Refining High-Risk Multiple Myeloma: Advancements in Genomic, Clinical, and Prognostic Criteria

Multiple myeloma (MM) is a heterogeneous disease, with MM patients experiencing different clinical outcomes depending on the disease's biological features. Novel insights into the molecular mechanisms of MM have led to the introduction of sophisticated drugs, which dramatically improved patient treatment and survival. To date, young patients with newly diagnosed MM could experience a median overall survival (OS) of 10 years. Nevertheless, a small proportion of patients still undergoes early disease progression and death. Indeed, cases defined as ultra-high-risk MM (uHRMM) and high-risk MM (HRMM) are destined for a worse outcome, with an OS of 2-3 and 3-5 years, respectively. In this regard, current risk stratification systems failed to identify this subset of patients better. The application of existing risk models has led to the identification of extremely heterogeneous categories of patients, and they have not taken into account biological and clinical differences. The concept of HRMM was initially formalised in 2015. Since then, a great effort has been made to identify those parameters whose presence pone MM patients at higher risk of developing an early relapse. The simultaneous presence of 2 or more unfavourable cytogenetic abnormalities, the identification of an extramedullary disease or the detection of circulating plasma cells, as well as high-risk gene expression profiling (GEP) signature, have shown to be well related to a worse outcome and are going to be incorporated into new prognostic systems. The introduction of the Individualised Risk Model for Multiple Myeloma (IRMMa) marks a significant advancement in the management of HRMM by integrating genomic and clinical data to tailor treatment strategies. This model demonstrates improved prognostic accuracy compared to traditional staging systems and emphasises the importance of personalised treatment approaches. The implementation of these advanced tools is essential for enhancing precision medicine in MM and improving outcomes for patients in high-risk categories.