High-Risk Genetic Multiple Myeloma: From Molecular Classification to Innovative Treatment with Monoclonal Antibodies and T-Cell Redirecting Therapies

High-risk genetic multiple myeloma (HRMM) remains a major therapeutic challenge, as patients harboring adverse genetic abnormalities, such as del(17p), TP53 mutations, and biallelic del(1p32), continue to experience poor outcomes despite recent therapeutic advancements. This review explores the evolving definition and molecular features of HRMM, focusing on recent updates in risk stratification and treatment strategies. The new genetic classification proposed at the 2025 EMMA meeting offers improved prognostic accuracy and supports more effective, risk-adapted treatment planning. In transplant-eligible patients, intensified induction regimens, tandem autologous stem cell transplantation, and dual-agent maintenance have shown improved outcomes, particularly when sustained minimal residual disease negativity is achieved. Conversely, in the relapsed or refractory setting, novel agents have demonstrated encouraging activity, although their specific efficacy in HRMM is under investigation. Moreover, treatment paradigms are shifting toward earlier integration of immunotherapy, and therapeutic strategies are individualized based on refined molecular risk profiles and clone dynamics. Therefore, a correct definition of HRMM could help in significantly improving both clinical and therapeutic management of a subgroup of patients with an extremely aggressive disease.