Future Research and Unmet Needs in High-Risk Smoldering Myeloma

In an interview with Targeted Oncology, Paula Rodriguez Otero, MD, PhD, consultant and deputy professor at the University of Navarra, discusses the future of the research landscape of high-risk smoldering multiple myeloma (HR-SMM).

The future of research in HR-SMM is focused on evaluating more potent, next-generation therapeutic platforms to potentially delay or even prevent progression to active multiple myeloma (MM).This research is driven by the established understanding that preemptive treatment can delay progression and improve overall survival in patients with HR-SMM, a finding demonstrated by prior studies involving lenalidomide (Revlimid) and daratumumab (Darzalex). Key directions and unanswered questions shaping future research include:

• T-cell Regulating Therapies: Studies are now evaluating the role of platforms such as CAR T T-cell therapy and bispecific antibodies as early intervention strategies.
• Linvoseltamab Research: The ongoing phase 2 LINKER-SMM1 trial investigating linvoseltamab (Lynozyfic), a BCMA/CD3 bispecific antibody, serves as a prime example of this new research direction. The early data from this study suggest that intervening in HR-SMM, when the immune system is potentially more intact, may significantly delay or prevent progression to active disease.
• Safety Profile in Early Intervention: Researchers are closely studying the safety profiles of these potent drugs in patients with HR-SMM, noting that the safety profile of linvoseltamab, for instance, appears more favorable in this setting compared with relapsed/refractory disease.

A major unanswered question for future research is determining the long-term activity of these active drugs, such as linvoseltamab, in preventing progression to active myeloma.Key end points for future clinical trials, such as the expansion phase of the LINKER-SMM1 trial, reflect this focus on durable disease control.

• Complete Response (CR) Rate and MRD Negativity: Primary endpoints include achieving complete response and minimal residual disease (MRD) negativity (at 10⁻⁵ or 10⁻⁶ sensitivity) after 12 and 24 months of treatment. The aim is to see if these deep responses, which appear to be occurring rapidly and deepening over time, can be sustained.
• Survival and Progression Metrics: Secondary and exploratory endpoints include duration of response, sustained MRD negativity, biochemical and clinical progression-free survival (PFS), time to a myeloma-defining event, and time to initiation of first-line MM treatment, as well as overall survival.

Future research will also involve extensive correlative studies to fully understand the mechanism of action of these T-cell regulating drugs within the unique biological setting of HR-SMM. This is considered a "very unique setting of high-risk smoldering myeloma with a very active drug," according to Rodriguez Otero. The overall goal is to advance the current paradigm of early intervention by employing more powerful therapeutics to achieve deeper, more durable responses, ultimately leading to significant delays or outright prevention of progression to symptomatic multiple myeloma.