Trials of Bispecifics in Smoldering Myeloma Look Beyond Delaying Progression

High-risk smoldering multiple myeloma (HR-SMM) represents a clinically critical window of disease where patients face a median time to progression of just 2 years before developing end-organ damage. Paula Rodríguez-Otero, MD, consultant and deputy professor at the University of Navarra, Spain, discusses the changing goals of treating HR-SMM in the context of the results from the phase 2 LINKER-SMM1 study (NCT05955508) she presented.

Historically, early intervention strategies in HR-SMM relied on lower-intensity regimens aimed merely at delaying disease progression rather than eradicating the clone. However, these traditional therapies achieved low rates of complete response (CR) and minimal residual disease (MRD) negativity, leaving the underlying risk of progression intact.

As highlighted by Rodríguez-Otero, the field is undergoing a fundamental shift toward early, highly potent immunotherapeutic intervention using T-cell redirecting modalities, such as bispecific antibodies and CAR T-cell therapies. Intervening at the HR-SMM stage allows T-cell engagers to leverage a fitter, non-exhausted immune system prior to the cumulative immunosuppression seen in multi-refractory, late-line settings. Utilizing potent agents like linvoseltamab (Lynozyfic) early aims to achieve deep, sustained MRD-negative remissions, completely preventing the onset of myeloma-defining events rather than simply extending progression-free intervals.

Delivering fixed-duration bispecific therapy for HR-SMM creates a path toward functional cure. If patients maintain durable MRD negativity for 5 years off therapy, this parallel’s the IMS’s new operational criteria for curing symptomatic multiple myeloma.

This paradigm shift underlines the rationale behind the ongoing phase 3 LINKER-SMM2 trial (NCT07393282) evaluating linvoseltamab against single-agent daratumumab (Darzalex) in HR-SMM. If validated, fixed-duration bispecific T-cell redirection could establish a new standard of care, moving the oncology community closer to functional cure in early-stage plasma cell disorders.