P-207: Targeting iron homeostasis in combination with IMiDs as a therapeutic strategy in Multiple Myeloma

Introduction: In most cases, multiple myeloma (MM) remains an incurable disease despite the survival improvement provided by current treatments. The persisting clinical challenge resides in its high ability to resist drugs as shown by the frequent relapses observed regardless of the treatment.
Abnormal iron homeostasis is implicated in tumorigenesis and the progression of several cancers. Ironomycin is a small synthetic derivative of salinomycin that induces DNA damage and non-apoptotic cell death by sequestering iron in lysosomes. Preclinical studies in Acute Myeloid Leukemia and Diffuse Large B-Cell Lymphoma have revealed the therapeutic interest of ironomycin in treating hematological malignancies. Here, we evaluate the therapeutic interest of targeting iron homeostasis with ironomycin to target MM cells.

Methods: The prognostic value of genes related to iron metabolism in cancer was evaluated in 4 independent MM cohorts and used to build the Iron Score (IS).
Cytotoxic effect of ironomycin on primary cells from MM patients was evaluated by flow cytometry. The response of 9 HMCLs (Human Myeloma Cell Lines) to ironomycin was evaluated by Cell-Titer Glo (CTG). Three cell lines with different sensitivities were selected for further characterization.
Metabolic and transcriptional changes induced by ironomycin in 3 HMCLs were evaluated by Seahorse assay, metabolomics analysis, and RNA-seq.
The synergistic effects of the combination of ironomycin and immunomodulatory drugs (IMiDs), lenalidomide and pomalidomide, were determined by synergy matrixes using R package “SynergyFinder”.

Results: High iron score value predicts a poor outcome of MM patients in 4 independent cohorts.
Ironomycin exerts cytotoxicity on HMCLs at nanomolar concentrations. Primary plasma cells from patients are more sensitive to ironomycin than other cell types from the microenvironment. Ironomycin reduces MM cells proliferation and viability, causes DNA damage and triggers caspase-dependent apoptosis. It also affects the expression of several oncogenes and causes epigenetic dysregulation.
Ironomycin induces a metabolic shift from energetic to quiescent or glycolytic metabolism, together with an activation of the interferon response.
Ironomycin synergizes with lenalidomide and pomalidomide to kill MM cells. Drug combination downregulates several oncogenes, increases DNA damage and interferon signaling, leading to apoptosis.

Conclusions: Ironomycin causes significant cytotoxicity on MM cells mediated by DNA damage, interferon signaling activation and triggering of apoptosis.
Targeting iron homeostasis with ironomycin is a new potential anti-myeloma strategy alone and in combination with IMiDs lenalidomide and pomalidomide.