Secure: A Prospective Long-Term Observational Study in Patients with Monoclonal Gammopathy of Undetermined Significance

Background and Significance:

Monoclonal gammopathy of undetermined significance (MGUS) is a precursor to multiple myeloma (MM), affecting approximately 3.2% of people over 50 years old. Whilst about 1% of MGUS cases progress to MM annually, most are asymptomatic and detected incidentally, leading to inconsistent management and follow-up practices. The SECURE study aims to address gaps in understanding routes to diagnosis, risk factors of MGUS progression and psychological effects of living with an MGUS diagnosis. This study will generate prospective data to fill these gaps in the literature.

Study Design and Methods:

SECURE is a national longitudinal observational study set to recruit 2000 MGUS patients from over 30 NHS sites across the UK. Recruitment started in September 2023 and is planned to end in December 2025, with each participant followed for 60 months. Data collection will conclude in December 2030, and final analysis will be completed by December 2031. Patients with MGUS aged 18 or older will be invited to participate and provide informed consent. Exclusion criteria include i) patients with a light chain ratio of 0.3 to 3.0 without monoclonal protein on serum electrophoresis or immunofixation, and ii) those with rapidly rising M-protein or serum free light chains (FLC) indicative of myeloma at diagnosis. Data collection involves baseline assessments, annual questionnaires, bone marrow and blood samples analysed and stored at the Botnar Research Centre, University of Oxford.

Recruitment is ongoing across 21 NHS sites in England and Wales, with 254 patients enrolled as of July 2024. Early data cut of 134 risk-stratified patients show a median age of 71 years (range 35-91), of which 53% are male, and 88.8% are of White ethnicity. Risk factors for MGUS progression were noted in 34 (25%) patients with a M-protein value ≥15 g/L, 85 (63.4%) with an abnormal FLC ratio, and 49 (36.6%) patients with non-IgG type MGUS. Risk stratification shows 22 (16.4%) patients at low risk, 55 (41%) at low-intermediate risk, 44 (32.8%) at high-intermediate risk, and 3 (2.2%) at high risk of disease progression.

The primary outcome is the incidence rate of MM during the follow-up period. Secondary objectives include MGUS monitoring patterns, incidence of MGCS, routes of MGUS diagnosis, family linkage, quality of life change, and psychological effects. Exploratory endpoints will include health resource utilisation and identifying biochemical and genomic predictive biomarkers for progression to MM.

The study will collect clinical and laboratory parameters, including protein, genomic and immune function markers. The primary outcome will be estimated yearly until the end of the follow-up, with 95% confidence intervals. Descriptive statistics will summarise the dataset overall and stratified by myeloma status at the end of the follow-up. Continuous variables will be summarised using mean (SD) or median (IQR), and binary/categorical variables using proportions. Analyses will be exploratory, identifying hypothesis generating observations that may guide future research. Kaplan-Meier survival analysis and Cox regression will be used for time-to-event data, linear regression for continuous measures, and logistic regression for binary outcomes. Multivariable analyses may control for confounding factors.

We propose to characterise circulating germline genetic variants and somatic variants to identify those associated with MGUS development and progression to MM. The study will investigate the clinical utility of a targeted sequencing panel for genomic risk stratification of MGUS. Metabolomic analysis will identify biomarkers of MGUS progression. We will also explore post-translational modifications (PTMs) of serum free light chains as potential biomarkers for MGUS progression.

The results of the SECURE study will be compared to the iSTOPMM study, an ongoing screening trial in Iceland. iSTOPMM actively screens the population to identify MGUS cases, whereas SECURE recruits prior incidentally detected MGUS patients. SECURE preliminary data showed that incidental MGUS patients had 36.6% (31.2% iSTOPMM) with non-IgG MGUS, 63.4% (35.8% iSTOPMM) with abnormal FLC, and 25.4% (3.3% iSTOPMM) with M-protein ≥15 g/L. These results highlight the differences in incidental MGUS (SECURE cohort) and can provide tools for managing MGUS monitoring in clinical practice.

Ramasamy:Menarini Stemline: Consultancy, Speakers Bureau; Sanofi: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding, Speakers Bureau; GSK: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Johnson and Johnson: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Recordati rare Disease: Consultancy, Speakers Bureau; Adaptive Biotech: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau. Heartin:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vifor Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Ariad: Speakers Bureau; Celgene: Speakers Bureau; Roche: Speakers Bureau; Abbvie: Speakers Bureau; Jazz: Speakers Bureau. Pratt:Sanofi: Consultancy, Honoraria; Prothena: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria; Binding Site: Consultancy, Research Funding; Beigene: Consultancy, Honoraria; Amgen: Honoraria; Takeda: Consultancy, Honoraria.