Addition of Selinexor to Bortezomib, Dexamethasone Improves Responses in Myeloma

May 29, 2020

The addition of selinexor, a selective inhibitor of nuclear export, to bortezomib and dexamethasone improved progression-free survival across all subgroups in a study of pretreated patients with multiple myeloma.

When added to bortezomib (Velcade) and dexamethasone in patients with multiple myeloma, selinexor (Xpovio), an inhibitor of XPO1-mediated nuclear export, improves progression-free survival (PFS) and overall response rate (ORR) and reduces the incidence of peripheral neuropathy.1

The findings came from BOSTON, the first Phase III study to evaluate the clinical benefit of this drug combination for relapsed/refractory multiple myeloma. Results of the global study were presented May 29 during the virtual scientific program of the American Society of Clinical Oncology (ASCO) 2020 Annual Meeting.

A first-in-class oral drug that reactivates tumor suppressor proteins, selinexor was approved in 2019 in combination with the steroid dexamethasone for heavily pretreated patients with relapsed or refractory myeloma that did not respond to at least two proteasome inhibitors, two immunomodulatory agents and an anti-CD38 monoclonal antibody. Selinexor targets the protein XPO1 (exportin 1), which is overexpressed in myeloma.  

The investigators embarked on the BOSTON study because twice-weekly administration of the subcutaneous proteasome inhibitor bortezomib as part of combination therapy is effective but can’t be used for extended periods as it sparks peripheral neuropathy in 50%-60% of patients. Previous research testing selinexor in combination with bortezomib and dexamethasone demonstrated anti-myeloma activity in patients whose cancers were sensitive to proteasome inhibition, the authors noted.

In the BOSTON study, patients received either the selinexor triplet regimen or a doublet of bortezomib and dexamethasone.

The study enrolled 402 adults with ECOG status scores of 0-2 who had previously taken 1 to 3 treatments for myeloma but had never been exposed to a selective inhibitor of nuclear export. Of those, 207 took 1.3 mg/m2 of bortezomib and 20 mg of dexamethasone twice weekly, while 195 took that combination plus 100 mg of selinexor once weekly. In the selinexor arm, researchers lowered the bortezomib dose by 40% and the dexamethasone dose by 25% at 24 weeks.

The median age of participants was 67, with 59.6% older than 65 years, and 57.1% male. Baseline characteristics were balanced across the 2 arms.

When randomized, patients were stratified by the number of prior regimens used and Revised International Staging System stage III (18.5%) vs stages I or II. If participants taking the doublet experienced progressive disease, they were allowed to cross over to either the drug triplet or, if they were intolerant to bortezomib, to selinexor plus dexamethasone. 

The primary endpoint of the study was PFS and secondary endpoints included ORR, overall survival (OS), duration of response, and peripheral neuropathy rates and outcomes.

Researchers found that the triplet significantly prolonged PFS compared with the doublet by a median 13.93 months versus 9.46 months (HR = 0.70; P = 0.0075). PFS was improved in all subgroups, including in patients with 17p deletions and those who had previously taken the immunomodulatory (IMiD) drug lenalidomide.

“As lenalidomide is often used in the frontline setting and with daratumumab, having an IMiD-free option in the relapsed setting with a novel mode of action is an important finding from the BOSTON trial,” 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 overall (76.4% vs 62.3%; P = 0.0012) and in all subgroups. Median OS was not reached in the selinexor group compared with 25 months in the doublet group (HR = 0.84; 95% CI, 0.57-12.3; P = 0.19).

Patients experienced a response sooner with the triplet than the doublet (1.1 months vs 1.4 months) and the median duration of response was longer with the selinexor combination (20.3 months vs 12.9 months). The time until next therapy was a median 16.1 months in the selinexor group compared with 10.8 months in the bortezomib/dexamethasone alone group (HR = 0.66; 95% CI, 0.50-0.86; P = 0.0012).

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

Using the European Organisation for Research and Treatment of Cancer’s questionnaire QLQ-CIPN20, the researchers found clinically important differences in motor, autonomic, and sensory scales. Peripheral neuropathy rates of grade 2 or higher were significantly lower with the selinexor combination compared with bortezomib plus dexamethasone alone (21.0% vs 34.3%; P = 0.0013).

The most frequent treatment-related adverse events of grade 3 or higher for the triplet versus the doublet was thrombocytopenia (39.5% vs 17.2%), fatigue (13.3% vs 1.0%), and nausea (7.7% vs 0%). The discontinuation rate due to adverse events was 17% in the triplet arm and 11% in the doublet arm.

Dimopoulos concluded that the selinexor regimen is effective, convenient, and IMiD-free, requiring approximately 40% fewer clinic visits while conferring a reduced rate of peripheral neuropathy.

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

Reference:

Dimopoulos MA, Delimpasi S, Simonova M, et al. Weekly selinexor, bortezomib and dexamethasone versus twice weekly bortezomib and dexamethasone in patients with multiple myeloma after 1-3 prior therapies: initial results of the phase III BOSTON study. Presented at: 2020 ASCO Virtual Scientific Program; May 29, 2020. Abstract 8501.