How to approach the high-risk myeloma from induction through relapse?

Abstract Despite the enormous progress made in the treatment of multiple myeloma (MM) with various treatment choices in frontline and relapse settings, treatment of high-risk (HR)MM remains a therapeutic challenge. Definition of HR disease is dynamic and mainly based on cytogenetic assessment showing typical cytogenetic abnormalities. Most recently, the International Myeloma Society and the International Myeloma Working Group published a revision of HR criteria, IMS-IMWG Consensus Genomic Staging. Immediate identification of HRMM at primary diagnosis is crucial to refer the patients to optimal treatment. Emerging data, especially from clinical trials designed explicitly for HR patients, demonstrated that upfront quadruplet treatment followed by consolidation and continuous combination maintenance, including high dose melphalan and autologous stem cell transplantation for patients who qualify, is the current best approach leading to a markedly improved prognosis. The primary treatment goal is the rapid achievement of sustained minimal residual disease– negative response with treatment continuation beyond to avoid early relapses and evolvement of resistant clones. A distinct subgroup of patients, the so-called functional HR patients, are defined as relapsing between 12 and 18 months despite optimal frontline treatment. The unmet need for effective treatment options in this challenging situation is now partially mitigated by the introduction of B-cell maturation antigen-directed T-cell-engaging immunotherapies. Early data show favorable outcomes, with treatments with chimeric antigen receptor T-cells achieving durable responses.