Xpovio-Kyprolis Combo Shows Good Response in Hard-to-treat Myeloma

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Xpovio (selinexor) combined with Kyprolis (carfilzomib) and low-dose dexamethasone leads to strong and durable responses in heavily pretreated multiple myeloma patients, results from a Phase 1/2b trial show.

The study, “Once weekly selinexor, carfilzomib and dexamethasone in carfilzomib non-refractory multiple myeloma patients,” was published in the British Journal of Cancer.

Xpovio, developed by Karyopharm Therapeutics, is an oral inhibitor of the XPO1 protein and prevents tumor suppressor proteins from leaving the cell nucleus. This leads to cancer cell death, but healthy cells remain unharmed.

The treatment works well in combination with proteasome inhibitors (PI), a class of myeloma treatments that prevent faulty and toxic proteins from being degraded in cells, leading to their death.

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Following promising results from the BOSTON Phase 3 trial (NCT03110562), selinexor was approved — in combination with the PI Velcade (bortezomib) and low-dose dexamethasone — for treating adult patients who had received at least one prior line of therapy

Kyprolis is an approved second-generation PI that’s been shown to be more potent than Velcade for treating myeloma. It’s approved for people who failed one to three prior lines of therapy.

In a previous Phase 1 trial (NCT02199665), the combination of Xpovio, Kyprolis, and low-dose dexamethasone was well-tolerated in heavily pretreated patients and induced at least a partial response in nearly half of them.

Researchers at Duke University Medical Center and Karyopharm set out to confirm these initial findings in the Phase 1/2b STOMP trial (NCT02343042), a multi-arm study to evaluate Xpovio and low-dose dexamethasone in combination with existing myeloma therapies.

The Kyprolis arm of STOMP enrolled 32 participants (63% male; median age 69.5 years) who had received a median four prior treatments. All had received Velcade and at least one immunomodulatory drug (IMiD). Half of them had failed to respond to both a PI and an IMiD, and 38% had failed a PI, an IMiD, and a CD38 inhibitor. More than half (53%) had high-risk chromosomal abnormalities.

Patients were given ascending doses of both Xpovio and Kyprolis, to determine the best to be used in this combination. At the time of the analysis, 10 patients (31.3%) were still receiving treatment, and 17 had discontinued treatment, mostly due to disease progression or side effects.

Overall, 78.1% of patients responded to treatment. There were 11 partial responses, nine very good partial responses, three complete responses, and two stringent complete responses. In patients who had received two or fewer prior therapies, the response rate was 88.9%.

Complete responses refer to total cancer eradication, while partial responses refer to partial cancer elimination. Very good partial responses and stringent complete responses are stronger types of partial and complete responses, respectively.

Responses lasted for a median of 22.7 months, and patients lived without disease progression signs for a median of 15 months. The median survival had not been reached, meaning more than half were still alive.

Results were similar among those who had failed at least three prior lines of therapy. In this group, the response rate was 66.7%, the response duration was 22.7 months, the median time to disease progression or death was 23.7 months, and median overall survival was 24 months.

The most commonly reported side effects were low platelet and red blood cell counts (anemia), as well as nausea and fatigue. All were manageable with supportive care and dose modifications.

Overall, these findings suggest that the weekly combination of Xpovio, plus Kyprolis and dexamethasone “is highly effective and well-tolerated,” the researchers wrote.

“These data support further investigation of [Xpovio-Kyprolis-dexamethasone] in patients with [multiple myeloma],” they reported.