Selinexor Shows Promise in Combination With Daratumumab, Dexamethasone in RRMM

November 20, 2020
Jared Kaltwasser

The oral selective inhibitor of nuclear export could provide a new therapeutic avenue in daratumumab-naive patients with relapsing refractory multiple myeloma (RRMM).

The combination of oral selinexor (Xpovio), dexamethasone, and intravenous daratumumab (Darzalex) can produce deep and durable responses in patients with heavily pretreated relapsing refractory multiple myeloma (RRMM), according to new research.

The promising data come from a new study published in the European Journal of Haematology, which was designed to evaluate the safety and efficacy of the therapy, as well as determine the appropriate maximum tolerated dose (MTD).

A number of different types of therapies, including proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and the anti-CD38 antibody daratumumab (Darzalex) have helped to restructure the treatment patterns of patients with MM. The drugs are typically administered in triplet combinations, but virtually all patients will eventually become refractory to multiple agents, leading to a low survival rate in patients with RRMM, according to corresponding author Christina Gasparetto, MD, of Duke University, and colleagues.

Selinexor is an oral selective inhibitor of nuclear export (SINE) that covalently binds to and inactivates Exportin 1 (XPO1), one of 8 nuclear export proteins. XPO1 is often overexpressed in patients with MM, according to the investigators.

By inactivating XPO1, selinexor leads to “the accumulation of [tumor suppressor proteins] in the nucleus, reducing translation of onco-proteins, enhancing glucocorticoid receptor signaling, and inducing cell cycle arrest, ultimately resulting in death of MM (and other malignant) cells but not in normal cells,” Gasparetto and colleagues wrote.

Selinexor has shown promise in combination with other anti-MM drugs. In the new study, the investigators sought to evaluate the drug’s safety, efficacy, and MTD in combination with daratumumab (16 mg/kg) and dexamethasone (40 mg), a combination known as SDd, in patients with RRMM.

Thirty-four patients with a median of 3 prior therapies were enrolled in the study. Eighty-five percent of patients had MM that was refractory to PIs, 76% were refractory to IMiDs, 74% were refractory to both, and 6% were refractory to daratumumab.

Initially, the authors sought to determine whether a 100 mg once-weekly dose or a 60 mg twice-weekly dose should be the recommended phase 2 dose. Two dose-limiting toxicities were reported in the twice-weekly group, and none were reported in the once-weekly group, which led the authors to choose 100 mg, once-weekly as the MTD and recommended phase 2 dose.

In terms of safety, 70.6% of patients reported thrombocytopenia, and the same number reported nausea. Fatigue and anemia were each reported by 61.8% of patients, and half of the patients had neutropenia.

Gasparetto and colleagues said they were expecting high rates of thrombocytopenia based on earlier research, but they noted that only one patient had concomitant bleeding, and nearly all cases were reversible and manageable.

Rates of grade 3 or higher neutropenia were lower than daratumumab-IMiD combinations, the authors said, and no patient reported febrile neutropenia. A total of 5 patients discontinued treatment due to adverse events.

However, the drug had strong efficacy data. The overall response rate was 73%, and the median progression-free survival was 12.5 months among patients who were daratumumab naive.

“Overall, selinexor 100 mg once-weekly was well tolerated while maintaining durable anti-MM efficacy,” they said.

Gasparetto and colleagues said further investigation is warranted specifically for patients who have previously been treated with a PI and an IMiD but who are daratumumab-naive.

Reference

Gasparetto, C,Lentzsch, S,Schiller, G, et al.Selinexor, daratumumab, and dexamethasone in patients with relapsed or refractory multiple myeloma. eJHaem. 2020; 1‐10. doi: 10.1002/jha2.122