Can a Selinexor Combination STOMP Out Relapsed/Refractory Multiple Myeloma?

The combination of selinexor plus low-dose bortezomib and dexamethasone produced high response rates in patients with relapsed or refractory multiple myeloma (MM), with a “manageable” safety profile, according to the phase Ib/II Selinexor and Backbone Treatments of Multiple Myeloma Patients (STOMP) study. Findings from the ongoing trial were published in Blood.

“Selinexor represents a new class of drugs targeting the nuclear export protein XPO1 and provides patients with myeloma access to a therapeutic option that does not include an immunomodulatory agent, proteasome inhibitor, or anti-CD38 monoclonal antibody,” lead study author Nizar Jacques Bahlis, MD, from the Charbonneau Cancer Research Institute at the University of Calgary, explained. “Of interest, when selinexor was combined with bortezomib, the gastrointestinal effects of selinexor were much attenuated and, with the weekly, low-dose subcutaneous administration of bortezomib, the neurotoxicity was minimal.”

In the dose-escalation and dose-expansion phases of the STOMP study, investigators enrolled 42 adults with MM whose disease had progressed following at least one treatment regimen. Patients who received prior treatment with and were refractory to bortezomib or a proteasome inhibitor (PI) were eligible for the trial; however, patients who were refractory to bortezomib as their most recent line of therapy were excluded. Patients with disease that was refractory to carfilzomib or ixazomib as the most recent line of therapy were included.

Participants’ median age was 64 years (range = 43-75 years), and the median number of prior lines of therapy was three (range = 1-11). Twenty-one patients (50%) had disease that was refractory to a PI and 19 (45%) had disease that was refractory to both a PI and an immunomodulatory agent.

During the dose-escalation phase, patients were randomized to receive once- or twice-weekly selinexor at one of three doses (60, 80, or 100 mg) in 21- or 35-day cycles. Patients also received bortezomib 1.3 mg/m2 and dexamethasone 20 mg (in the 21-day cycle) or 40 mg (in the 35-day cycle).

As of data cutoff, patients had received treatment for a median of 225 days (range = 18-707 days). Seven patients (17%) were still receiving treatment: 22 (52%) discontinued due to progressive disease, eight (19%) due to adverse events (AEs), and five (12%) for other reasons.

The most commonly reported non-hematologic AEs of any grade included nausea (62%), fatigue (60%), and decreased appetite (60%); most of these AEs were grade 1 or 2 and were reversible with dose interruptions. “Of particular interest, and despite the fact that 86 percent of the patients were previously exposed to bortezomib, the overall rate of peripheral neuropathy was minimal with only 5 percent of the patients experiencing grade 2 neuropathy and no grade 3 [events] reported,” the authors wrote.

The most commonly reported hematologic grade ≥3 AEs included:

  • thrombocytopenia (50%)
  • neutropenia (26%)
  • anemia (19%)

“Clinical sequelae of these hematologic AEs were low as bleeding (5%, both cases grade 1) and febrile neutropenia (5%) were uncommon,” the researchers noted.

Six patients developed pneumonia during the study but all, including one death, were considered unrelated or unlikely related to selinexor treatment. There were no dose-limiting toxicities reported during the dose-escalation phase, however, the investigators found that the side effects of treatment with twice-weekly bortezomib “were not sustainable for long-term treatment and this dosing schedule was abandoned.”

The recommended phase II dose, therefore, was set at once-weekly selinexor 100 mg, dexamethasone 40 mg, and bortezomib 1.3 mg/m2. The dose-expansion phase enrolled an additional 20 patients at the once-weekly schedule to establish the safety and efficacy profile.

For the 40 patients across the dose-escalation and -expansion cohorts who were evaluable for response, the overall response rate (ORR) was 63 percent, which the researchers deemed “encouraging” considering the large portion of patients with refractory and heavily pretreated disease. The ORR included: three complete responses (8%), nine very good partial responses (23%), and 13 partial responses (33%). An additional seven patients (18%) experienced a minimal response, for a clinical benefit of 80 percent.

Specifically, among patients treated at the recommended phase II dose, the ORR was 58 percent, and the authors observed a higher ORR in PI-nonrefractory patients compared with PI-refractory patients (84% vs. 43%, respectively). This higher ORR among PI-nonrefractory patients “supports the nonclinical synergy observed between XPO1 inhibitors and PIs,” the researchers added. “Responses were sustained over time with an overall median progression-free survival (PFS) of 9.0 months [in the 40 evaluable patients], including a median PFS of 17.8 months in PI-relapsed/naïve patients.”

The authors noted several limitations of the study, including its small number of participants and the lack of a comparator or control group.

Additionally, while the results of this study are encouraging, Dr. Bahlis stated that the findings require further validation in a future randomized trial. One such study, the ongoing Bortezomib, Selinexor, and Dexamethasone in Patients With Multiple Myeloma (BOSTON) trial, compares once-weekly selinexor, bortezomib, and dexamethasone with the combination of bortezomib and dexamethasone in patients with relapsed and/or refractory myeloma. “This randomized phase III trial will confirm the [selinexor and bortezomib] combination’s efficacy, and establish it as an anti-myeloma regimen,” Dr. Bahlis explained. “Additional combination studies of selinexor and pomalidomide or daratumumab also are ongoing.”

The authors report financial relationships with Karyopharm Therapeutics, which sponsored the trial.


Reference

Bahlis NJ, Sutherland H, White D, et al. Selinexor plus low-dose bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma. Blood. 2018;132:2546-54.

This trial is the first to demonstrate the effectiveness of weekly selinexor when given in combination with other anti-myeloma drugs. Half the patients required a dose reduction of selinexor, most often due to cytopenias, nausea, or fatigue. At the recommended phase II dose, 73 percent suffered grade 1/2 nausea and 62 percent grade 1/2 fatigue, despite protocol-mandated antiemetics. In comparison, when adjusted for grade, about half as many patients had similar side effects in trials of carfilzomib, lenalidomide, and dexamethasone or daratumumab, lenalidomide, and dexamethasone – although both lenalidomide-related combinations caused more diarrhea.

In the phase III BOSTON trial, selinexor has shown similar responses in diffuse large B-cell lymphoma It crosses the blood-brain barrier, potentially allowing it to target glial tumors, and targeting this pathway may have a bright future.

Craig Hofmeister, MD, MPH
Winship Cancer Institute
Emory University School of Medicine
Atlanta, GA

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