Serum Free Light Chain Assays in the Risk Stratification of Monoclonal Gammopathy of Undetermined Significance: Results from a Pharmacoeconomic Evaluation
Authors: Pratt Guy , Cranmer Holly , Almond Christine , Harding Stephen , Powner Dale John , Hughes Richard Geir , Cook Mark 
Published: October 2019

Abstract
Monoclonal gammopathy of undetermined significance (MGUS) has a 1% overall risk of progression to symptomatic disease per year. Previously, monoclonal Ig (M-protein) isotype (IgA or IgM) and concentration (≥10g/L) have been used to risk stratify patients. In 2005, Rajkumar et al. reported on three independent risk factors: M-protein concentration ≥15g/L, M-protein isotype IgA or IgM, and an abnormal free light chain ratio (FLCr). An abnormal FLCr, determined by polyclonal antibody-based nephelometric analysis, had a 7.4 fold relative risk for MGUS progression in the absence of the other two factors. The International Myeloma Working Group (IMWG) recommends inclusion of all three factors for MGUS risk stratification, with low risk patients being referred to primary care while, intermediate and higher risk patients have bone marrow biopsies and skeletal surveys at presentation and are then followed annually by a haematologist. Here, we compare costs and resource use associated with the IMWG recommendations with the previous risk stratification approach.
The model consists of a decision tree structure from incidental finding of an M-protein level <30g/L to risk stratification, followed by a Markov structure comprising health states for non-stratified, low risk and ≥1 risk factor MGUS, smouldering multiple myeloma, symptomatic disease and death. The distribution of patients in the health states was based on incidence data and the proportion of patients in each risk strata in a US cohort, published by Rajkumar et al. (2005). The proportion of patients stratified as low risk in the previous approach was 33% compared with 39% when following IMWG recommendations.
Patients with MGUS experience higher mortality relative to age- and sex-matched healthy individuals; survival was therefore estimated by applying a relative risk of death to general population life tables (Office for National Statistics, 2014). Risk of progression to symptomatic disease was obtained by fitting exponential curves to the published data of Rajkumar et al. (2005) and Kyle et al. (2002) from the Mayo Clinic.
Costs of laboratory tests and resources were derived from the 2013-14 NHS and PSSRU 2014 data. Resource use was based on IMWG guidelines and clinician advice. The model used a 5-year time horizon, with outcomes discounted at an annual rate of 3.5%.
The model predicts that following IMWG recommendations results in lower costs, fewer bone marrow biopsies, skeletal surveys and haematologist consultations, and more referrals to primary care (Table 1). The pathway following IMWG recommendations increases referrals to primary care; however, the model shows, at Year 5, only 1.5% of those in primary care are predicted to progress to symptomatic disease compared to 3% of those in the previous risk stratification pathway.
Cost savings in the diagnostic pathway were driven by fewer skeletal surveys and bone marrow biopsies: -₤13.75 and -₤19.90 per patient, respectively. In the Markov model, savings were driven by the reduction in haematologist consultations, -₤85.91 per patient.
One-way sensitivity and scenario analyses indicated that results remained stable unless the proportion of patients referred to primary care in the IMWG pathway was ≤32% or the proportion of patients referred back to primary care in the previous risk stratification approach was ≥39%.
Probabilistic sensitivity analysis, based on 10,000 probabilistic simulations, showed that the IMWG recommendations have a 92.5%, 95.4%, 95.4% and 92.1% probability of reducing costs, bone marrow biopsies, skeletal surveys and haematology consultations, respectively, and a 95.4% probability of more patients being referred back to primary care.
The UK incidence of newly identified MGUS cases is estimated to be >7000 per year. Applying the IMWG recommendations, including FLCr analysis, therefore leads to substantial cost savings and reduced resource use in both the diagnostic and long-term pathways.
Benefits to patients include fewer required bone marrow biopsies and skeletal surveys, while fewer patients identified as low risk are predicted to progress to symptomatic disease.
As practice moves towards a more systematic out-of-hospital approach, further benefits are anticipated for the management of patients with MGUS. Haematology clinic resources can then be allocated to other conditions, while maintaining confidence that all MGUS patients are appropriately managed.

Disclosures
Pratt: The Binding Site Group Ltd: Other: Member of Medical Advisory Board. Harding:The Binding Site Group Ltd: Employment, Membership on an entity's Board of Directors or advisory committees. Powner:The Binding Site Group Ltd: Employment. Hughes:The Binding Site Group Ltd: Employment. Cook:The Binding Site Group Ltd: Other: Member of Medical Advisory Board.