REVIEW article
Front. Hematol.
Sec. Gene Therapy, Cell Therapy and Hematology
The Role of Necroptosis as a Possible Therapeutic Target in Multiple Myeloma: The Emerging Roles of Necroptosis
Provisionally accepted
- Istanbul Universitesi, Fatih, Türkiye
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Abstract Multiple myeloma (MM) is a malignant plasma cell disorder characterized by clonal proliferation within the bone marrow, systemic organ dysfunction, and inevitable relapse due to therapeutic resistance. Despite advances in proteasome inhibitors, immunomodulatory agents, monoclonal antibodies, and autologous stem cell transplantation, MM remains incurable, primarily due to the evasion of apoptosis, which remains a central driver of relapse in multiple myeloma, necessitating alternative cytotoxic strategies. Necroptosis, a caspase-independent and immunogenic form of regulated cell death (RCD) mediated by the RIPK1– RIPK3–MLKL signaling axis, has emerged as a promising alternative mechanism to circumvent apoptotic resistance. Activation of necroptosis triggers the release of damage-associated molecular patterns (DAMPs), including high-mobility group box 1 (HMGB1), ATP, and nucleic acids, which promote dendritic cell maturation, tumor antigen presentation, and the activation of cytotoxic T cells. These features position necroptosis as both a direct cytotoxic mechanism and a driver of anti-tumor immunity. However, its dysregulated activation may foster chronic inflammation, immune suppression, and tumor progression, highlighting the need for precise therapeutic control. Recent findings reveal that necroptosis-associated genes and their polymorphisms (e.g., RIPK1, RIPK3, MAPKAPK2) influence MM pathogenesis, treatment response, and survival outcomes, suggesting potential prognostic utility. Pharmacological agents, such as SMAC mimetics, proteasome inhibitors, natural compounds, and peptidomimetics, can modulate necroptotic signaling and synergize with standard regimens to overcome drug resistance. This review integrates current evidence on necroptotic pathways to harness necroptosis in a controlled, biomarker-guided manner, offering a novel therapeutic avenue to overcome apoptosis resistance, enhance immunogenicity, and improve clinical outcomes in MM.
Keywords: Multiple Myeloma, necroptosis, Regulated cell death, therapeutic resistance, tumor immunology
Received: 15 Aug 2025; Accepted: 06 Feb 2026.
Copyright: © 2026 Aydemir. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Duygu Aydemir
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