Adding Xpovio to Standard Drugs for Multiple Myeloma Delays Disease Progression and Reduces Neuropathy

Adding a first-of-its kind drug to a regimen for advanced multiple myeloma delayed the time until disease progression and reduced the rate of peripheral neuropathy, a side effect that causes numbness and tingling in the extremities.

Xpovio (selinexor) is an inhibitor of nuclear export that disables the activity of the protein XPO1 in myeloma cells; this reactivates tumor-suppressor proteins that are naturally made in the body to help fight cancer. In the BOSTON study, Xpovio improved outcomes when it was added to a pairing of two drugs commonly used to treat myeloma: the proteasome inhibitor Velcade (bortezomib) and the steroid dexamethasone.

The global phase 3 study was the first to evaluate the benefit of this drug combination in patients with multiple myeloma that is refractory (has progressed on previous therapy) or relapsed (has recurred). Results were presented May 29 during the virtual scientific program of the American Society of Clinical Oncology (ASCO) 2020 Annual Meeting.

Xpovio is already approved for a related use. It got the green light in 2019, in combination with dexamethasone, as therapy for heavily pretreated patients with relapsed or refractory myeloma that did not respond to several other types of medications.

Multiple myeloma is a cancer that forms in white blood cells, which then accumulate in the bone marrow, producing abnormal proteins and crowding out healthy cells.

Researchers embarked on the BOSTON study because, while Velcade is effective as part of combination therapy, it can’t be used for extended periods as it sparks peripheral neuropathy in 50%-60% of patients. In addition, previous research testing Xpovio in combination with Velcade and dexamethasone demonstrated anti-myeloma activity in certain patients, the authors noted.

In the BOSTON study, patients received Velcade and dexamethasone with or without Xpovio.

The study enrolled 402 adults who were in fairly good health besides their cancer and had previously taken between one and three treatments for myeloma, not including a selective inhibitor of nuclear export. Of the participants, 207 took Velcade and dexamethasone twice weekly, while 195 took that combination plus Xpovio once weekly. In the Xpovio group, researchers lowered the Velcade dose by 40% and the dexamethasone dose by 25% after 24 weeks of treatment.

The median age of participants was 67, with 59.6% older than 65 years and 57.1% male.

The primary goal of the study was to measure progression-free survival (PFS), meaning the length of time until disease progression, and secondary measures included overall response rate (ORR; the proportion of patients who had a partial or complete response to therapy), overall survival (OS; the length of life from the start of treatment), duration of response and peripheral neuropathy rates and outcomes.

If participants taking the Velcade/dexamethasone doublet experienced progressive disease, they were allowed to switch to either the drug triplet or, if they were intolerant to Velcade, to Xpovio plus dexamethasone.

Researchers found that the drug triplet significantly prolonged PFS compared with the doublet by a median 13.93 months versus 9.46 months, respectively. PFS was improved in all subgroups of the study population that were evaluated by researchers, including patients with 17p deletions (a portion of chromosome 17 missing) and those who previously took the immunomodulatory drug Revlimid (lenalidomide).

Because Revlimid is often given as part of initial therapy for myeloma, having a new option to treat relapsed disease that works differently within the body, such as Xpovio, is helpful, said the study’s lead author, Meletios A. Dimopoulos, of the National and Kapodistrian University of Athens School of Medicine in Greece.

The triplet was associated with a significantly higher ORR than the doublet overall (76.4% vs 62.3%) and in all subgroups. Median OS had not yet been reached in the Xpovio group and was 25 months in the doublet group.

Patients experienced a response sooner with the triplet than with the doublet (1.1 months versus 1.4 months) and the median duration of response was longer with the Xpovio combination (20.3 months vs 12.9 months). The time until a next therapy was needed was a median 16.1 months in the Xpovio group compared with 10.8 months in the Velcade/dexamethasone-alone group.

More patients in the doublet arm than in the triplet arm discontinued treatment due to disease progression (52% versus 34%). Of the patients in the Xpovio and doublet groups, respectively, a total of 47 versus 62 of the patients died during the study’s follow-up period.

Using a validated questionnaire, the researchers found clinically important differences in motor, autonomic and sensory scales. Peripheral neuropathy rates of grade 2 (moderate) or higher were significantly lower with the Xpovio combination compared with Velcade/dexamethasone alone (21.0% versus 34.3%).

The most frequent treatment-related side effects that were serious or severe with the triplet versus the doublet were a deficiency of platelets in the blood (39.5% vs 17.2%), fatigue (13.3% vs 1%) and nausea (7.7% vs 0%). The rate of treatment discontinuation due to side effects was 17% in the triplet group and 11% in the doublet group.

Dimopoulos concluded that the Xpovio regimen, in addition to being effective, convenient and having a novel mechanism of action, requires approximately 40% fewer clinic visits and causes less peripheral neuropathy.

“Overall, this data indicates that the once-weekly regimen of (Xpovio) plus (Velcade) and dexamethasone could be a new standard of care and a most convenient triplet therapy … in patients with multiple myeloma,” he said.