Skip to main content
IMS Events Main banner

    Plasma Cell precursor and Other Disorders

    Category: Plasma Cell precursor and Other Disorders

    Light-Chain Smoldering Multiple Myeloma: Natural History and Risk Stratification Based on the iStopMM Definition

    (PA-356) Light-Chain Smoldering Multiple Myeloma: Natural History and Risk Stratification Based on the iStopMM Definition

    Thursday, September 18, 2025

    • Cecilie Velsoe Maeng, MD

      MD, PhD student
      Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark

    Introduction: Light-chain (LC) smoldering multiple myeloma (SMM) is a precursor condition of LC multiple myeloma. We recently proposed a new definition of LC SMM based on the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study, defined by an abnormal FLC ratio, elevated involved FLC levels, and >10% clonal bone marrow plasma cells, in the absence of detectable intact monoclonal immunoglobulins or myeloma-defining events. The aim of the current study was to identify a cohort of individuals with LC SMM in a population-based Danish cohort to describe the natural history of the condition and assess progression risk

    Methods:

    LC SMM cases were identified from the Danish Lymphoid Cancer Research (DALY-CARE) cohort as individuals with diagnosis of multiple myeloma (MM) after 2011, were alive and had not received MM-related treatment prior to or within 90 days and fulfilled the iStopMM criteria for LC SMM described above. The cumulative incidence was examined overall and by the 20/2/20 risk stratification group using Aalen-Johanson and Kaplan Meier estimation with and without death as competing risk.

    Results:

    A total of 91 individuals with LC SMM were identified and followed for a median time of 2.2 years. During follow-up, 14(15%) progressed and 36(40%) died. According to FLC analysis, 68% had kappa and 32% had lambda light chain isotype. Bone marrow assessment data was accessible for 87(96%), confirming plasma cell infiltration of 10–60% within 90 days of diagnosis. In total, 45 had available data on 24-hour urine testing. Of these, 18(40%) had a negative urine protein electrophoresis. The cumulative incidence of progression was 10%(95%CI: 6-20%) 2 years from diagnosis and 27%(95%CI: 11-39) at 5 years. When death was considered a competing risk, the cumulative incidence was 9%(95%CI: 3-15) after 2 years and 19%(95%CI: 10-29) at 5 years.

    Based on the 20/2/20 risk stratification model, 39% classified as low risk, 48% as intermediate risk, and 13% as high risk. The cumulative incidence of progression was lower (12% at 5 years) in the low-risk group compared to the intermediate or high-risk group (27% at 5 years), considering death as a competing risk, but statistical significance was not reached (Gray’s test p=0.12).

    Conclusions:

    This study provides clinical support for the iStopMM definition of LC SMM and characterizes a cohort with asymptomatic plasma cell dysplasia not covered by existing SMM subgroup definitions. Additionally, the results suggest superior diagnostic sensitivity of serum FLC analysis compared to urine M protein measurements and underscores the need for a revised LC SMM definition. The cumulative risk of progression was approximately 27% at five years, corresponding to an annual risk of 5.4%. These findings help fill a gap in the understanding of the previously uncharacterized subgroup of SMM without detectable M protein. Adoption of this new definition may support earlier identification, improved risk assessment, and more targeted clinical trial design for SMM.