Selinexor compared with the current standard of care in penta-treated, triple-class refractory patients with MM

Patients with multiple myeloma (MM) who relapse or become refractory to therapeutic agents tend to have a poor prognosis—often only a few months of survival. Within this group are patients that have been treated with five lines of therapy, referred to as penta-treated. In addition, as many patients initially receive triplet and quadruplet therapies, there is a cohort of patients who become triple-class refractory (TCR). This group of penta-treated TCR patients was the focus of the study by Robert Cornell and colleagues, published in the American Journal of Hematology.¹

Selinexor inhibits exportin 1 to reduce the transportation of molecules from the nucleus along with the activation of tumor suppressors and the inhibition of translation of oncoproteins. Selinexor, in combination with dexamethasone, is a possible treatment for this group of multidrug-refractory patients with MM.

Study design

The present study analyzed patients refractory to anti-CD38 monoclonal antibodies from the MAMMOTH dataset, who resembled patients enrolled in the phase IIb trial of selinexor treatment for refractory myeloma (STORM; NCT02336815). The study aimed to generate a cohort for comparison of patients treated with the current standard of care compared with selinexor plus dexamethasone (sel+dex). The MAMMOTH dataset has been previously reported on by the Multiple Myeloma Hub, and the article can be found here.

Out of 122 patients in the STORM study, 64 were selected. From the MAMMOTH dataset, 128 of the 275 patients were chosen, and the two groups had similar characteristics in terms of age, presence of high-risk cytogenetics, and the number of prior treatments.

The patients in the MAMMOTH study were treated previously with

• pomalidomide-based therapies (36.8%)
• traditional chemotherapy (33.6%)
• daratumumab-based therapies (19.5%), and
• carfilzomib-based (18.8) therapies.

Differences between the two populations include a longer time between MM diagnosis and post-study treatment, indicating a less aggressive disease and a higher proportion refractory to carfilzomib, pomalidomide, and daratumumab.

Patients included in the STORM trial were treated with 80 mg sel and 20 mg dex twice a week (Days 1 and 3) until disease progression. Patients were monitored even after discontinuing treatment to measure overall survival (OS).

Key findings

Patients in the STORM trial had a significantly improved OS of 10.4 months compared with 6.9 months for patients in the MAMMOTH dataset (95% CI; p = 0.043).

Shorter OS was significantly associated with high-risk cytogenetics and refractoriness to carfilzomib.

Multivariate analysis showed that patients in the STORM study treated with sel+dex had a significantly reduced risk of death compared with patients in the MAMMOTH study (HR, 0.55; 95% CI, 0.36−0.86; p = 0.009).

The overall response rates in the different patient subgroups are shown in Table 1. The difference between cohorts was not significant in any of the groups analyzed.

Table 1. Overall response rates¹

While the STORM and MAMMOTH studies were comparable, some differences between the datasets may have impacted the analysis despite Cox regression adjustment. For instance, the MAMMOTH dataset permitted the inclusion of frail patients that may not have been eligible for clinical trials. On the other hand, the small number of patients included in the STORM study may also have affected the analysis and highlights the need to further investigate treatment options in this cohort of multidrug-resistant patients.

Conclusion

Patients treated with sel+dex show a significantly longer OS than those in the MAMMOTH dataset treated with the current standard of care. While these results need to be confirmed in a larger, randomized clinical trial, these results are positive and show the potential benefit of sel in the treatment of penta-treated/TCR patients with MM.

Sel is currently being investigated combined with other novel agents, i.e., bortezomib, carfilzomib, or daratumumab. You can read the preliminary results here in a recent piece on the Multiple Myeloma Hub.