Closing the disease modification gap: Emerging therapies in myelofibrosis beyond JAK inhibition

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by dysregulated myeloid proliferation and hyperactive JAK-STAT signaling pathway. While JAK inhibitors have become standard therapies for the management of these conditions, significant challenges remain due to resistance to these medications and adverse effects such as cytopenias and infectious complications. This review explores novel therapeutic strategies that target pathways beyond JAK-STAT signaling. We discuss BET inhibitors (pelabresib), PIM kinase inhibitors (TP-3654), telomerase inhibition (imetelstat), nuclear export inhibition (selinexor), LSD1 inhibition (bomedemstat), MDM2 antagonism (navtemadlin), mutant CALR-directed immunotherapies, and activin receptor ligand traps (elritercept). Emerging data suggest that pairing JAK inhibitors with agents that target transcriptional regulation, clonal persistence, anemia, or fibrosis can demonstrate improved responses and enhance safety profiles. Strategies such as high-molecular-risk mutation profiling and variant allele frequency monitoring to assess disease progression and clonal burden will also be discussed. As the focus of MPN management shifts towards curative nontransplant options, a combination of improved access to clinical trials and accounting for patient-reported outcomes will be vital if we are to realize the promise of these next-generation therapies.