Real-World Multicenter Data of Venetoclax Use in Multiple Myeloma with t(11-14). Time to Consider It Again
Authors: Higué Jules , Basile Gaetan , Cazaubiel Titouan , Banos Anne , Beziat Guillaume , Gauthier Martin , Carreiro Miguel , Gadaud Noemie , Hebraud Benjamin , Granell Miguel , Bories Pierre , Récher Christian , Corre Jill , Hulin Cyrille , Perrot Aurore , Lapierre Leopoldine , Mouchel Pierre Luc 
Published: December 2024

Introduction: Multiple myeloma (MM) remains incurable despite advanced treatment protocols. Data suggest that venetoclax (VEN), a selective oral inhibitor of Bcl-2 (an anti-apoptotic protein), is effective in MM harboring the translocation t(11;14) (Matulis, Leukemia 2016). Unfortunately, recent clinical trials have shown negative results (Kumar, Lancet Oncol 2020), and VEN has not been approved in Europe for the treatment of MM with t(11;14). However, venetoclax can be used off-label. In this study, we report multicenter real-world experience using VEN as monotherapy or in combination for the treatment of patients (pts) with relapsed / refractory MM with t(11-14).

Methods: Data from 9 French hospitals of all MM with t(11-14) pts treated with at least one cycle of VEN as monotherapy or in combination since 2019 were retrospectively collected. Combination treatment generally included proteasome inhibitor (PI), carfilzomib, or anti-CD38 monoclonal antibody (anti-CD38), daratumumab. VEN was given orally at a starting dose between 400 and 800 mg/day, with a duration determined at the discretion of each physician. Ramp-up was possible, but uncommon. Carfilzomib was administrated intravenously at 56mg/m2 once or twice a week, or at 70 mg/m2 weekly according to each center, and daratumumab subcutaneously at 1800mg weekly on cycle 1-2, every 2 weeks on cycle 3-6 and monthly since cycle 7.

Results: 46 pts treated between July 2019 and July 2024 were included. Forty-one percent were treated with a combination of VEN, PI and dexamethasone (DXM), 26% with VEN, anti-CD38 and DXM, 24% with VEN +/- DXM and 9% with other combination included VEN (2 patients were treated with IP and anti-CD38 and VEN, 2 patients with pomalidomide and VEN). VEN was generally administrated at 400 mg per day continuously (74% of pts), and the median exposure to VEN was 7 months (IQR 1-12.5). The main characteristics were: majority of male (57%), median age at diagnosis of 61 years (IQR 54-67), median prior treatment lines of 2 (IQR 1-3), complete immunoglobulin secretion at start of VEN (58%). Most of patient had aggressive disease, 72% were refractory to lenalidomide and 63% were refractory to anti-CD38 at start of VEN.

With a median follow up of 11 months (IQR 4-19), the median progression free survival was 16 months, and the median overall survival was 26 months with no significant difference between VEN as monotherapy or in combination. Median time to next treatment was 17 months. 78% of pts responded, with the best responses being complete response, very good partial response, partial response, or stable disease in 13%, 39%, 15% and 11% of pts respectively. Approximatively one third (n=19) transitioned to the next line of treatment at progression, with 10 pts receiving immunotherapy targeting BCMA, including 2 successfully bridged to CAR-T cell therapy.

Eighteen pts died, 78% (n=13) due to MM progression, 11% (n=2) due to infections and 11% (n=2) due to other reason.

Toxicity was acceptable with only 20% of pts who requiring hospitalization for adverse events. We report 24% grade ≥3 infections, almost all of bacterial origin; however, only 23% of patients were on antibiotic prophylaxis and 11% on immunoglobin supplementation, while 95% and 96% were on prophylaxis for pneumocystis and HSV respectively. Hematological toxicity grade ≥3 was reported in 35% of pts, especially thrombocytopenia when VEN was combined with carfilzomib. Only one patient suffered from grade ≥3 cardiologic toxicity related to carfilzomib. Dose and/or duration of VEN were reduced in 20% of pts.

Conclusion: This study shows that VEN use in RRMM with t(11-14) is safe and effective. Despite the negativity of phase 3 registration studies, this drug with a different mode of action appears to be a viable alternative for pts with refractory MM. Further rigorous clinical trials with extensive infection prevention could carried out again in RRMM with t(11-14), unless authorization for use can eventually be granted on the basis of large real-world cohorts.