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Low dose venetoclax as a single agent treatment of plasma cell malignancies harboring t(11;14)
Author(s) -
Nahi Hareth,
Kashif Muhammad,
Klimkowska Monika,
Karvouni Maria,
Wallblom Ann,
Gran Charlotte,
Hauenstein Julia,
Frengen Nicolai,
Gustafsson Charlotte,
Afram Gabriel,
Uttervall Katarina,
Lund Johan,
Månsson Robert,
Wagner Arnika K.,
Alici Evren
Publication year - 2021
Publication title -
american journal of hematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.456
H-Index - 105
eISSN - 1096-8652
pISSN - 0361-8609
DOI - 10.1002/ajh.26207
Subject(s) - venetoclax , medicine , multiple myeloma , oncology , mcl1 , gastroenterology , leukemia , biology , gene , biochemistry , downregulation and upregulation , chronic lymphocytic leukemia
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 AL‐amyloidosis 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.