XPO1 Inhibitor Offers Novel Mechanism for Treating Penta-Refractory Myeloma

Dan T. Vogl, MD

Selinexor (KPT-330), a small-molecule inhibitor with a novel mechanism of action, is being investigated in patients with multiple myeloma (MM) who have become refractory to the many new options that have been introduced in recent years for patients with the malignancy.

The drug, which targets the chromosomal maintenance protein exportin-1 (XPO1), is being administered in combination with low-dose dexamethasone to treat patients with MM who are refractory to four therapies (quad-refractory) or to five treatments (penta-refractory) in the single-arm phase 2 STORM trial (NCT02336815). In this study, refractory is defined as a less than 25 percent response to therapy, progression during therapy, or progression within 60 days after completion of therapy. There is no upper limit on the number of prior therapies the patient can receive before enrollment. Eligible patients will have active (versus smoldering) MM. Quadrefractory is defined as patients who have stopped responding to the MM backbone therapies of Revlimid (lenalidomide), Pomalyst (pomalidomide), Velcade (bortezomib) and Kyprolis (carfilzomib). Pentarefractory refers to patients who no longer respond to those drugs plus Darzalex (daratumumab), an anti-CD38 monoclonal antibody.

The trial is divided into 2 parts: part 1 is composed of patients with quad- and penta- refractory MM, while part 2 will consist of individuals with pentarefractory disease. The study has completed enrollment of 79 patients for the part 1 cohort; an additional 122 patients are being recruited for part 2. (Figure).

Figure. Selinexor in Refractory Multiple Myeloma

Selinexor inhibits XPO1, a nuclear export protein, by binding to other proteins within the nucleus of the cell and shuttling them through the nuclear pores into the cytoplasm in the rest of the cell. “For reasons that are definitely advantageous in terms of cancer treatment, XPO1 is the carrier for the vast majority of tumor suppressor proteins that keep cancer cells from growing,” said Dan T. Vogl, M.D., assistant professor of medicine in the Hematologic Malignancies and Bone Marrow Transplant programs at the Abramson Cancer Center of the University of Pennsylvania and a leading investigator for the STORM trial.

By blocking the export process, selinexor enables tumor suppressor proteins to remain in the cell nucleus and promote apoptosis. Additionally, selinexor inhibits XPO1 from exporting the glucocorticoid receptor to which corticosteroids bind.

“By keeping the glucocorticoid receptor in the nucleus, it potentiates the effects of steroids in the cell, and since in multiple myeloma corticosteroids can induce a response by themselves, the selinexor and the dexamethasone are working synergistically, with the selinexor having its own effect through other tumor suppressor proteins that it’s keeping in the nucleus, but then also potentiating the effect of the dexamethasone,” Vogl said.

Vogl said selinexor provides a unique method for attacking cancer. “The most attractive thing about selinexor is that it has a novel mechanism of action. I don’t think there is any drug that targets the nuclear export system, and so it’s a completely new way to think about targeting cancer cells,” he said. “Its efficacy is theoretically not restricted to multiple myeloma, but could potentially have preclinical efficacy in a broad range of tumor models.”

For the STORM trial, investigators predicted that the response rate to dexamethasone as monotherapy in patients with penta-refractory MM would be 0 percent and that the response rate to any other treatment would be less than 20 percent. In this patient population, an overall response rate (ORR) of 15 percent to 20 percent or greater would be significant. “If you can get a response in at least one of five people, that’s clinically meaningful, and it would be good to have new agents with new mechanisms of action that had that efficacy,” Vogl said.

The most common adverse events (AEs) experienced with selinexor are fatigue, anorexia, nausea, and vomiting. Other AEs seen in past trials have included low blood counts, primarily thrombocytopenia, and to some extent neutropenia, anemia and hyponatremia. The STORM study has a proactive symptom management regimen to help counteract these AEs, Vogl said.

Selinexor has demonstrated positive responses in heavily pretreated patients with MM. Preliminary results were reported at the 2016 American Society of Hematology Annual Meeting for 48 quadrefractory and 31 penta-refractory patients initially enrolled in the study. One patient did not have measurable disease, so 78 patients were evaluable for efficacy. The ORR was 20.5 percent among the entire patient population, with an ORR of 20.8 percent for quad-refractory patients and 20 percent for pentarefractory patients.¹

The results marked the first report of antitumor activity in penta-refractory MM, investigators said in their abstract.¹ “I think that if we can demonstrate a robust response rate in the 20 percent to 30 percent range and show that the responses continue to look clinically meaningful, this would then place selinexor and dexamethasone as a treatment option, especially for patients who don’t have any other available treatments,” said Vogl.

Selinexor is among several novel compounds using SINE (selective inhibitor of nuclear export) technology developed by Karyopharm Therapeutics, based in Newton, Massachusetts, which is sponsoring the STORM trial.

Vogl DT, Dingli D, Cornell RF, et al. Selinexor and low dose dexamethasone (Sd) in patients with Revlimid, Pomalyst, Velcade, Kyprolis and anti-CD38 Ab refractory multiple myeloma (MM): STORM study. Blood. 2016;128(22):491. bloodjournal.org/content/128/22/491?sso-checked=true.