A Phase 2b Study of Selinexor in Combination with Pomalidomide in Patients with Pomalidomide-Refractory Multiple Myeloma
Authors: Biran Noa , Vesole David H. , Parmar Harsh , Phull Pooja , Doucette Kimberly R. , Feinman Rena , Geng Xue , Ahn Jaeil , Zenreich Joshua , Anand Palka , Ivanovski Kristin , Pace Monique , Della Pia Alexandra , DeAgresta Bianca , Biamonte Lisa , Campanaro Martha , McClendon Trina , BaboolallAracena Samanta , Aleman Adolfo , Rutanen Ella , Layton Marie , Breeze Genevieve , Chappell Aimee , Kumka Susan , Siegel David S. 
Published: December 2024

Recent advances in multiple myeloma (MM) have significantly improved patient outcomes; however, prior exposure to proteasome inhibitors, immunomodulators, and CD38 monoclonal antibodies (i.e., triple class exposed) leads to poorer outcomes. Findings from the MAMMOTH study reported an overall response rate (ORR) of 31% with median overall survival (OS) of 9.3 months in triple class exposed, refractory MM patients (Gandhi 2019), indicating an unmet need for effective therapies in this heavily pretreated population.

Selinexor is an oral, selective inhibitor of exportin 1 (XPO1), leading to malignant cell apoptosis. Studies suggest synergistic activity and safety when selinexor is combined with other MM treatments (Gao 2014; Nahils 2016). In the STORM study, selinexor plus low-dose dexamethasone (Sd) demonstrated anti-tumor activity in triple-refractory, penta-exposed (i.e., lenalidomide, pomalidomide, bortezomib, carfilzomib and daratumumab exposed) MM patients (Chari 2019).

This is an ongoing investigator-initiated, multi-center, multi-arm, phase 2 study evaluating the efficacy and safety of adding selinexor upon disease progression in relapsed/refractory MM patients currently undergoing treatment with a carfilzomib, pomalidomide, and daratumumab-based regimen. Herein, we report interim results from the pomalidomide-refractory cohort. MM patients with documented disease progression or refractory disease while on current pomalidomide-containing treatment were eligible. Key exclusion criteria were unresolved grade ≥3 toxicity with prior pomalidomide, contraindication to glucocorticoids, and BSA &lt;1.4m2.

Patients actively progressing on a pomalidomide-based regimen received selinexor 60 mg orally on days 1, 8, 15; pomalidomide 4 mg orally on days 1-21; and dexamethasone 40 mg or 20 mg if ≥75 years old on days 1, 8, 15, 22. The primary endpoint was ORR based on International Myeloma Working Group criteria (Kumar 2016).

At data cutoff (July 5, 2024), 12 patients were enrolled with the following characteristics: median age of 57 years (range 41-70), 58% male, 58% non-Hispanic White, 17% Asian, 8% non-Hispanic Black, 33% International Staging System stage III, 83% refractory to the last treatment, 100% prior autologous transplant, 8% prior allogeneic transplant, 25% extramedullary disease, 42% triple-refractory, 42% quadruple-refractory, and 8% penta-refractory. Eleven (92%) unique patients had high-risk cytogenetics, including 1q21 duplication (n=5), t(4;14) (n=5), del(17p)/monosomy 17 (n=3), TP53 mutation (n=4), and complex karyotype (n=3).

Eleven patients were evaluable for response; 1 withdrew consent before response evaluation. Median PFS was 4.9 months (95% CI, 1.1-6), and median OS was 15 months (95% CI, 7,5-NR). Median DOR was 4.03 months (IQR, 2.3-5.5) with a median treatment duration of 1.5 months (range 0-7). The ORR was 27% (3/11; PR, 3 [27%]) and CBR was 82% (9/11; PR, 3 [27%]; SD, 6 [54%]).

Nine (82%) and 8 patients (73%) experienced grade 1-2 and grade 3 TEAEs, respectively. The most common hematologic TEAEs were anemia (45%; 36% grade 1-2) neutropenia (55%; 18% grade 1-2), and thrombocytopenia (36%; 36% grade 1-2). The most common non-hematologic TEAEs were fatigue (27%; 27% grade 1-2) and cough (27%; 27% grade 1-2). The most common grade 3 TEAEs were neutropenia (55%), thrombocytopenia (27%), anemia (18%), hypophosphatemia (9%), hyperglycemia (9%), and elevated liver enzymes (9%). One patient discontinued treatment due to a TEAE of poor oral intake.

Two patients experienced non-treatment related grade 3 SAEs of pneumonia that required hospitalization and resolved with supportive care, and one experience an SAE of fall. Seven discontinued treatments due to disease progression and 3 due to withdrawal of consent. No treatment-related deaths occurred; two patients died on study due to disease progression.

Results suggest the combination of selinexor, pomalidomide, and dexamethasone is safe and may restore response in MM patients actively relapsing on a pomalidomide-based regimen. Although the ORR and median PFS were similar to that with Sd alone (Chari 2019), all patients in our study were pomalidomide-refractory and actively progressing on a pomalidomide-based regimen. This is proof-of-principle that selinexor can restore sensitivity to pomalidomide and warrants future prospective studies.Clinical trial information: NCT04661137.