Screening for monoclonal gammopathy of undetermined significance: A population-based randomized clinical trial

Monoclonal gammopathy of undetermined significance (MGUS) is a very common precursor condition to multiple myeloma (MM), and related diseases, and can be found in approximately 4-5% of individuals over the age of 50 years. MM is always preceded by MGUS. Current risk stratification schemes, designed to predict those that will progress, are based on retrospective data and rely almost solely on serum protein markers. While they can differentiate high and low-risk patients, they cannot predict outcome for individual patients, are not integrated with one another, and have limited biological correlation. Based on retrospective data, it is recommended that individuals with MGUS are followed indefinitely; however no prospective study has ever been performed to evaluate this or identify optimal monitoring in MGUS individuals.

We recently showed that MM patients with a prior knowledge of MGUS had superior survival compared to MM patients without, which raises the question whether routine screening for MGUS in the population might improve survival. To evaluate the impact of screening for MGUS on overall survival, to provide evidence for the optimal MGUS follow-up, and to integrate biological, imaging, and germline genetic markers in evaluating individual risk of progression, we propose to invite all individuals >50 years in Iceland (N=104,000) to participate in a screening study for MGUS. This will be done by utilizing already present infrastructure for screening in Iceland and the fact that most individuals >50 years have their blood drawn for various reasons during 3 years.

We plan to perform electrophoresis and free light chain analyses in these individuals to diagnose MGUS. Individuals with MGUS will be invited to be included in a randomized clinical trial with 3 different arms to identify the optimal work-up and follow-up strategy and to build a new risk model for progression. Our large, unique, population-based study has major clinical and scientific implications.

After the first phase of the project 80,759 people, or about 54% of the target population (everyone in Iceland born 1975 or earlier) have given their informed consent. At the end of the blood sampling phase 75,423 blood samples have been collected and sent to The Binding Site in Birmingham, UK for screening by serum protein electrophoreses (SPEP) and free light chain (FLC) analysis. Those who screened positive were randomized to 3 separate arms. Arm 1, functions as the “placebo“ arm of the trial. Participants in arm 1 do not undergo any further work-up and remain in the Icelandic health care system as if they were never screened. Arm 2, the “guidelines“ arm, receives MGUS follow-up according to current guidelines by the International Myeloma Working Group. Arm 3, the “intensive” arm of the study, undergoes a more extensive work-up, including bone marrow biopsies, low dose computerized tomography (CT) of bones for all, in addition to more intensive follow-up. In participants that test positive for SMM or MM are not randomized to those arms but followed closely or treated as active MM.

At this time 3472 people with MGUS have been identified and randomized. A study clinic has been established in Reykjavík with temporary centers being put up regularly in rural areas. Participants in arm 2 and 3 have been visiting the clinic and receiving thorough information, clinical work up, including bone marrow biopsies and imaging. From these participants nearly 35.000 samples of bone marrow, blood, and urine have been collected and are stored in the study biobank. A population-based patient reported outcome questionnaire has been sent out to all individuals by email, both to those with MGUS and those without. Participation has been far higher than expected with 61% answering all 13 long questionnaires on occupation, symptoms, anxiety, depression, quality of life, and other important aspects of environment and symptomatology.

Interim analyses performed and evaluated by the independent data monitoring committee have been done biannually according to protocol. The study endpoint has not been met; however, this is not unexpected since our power calculations expect the study to take 5 years before meeting the study endpoints.