A Novel Approach to Lower Risk Monoclonal Gammopathy of Undetermined Significance (MGUS) Follow-up Based on Isotype-Specific Annualised Progression Risk: A Retrospective Real World Evidence Single Centre UK Study
Authors: Belcher Hannah , Duffell James , Williams Laura , Bygrave Ceri 
Published: December 2024

Key findings and conclusions
Our findings show that most plasma cell dyscrasias demonstrate expression of the IgG isotype and that this form presents as lower risk MGUS in the majority of cases; our data show that this rarely advances to conditions requiring further investigation by Haematologists, using British Society of Haematology (BSH) guidance. In contrast, the progression risk of non-IgG dyscrasias - notably IgA - is elevated within one year of initial testing and falls to IgG-like rates thereafter. We propose a novel approach to lower risk MGUS follow-up, using these findings, advocating six monthly testing until the first anniversary of diagnosis. For those progressing to a higher risk state during this period, specialist review should be conducted within six weeks. If progression has not occurred, patients are discharged from regular follow-up with targeted education and appropriate safety netting, due to the low annualised risk of progression observed here.
Background
MGUS is a common, benign plasma cell dyscrasia (3.2%, &gt; 50 years old); most cases will never develop into myeloma (1%) and yet many live with this fear. The BSH advises enhanced investigation for those with higher risk MGUS, to identify myeloma earlier and avoid devastating complications. Guidance for those with the lowest risk of progression is not standardised, which contributes to uncertainty about management for patients and clinicians.
Methods
Data from 72,241 patients, who underwent investigation for myeloma, between 24/11/14 - 26/03/24 in Cardiff, Wales was analysed. Patients were stratified using the Mayo Clinic criteria into lower (low & low-intermediate) and higher risk (high-intermediate & high risk) MGUS groups at baseline and during repeat testing.
Results
Our cohort, who exhibited a paraprotein, had serum free light chain investigation, and received follow-up testing on two or more occasions included 1,577 patients. The average age is 69 years (range 18-97; +2SD 94, -2SD 43). IgG dyscrasias were the most common subtype (65.9%), followed by IgA (16.3%), IgM (12.8%), and FLC only (4%). Two patients had IgD dyscrasias (0.1%). The majority of patients with IgG dyscrasias had lower risk disease at diagnosis (856/1039, 82%); this majority was not seen in other isotypes (IgA, 88/257, 34%, OR 8.9, 95% CI 6.6 - 12.2; IgM, 81/201, 40%, OR 6.9, 95% CI 5.0 - 9.6). IgA dyscrasias are associated with the greatest risk of progression to the higher risk group in the first follow-up year of any isotype (13/88, 14.8%, OR 3.1, 95% CI 2.0 - 7.5), but this fell to &lt; 3% in subsequent years. IgG dyscrasias have the lowest risk of progression in the first year (37/856, 4.3%) and fell to &lt; 2.5% thereafter.
Conclusion
This retrospective real-world study informs a proposed framework of patient centred, fixed duration monitoring for lower risk MGUS that can reduce anxiety, conserve resources, and drive clarity for all involved in MGUS care. We plan to assess reproducibility across Wales and implement our model using an enhanced service between primary and secondary care physicians with the additional benefit of providing education in this controversial and complex area of plasma cell disorder care.