Simple SummaryProteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies (triple class drugs), and autologous stem cell transplantation (ASCT) are promising myeloma treatments that have resulted in minimal residual disease (MRD) negativity and improvement in the bone marrow microenvironment. In the MASTER trial, a four-drug induction therapy, comprising triple-class drugs followed by ASCT, resulted in MRD negativity and long progression-free survival in patients with standard- and high-risk cytogenetics; however, it proved insufficient to overcome the poor outcomes in patients with ultra-high-risk chromosomal aberration (UHRCA). Hence, MRD negativity in autografts could signal positive clinical outcomes after ASCT. Additionally, high-risk myeloma cells lead to poor clinical outcomes owing to aggressive myeloma behavior as well as a poor bone marrow microenvironment. Thus, several new approaches for treating patients with MRD-positive UHRCA myeloma before and after ASCT are needed.AbstractDespite the development of anti-myeloma therapeutics, such as proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, and autologous stem cell transplantation (ASCT), multiple myeloma remains incurable. A trial treatment combining four drugs—daratumumab, carfilzomib, lenalidomide, and dexamethasone—followed by ASCT frequently results in minimal residual disease (MRD) negativity and prevents progressive disease in patients with standard- and high-risk cytogenetics; however, it is insufficient to overcome the poor outcomes in patients with ultra-high-risk chromosomal aberration (UHRCA). In fact, MRD status in autografts can predict clinical outcomes after ASCT. Therefore, the current treatment strategy might be insufficient to overcome the negative impact of UHRCA in patients with MRD positivity after the four-drug induction therapy. High-risk myeloma cells lead to poor clinical outcomes not only by aggressive myeloma behavior but also via the generation of a poor bone marrow microenvironment. Meanwhile, the immune microenvironment effectively suppresses myeloma cells with a low frequency of high-risk cytogenetic abnormalities in early-stage myeloma compared to late-stage myeloma. Therefore, early intervention might be key to improving clinical outcomes in myeloma patients. The purpose of this review is to improve clinical outcomes in patients with UHRCA by considering MRD assessment results and improvement of the microenvironment.