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Their treatment relies on risk classification as lower or higher\u2010risk categories by the original International Prognostic Scoring System (IPSS) or the current revised (IPSS\u2010R) or molecular IPSS\u2010M. Higher\u2010risk MDS (HR\u2010MDS) are clonal hematopoietic disorders characterized by significant cytopenias, dysplastic changes, and a high propensity for progression to acute myeloid leukemia (AML). Up to 40% of them usually progress to AML within two years of diagnosis. Allogeneic stem cell transplantation (HSCT) remains the only potential cure and standard of care for eligible patients. Despite standard treatments such as Allo\u2010HSCT and hypomethylating agents (HMAs), outcomes remain suboptimal. Recent advances have led to the development of novel therapeutic strategies, such as BCL\u20102 inhibitors (venetoclax), IDH1\/2 inhibitors (ivosidenib, enasidenib), CD47 inhibitors (magrolimab), TIM\u20103 inhibitors (sabatolimab), XPO1 inhibitors (eltanexor), NEDD8\u2010activating enzyme inhibitors (pevonedistat), TP53\u2010targeted agents (eprenetapopt), liposomal chemotherapy (CPX\u2010351), and oral HMA formulations. Combinations of hypomethylating agents with these new drugs, as first\u2010line treatment, have to date not proven more efficacious than HMA monotherapy. 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