Association of Progression Patterns in Monoclonal Gammopathy of Undetermined Significance (MGUS) with Outcome in Multiple Myeloma: A Cohort Study of over 35 Years
Authors: Späth Florentin , Tahiru Widad , Izarra Antonio , Hultdin Johan , Wu Wendy Yi-Ying 
Published: November 2021

Abstract
Introduction: Guidelines suggest following monoclonal gammopathy of undetermined significance (MGUS) according to risk of multiple myeloma progression. Follow-up of low-risk MGUS is debated as progression risk is low. Worse myeloma-related outcome was observed in patients followed for low-risk MGUS, potentially due to less optimal follow-up (Bianchi et al. Blood 2010, Sigurdardottir et al. Jama Oncology 2015). However, it is not clear if progressing low-risk MGUS by its nature displays more aggressive biological behavior. To gain better understanding of progression patterns in MGUS, we investigated, independent of follow-up, whether progression from low-risk MGUS is associated with worse outcome in multiple myeloma. The main outcome was overall survival from the time of myeloma diagnosis.
Methods: The Northern Sweden Health and Disease Study (NSHDS) is a longitudinal prospective cohort with more than 100,000 participants. Typically, NSHDS participants donate repeated blood samples at intervals of several years. Samples are frozen within one hour and stored at -80° C at Umea University Hospital. Linkage to the Swedish Cancer Registry facilitated identification of myeloma patients with two pre-diagnostic samples in NSHDS (N = 61). Of these, we screened repeated pre-diagnostic samples using protein- and immunofixation electrophoresis and free light chain assays. We identified 42 individuals who had detectable monoclonal gammopathy in both pre-diagnostic samples without MGUS follow-up before myeloma diagnosis, allowing to investigate natural progression patterns in relation to outcome. Overall survival was determined using Kaplan-Meier plots. Hazard ratios and 95% confidence intervals were calculated using multivariable Cox regression including known prognostic factors. Fisher's exact test was used to compare categorical variables.
Results: The first pre-diagnostic sample was collected in November 1986 and the last follow-up since myeloma diagnosis was in February 2021, resulting in a 35-year study duration. Median age at myeloma diagnosis was 62 (range 48-84) with a median follow-up of 7 years (range 0.2-18). At first pre-diagnostic blood draw, 12 had low-risk and 30 had MGUS of other risk (Mayo Clinic criteria). Characteristics at myeloma diagnosis except sex were similarly distributed between the two groups. Comorbidities, myeloma treatment and access to novel drugs were balanced between groups. Bone disease (osteolytic lesions and/or vertebral compression fractures attributable to myeloma) at myeloma diagnosis was more common in patients who had low-risk MGUS at first pre-diagnostic blood draw (P = 0.04). This association was pronounced excluding light chain myeloma (P = 0.01). Access to other radiographic imaging than conventional skeletal survey such as CT or MRI was similar for both groups.
In low-risk vs. other MGUS, median overall survival since myeloma diagnosis was 2.3 (95% CI, 1.8-2.9) years and 7.5 (95% CI, 4.8-10.2) years (Figure A). Results were similar investigating overall survival since frontline therapy start (excluding 5 patients not requiring therapy) (Figure B). Sex and bone disease were not associated with survival.
At repeated pre-diagnostic blood draw (in median 3.7 years prior myeloma diagnosis), 67% vs. 19% had low- or low-intermediate risk MGUS in patients with low-risk vs. other MGUS at first pre-diagnostic blood draw (P = 0.01), suggesting more rapid progression close to myeloma diagnosis in patients with low-risk MGUS at first blood draw. Investigating this further, we plotted M spikes in low-risk vs. other MGUS of IgG isotype (Figures C-D). M spike trajectories were largely similar between groups, although the annual median M spike increase from repeated pre-diagnostic blood draw to myeloma diagnosis was 6.0 g/L in low-risk vs. 2.3 g/L in other MGUS (P = 0.14).
Conclusions: Progression from low-risk MGUS is, independent of MGUS follow-up, associated with a higher proportion of bone disease and worse survival. Based on the known phenotypic heterogeneity in multiple myeloma, we speculate that low-risk MGUS in case of malignant progression belongs to a group of more aggressive tumors. Our results need to be interpreted carefully because of the small sample size. Replication and further investigation are needed. If replicated, these findings could help to improve current MGUS follow-up strategies, which are solely based on progression risk.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.