High-Risk Multiple Myeloma in 2026: Evolving Definitions and Therapeutic Options

Résumé

Multiple myeloma (MM) is a plasma cell malignancy characterized by osteolytic bone disease, anemia, kidney disease, and hypercalcemia, resulting in significant morbidity compared to age-matched controls. Treatment has advanced considerably over the past 20 years; the current standard of care involves treatment with quadruplet regimens combining a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and dexamethasone, with a CD38 monoclonal antibody. Eligible and fit patients will proceed with autologous stem cell transplantation (ASCT), and, following initial therapy, all patients receive maintenance therapy, typically lenalidomide and a CD38 monoclonal antibody. For elderly or frail patients, regimens such as daratumumab plus lenalidomide, or lenalidomide plus bortezomib, with or without dexamethasone, may be considered, but most patients will tolerate four drug regimens well. These treatment combinations have resulted in dramatic improvements in both progression‑free survival (PFS) and overall survival (OS); the phase III PERSEUS trial reported a 2-year PFS of 84.3%. Even with the use of older triplet regimens and ASCT, real-world data document a median OS of ~10 years.

However, not all patients will achieve these outcomes. A subset of patients with MM has poorer outcomes even with state-of-the-art treatment with quadruplet regimens, which is broadly defined as high-risk multiple myeloma (HRMM). Patients with HRMM have earlier relapses, more aggressive disease biology, and shorter remissions with standard-of-care treatments. They can also be more prone to the development of aggressive presentations, such as extramedullary plasmacytomas (EMP), anaplastic morphology, and secondary plasma cell leukemia. The hallmark of all these subtypes is treatment refractoriness—defined as a lack of durable responses to standard effective treatments.

Herein, we review the definition of HRMM, outcomes with standard treatment, and preferred treatment approaches for a patient with de novo or functional HRMM in the Canadian treatment landscape.