Periodic Reporting for period 4 - MGUS screening RCT (Screening for monoclonal gammopathy of undetermined significance: A population-based randomized clinical trial)
Okres sprawozdawczy: 2021-08-01 do 2022-01-31
Multiple myeloma (MM) is an incurable and debilitating cancer of cells of the immune system located in the bone marrow called plasma cells. MM develops over years from a precursor condition, monoclonal gammopathy of undetermined significance (MGUS) at a rate of 1-2% per year. MGUS is common in the general population, with 4-5% of individuals over 50 years old. Current guidelines recommend indefinite follow-up of individuals with MGUS but there are no prospective studies to guide this follow-up. Recently there have been indications that treating MM at a precursor state, at the more advanced state of smoldering MM (SMM), improves outcomes, including overall survival. Individuals with previous knowledge of MGUS, i.e. were under surveillance for MM, had a superior survival when diagnosed with MM. These findings indicate that early treatment in MM leads to better outcomes in this deadly and debilitating disease. However, MGUS and SMM are asymptomatic and are currently always diagnosed incidentally during work-up for other medical problems limiting the availability of early treatment in MM. This project aims to close this gap of detection by population wide screening for MM and its precursors and performing a randomized trial, including early treatment, to evaluate the potential benefits and harms of screening. Importantly, this includes assessing the psychological effects of MGUS diagnosis (quality of life, anxiety, psychological trauma) and developing optimal follow-up strategies. Furthermore, since most individuals with precursors of MM do not progress and will remain asymptomatic, this includes integrating clinical, biological, imaging, and germline genetic markers to create a comprehensive risk assessment tool to evaluate individual risk of progression from precursor to active disease. Additionally, data from the study will be cross linked to accurate and complete government registries on cancers, prescription medications, and causes of death as well as all medical records in Iceland, including laboratory testing. This data provides unprecedented completeness of relevant medical data. Furthermore, blood, bone marrow, and urine samples provided regularly will be stored in a biobank for future studies.
By early detection and early treatment of MM at a precursor state, we believe MM can move from an incurable and debilitating disease, to a manageable, if not curable, disorder. In addition to this paradigm shift in MM management the study will also provide evidence for optimal diagnostics and follow-up in MGUS, as well as improved risk stratification. Also, by including extensive epidemiologic and biologic data and by collecting samples into a large biobank, the study will be able to greatly improve our understanding of the biology underlying MM development. Furthermore, by conducting a population-based screening study including a focus on the psychological effects of cancer screening, the project will also impact screening programs for other cancers and may create a new „gold-standard“ for conducting cancer screening trials.
By early detection and early treatment of MM at a precursor state, we believe MM can move from an incurable and debilitating disease, to a manageable, if not curable, disorder. In addition to this paradigm shift in MM management the study will also provide evidence for optimal diagnostics and follow-up in MGUS, as well as improved risk stratification. Also, by including extensive epidemiologic and biologic data and by collecting samples into a large biobank, the study will be able to greatly improve our understanding of the biology underlying MM development. Furthermore, by conducting a population-based screening study including a focus on the psychological effects of cancer screening, the project will also impact screening programs for other cancers and may create a new „gold-standard“ for conducting cancer screening trials.
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.
A treatment trial has been initiated (clincialtrial.gov no NCT03815279) that will include 80 patients with SMM and MM, that will get 2 years of treatment.
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.
A treatment trial has been initiated (clincialtrial.gov no NCT03815279) that will include 80 patients with SMM and MM, that will get 2 years of treatment.
The recruitment phase of the project is now over and has been very successful. By community engagement through social media, mainstream media outlets, and a nation-wide promotional campaign to health care professionals in addition to close collaboration to patient organizations, an unprecedented 54% of the Icelandic population over the age of 40, provided informed consent. Furthermore, > 75,000 have provided a blood sample through a novel passive form of screening with samples being collected by clinical laboratories, including blood banks, all around the nation in parallel to other clinical sampling. Furthermore, questionnaires have been mailed to participants, regardless of screening outcome, with a participation rate of 64%.
This modern form of a nationwide clinical study is therefore a resounding success. By having a strong presence in the national conversation by using modern marketing tools like social media, the study is exemplary of how to initiate large population wide trials and proves the feasibility of truly nation-wide clinical studies.
Although randomization of individuals with positive screening is well underway and the study clinic has been seeing participants, sample collection is completed. Furthermore, due to the limited follow-up period, the main study endpoints have not been met at regularly scheduled interim analyses.
This modern form of a nationwide clinical study is therefore a resounding success. By having a strong presence in the national conversation by using modern marketing tools like social media, the study is exemplary of how to initiate large population wide trials and proves the feasibility of truly nation-wide clinical studies.
Although randomization of individuals with positive screening is well underway and the study clinic has been seeing participants, sample collection is completed. Furthermore, due to the limited follow-up period, the main study endpoints have not been met at regularly scheduled interim analyses.