The definition and management of high-risk multiple myeloma (HRMM) continue to evolve as advances in genomics, measurable residual disease (MRD) assessment, and immune-based therapies reshape treatment strategies. Several presentations at the recent 2026 ASCO Annual Meeting covered frontline therapy, maintenance treatment, and the role of BCMA-directed therapies in the treatment of HRMM.

Following these presentations, featured expert Kenneth C. Anderson, MD, was interviewed by Conference Reporter Medical Director Lauren Weinand, MD. Clinical perspectives from Dr Anderson on these findings are presented here.

MM treatment has undergone a revolution in recent decades. High-dose therapy and autologous stem cell transplant transformed outcomes in the 1980s and 1990s, followed by the targeted therapies of proteasome inhibitors (PIs), immunomodulatory drugs, and monoclonal antibodies (mAbs) beginning around 2000. Since 2020, the field has entered an immunotherapy revolution. These advances have not only improved outcomes but also led to a redefinition of HRMM.

At ASCO 2026, an education session presentation on HRMM by Gareth Morgan, MD, PhD, provided an evolutionary perspective on disease progression, from monoclonal gammopathy of undetermined significance to smoldering MM to, ultimately, active MM. As the disease progresses from newly diagnosed to relapsed/refractory stages, the biology changes substantially. Early disease is characterized by lower proliferation and dependence on the bone marrow microenvironment, whereas advanced disease is often marked by high proliferation, extramedullary involvement, plasma cell leukemia, and treatment refractoriness. Approximately 20% of patients present with high-risk disease at diagnosis, but, as they progress to relapsed/refractory disease, that number increases to most patients.

Methods for characterizing HRMM include not only fluorescence in situ hybridization but also genomic panels that can identify mutations while also providing insights into functional risk and treatment response. The International Myeloma Working Group (IMWG) and the International Myeloma Society (IMS) redefined HRMM by the presence of at least 1 of the following abnormalities: a chromosome 17 deletion (with a >20% clonal fraction) and/or TP53 mutation; an IgH translocation (ie, t[4;14], t[14;16], or t[14;20]), along with chromosome 1 abnormalities (ie, 1q+ and/or del[1p32]); the monoallelic deletion of the short arm of chromosome 1 (ie, del[1p32]), along with another chromosome 1 abnormality (ie, biallelic del[1p32] or 1q+); or elevated levels of β2 microglobulin (ie, >5.5 mg/L) in the setting of a normal creatinine level.

Next, Sagar Lonial, MD, FACP, FASCO, gave a wonderful talk at this year’s ASCO meeting on HRMM in the setting of recent therapeutic advances. He emphasized the importance of improving induction treatment for newly diagnosed patients, consolidation therapy, and maintenance therapy, and using MRD in this context. Quadruplet regimens with the addition of a CD38-targeted mAb to standard induction therapy (ie, a PI, lenalidomide, and dexamethasone) have significantly improved outcomes for patients with high-risk disease.

Dr Lonial also highlighted the continued importance of high-dose therapy and autologous stem cell transplant as consolidation strategies and dual maintenance therapy (eg, lenalidomide plus daratumumab or a PI), especially in HRMM. Although data from the MASTER trial suggested that maintenance therapy may be discontinued in someone who has sustained MRD negativity and 1 or 0 cytogenetic abnormalities, this approach should not be applied to patients with HRMM, even in the setting of sustained MRD negativity.

Another speaker at ASCO 2026, Jesus San-Miguel, MD, PhD, discussed whether current immunotherapies can overcome the adverse features of HRMM, particularly in patients with extramedullary disease, advanced International Staging System (ISS) disease, high bone marrow plasma cell burden, and functional high-risk disease characterized by relapse within 12 to 18 months despite therapy. Dr San-Miguel reinforced the importance of frontline quadruplet regimens and emphasized several overarching goals for HRMM management: to eradicate all detectable disease, achieve MRD negativity, intervene early at first signs of relapse, and incorporate novel immunotherapies as early as possible. BCMA CAR T-cell therapy, bispecific TCEs, and ADCs are typically used first in the multiply relapsed disease setting, but these very active agents should be used earlier, especially in high-risk disease.

Indeed, 2 clinical trials, MajesTEC-3 and MajesTEC-9, demonstrated that BCMA-directed immunotherapies, either in combination with daratumumab or as a monotherapy, can achieve deeper and more durable responses compared with conventional regimens, including in patients with HRMM. The results from these studies provide a hint that these new agents can, to some extent, overcome high-risk features, but it is important to try to achieve sustained MRD negativity and continue maintenance, especially in the context of high-risk disease.

In a poster session at ASCO 2026, Stefan Longobardi, MD, presented the results of a study on the prognostic value of genomic and clinical high-risk features on outcomes after BCMA-directed bsAb therapy in patients with extramedullary disease, plasma cell leukemia, or focal lesions (abstract 7534). Here, the outcomes with bsAb therapy were inferior in this patient population. Most of the adverse outcomes reported in this study were also attributable to genomic high-risk features.

Overall, it is exciting that immunotherapies are achieving high rates and extent of response even in HRMM, but the durability of responses still suggests that HRMM represents an unmet medical need.