Selinexor plus dexamethasone shows activity for multiple myeloma
The addition of dexamethasone to selinexor improved objective response rate in heavily pretreated patients with multiple myeloma, according to a study published in Blood.
Selinexor (KPT-330, Karyopharm Therapeutics) is a first-in-class selective inhibitor of nuclear export that inhibits exportin 1, which is overexpressed in multiple myeloma.
“Treatment options are limited for patients with [multiple myeloma] whose disease has relapsed or is refractory to standard immunomodulatory drugs and proteasome inhibitors,” Christine Chen, MHPE, MD, FRCPC, of the clinical cancer research unit at Princess Margaret Cancer Centre and University of Toronto, and colleagues wrote. “[Although] new monoclonal antibodies and small molecule therapeutics have shown activity in [multiple myeloma], none are curative and nearly all patients will succumb to their disease, highlighting the need for effective agents with novel mechanisms of action.”
The analysis included patients with multiple myeloma (n = 81) or Waldenström’s macroglobulinemia (n = 3). Twenty-seven percent of patients had received previous treatment with lenalidomide (Revlimid, Celgene), bortezomib (Velcade, Takeda), carfilzomib (Kyprolis, Amgen), pomalidomide (Pomalyst, Celgene) and daratumumab (Darzalex, Janssen).
Researchers treated 25 of these patients — including three with Waldenström’s macroglobulinemia — in the dose-escalation phase of the trial, with eight or 10 3-mg/m2 to 60-mg/m2 doses per 28-day cycle.
In the dose-expansion phase, 59 patients with myeloma received 45-mg/m2 or 60-mg/m2 doses of selinexor with 20 mg dexamethasone twice weekly in 28-day cycles, or flat selinexor doses at 40 mg or 60 mg without corticosteroids in 21-day cycles.
Researchers determined a recommended phase 2 dose of 45 mg/m2 (80 mg) plus 20 mg dexamethasone administered twice-weekly, but they did not determine maximum-tolerated dose.
Median treatment duration was 45 days.
Results showed a 4% ORR and a 21% clinical benefit rate among patients treated with selinexor alone. ORR increased to 50% among patients assigned 45 mg/m2 selinexor plus 20 mg dexamethasone twice weekly.
Median time to response was 1 month (range, 1-3) and median duration of response was 5 months (range, 2-11).
Forty-six percent of all patients showed a reduction in multiple myeloma markers from baseline.
The most common grade 1 or grade 2 adverse events associated with selinexor included nausea (75%), fatigue (70%), anorexia (64%), vomiting (43%), weight loss (32%) and diarrhea (32%). Grade 3 or grade 4 adverse events included thrombocytopenia (45%), hyponatremia, (26%), anemia (23%) and neutropenia (23%).
“Given the activity of selinexor plus dexamethasone in heavily pretreated patients with [multiple myeloma], this combination is being tested in the phase 2 STORM study in quad- and pentarefractory [multiple myeloma] with preliminary reports supporting activity and tolerability,” the researchers wrote. “In addition, based on strong preclinical results, studies of selinexor in combination with standard [multiple myeloma] agents are underway.” – by Cassie Homer
Disclosures: Chen reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.