STORM Study: Selinexor Shows Activity in Patients With Heavily Refractory Myeloma

Selinexor, an oral selective XPO1 inhibitor, when combined with low-dose dexamethasone, could be a new treatment option for patients with heavily pretreated multiple myeloma (MM) who have become refractory to immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and investigational anti-CD38 antibodies.

“This approach has the potential to be a new treatment option for patients with myeloma who really don’t have [any other treatment options],” lead investigator Dan T. Vogl, MD, from the Abramson Cancer Center of the University of Pennsylvania in Philadelphia, told ASH Clinical News. “It represents a life-saving opportunity for them.”

The selinexor and low-dose dexamethasone combination was evaluated in the ongoing phase II STORM study, which enrolled 78 patients with MM. These patients had received a median of seven prior therapies and were refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (“quad-refractory;” n=48); a subset of 30 patients was refractory to an investigational anti-CD38 antibody (either daratumumab or isatuximab; “penta-refractory”). “The median time from diagnosis to the time [these patients] went on study was four years,” Dr. Vogl noted, “which meant that they had gone through all of the available therapies very quickly.”

Patients were treated with 80 mg of selinexor (twice a week) for six or eight doses per 28-day cycle and 20 mg of dexamethasone (twice a week). Most patients who were refractory to IMiDs and PIs received eight doses of selinexor per cycle (65%) and most patients who were refractory to IMiDs, PIs, and anti-CD38 antibodies received six doses of selinexor per cycle (83%).

Primary endpoints included overall response rate (ORR; per International Myeloma Working Group criteria) and duration of response. Secondary endpoints included progression-free survival (PFS) and overall survival (OS).

The ORR (including partial responses [PR] and very-good PR [VGPR]) was 21 percent for all patients – 21 percent in the quad-refractory group and 20 percent in the penta-refractory group (TABLE). Dr. Vogl added that the responses were “of reasonable duration,” with a median duration of response five months.

Researchers also reported that the overall clinical benefit rate (defined as ORR + molecular response) was 32 percent for all patients – 29 percent in the quad-refractory group and 37 percent in the penta-refractory group.

The median PFS for all patients was 2.1 months, and the median OS was 9.3 months. Among the patients who responded to treatment, the median OS was not reached at the time of data reporting (>11 months), compared with 5.7 months for non-responders.

The most common treatment-related hematologic adverse events (AEs) included thrombocytopenia (72%), anemia (48%), and neutropenia (29%), while the most common non-hematologic AEs included nausea (72%), fatigue (62%), anorexia (49%), vomiting (43%), asymptomatic hyponatremia (42%), diarrhea (42%), and weight loss (33%). There was one case of febrile neutropenia (1%) and one case of clinically significant bleeding related to thrombocytopenia (1%).

Seventy patients discontinued therapy due to progressive disease (73%), AEs (17%), or physician or patient preference (1%). Six deaths were reported, one of which was deemed related to selinexor. The other nine patients are still part of the study.

Though most AEs were low grade, the researchers observed some grade 3 gastrointestinal toxicities and moderately severe hematologic toxicities, Dr. Vogl said. “We managed those toxicities reasonably well, by giving patients supportive care and modifying the treatment protocol over the course of the study.” For example, original study protocol called for six doses of selinexor and dexamethasone per month, but the treatment was modified to eight doses per month to allow physicians to “build in treatment interruptions for side effects,” he explained.

The phase IIb STORM trial is ongoing, and investigators plan to enroll another 122 patients to confirm these encouraging preliminary results in larger trials.


Reference

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. Abstract #491. Presented at the ASH Annual Meeting and Exhibition, December 4, 2016; San Diego, California.

TABLE. Efficacy of Selinexor and Low-Dose Dexamethasone
N ORR CBR VGPR PR MR SD PD
Overall 78 16 (21%) 26 (33%) 4 (5%) 12 (15%) 10 (13%) 27 (35%) 9 (12%)
Quad-refractory 48 10 (21%) 14 (29%) 2 (4%) 8 (17%) 4 (8%) 21 (44%) 4 (8%)
Penta-refractory 30 6 (20%) 12 (40%) 2 (7%) 4 (13%) 6 (20%) 6 (20%) 5 (17%)
6 Doses/month 51 10 (20%) 15 (29%) 3 (6%) 7 (14%) 5 (10%) 21 (41%) 4 (8%)
8 Doses/month 27 6 (22%) 11 (41%) 1 (4%) 5 (19%) 5 (19%) 6 (22%) 5 (19%)
ORR = overall response rate; VGPR = very good partial response; PR = partial response; CBR = clinical benefit rate; MR = molecular response; SD = stable disease; PD = progressive disease

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