The FDA granted accelerated approval to selinexor plus low-dose dexamethasone for triple-class refractory multiple myeloma, despite an advisory panel's concerns about the drug's toxicity and the lack of randomized clinical data.

Patients with multiple myeloma who have exhausted treatment options can now try selinexor (Xpovio; Karyopharm Therapeutics), but the first-in-class selective inhibitor of nuclear export that inhibits XPO1 can cause debilitating side effects.

The FDA granted conditional approval to selinexor in combination with dexamethasone for patients with triple-class refractory myeloma, meaning the disease no longer responds to three standard types of therapy. By preventing the shuttling of molecular cargo through XPO1, tumor suppressor proteins accumulate in the nucleus, blunting the expression of genes that can fuel cancer growth.

“Selinexor has a novel mechanism of action, and it appears to be active when all of our other major drug classes have failed,” says Paul Richardson, MD, of Dana-Farber Cancer Institute in Boston, MA, a lead investigator in the phase II, single-arm STORM trial of the drug. “It is a challenging drug to administer, but in one of the sickest populations of patients with relapsed and refractory disease that's been studied to date, we saw a meaningful response rate—and in a subset of our patients, these responses proved durable.”

In the trial, 32 of 122 patients responded to selinexor plus low-dose dexamethasone (Blood 2018;132:598). Two participants achieved stringent complete responses, six exhibited very good partial responses, and the rest experienced partial responses. Responses lasted 4.4 months on average, with the longest duration of response exceeding 18 months.

Exploratory analyses also suggest a survival benefit. At the 2019 American Society of Clinical Oncology Annual Meeting in Chicago, IL, Richardson reported that STORM participants who received selinexor and dexamethasone right after their myeloma had become triple-class refractory lived a median of 10.4 months (J Clin Oncol 37, 2019 [suppl; abstr 8014]). In comparison, patient records in the Flatiron Health Analytic Database indicated a median survival of 5.2 months for patients who received other types of therapy. Richardson describes the survival data as “supportive” of the favorable responses observed in STORM and other trials.

Selinexor's safety profile proved less auspicious. In the STORM study, 89% of patients experienced a serious (grade 3 or worse) drug-related adverse event, with most decreasing the drug or discontinuing treatment. At least two participants died because of selinexor-associated toxicities—one from sepsis, the other from pneumonia. (Eight other adverse event–related deaths could not be directly attributed to the drug.) Additionally, patients commonly experienced side effects such as thrombocytopenia, hyponatremia, anemia, and nausea.

graphic

Selinexor is a selective inhibitor of nuclear export. By blocking XPO1, it prevents molecular cargo from moving through the nuclear pore complex, causing cell-cycle arrest, apoptosis, and other antitumor activity. (Courtesy of Karyopharm Therapeutics; modified with permission.)

Those safety issues prompted an FDA advisory committee of outside experts to vote 8–5 against recommending approval until additional data are available. Onlookers like David Iberri, MD, of Stanford Cancer Center in California, and Al-Ola Abdallah, MD, of the University of Kansas Medical Center in Westwood, support that decision.

STORM provides “really insufficient data upon which to base a recommendation for this drug,” Iberri says. “I know a lot about its toxicity now, but I really don't know if it's going to improve outcomes in anyone because we don't have randomized data.”

Abdallah adds, “We need more mature studies.”

But citing the need for new medicines, the agency granted accelerated approval contingent on verification of clinical benefit. The phase III BOSTON study is evaluating progression-free survival among patients taking selinexor with bortezomib (Velcade; Millennium Pharmaceuticals) and dexamethasone or bortezomib and dexamethasone alone. Results are expected later this year or in early 2020.

Until then, Iberri will not prescribe selinexor. In addition to wanting more data, he cites the drug's price—$22,000 per month—as another major strike against it. “Without randomized data,” he says, “I can't fathom that cost.” –Elie Dolgin

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©2019 American Association for Cancer Research.
2019
American Association for Cancer Research.