Of Seven Molecular Subtypes in MGUS the Low Bone Disease (LB) Subtype Exhibits Resistance to Multiple Myeloma Progression

Introduction: Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic pre-cancer stage for multiple myeloma (MM). MGUS and MM are mostly indistinguishable at the molecular level. To elucidate the molecular basis of MM, our previous studies defined seven molecular subgroups: CD-1, CD-2 (CCND1/CCND3), HY (hyperdiploidy), LB (low bone disease), MF (MAF/MAFB), MS (MMSET), and PR (proliferation). Each subgroup is characterized by a unique gene expression signature driven by recurrent translocations and ploidy alterations. The LB subtype is a hyperdiploid form of the disease, lacing recurrent translocations and harboring the typical gains of odd-numbered chromosomes seen in HY, but being distinguished by the absence of chromosome 11 gains, and the frequent presence of gains of 1q and del13q. The low expression of DKK1, a suppressor of osteoblasts and high expression of the osteoclast inhibitor CST6 can account for the lower incidence of magnetic resonance imaging (MRI)-defined focal lesions in LB (Zhan, F, et. al. Blood 2006). We recently developed a gene expression based GS36 risk score to predict the progression of MGUS to MM (Sun, F, et. al. J Hematol Oncol. 2023). However, whether a difference in the incidence of MGUS progression within the seven subgroups is unknown.

Methods: At our center between 1971-2018, 1,157 patients were initially diagnosed with MGUS. Of the 1157, a bone marrow aspirate for GEP analysis was obtained from 584 patients. Six patients who progressed to MM prior to the sample collection date were excluded from cohort. A total of 578 patients were included in the final analysis. 508 (87.9%) were stable (remained as MGUS, only progressed to SMM, or progressed to MM after 10 years) and 70 (12.1%) were progressive (progressed to MM within 10 years). We applied the same molecular classifications used for MM to evaluate which subgroups MGUS belonged to and analyzed which subgroups had a higher risk of progression. A logistic regression analysis was utilized to assess the correlation between progression and subgroups. The GS36 risk score was used to evaluate if the LB group was more resistant to MM compared to other subgroups. Because LB was more common in MGUS (114/584, 19.5%) than in MM (383/3786, 10.1%) and the distribution of other subgroups was similar in both conditions, LB was used as the reference group for the comparison. SAS 9.4 was used for the data analysis, and the statistically significant level was chosen as 0.05.

Results: Among 578 MGUS patients, LB group had the lowest progression rate of 8/115 (7.0%) compared to all other 6 subgroups. However, only HY (26/166, 15.7%), MS (8/34, 23.5%), and PR (3/7, 42.9%) were significantly higher than LB (p<0.0001). A univariate logistic regression analysis showed that the progression was independently affected by subgroups. The HY patient group was 2.48 times (95%CI: 1.08,5.71) more likely to progress to MM; MS 4.12 times (95%CI: 1.41,11.99); and PR 10.03 times (95%CI: 1.91,52.78). And although the CD1, CD2, and MF weren’t significantly different, they also showcased a higher likelihood to progress (OR=0.907, 95% CI: 0.75,8.18; OR=0.237, 95% CI: 0.47, 3.42; and OR=0.859, 95% CI: 0.86, 6.47 times more likely respectively). The mean GS36 score is significantly higher (p<0.0001) in the progressive group (1.5±1.0) compared to the stable group (0.5±0.9). The Bonferroni Adjusted multi-comparison test showed the mean GS36 score in the HY group (1.0±1.0) and PR group (1.9±0.7) was significantly higher than the LB group (0.4±0.8); the p-values were all <0.0001.

Conclusion: This study confirmed that the seven molecular subgroups model can serve as an effective tool for predicting the progression of MGUS patients. The LB subgroup of MGUS is significantly more resistant to MM progression compared to HY, MS, and PR, and although the CD1, CD2 and MF subgroups were not significant, they still showed a higher likelihood. It also validated the ability to use the GS36 risk score in MGUS subgroups, as it showed that LB did have the lowest risk of progression. Integration of molecular signatures into the routine management of MGUS patients may enhance the implementation of risk-adapted strategies to prevent progression to overt MM.