Results from the screened iSTOPMM study

Dr Sigrún Thorsteinsdóttir, a haematologist at Rigshospitalet in Copenhagen, Denmark, also holds a position as a postdoctoral researcher in the iStopMM study at the University of Iceland. The iSTOPMM study (Iceland Screens, Treats, or Prevents Multiple Myeloma) aims to investigate smoldering multiple myeloma (SMM) and monoclonal gammopathy of undetermined significance (MGUS). All Icelandic residents over the age of 40 were offered screening through serum protein electrophoresis (SPEP) and free light chain (FLC) assay.

Epidemiological data consistently demonstrate that MM and its precursor MGUS are more prevalent in men compared to women. In the iSTOPMM study, individuals with abnormal screening results were classified as MGUS cases, while those with normal screening results served as controls. The study identified 3,554 individuals with MGUS and 71,049 controls. Among those with MGUS, 54% were male, compared to 45% of the controls. Males exhibited a higher risk of MGUS and were more likely to present with clinical features indicative of more aggressive disease, such as elevated M-protein concentration, abnormal FLC ratios, and non-IgG isotypes. Furthermore, it was observed that exogenous oestrogen exposure for a duration of at least five years potentially offered a protective effect against MGUS in women.

SMM is recognised as a precursor to MM. Cases of MM that exclusively secrete FLC proteins are classified as light chain multiple myeloma (LC-MM). The entity LC-SMM was identified based on the presence of urinary monoclonal light chain excretion. However, with the availability of more sensitive FLC assays for serum, there is a need to redefine this precursor condition. Based on our population-based screening of 75,422 individuals, we propose a new definition for LC-SMM: the presence of pathological FLC values as determined by FLC assay, absence of detectable intact immunoglobulins, and bone marrow plasma cells constituting over 10%, in the absence of myeloma-defining events. Our findings underscore the limitations of traditional urine protein electrophoresis-based diagnostics, which failed to identify 28% of individuals diagnosed with LC-SMM in our cohort. Consequently, we conclude that LC-SMM is a distinct precursor of LC-MM, which can be effectively diagnosed using serum FLC testing and bone marrow sampling. This warrants further investigation into its clinical outcomes and the formulation of evidence-based management guidelines.