Background:

Bortezomib-Lenalidomide-dexamethasone (VRd) is a standard therapy for newly diagnosed transplant-ineligible myeloma patients (ND-TIE-MM). Selinexor, a first in class XPO-1 inhibitor, has demonstrated efficacy both as single-agent and in combinations. In order to increase the efficiency of VRd without increasing toxicity, we are investigating a backbone regimen of selinexor-dexamethasone with alternating lenalidomide and bortezomib, given as alternating triplets, in the first line setting of ND-TIE MM in a phase 2 study. Presented here are updated results of this study, as earlier presented at ASH 2024 (abstract #1988).

Methods:

This is an academic single-arm, open-label, multicenter international phase 2 study of ND-TIE-MM including 47 patients treated with selinexor combination therapy. Patients received induction with up to 16 alternating 28 day cycles of selinexor: Even numbered cycles: Selinexor 40mg QW, lenalidomide 25mg d1-21, dexamethasone 20mg d1+2, 8+9, 15+16. Odd numbered cycles: Selinexor 80mg QW, bortezomib sc 1.3mg/m2 d 1, 8 and 15 and dexamethasone 20mg d1+2, 8+9, 15+16.

After induction patients were treated with selinexor 40mg QW, lenalidomide 25mg d1-21, and dexamethasone 20mg d1, 8 and 15.

The primary endpoint is ORR, with secondary endpoints including progression free survival, overall survival, safety evaluations, and QoL measurements.

Results:

Enrollment completed in April 2024.

With a data cut-off of 06JUN2025 45 out of 47 patients reached the primary endpoint. The primary end-point will be mature for all patients at ASH 2025.

Baseline characteristics of the selinexor treated patients (N=47) were: median age of 76 years (range 67-84). ECOG PS 0, 1, 2 and 3 (due to MM) were N= 16/18/9/4, respectively. Myeloma type distribution (IgG/IgA/light chain) were N=25/13/9. ISS stage I/II/III /NA were N= 12/18/15/2. FISH analysis was performed in 43/47 patients: t(4;14) was found in 1 out of 42 evaluated patients, t(14;16) in 1 out of 40 evaluated patients and del17p in 5 out of 42 evaluated patients. Two patients had 1q+ in combination with del17p, and 1 had 1q+ in combination with t(4;14).

Median PFS of the 47 patients receiving at least one dose of selinexor was 30.6 months with a median follow-up of 15.1 months.

In the 47 patients in the selinexor arm, response data are available for 41 patients: Two died during cycle 1: one due to febrile neutropenia (patient was taken off-study and died 10 days later), and one due to intestinal ischemia (death on study). Three patients withdrew consent during C1, and one patient stopped treatment during C1 based on doctors' choice, leaving 41 patients response evaluable after at least 1 cycle of treatment.

Of the response evaluable 41 patients ORR was 98% (40/41) with >very good partial response rates of 73% (30/41), including 10 sCR/CR. Twenty-three patients remain on study on 06Jun2025.

Nine non-hematological G4 events were reported (one of each: hyperkalemia, thromboembolic event, anal hemorrhage, hypercalcemia, pneumonia, acute kidney injury, multi-organ failure, febrile neutropenia and sepsis), 99 non-hematological G3 events were reported. Those reported in ≥ 1 patient were 11 lung infections, 9 other infections (including COVID-19), 6 urinary tract infections, 5 hyponatremia, 5 cataract, 5 diarrhea, 4 atrial-fibrillation/flutter, 3 acute kidney injury, 3 osteonecrosis of the jaw, 3 thrombo-embolic-events, 2 back pain, 2 fatigue, 2 febrile neutropenia, 2 hypophosphatemia, 2 hypotension, and 2 spinal fractures.

Adverse events of special focus were reported: Anorexia 13 events (6 G1, 7 G2), fatigue 26 events (9 G1, 15 G2, 2 G3), weight loss 12 events (7 G1, 5 G2), diarrhea 22 events (10 G1, 5 G2, 6 G3) and dysgeusia 14 events (9 G1, 5 G2).

Hematological G3 and G4 adverse events were anemia 4 G3, neutropenia 20 G3, 6 G4 and thrombocytopenia 10 G3, 6 G4.

Conclusions

Selinexor-dexamethasone in alternating combination with lenalidomide and bortezomib in the ND-TIE-MM with a median age of 76 years demonstrated a median PFS of 30.6 months and a preliminary ORR of 98% in response-evaluable patients, compared to historical ORR of 87.5% in VRd (Durie et al, Lancet 2017). Non-hematological G3 adverse events were mostly infections. Follow-up is ongoing, and updated data will be presented, with the primary endpoint of all patients.

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2025
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