Oral selinexor/pomalidomide/dexamethasone shows activity in heavily pre-treated multiple myeloma

Dr Christine Chen (Princess Margaret Cancer Centre, University of Toronto, Canada) presented the results of 51 heavily pre-treated multiple myeloma (MM) patients in an open-label, dose escalation (phase 1) and expansion (phase 2) study evaluating selinexor in combination with pomalidomide and low-dose dexamethasone. Although the numbers were small, the investigators observed a manageable safety profile of this triple oral combination, a robust overall response rate, and determined a dose and scheduling regimen for the phase 2 follow-up of this study [1].

Selinexor is an oral selective XPO1 inhibitor. XPO (exportin-1, the major nuclear exporter for tumour suppressor proteins, the glucocorticoid receptor, and elF4E-bound oncoprotein mRNAs such as c-Myc, Bcl, MDM2, and cyclins) is overexpressed in MM. In vitro and in vivo data demonstrate that selinexor reactivates tumour suppressor pathways and glucocorticoid receptor signalling in MM models that were resistant to other therapies [2]. The study presented by Dr Chen is a sub-study of the larger phase 2 Selinexor and Backbone Treatments of Multiple Myeloma Patients (STOMP study), which exclusively analysed the 51 patients treated with selinexor in combination with pomalidomide and dexamethasone (SPd) [3]. The rationale of this study was that additional oral combination strategies are needed to improve outcomes in MM.

The primary endpoint for the SPd sub-study was the maximum-tolerated dose and recommended phase 2 dose. The secondary endpoint was objective response rate and duration of response for each arm independently. The key inclusion/exclusion criteria for the SPd arm were based on the fact that both selinexor and pomalidomide can be myelosuppressive; haemoglobin had to be ≥8.0 g/dL and platelet count had to be ≥75,000/mm³. The patients had to have had ≥2 cycles of lenalidomide and a proteasome inhibitor previously, which allowed the investigators to use the MM-003 study data with pomalidomide/dexamethasone as a historical comparator arm [4]. These were heavily pre-treated patients; the median time from diagnosis to SPd treatment was 4.8 years (1-23), and patients had been given a median of 4 prior lines of therapy (1-13).

Dose levels and scheduling were tested with either selinexor once or twice weekly schedules, together with a total weekly dose of 40 mg dexamethasone. Pomalidomide was taken 2-4 mg per day. Because nausea and gastrointestinal (GI) problems were to be expected, aggressive prophylactic antiemetic therapy was encouraged as supportive therapy. Two potentially toxicity-related deaths after the first cycle lead to the cessation of the twice-weekly selinexor schedule.

Of the pomalidomide-naïve patients (n=32), 56% had an objective response rate and 78% demonstrated clinical benefit. Surprisingly, re-challenge in pomalidomide-refractory patients (n=14) provided a 36% objective response rate and a 64% clinical benefit.

About half the patients on selinexor once weekly plus pomalidomide and dexamethasone developed grade 3-4 neutropenia, and an additional quarter of those patients developed thrombocytopenia. Aggressive prophylactic antiemetic treatment ensured that GI toxicities were minor. Hyponatraemia was noted but was not clinically significant.

Median progression-free survival among all evaluable patients was 10.4 months. In the pomalidomide-naïve patients, the median progression-free survival was even higher, at 12.2 months (vs 4 months from the MM-003 trial).

All doses had similar toxicity profiles, but cytopenias were somewhat reduced with the lower selinexor dose of 60 mg and higher pomalidomide dose (4 mg once daily), which formed the basis of the recommended phase 2 dose decision.

In conclusion, once-weekly selinexor can be safely combined with pomalidomide and low-dose dexamethasone in patients with heavily pre-treated MM. The recommended phase 2 dose for SPd is selinexor 60 mg once weekly, combined with pomalidomide 4 mg once daily + dexamethasone 40 mg once weekly. The most common adverse events were nausea, anorexia, fatigue, neutropenia, anaemia, and thrombocytopenia, all of which are thought to be manageable with appropriate supportive care and/or dose modification.

1. Chen CI, et al. Abstract 141, ASH 2019, 7-10 December, Orlando, USA.
2. Muz B, et al. Transl Oncol. 2017 Aug;10(4):632-640.
3. Chari A, et al. N Engl J Med. 2019 381:727-38.
4. San Miguel J. Lancet Oncol 2013 14: 1055-66.

Posted on 5 March 202030 March 2021