Selinexor Combo Highly Active in Relapsed/Refractory Myeloma

Article

Selinexor combined with weekly bortezomib and low-dose dexamethasone produced rapid and durable responses in a dose escalation/expansion trial of patients with relapsed/refractory multiple myeloma.

Nizar J. Bahlis, MD

Nizar J. Bahlis, MD

Nizar J. Bahlis, MD

Selinexor combined with weekly bortezomib (Velcade) and low-dose dexamethasone (Vd) produced rapid and durable responses in a dose escalation/expansion trial of patients with relapsed/refractory multiple myeloma (RRMM).

In the phase Ib/II open-label study, the overall response rate (ORR) was 84% in patients who had relapsed after a proteasome inhibitor (PI) or were naïve to a PI, and 43% in patients whose disease was refractory to a PI, “supporting preclinical findings that selinexor resensitizes and overcomes resistance to proteasome inhibitors,” lead study author Nizar J. Bahlis, MD, said at the 2017 ASH Annual Meeting. Responses typically occurred within 1 cycle of treatment and often improved over time.

The median progression-free survival (PFS) among all evaluable patients was 9 months with a median follow-up of 11.3 months.

Selinexor is a first in-class selective inhibitor of XPO1-mediated nuclear export compound. It reactivates multiple tumor suppressor proteins relevant to MM, reactivates the glucocorticoid receptor when given with steroids, reduces levels of c-Myc, and overcomes MDM2-mediated p53 degradation, explained Bahlis.

A total of 42 patients with RRMM after ≥ 1 prior therapy were enrolled, including those with prior exposure or refractoriness to PIs, provided they were not refractory to bortezomib as a last therapy. The dosage of selinexor was escalated in once-weekly (80 to 100 mg) or twice-weekly (60 to 80 mg) regimens. Bortezomib, 1.3 mg/m2 subcutaneously, was administered weekly or twice weekly. Dexamethasone was given orally at 40 mg/week or 20 mg biweekly. Twenty-six patients enrolled were dose escalated to 100 mg of selinexor every other week plus 1.3 mg/m2 of bortezomib weekly.

“We saw dramatic responses in combination with bortezomib,” said Bahlis, associate professor, University of Calgary, Alberta, Canada. “Somehow selinexor is sensitizing leukemia cells to bortezomib/dexamethasone.”

The median time from diagnosis to selinexor plus Vd was 5 years. In the proteasome-relapsed or -naïve patients, the 84% ORR included 2 patients (11%) with complete response (CR) and 5 (26%) with a very good partial response (VGPR). The 43% ORR in the proteasome refractory patients included 1 patient (5%) with a CR and 4 (19%) with a VGPR.

In the relapsed or naïve patients who had 3 or fewer prior lines of therapy, the ORR was 83%, the CR rate was 11%, and the VGPR was 33%.

“One thing to keep in mind is that we tested 1.3 mg/m2 of bortezomib; this is low-dose bortezomib and we’re getting these responses,” Bahlis said.

The median PFS in the PI-naïve or relapsed patients was >13 months.

Among the 25 responders, the median time to response was 1.1 months and the median duration of response was approximately 12 months. Thirty-eight of 40 patients evaluable for response had reductions in M-protein, 27 (68%) of whom had reductions of ≥50%, including 13 (33%) with M-protein reductions ≥90%.

The maximum-tolerated dose was not reached. All 3 patients in the twice weekly bortezomib cohort had their dosage frequency reduced to weekly after cycle 1. The most common treatment-related grade 1/2 adverse events included anorexia (60%), nausea (62%), fatigue (60%), thrombocytopenia (50%), diarrhea (43%), and vomiting (31%). Grade 3/4 adverse events included thrombocytopenia (45%), neutropenia (24%), and anemia (12%). Importantly, peripheral neuropathy across all patients was limited to 6 patients (14%), 5 of whom had prior bortezomib exposure.

“One-third of the patients get nausea and vomiting but two-thirds of the patients do fine,” Bahlis said. “When we combined it with bortezomib, for some reason the nausea became less.”

Based on tolerability and efficacy, the recommended phase II dose of selinexor plus Vd is selinexor at 100 mg, bortezomib at 1.3 mg/m2, and dexamethasone at 40 mg, all weekly. These doses represent 40% less bortezomib and 25% less dexamethasone compared with the standard approved twice weekly schedule of Vd, Bahlis said.

Bahlis NJ, Sutherland H, White DJ, et al. Selinexor in combination with weekly low dose bortezomib and dexamethasone (SVd) induces a high response rate with durable responses in patients with refractory multiple myeloma (MM). Presented at: American Society of Hematology 59th Annual meeting; December 9-12, 2017; Atlanta, GA. Abstract 3135.

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