Selinexor with Alternating Bortezomib or Lenalidomide Plus Dexamethasone in Transplant Ineligible Newly Diagnosed Multiple Myeloma Patients (SABLe), Nordic Myeloma Study Group 29/21

Background:

Bortezomib-Lenalidomide-dexamethasone (VRd) is a standard therapy for newly diagnosed transplant-ineligible myeloma patients (NDTIE-MM). Selinexor is a first in class XPO-1 inhibitor with effect both as single-agent and in combinations. In order to increase the efficiency of VRd to a four drug combination without increasing toxicity, we are investigating a regimen with a backbone regimen of selinexor-dexamethasone with alternating lenalidomide and bortezomib in the first line setting of ND-TIE MM in a phase 2 study. Presented here are initial results of this study.

Methods:

This is an academic single-arm, open-label, multicenter international phase 2 study of ND-TIE MM including 50 patients. The study was originally designed as a randomized phase 2 study, but the standard arm was closed due to recruitment problems, leaving 47 patients in the selinexor containing arm. In the selinexor containing arm, patients recieve induction with up to 16 alternating 28 day cycles of selinexor: Even numbered cycles: Selinexor 40 mg QW, lenalidomide 25mg d1-21, dexamethasone 20mg d1+2, 8+9, 15+16. Uneven 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 continue selinexor 40mg QW treatment with 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.

Baseline characteristics of the selinexor treated poatients who fulfilled at least one treatment cycle and were evaluable (N=41) were: Median age of 75 years (range 67-84). ECOG PS 0,1,2 and 3 (due to MM) were 13, 16, 8 and 4. Myeloma type distribution (IgG/IgA/LightChain) were 20/13/8. ISS stage I/II/III/NA were 12/ 14/ 13/ 2. At a median follow up of 10 cycles (range 2-35) in these 41 patients ORR was 95% (39/41) with >very good partial response rates of 68% (28/41). 29 patients remain on study in the selinexor-containing arm.

Of the 47 patient in the selinexor arm 2 died during cycle 1: One due to febrile neutropenia, one due to intestinal ischemia (heavily predisposed due to diabetes mellitus type 2). Three patients withdrew consent during C1, and 1 patient were stopped during C1 based on doctors choice, leaving 41 evaluable after at least 1 cycle of treatment.

Thirty-four patients developed 89 ≥ grade 3 non-hematological AE. Grade 4 events included: Hypercalcemia, anal hemorrhage, hyperkalemia, sepsis, thromboembolic event, febrile neutropenia (all, N=1). Grade 3 events included: Infections (N=26), diarrhea (N=6), hyponatremia (N=5), increase of creatinine / kidney failure (N=5), fracture, incl spinal cord compression (N=5), skeletal pain (N=4), thromboembolic event (N=4), osteonecrosis of the jaw, hypotension, fatigue, urticaria/ rash, atrial fib/flutter, hypophoshatemia (all N=2), confusion, hypocalcemia, hypercalcemia, hypoxia, syncope, cataract, metabolic acidosis, hyperkalemia, malaise, hypertension, hypokalemia, peripheral sensory neuropathy, nausea and anxiety (all N=1).

Conclusion: Selinexor combinations in the NDTIE-MM with a median age of 75 years shows a promising preliminary ORR of 95% and has a manageable safety profile in ND-TIE MM patient. Follow up is ongoing, and updated data will be presented.