iStopMM: A Monumental Effort

Cancer screening for early disease has been successful for various cancer types and is one of the key reasons why an accurate understanding of precursor disease states can save lives. Multiple myeloma (MM) is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS),¹  and there are indications that patients with a known MGUS have a better prognosis when diagnosed first with MM.^2,3  To assess potential benefits of screening for MM precursor disease, the iStopMM (Iceland Screens Treats or Prevents Multiple Myeloma) trial was started in 2016 as a large population-based screening study in Iceland.⁴  All individuals in Iceland born before 1976 were invited to participate (N=148,708) via direct mail as well as campaigns via traditional and social media. More than 50 percent of the population (N=80,759) provided informed consent, and 93.4 percent (N=75,422) of enrolled individuals provided serum samples for the study. These samples were analyzed in a central lab (Binding Site, Birmingham, UK) for monoclonal proteins (M-proteins) and serum-free light-chain levels.⁴ 

Of the 75,422 screened individuals, 4.94 percent were found to have MGUS by current definitions.^4-7  MGUS was more common among men; 5.9 percent of patients with MGUS were men, and 4.1 percent were women. The prevalence of MGUS increased with age, and 2.3 percent, 6.2 percent, and 12.9 percent of individuals were found to have MGUS in the age groups 40 to 59 years, 60 to 79 years, and 80 to 103 years, respectively. The majority of individuals had low-risk (38%) or low-intermediate–risk (36%) MGUS, while high-intermediate risk was found in 26 percent and high-risk MGUS was 0.2 percent.^4,5  This is the first study to report prevalence of smoldering MM (SMM) based on a screened population — 0.5 percent in individuals 40 years or older.⁸ 

Individuals with MGUS in the iStopMM study were randomized to three different monitoring strategies: arm 1 consisted of no monitoring, arm 2 of standard workup and monitoring per the International Myeloma Working Group criteria,⁹  and arm 3 involved more thorough baseline work-up and monitoring. After three years of follow-up, 194 patients were diagnosed with lymphoproliferative disorders – nine patients in arm 1, 92 in arm 2, and 133 in arm 3 (p<0.001).⁴  Outcomes were obtained from the study as well as the National Cancer Registry. Most of the identified lymphoproliferative disorders were SMM and MM, but cases of smoldering Waldenstrom macroglobulinemia, non-Hodgkin lymphoma, and chronic lymphocytic leukemia were also identified. The trial also sheds light on the prognostic implications of circulating tumor plasma cells in precursor disease as predictors of progression to active disease and new proposed definitions of the renal reference range for light-chain MGUS.^10,11 

What makes this study so important? The prospective design and large population-based setting including more than 75,000 screened individuals is unique. MGUS was found to be more common than previously reported; however, most MGUS cases were low- or low-intermediate–risk in terms of progression.^5,6,12  With three years of follow-up, iStopMM has identified a higher than expected number of individuals with SMM and MM. One caveat with this study is the homogeneous population in Iceland, which consists largely of white individuals. This poses questions about the generalizability of the findings, particularly as the prevalence of MGUS differs based on population background and is more common among African Americans.¹²  The trial is still ongoing, and over the coming years, this study ought to significantly illuminate the natural history and driver mechanisms in MM precursor disease.