Despite significant advancements in multiple myeloma (MM) treatment, high-risk (HR) and ultrahigh-risk (uHR) populations remain underserved, with poorer outcomes and shorter survival. Ultrahigh-risk MM, defined as MM leading to death within 24 to 36 months of diagnosis, and high-risk MM, leading to death within 36 to 60 months, are characterized by features such as multihit cytogenetic abnormalities, extramedullary disease, plasma cell leukemia, and high-risk gene expression profiles. These patients often experience early relapses and reduced efficacy of existing therapies, emphasizing the need for precise risk stratification and tailored treatment strategies. 

To improve outcomes, achieving measurable residual disease (MRD) negativity has emerged as a key prognostic factor for durable disease control in HRMM and uHRMM. Quadruplet regimens, including proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, and dexamethasone, are now considered the standard of care for patients who are transplant eligible. Novel approaches integrating BCMA-targeted therapies, CAR-T cells, and bispecific antibodies show promise for both transplant-eligible and non-eligible populations. Prospective trials focusing on MRD dynamics, genomics, and immunotherapies will be crucial in advancing treatment options and addressing the unmet needs of patients with HRMM and uHRMM.

Reference: Rees MJ, D’Agostino M, Leypoldt LB, Kumar S, Weisel KC, Gay F. Navigating High-Risk and Ultrahigh-Risk Multiple Myeloma: Challenges and Emerging Strategies. Am Soc Clin Oncol Educ Book. 2024;44(3):e433520. doi: 10.1200/EDBK_433520.