Low dose venetoclax as a single agent treatment of plasma cell malignancies harboring t(11;14)

Abstract

Approximately 20% of newly diagnosed multiple myeloma (NDMM) patients harbor t (11;14), a marker of inferior prognosis, resulting in up-regulation of CCND1. These patients respond to BCL2 inhibitor experimental drug venetoclax. Furthermore, t(11;14) is reported to be associated with increased BCL2/MCL1 ratio. We investigated the use of venetoclax (400 mg daily) in a cohort of 25 multiple myeloma (MM) and ALamyloidosis patients harboring t(11;14) and assessed safety and efficacy. Efficacy was assessed by response rate (RR) and time on treatment. Furthermore, immunohistochemistry (IHC), for BCL2 family member expression was assessed at diagnosis and relapse in the venetoclax-treated group and analyzed for correlation with clinical RR. Additionally, patient material from venetoclax non-treated group including non-t(11;14) diagnosis (n = 27), t(11;14) diagnosis (n = 17), t(11;14) relapse (n = 7), hyperdiploidy (n = 6) and hyperdiploidy + t(11;14) (n = 6) was used for RNA sequencing (RNASeq) and validation by qPCR. Venetoclax treatment in t(11;14) patients demonstrated manageable safety and promising efficacy. Partial responses or better were observed in eleven patients (44%). Responding patients had significantly higher BCL2/MCL1 (p = 0.031) as well as BCL2/BCL-XL (p = 0.021) ratio, regardless of time of measurement before venetoclax treatment. Furthermore, an IRF5 motif was enriched (p < .001) in the downregulated genes in t(11;14) relapses vs diagnoses. The RR with single agent venetoclax was 71% in AL-amyloidosis and 33% in MM, and IHC proved useful in prediction of treatment outcome. We could also demonstrate possible resistance mechanisms of t(11;14), downregulation of IRF5 targeted genes, which can be exploited for therapeutic advantages.

How do we manage t(11;14) plasma cell disorders with venetoclax?

“…Subsequently, multiple case reports and case series demonstrated the activity of venetoclax, both in single agent and in combinations, in AL amyloidosis. 8,10,[33][34][35] Our experience with venetoclax-based combination regimens in relapsed/ refractory AL amyloidosis from a multicenter retrospective cohort study showed a haematological response rate of 81% and VGPR or better in 78% of t (11;14) patients. 36 The median PFS was not reached for t(11;14) patients and 6.7 months for non-t(11;14) patients (p < 0.01).…”

“…7 Several retrospective cohort studies also demonstrated impressive activity of venetoclax in patients harbouring t (11;14). [8][9][10] However, the initial optimism about venetoclax was tempered by data from BELLINI trial, which showed a higher mortality in the venetoclax arm despite deeper haematological responses, likely due to infection-related deaths in the non-t (11;14) cohort. 11 Currently, venetoclax continues to be used offlabel in the US in t (11;14) plasma cell disorders and is also included in the National Comprehensive Cancer Network (NCCN) guidelines.…”

“…However, the ORR was significantly higher at 40% in the t(11;14) subgroup 7 . Several retrospective cohort studies also demonstrated impressive activity of venetoclax in patients harbouring t(11;14) 8–10 . However, the initial optimism about venetoclax was tempered by data from BELLINI trial, which showed a higher mortality in the venetoclax arm despite deeper haematological responses, likely due to infection‐related deaths in the non‐t(11;14) cohort 11 .…”

Novel Approaches Outside the Setting of Immunotherapy for the Treatment of Multiple Myeloma: The Case of Melflufen, Venetoclax, and Selinexor

“…A real-world experience of 18 RRMM patients with t(11;14) at diagnosis treated with venetoclax as a single agent (starting with a dose of 100 mg daily and increasing to a maximum dose of 400 mg daily) was recently reported (44). Six patients (33%) achieved a response ≥PR; the dominant nonhematological adverse event (AE) was nausea, while the hematological AEs were neutropenia and thrombocytopenia.…”

“…An open-label, randomized, multicenter, three-arm phase 1b/ 2 study (NCT03312530) of cobimetinib (a MEK inhibitor) administered as a single agent and in combination with venetoclax +/-atezolizumab (an engineered MoAb of IgG1 isotype against protein programmed cell death-ligand 1) is currently under investigation in 49 RRMM patients who had received three to five prior therapies, including a PI and an IMiD (43). The patients are randomized 1:2:2 to cobimetinib (arm A), cobimetinib+venetoclax (arm B), or cobimetinib+venetoclax+ atezolizumab (arm C).…”