed and relapsed/refractory multiple myeloma.3 All arms of the STOMP study have a common primary objective of determination of the maximum tolerated dose (MTD) and a recommended phase II dose of their respective combinations with selinexor.

To be eligible for enrollment, patients must have received ≥1 prior therapy. Selinexor was dose-escalated in 3 regimens: once weekly at 80 mg and either twice weekly or weekly at 60 mg, each followed by lenalidomide at 25 mg once daily in 21-day cycles and dexamethasone at 20 mg twice weekly or 40 mg weekly.

Twenty-four patients were enrolled, completing enrollment; results as of August 1, 2019 were presented. The median age was 67 (range, 49-84 years); 54% of patients were male. The median number of prior treatments was 1 (range, 1-8); 38% had received lenalidomide, of whom 21% had lenalidomide-refractory disease. All patients had received a PI and 65% were refractory to the class of drugs.

Following dose reductions in the first 5 or 6 cycles for selinexor and the first 4 or 5 cycles for lenalidomide, patients were able to continue and tolerate long-term treatment with SRd.

Dose-limiting toxicities (DLT) included grade 3 anorexia and weight loss, grade 4 thrombocytopenia, and grade 3 fatigue in the selinexor 60-mg twice-weekly group; there was grade 4 thrombocytopenia in the selinexor 80-mg weekly group. Moreover, there were no DLTs in the selinexor 60-mg weekly group. The recommended phase II dose, therefore, was selinexor at 60 mg weekly plus lenalidomide 25 mg once daily, and dexamethasone 40 mg weekly. Of the 24 patients, 13 received the recommended phase 2 dose in the expansion phase.

Twenty patients were evaluable for response. M-protein was reduced from baseline in most patients; 15 patients (75) had M-protein reductions >50%; 4 patients (20%) had M-protein reductions of ≥90%.

Efficacy data also showed that in the 12 lenalidomide-naïve patients, the sCR was 8%, the VGPR was 25%, the PR was 58%, and there were no MRs; the ORR and CBR were each 92%. In the 8 patients who received prior lenalidomide, the ORR was 13%; 13% of patients had a PR and 25% had a MR, and the CBR was 38%.

Regarding safety, White explained that the adverse events (AEs) were expected to what was observed in the STORM trial. Across both doses, common treatment-related AEs, which were typically grade 1/2 and reversible, included nausea (62.5%), anorexia (50%), fatigue (54.2%), weight loss (41.7%), vomiting (33.3%), constipation (25%), and diarrhea (25%). Common grade ≥3 AEs were thrombocytopenia and neutropenia (31.2% each).

The low-grade gastrointestinal AEs were common and as expected, and White said they are manageable with appropriate supportive care, particularly anti-emetics, and/or dose modifications.

White concluded that although selinexor combined with bortezomib was effective in bortezomib-refractory multiple myeloma, it was not the case in this study that selinexor/lenalidomide was as effective in patients with lenalidomide-refractory myeloma. Therefore, he said, the combination of selinexor plus lenalidomide might be more effective when combined with a PI in lenalidomide-naïve patients.

References

1. White D, LeBlanc R, Venner C, et al. Safety and efficacy of the combination of selinexor, lenalidomide and dexamethasone (SRd) in patients with relapsed/refractory multiple myeloma (RRMM). Presented at: 17th International Myeloma Workshop; September 12-15, 2019; Boston, MA. Abstract 353.
2. Selinexor Prescribing Information. FDA. Published July 3, 2019. https://bit.ly/309qeU6. Accessed July 3, 2019.

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