Selinexor, Bortezomib, and Dexamethasone Combination Proves Effective for Myeloma

Joseph Mikhael, MD

Selinexor (Xpovio), an oral inhibitor of nuclear export, has gained an expanded role in the treatment landscape for adult patients with multiple myeloma (MM). In December 2020, the FDA approved the agent in combination with the proteasome inhibitor bortezomib (Velcade) and dexamethasone for patients with MM who have received at least 1 prior therapy.¹

The first-in-class agent initially was approved in combination with dexamethasone for refractory MM after 4 prior therapies in 2019 and later added an indication for relapsed or refractory diffuse large B-cell lymphoma.

The latest MM indication is based on findings from the phase 3 BOSTON trial (NCT03110562), in which the combination improved progression-free survival (PFS) compared with the standard regimen of bortezomib plus low-dose dexamethasone.² “The BOSTON study is the first study to assess the efficacy of once-weekly selinexor as part of a triplet therapy in patients with multiple myeloma who have had 1 to 3 prior therapies,” said Joseph Mikhael, MD, in an interview with OncologyLive®. Mikhael is a professor in the Applied Cancer Research and Drug Discovery Division of the Translational Genomics Research Institute (TGen), an affiliate of City of Hope Cancer Center in Phoenix, Arizona.

Selinexor reversibly inhibits nuclear export of tumor suppressor proteins, growth regulators, and mRNAs of oncogenic proteins by blocking exportin 1 (XPO1). XPO1 inhibition leads to the accumulation of tumor suppressor proteins, reductions in multiple oncoproteins, and apoptosis of cancer cells.3 “The combination of selinexor and dexamethasone and bortezomib demonstrates synergistic cytotoxic effects in multiple myeloma in vitro, and increased antitumor activity in murine xenograft multiple myeloma models in vivo, including those resistant to proteosome inhibitors,” Mikhael explained.

In the BOSTON study, investigators randomly assigned 402 adult patients previously treated with 1 to 3 lines of therapy to receive the selinexor, bortezomib, plus dexamethasone (SVd) regimen (n = 195) or bortezomib plus dexamethasone (Vd; n = 207).² Patients in the SVd arm received 100 mg of selinexor once weekly, 1.3 mg/m2 of bortezomib once weekly, and 20 mg of dexamethasone twice per week. In the Vd group, patients received 1.3 mg/m2 of bortezomib twice per week for the first 24 weeks and once per week thereafter and 20 mg of dexamethasone 4 times per week for the first 24 weeks and twice per week thereafter. The primary end point was PFS and the secondary end point was overall response rate (ORR). The median follow-up duration was 13.2 months for the SVd group and 16.5 months for the Vd group.^2,3

“[In] the primary end point data, we can see that the SVd group demonstrated a sustained progression-free survival advantage over the twice-weekly Vd group with a 30% reduced risk of progression or death,” Mikhael said. Specifically, the SVd regimen had a median PFS of 13.9 months (95% CI, 11.7-not reached) vs 9.5 months (95% CI, 7.6-10.8) for Vd (HR 0.70; 95% CI, 0.53-0.93; P = .0075).²

“[Further,] there was a consistent PFS benefit with SVd across multiple patient subgroups,” Mikhael added. “The risk of progression or death was noticeably lower in all subgroups including patients [aged] 65 years and older, those with high-risk cytogenetic abnormalities, and patients who received 1 prior line of therapy.”

In 241 patients aged 65 years or older, treatment with selinexor reduced the risk of progression by 45% (HR, 0.55; 95% CI, 0.37-0.83). Patients with high-risk cytogenetic abnormalities were divided into 3 subgroups. The first combined all patients (n = 192) with either deletion (del)17p, translocation (t) 4;14, t(14;16), or 1q21 microdeletions; selinexor demonstrated an HR of 0.67 (95% CI, 0.45-0.98). Patients with (del)17p derived the most benefit with a 62% reduction of risk of progression. Finally, 198 patients treated with 1 prior line of therapy had an HR of 0.63 favoring selinexor (95% CI, 0.41-0.96).²

The triplet also elicited an overall response rate of 76.4% (95% CI, 69.8%-82.2%), compared with 62.3% (95% CI, 55.3%-68.9%) for Vd (P = .0012). In the selinexor group, 10% of patients had a stringent complete response (sCR), 7% had a complete response (CR), 28% had a very good partial response (VGPR), and 32% had a partial response (PR). In the Vd arm, 6% of patients had an sCR, 4% had a CR, 22% had a VGPR, and 30% had a PR.²

“Patients in the SVd group also experienced significantly higher rates of deep responses than the Vd arm with 16.9% of patients experiencing a [CR plus sCR] and 44.6% of patients experiencing a VGPR [or better] as compared with 10.6% and 32.4% for CR [plus sCR] and VGPR [or better], respectively in the Vd group,” Mikhael said.¹

“The median time to response was shorter in patients who were given SVd, [and] The duration of response was longer in the SVd arm,” Mikhael added. The median time to response was 1.4 months in the SVd arm and 1.6 months in the Vd arm; the median duration of response was 20.3 months and 12.9 months, respectively.

In terms of safety, peripheral neuropathy of grade 2 or above was less frequent in the SVd arm at 21% of patients compared with 34% in the Vd group (OR, 0.50; 95% CI, 0.32-0.79; P = .0013). The most frequent grade 3/4 adverse events were thrombocytopenia, occurring in 39% of the SVd group and 17% of the Vd group; fatigue (13% vs 1%, respectively); anemia (16% vs 10%); and pneumonia (11% for both SVd and Vd). Additionally, 24% of patients in the SVd arm died compared with 30% of patients in the Vd arm.

Permanent discontinuation of selinexor due to an adverse reaction occurred in 19% of patients, dosage interruptions occurred in 83%, and dose reductions occurred in 64%.

“Collectively, these findings suggest that SVd provides significantly higher PFS, overall response, and duration of response than Vd. Patients also experienced deeper and faster response than those not given selinexor,” Mikhael said.

References

1. FDA approves selinexor for refractory or relapsed multiple myeloma. FDA. December 18, 2020. Accessed March 16, 2021. http://bit.ly/3vPVZ5j
2. Grosicki S, Simonova M, Spicka I, et al. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Lancet. 2020;396(10262):1563-1573. doi:10.1016/s0140-6736(20)32292-3
3. Xpovio. Prescribing information. Karyopharm Therapeutics; 2020. Accessed March 16, 2021. https:// bit.ly/3kUSxS5