Selinexor Induces Responses in a Quarter of Patients with Heavily Pretreated MM

Ajai Chari, MD

A Selinexor combination regimen induced an overall response rate (ORR) of 26.2% in heavily pretreated patients with penta-refractory multiple myeloma (MM), making the oral XPO1 inhibitor the first investigational oral therapy to show activity in this patient population, according to data from part 2 of the pivotal STORM trial, presented at the 2018 ASH Annual Meeting.

Moreover, Selinexor in combination with low-dose dexamethasone demonstrated a median progression-free survival (PFS) of 3.7 months and a median overall survival (OS) of 8.6 months in patients with disease that was documented to be refractory to at least 1 proteasome inhibitor, at least 1 immunomodulating drug, daratumumab (Darzalex), a glucocorticoid, and the patient’s last line of therapy.¹

“STORM Part 2 represents the largest, most heavily pretreated population with MM in a prospective clinical trial to date,” Ajai Chari, MD, director of clinical research, Multiple Myeloma Program, Mount Sinai School of Medicine in New York City,” said during a presentation at the conference. “Patients received a median of 7 prior therapies over 6.6 years. These patients have no known available therapies with clinical benefit.”

A growing number of patients with MM have been treated with the proteasome inhibitors bortezomib (Velcade) and carfilzomib (Kyprolis); the immunomodulatory agents lenalidomide (Revlimid) and pomalidomide (Pomalyst); or the anti-CD38 monoclonal antibody daratumumab, Chari explained. “Eventually, patients develop penta-exposed MM and MM refractory to all of these 3 classes,” he added. “Their prognosis is dismal, with a median overall survival as short as 1.3 to 3.5 months, (and) there are no approved drugs with established clinical activity in triple class refractory myeloma.”

In the phase I dose-escalation study, doses of 3-60 mg/m² without dexamethasone showed limited activity; however, the combination of 45 mg/m2 of selinexor plus 20 mg of dexamethasone twice weekly was associated with an overall response rate (ORR) of 50%. Of note, these patients were not exposed to daratumumab nor was it quad-refractory. In the phase IIb study, patients were treated with 80 mg of selinexor plus 20 mg of dexamethasone twice weekly, yielding an ORR of 21% in a blend of patients with quad- and penta-refractory MM.²

At the meeting, Chari reported on the continued assessment of dosing in 123 patients with penta-exposed and triple class refractory MM who were previously treated with bortezomib, carfilzomib, pomalidomide, daratumumab, an alkylator, and glucocorticoids.

Patients received a dose of 80 mg of oral with selinexor in combination with 20 mg of dexamethasone twice weekly, on days 1 and 3, for each 28-day cycle.

Eligibility criteria were “permissive” and included a creatinine clearance (CrCl) 20 mL/min, neutrophil count 1,000/mm3, platelets 75,000/mm³ (or >50,000/mm³ if bone marrow plasma cells >50%), and a hemoglobin 8.5 g/dL.

Median age was 65 years (range, 40—86) and median time from diagnosis was 6.6 years (range, 1.1–23.4). One-third of patients had a CrCl <60 mL/min and 12% had CrCl <40 mL/min, while 53 percent had high-risk cytogenetics. The median percentage change in MM markers between screening and day 1 of the first cycle of treatment was 22%, demonstrating the rapidly progressing nature of patients’ disease, Chari said.

The median number of prior treatment regimens was 7, and 29.5% had 9 or more lines of prior therapy. “These are high-risk patients that are really sequencing through many lines of therapy in a short time,” he said. “These patients were refractory to the most active and potent and the most recent approved agents in each class. Importantly, 96% of patients were refractory to carfilzomib, pomalidomide, and daratumumab.”

Overall, 68% of patients had penta-refractory MM and 84% had a prior stem cell transplant. Daratumumab was the most recent therapy in 48% of patients, followed by a daratumumab combination regimen in 70%.

At data cutoff on August 17, 2018, 5 patients (4.1%) remain on treatment and 118 (95.9%) have discontinued treatment55.1% due to disease progression and 32.2% due to an adverse event (AE), of which 19.5% were related to selinexor plus dexamethasone as determined by the investigators.

The 26.2% ORR comprised 19.7% of patients with a very good partial response (PR) and 6.5% with ≥ very good PR, including 2 patients with stringent complete responses, with minimum residual disease (MRD) negativity at a level of 10-6 in 1 patient and 10-4 in the second patient. Notably, 2 patients who progressed after CAR T-cell therapy achieved a PR. The median time to response was 1 month (range, 1-14 weeks) and the median duration of response was 4.4 months. Of the evaluable patients, 71% experienced a reduction in the M-protein. Response rates were similar regardless of the patient’s last prior therapy.

The dire need of penta-refractory patients is highlighted by the median OS of 1.7 months in patients with progression, said Chari. The median OS improved to 5.9 months in patients who achieved stable disease and increased further to 15.6 months in those with minimal response or PR.

Frequently reported treatment-related non-hematologic AEs of any grade included nausea (69.1%), fatigue (56.1%), anorexia (52.0%), weight loss (47.2%), hyponatremia (30.9%), vomiting (35.0%), and diarrhea (33.3%). The most frequent grade 3 AEs were fatigue (18.7%), hyponatremia (16.3%), and nausea (9.8%).

Treatment-related hematologic AEs of any grade included thrombocytopenia (67.5%), anemia (48.0%), neutropenia (36.6%), leukopenia (29.3%), and lymphopenia (13.8%). Meanwhile, the rate of grade 3/4 thrombocytopenia increased as baseline platelet counts decreased.

The median duration of selinexor plus dexamethasone treatment was 9 weeks (range: 1-60+), during which 79.7% of patients required a dose modification, most of which occurred in the first 2 cycles. “Side effects were reversible without evidence of major organ toxicities nor cumulative toxicity,” said Chari.

References

1. Chari A, Vogl DT, Dimopoulos MA, et al. Results of the pivotal STORM study (Part 2) in penta-refractory multiple myeloma (MM): deep and durable responses with oral selinexor plus low dose dexamethasone in patients with penta-refractory MM. Presented at: 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego. Abstract 598.
2. Vogl DT, Dingli D, Cornell RF, et al. Selective inhibition of nuclear export with oral selinexor for treatment of relapsed or refractory multiple myeloma. J Clin Oncol. 2018;36:859-66.

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