Selinexor Combination Regimens Added to NCCN Guidelines for Multiple Myeloma

The National Comprehensive Cancer Network (NCCN) has added 3 selinexor (Xpovio) combination regimens to its Clinical Practice Guidelines in Oncology for previously treated patients with multiple myeloma.¹

The combinations that have been added include: once-weekly selinexor/bortezomib (Velcade)/dexamethasone, selinexor/daratumumab (Darzalex)/dexamethasone; and the all-oral triplet of selinexor/pomalidomide (Pomalyst)/dexamethasone.

The once-weekly regimen of selinexor, bortezomib, and dexamethasone received a Category 1 recommendation.

"We are honored to have Xpovio receive this important recognition through its addition to the NCCN Guidelines," said Michael G. Kauffman, MD, PhD, chief executive officer of Karyopharm, the manufacturer of selinexor. "The NCCN Guidelines are utilized by healthcare providers across the country to inform optimal treatment decision making. The inclusion of three different Xpovio combination regimens into these guidelines further validates the importance Xpovio may have in the future multiple myeloma treatment landscape."

Recently in December 2020, the FDA approved selinexor in combination with bortezomib and dexamethasone for the treatment of patients with myeloma who have received at least 1 prior therapy, based on findings from the phase 3 BOSTON trial.²

Updated data from the trial were recently published in Lancet Oncology, which showed that the median progression-free survival (PFS) with the selinexor triplet was 13.93 months compared with 9.46 months for bortezomib/dexamethasone alone, leading to a 30% reduction in the risk of disease progression or death (HR, 0.70; P = .0075).³ The PFS benefit was consistent across all prespecified subgroups, including age, high-risk cytogenetics, frailty, prior proteasome inhibitor treatment, prior lenalidomide (Revlimid), and number of prior lines of treatment.

In the international, open-label, controlled phase 3 BOSTON trial, investigators randomized patients with multiple myeloma who had received 1 to 3 previous therapies to receive selinexor plus bortezomib/dexamethasone or bortezomib/dexamethasone alone.

To be eligible for enrollment, patients must have had progressive measurable multiple myeloma per International Myeloma Working Group criteria, had to have received 1 to 3 prior lines of therapy, an ECOG performance status of 0 to 2, and acceptable hepatic and hematopoietic function. Those with moderate or severe renal impairment were permitted, but patients who required dialysis were excluded.

Selinexor was administered at 100 mg on days 1, 8, 15, 22, and 29, while bortezomib was given subcutaneously at 1.3 mg/m2 on days 1, 8, 15, and 22, and dexamethasone orally at 20 mg on days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30.

Additional data showed that the median time to next therapy in the investigative arm was 16.1 months vs 10.8 months in the control arm (HR, 0.66; 95% CI, 0.50-0.86; P = .0012). At a median follow-up of 17.5 months, the median overall survival had not yet been reached with the selinexor regimen vs 25 months with bortezomib/dexamethasone alone (HR, 0.84; 95% CI, 0.57-1.23; P = .1852).

The selinexor regimen was also associated with a higher overall response rate (ORR) in the overall population and across patient subsets. The ORR in the total study population was 76.4% with the selinexor triplet vs 62.3% with the doublet (P = .0012). The median time to response was 1.1 months with the triplet vs 1.4 months with the doublet, and the median duration of response was 20.3 months vs 12.9 months, respectively.

In those who received 1 prior line of treatment, the triplet elicited an ORR of 80.8% vs 65.7% in those who received the doublet (P = .0082); these rates were 77.6% vs 59.3% (P = .0005), respectively, in those who received prior bortezomib and 67.5% vs 53.2% (P = .035), respectively, in those who had previously received lenalidomide.

Regarding safety, 32.3% of patients in the selinexor arm experienced peripheral neuropathy vs 47.1% of those in the control arm (P = .0010). This was the most common toxicity to result in treatment discontinuation; 5% of patients on the triplet discontinued due to this adverse effect vs 7% of those on the doublet.

A subgroup analysis of the BOSTON trial was presented during the 2020 ASH Annual Meeting and Exposition. Findings showed that the once-weekly regimen vs bortezomib/dexamethasone alone led to an increased ORR (77.3% vs 55.8%, respectively; P = .0008) and median PFS (12.9 months vs 8.1 months; HR, 0.67; 95% CI, 0.45-0.98; P = .0192) despite a dosing schedule that utilized 40% less bortezomib and 25% less dexamethasone during the first 24 weeks of treatment in patients with high cytogenetic risk disease.⁴

In the standard-risk group, the median PFS was 16.6 vs 9.7 months with the selinexor triplet vs bortezomib/dexamethasone alone (HR, 0.63; 95% CI, 0.42-0.95; P = .0131). 

Data from an additional selinexor combination were presented during the 2020 ASH Annual Meeting and Exposition. In heavily pretreated patients with multiple myeloma who received the recommended phase 2 dose of selinexor plus pomalidomide/low-dose dexamethasone, the ORR was 60.0% and most patients achieved a deep response.⁵ The median PFS in those receiving the RP2D was not reached at the time of data reporting and was over 1 year in all patients treated with selinexor plus pomalidomide/dexamethasone.

In July 2019, the FDA granted an accelerated approval to selinexor for use in combination with dexamethasone for the treatment of adult patients with relapsed/refractory multiple myeloma who have received 4 or more prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and a CD38-targeted monoclonal antibody.

References

1. Karyopharm announces National Comprehensive Cancer Network adds three Xpovio (selinexor) treatment regimens to its Clinical Practice Guidelines in Oncology for multiple myeloma. Karyopharm Therapeutics Inc. News release. December 11, 2020. Accessed December 20, 2020. https://bit.ly/38jrry5.
2. Karyopharm announces FDA approval of Xpovio (selinexor) as a treatment for patients with multiple myeloma after at least one prior therapy. News release. Karyopharm Therapeutics, Inc. December 18, 2020. Accessed December 18, 2020. http://bit.ly/37weIcb.
3. 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
4. Richard, S. Once weekly selinexor, bortezomib, and dexamethasone (SVd) versus twice weekly bortezomib and dexamethasone (Vd) in relapsed or refractory multiple myeloma: high risk cytogenetic planned subgroup analyses from the phase 3 BOSTON study. Presented at: 2020 ASH Annual Meeting and Exposition; December 4-8, 2020; virtual. Abstract 1385.
5. Chen CI, Bahlis N, Gasparetto C, et al. Selinexor in combination with pomalidomide and dexamethasone (SPd) for treatment of patients with relapsed refractory multiple myeloma (RRMM). Presented at: 2020 ASH Annual Meeting; December 4-8, 2020; virtual. Abstract 726.