Abstract
Therapy resistance remains a major challenge in the management of multiple myeloma (MM). We evaluated the expression of FLT3 tyrosine kinase receptor (FLT3, CD135) in myeloma cells as a possible clonal driver. FLT3 expression was analyzed in bone marrow biopsies of patients with monoclonal gammopathy of undetermined significance or smoldering myeloma (MGUS, SMM), newly diagnosed MM (NDMM), and relapsed/refractory MM (RRMM) by immunohistochemistry (IHC). FLT3 gene expression was analyzed by RNA sequencing (RNAseq) and real-time PCR (rt-PCR). Anti-myeloma activity of FLT3 inhibitors (midostaurin, gilteritinib) was tested in vitro on MM cell lines and primary MM cells by 3H-tymidine incorporation assays or flow cytometry. Semi-quantitative expression analysis applying a staining score (FLT3 expression IHC-score, FES, range 1–6) revealed that a high FES (>3) was associated with a significantly shorter progression-free survival (PFS) in NDMM and RRMM patients (p = 0.04). RNAseq and real-time PCR confirmed the expression of FLT3 in CD138-purified MM samples. The functional relevance of FLT3 expression was corroborated by demonstrating the in vitro anti-myeloma activity of FLT3 inhibitors on FLT3-positive MM cell lines and primary MM cells. FLT3 inhibitors might offer a new targeted therapy approach in a subgroup of MM patients displaying aberrant FLT3 signaling.
Highlights
The therapy spectrum for multiple myeloma (MM) has considerably broadened over the past decade, which has led to an improved overall survival (OS), in patients up to 80 years of age [1,2,3]
FMS-like tyrosine kinase 3 (FLT3) Protein Is Expressed in Bone Marrow Samples of monoclonal gammopathy of undetermined undetermined significance (MGUS), newly diagnosed MM (NDMM), and refractory MM (RRMM) Patients
FLT3 is expressed in bone marrow biopsies of all groups of MGUS/MM
Summary
The therapy spectrum for multiple myeloma (MM) has considerably broadened over the past decade, which has led to an improved overall survival (OS), in patients up to 80 years of age [1,2,3]. The shift from a disease defined by symptoms to a disease defined by biomarkers enables diagnosis and treatment of MM prior to the occurrence of end-organ damage [4,5,6]. In order to provide patients with personalized therapy regimens, it is an unmet medical need to find additional biomarkers for improved patient stratification and prediction of therapy response as well as new druggable targets for therapeutic intervention [9,10]
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