Advanced Myeloma Patients Responding to Selinexor Plus Standard Therapies in Trial, Data Show

Updated clinical trial data show that selinexor added to standard therapies can benefit multiple myeloma patients who have failed multiple prior lines of therapy, Karyopharm Therapeutics announced.

This data — from the ongoing Phase 1b/2 STOMP (NCT02343042) trial — was presented in three posters at the European Hematology Association (EHA) annual meeting that recently concluded in Stockholm.

STOMP is a multi-arm trial evaluating selinexor and low-dose dexamethasone in combination with existing therapies for multiple myeloma — Velcade (bortezomib), Pomalyst (pomalidomide), Revlimid (lenalidomide), Darzalex (daratumumab), and Kyprolis (carfilzomib).

Selinexor is a selective inhibitor of the XPO1 protein, a nuclear export protein. Usually, cancer cells get rid of tumor suppressor proteins, which activate the apoptotic (cell death) pathways of defective cells. But by blocking their transport, selinexor leads to the accumulation of these suppressor proteins in a cell’s nucleus, inducing cell death in  cancer cells but not in healthy ones.

In the poster titled, “Selinexor combined with low dose bortezomib and dexamethasone (SVd) induces a high response rate in patients with relapsed or refractory multiple myeloma (MM),” Nizar Bahlis, MD, with Southern Alberta Cancer Research Institute presented data on the combination of selinexor and dexamethasone together with Velcade.

A study arm tested oral, increasingly higher doses of selinexor in once a week (80 or 100 mg) or twice-weekly (60 or 80 mg) regimens, together with dexamethasone. Velcade was injected under the skin as a 1.3mg/m² dose – a lower dose than currently approved – once or twice each week.

Overall, 63 percent of patients responded to the combination, including 13% complete responses and 18% very good partial responses. The median time a patient lived without the disease worsening was 9.2 months.

However, the best response rate (84%) was seen in patients who had never received a proteasome inhibitor (like Velcade or Kyprolis, which block protein degradation in cells) or who had relapsed after receiving one. These patients lived a median of 17.8 months before their disease progressed.

For treatment naive or relapsed patients who had received fewer than three prior treatments, a subset called the BOSTON population, the response rates were 83%.

The most common adverse events included fatigue, nausea, diarrhea, and anorexia, and were mostly mild and reversible. This was in agreement with what was reported in an initial cohort of the STOMP study.

Mild damage to peripheral nerves was experienced by 14% of patients, mostly those previously treated with Velcade.

“Updated data from the SVd [selinexor-Velcade-dexamethasone] arm of the STOMP study continue to show rapid time to response, high response rates, including an 83% ORR and the emergence of complete responses, along with a 17.8-month median PFS [progression-free survival], in patients with relapsed or refractory myeloma,” Bahlis said in a press release.

“The combination also continues to be well tolerated with low rates of peripheral neuropathy.  Importantly, these results are being achieved with 40% less Velcade and 25% less dex than the standard approved regimen, with no overt major organ toxicities,” he added.

In a second poster, “A Phase 1b study using the combination of selinexor, daratumumab, and dexamethasone in multiple myeloma patients previously exposed to proteasome inhibitors and immunomodulatory drugs,” Cristina Gasparetto, MD, at Duke University Cancer Center, presented data for selinexor and dexamethasone in combination with the CD38 antibody Darzalex.

In this arm of the study, 19 patients were dosed with selinexor (100 mg once weekly or 60 mg twice weekly) and dexamethasone (40mg once weekly or 20mg twice weekly) together with Darzalex (16 mg/kg intravenously once weekly).

All patients had received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory treatment.

Among these patients, 14 (or 74%) experienced a significant reduction in their tumors. For patients who had never been treated with Darzalex, the response rate was 82%.

“These preliminary results from the SDd [selinexor-Darzalex-dexamethasone] arm of the STOMP study show high response rates, including an 82% ORR in Darzalex-naïve patients with refractory myeloma. This combination regimen appears to be well tolerated with responses observed rapidly occurring within a median one cycle of treatment. We look forward to continuing enrollment in this treatment arm,” Gasparetto said.

In a third presentation, “Selinexor combined with pomalidomide and low dose dexamethasone (SPd) in a relapsed/refractory multiple myeloma patient population,” Christine Chen, MD, FRCP, with the University of Toronto, Princess Margaret Cancer Center, shared data for selinexor and dexamethasone together with oral Pomalyst (3 or 4 mg, once daily).

In this group, patients had been previously treated with Revlimid and a proteasome inhibitor.

Those naive to Pomalyst who had progressed during or after Revlimid treatment had a response rates of 55%, with a median time to disease progression or death of 11.6 months.

Outcomes were worse for patients who had failed to respond to both Pomalyst and Revlimid. Thirty-eight percent saw a reduction in their tumors, and the disease worsened in an average of 4.8 months.

“This novel, all oral regimen continues to demonstrate strong response rates, including a 55% ORR, along with an 11.6-month median PFS, in Pomalyst-naïve and Revlimid-relapsed or -refractory patients. In this STOMP arm, once-weekly selinexor has been generally well tolerated and rapidly induced durable responses in patients with PI- and Revlimid-exposed myeloma,” said Chen.

“The Phase 1b/2 STOMP study continues to generate important efficacy and safety data from the multiple ongoing arms evaluating selinexor and dexamethasone (dex) in combination with the standard approved therapies Velcade, Pomalyst and Darzalex in patients with multiple myeloma following at least one prior therapy,” said Sharon Shacham, PhD, MBA, president and chief scientific officer of Karyopharm.

The results led researchers to open a new study group, or arm, evaluating selinexor and dexamethasone with the  Revlimid in newly diagnosed patients.

“Based on the positive STOMP results reported to date, we have initiated a new, all-oral STOMP arm to investigate selinexor plus Revlimid and dex in the front-line setting,” Shacham said.

“Given the observed synergistic activity of selinexor with standard approved myeloma therapies, we believe oral selinexor has the potential to be a future backbone therapy in myeloma, and we look forward to elucidating its activity as part of a front-line treatment regimen.”