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This review summarizes MM cancer biology, emphasizing the role of tumor protein p53, and surveys current clinical and pre-clinical therapies targeting vulnerabilities in the apoptotic machinery. 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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.  \nVISKA.Bio, Cambridge, MA 02139, USA  \n* Correspondence: [iulianna@viska.bio](iulianna@viska.bio) (I.T.); [eric@viska.bio](eric@viska.bio) (E.F.)  \nAbstract  \nMultiple myeloma (MM) is the second most common hematological malignancy in the US and Europe—comprising approximately 10% of all hematologic cancer cases—and its incidence has increased over the last three decades by approximately 120% due to an aging world population. It remains an incurable cancer among diseases in modern medicine. This review outlines the relevant cancer biology of MM, with a special emphasis on the role of tumor protein p53. We provide the most up-to-date summary of the current drugs in clinical or pre-clinical trials targeting weaknesses in the MM apoptotic mechanism. In addition, we highlight the potential for new routes to strike and kill myeloma cells, possibly creating a vaccine-like effect that prevents relapse, using the principles of immunogenic cell death (ICD) .  \nKeywords: multiple myeloma; cancer; therapeutics; p53; genomics; antibody-drug conjugates; CAR T-cell therapy; immunotherapy  \n1. Introduction  \nMultiple myeloma (MM) remains an incurable cancer among diseases in modern medicine. It is defined as a malignancy of clonal plasma cells, which are antibody-secreting terminally differentiated B cells that proliferate in the bone marrow. The overwhelming number of plasma cells cause end organ destruction, particularly renal failure, as well as anemia and osteolytic bone lesions. MM is the second most common hematological malignancy in the US and Europe—comprising approximately 10% of all hematologic cancer cases—and its incidence has increased over the last three decades by approximately 120% due to an aging world population [1,2] . The disease primarily affects older adults, with a median patient age of 69 years at diagnosis, and 87% of diagnoses affect patients over 55 years of age [3] . With an aging world population, the number of individuals diagnosed with MM continues to increase.  \nBefore the 1990s, traditional chemotherapy for multiple myeloma was a temporizing measure, with the disease leading to death after approximately 3 years from diagnosis [2] . The treatment regimens for MM now involve three-to four-drug combination regimens comprising proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs), such as bortezomib, lenalidomide, and dexamethasone. The likelihood of progression-free survival is greatest when medical therapy is followed by autologous stem cell transplantation (ASCT) . High-dose therapy (HDT) was first combined with ASCT plus melphalan conditioning in the 1980s to reduce the duration and toxicity associated with severe myelosuppression. Its use in MM therapies expanded greatly in the 1990s and early 2000s. While ASCT is not curative, it has been shown to extend patient survival when compared to  \nchemotherapy alone. The DETERMINATION trial established the efficacy of ASCT for patients newly diagnosed with MM, with results showing a significantly greater period of progression-free survival (PFS; 67.5 months) after being treated with ASCT and lenalidomide, bortezomib, and dexamethasone than with chemotherapy alone (46.2 months) [4] . This study along with others, such as the IFM-2009 trial, helped establish ASCT as the standard of care for patients with MM [5] .  \nAlthough ASCT has proven effective for increasing PFS in MM, its availability and utilization remain somewhat limited in","cbCaijDL0RyhL93K","https://ap.wps.com/l/cbCaijDL0RyhL93K","pdf",1431339,17,"English","# Introduction\n## Treatment landscape and clinical context\n# Genetic Disruptions in Multiple Myeloma and Prognostic Implications","[{\"question\":\"What is multiple myeloma and why is it difficult to treat?\",\"answer\":\"Multiple myeloma is a malignancy of clonal plasma cells that proliferate in bone marrow and can cause end-organ destruction such as renal failure, anemia, and bone lesions. It remains incurable in modern medicine.\"},{\"question\":\"What role does tumor protein p53 play in this review’s framework?\",\"answer\":\"The review highlights tumor protein p53 as a central focus within MM cancer biology. It connects p53-related mechanisms to therapeutic targeting of apoptotic vulnerabilities.\"},{\"question\":\"How do newer strategies aim to prevent relapse in multiple myeloma?\",\"answer\":\"The review discusses potential new routes to strike and kill myeloma cells by leveraging immunogenic cell death principles. This approach is framed as potentially creating vaccine-like protection against relapse.\"}]","Pathways of Resistance: Modern Multiple Myeloma Therapies and Overcoming Reliance on Genomic Integrity | PDF",1790106695,43]