Selinexor Induces Deep Responses in Refractory Multiple Myeloma

More than one-quarter of patients with refractory multiple myeloma (MM) responded to treatment with a combination of selinexor and low-dose dexamethasone, according to results from the pivotal STORM Part 2 trial presented at the 2018 ASH Annual Meeting. Further, responses occurred rapidly and most patients achieved stable disease with this oral combination regimen.

“A growing number of patients are exposed to the proteasome inhibitors [bortezomib and carfilzomib], immunomodulatory agents, and the anti-CD38 monoclonal antibody daratumumab,” lead investigator Ajai Chari, MD, from Mount Sinai School of Medicine in New York, said during his presentation. “But eventually these patients develop penta-exposed and triple class–refractory myeloma and have a dismal prognosis.”

In the STORM Part 2 trial, investigators evaluated the safety and efficacy of selinexor, a first-in-class selective inhibitor of XPO1, with low-dose dexamethasone in 122 heavily pretreated patients. All participants had been previously treated and had disease that was refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, an alkylator, and glucocorticoids.

The inclusion criteria were “relatively permissive,” Dr. Chari noted, although patients were required to have a creatinine clearance ≥20 mL/min, absolute neutrophil count ≥1,000/mm3, platelets ≥75,000/mm3, and hemoglobin ≥8.5 g/dL.

Participants’ median age was 65 years (range = 40-86 years) and more than half (53%) had high-risk cytogenetics. The median number of prior lines of therapy was seven (range = 3-18), with 29.5 percent having received at least nine prior therapies.

“Patients had rapidly progressive disease and were sequencing through many lines of therapy in a short time,” Dr. Chari reported. He noted that two patients (1.6%) had disease that progressed even after treatment with chimeric antigen receptor T-cell therapy.

In STORM, patients were treated with twice-weekly selinexor 80 mg and dexamethasone 20 mg in 28-day cycles. “Due to aggressiveness of this disease and based on preclinical data from phase I studies, STORM treatment begins with high doses of selinexor to obtain rapid disease control,” Dr. Chari explained.

As of August 17, 2018 (data cutoff), five patients (4.1%) remained on treatment. The most common reasons for discontinuation were: disease progression (55.1%) and adverse events (AEs; 32.2%).

At three-month follow-up, the overall response rate (ORR; primary endpoint) was 26.2 percent, including:

  • partial response (PR): 19.7%
  • very good PR (VGPR): 4.9%
  • stringent complete response (sCR): 1.6%

The two patients who achieved sCRs also had minimal residual disease–negative status, the authors reported, and an additional 13.1 percent of patients achieved a minimal response (MR). Dr. Chari noted that the time to response was “quite short – only one month – and the median duration of response was 4.4 months.”

In subgroup analyses, response rates were similar, regardless of the last prior therapy.

The median progression-free survival (PFS) and overall survival (OS) were 3.7 months and 8.6 months, respectively (TABLE). Importantly, Dr. Chari said, “the median overall survival was 15.6 months for both patients who achieved a minimal response or a partial response – highlighting the importance of looking at both partial and minimal responses in heavily pretreated patient populations.” 

Median duration of selinexor treatment was 9 weeks (range = 1-60+ weeks), and 79.7 percent of patients required a dose modification – most of which occurred in the first two cycles. The most common non-hematologic AEs included nausea, fatigue, weight loss, anorexia, vomiting, and diarrhea. The most common hematologic AE was thrombocytopenia (67.5%), followed by anemia (48%).

AEs were generally reversible, and the investigators found that the side effects of selinexor were dose- and schedule-dependent. Because selinexor crosses the blood-brain barrier, they stressed the importance of early identification, frequent assessment, and implementation of supportive care measures for AE management.

Limitations of the study include the lack of a comparator or placebo arm, as well as a relatively small number of participants included in the final cohort. Dr. Chari added that ongoing studies are investigating potential biomarkers of selinexor resistance, as well as selinexor in combination with various MM backbone agents.

The authors report financial relationships with Novartis, Array Biopharma, Celgene, Amgen, Pharmacyclics, Takeda, Janssen, Millennium Takeda, Bristol-Myers Squibb,  Sanofi, Jazz Pharmaceuticals, and Karyopharm Therapeutics(which sponsored the trial).


Reference

Chari A, Vogl DT, Dimopoulos MA, et al. Results of the pivotal STORM study (part 2) in penta-refractory multiple myeloma (MM): deep and durable responses with oral selinexor plus low dose dexamethasone in patients with penta-refractory MM. Abstract #598. Presented at the 2018 ASH Annual Meeting, December 3, 2018; San Diego, CA.

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