Progression Of Monoclonal Gammopathy Of Undetermined Significance Research Articles

Association between GLP-1RA use and progression of MGUS to Multiple Myeloma among diabetic patients.

In patients with diabetes mellitus (DM) and monoclonal gammopathy of undetermined significance (MGUS), the impact of GLP-1 receptor agonists (GLP-1RAs) on the natural history of MGUS is unknown. We aimed to assess the association of GLP-1RA use in the progression of MGUS to multiple myeloma (MM) in patients with DM. This is a population-based cohort study of Veterans diagnosed with MGUS from 2006-2021 with a prior diagnosis of DM. A validated natural language processing-algorithm was used to confirm MGUS and progression to MM. Gray's test was performed to detect the difference in cumulative Incidence functions (CIFs) for progression by GLP-1RA use status. The association between time-varying GLP-1RA use and progression was estimated in the 1 (exposed):2 (unexposed) matched cohort via multivariable-adjusted hazard ratio (aHR) using stratified Fine-Gray distribution hazard model with death as a competing event and stratum for the matched patient triad. Our analytic cohort included 1,097 MGUS patients who ever used GLP-1RAs, and the matched 2,194 patients who never used GLP-1RAs. Overall, 2.55% progressed in the GLP-1RA ever use group, compared to 5.01% in the GLP-1RA never use group. CIFs were significantly different between the exposed and unexposed groups (P = .02). GLP-1RA use, compared to no-use, was associated with decreased progression to MM (aHR 0.45, 95% confidence interval 0.22 to 0.93, P = .03). For patients with DM and MGUS, GLP-1RA use is associated with a 55% reduction in risk of progression from MGUS to MM, compared to no use.

Comparison of progression risk of monoclonal gammopathy of undetermined significance by method of detection

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic pre-malignant disorder. The current standard of care is not to screen for MGUS, so it is often incidentally diagnosed in the clinic. It is unknown whether the outcomes of screened versus clinically detected MGUS differ. We compared the progression risk between screened versus clinical MGUS cohorts and assessed whether the MGUS detection method impacted risk prediction of established clinical factors (score). We included 379 screened MGUS from the Olmsted County population based study and 1384 MGUS patients diagnosed during routine clinical evaluation at Mayo Clinic. Median follow-up time for the screened versus clinical cohort was 26.6 and 40.1 years, respectively. Accounting for death as a competing risk, the cumulative incidence of progression at 25 years was similar in the screened (11.1% [95% CI 8.3-14.8]) versus clinical (10.1% [95% CI 8.6-11.8%]) MGUS cohorts, even when stratified by sex, age, or the baseline MGUS risk score. Overall, 0.9 (95% CI 0.6-1.2) screened versus 1.0 (95% CI 0.9-1.2) clinically detected MGUS patients experienced disease progression for every 100 person years of follow-up. MGUS detection method did not modify the association between MGUS risk score and progression risk (pinteraction=0.217) and did not add to known risk factors for progression (likelihood ratio test, p=0.839). Here we show that progression risk among patients with screened versus clinically detected heavy-chain MGUS was similar. Future studies are needed to assess if tailored follow-up of screened MGUS patients affects clinical outcomes.

Comparison of 2 Free Light Chain Assays: Performance of the Free Light Chain Ratio as a Risk Factor for MGUS Progression.

New immunoglobulin free light chain (FLC) assays are available. Despite analytical differences, it seems possible to use free light chain ratios (FLCr) generated by different assays and apply similar cut-points for the diagnosis of multiple myeloma. It is still unknown if we can use different assays for risk stratification of patients with monoclonal gammopathy of undetermined significance (MGUS). Patients diagnosed with MGUS (N = 923) had FLC tested using a nephelometric FreeLite (Binding Site) assay on BNII instruments (Siemens) and a Sebia FLC assay (Sebia) on a DS2 ELISA analyzer (Dynex). Patients were followed up for progression to any plasma cell dyscrasia (PCD) for several decades. The Mayo MGUS risk stratification model for progression was assessed with both assays (M-spike >1.5 g/dL; non-IgG isotype and abnormal FLCr), using package insert reference intervals (RI) and a new metric called principal component 2 (PC2). There were 94 events of progression to PCD in the cohort during a median of 38 years of follow-up. Freelite and Sebia FLC showed similar hazard ratios in the risk models for elevated FLCr. An alternative clinical decision point lower than the package insert RI was evaluated for the Sebia assay, which improved risk stratification for patients with a low FLCr. The PC2 metric showed similar performance to the FLCr in models, without superior benefit. The Sebia ELISA-based FLC assay can be employed in an MGUS risk stratification model with similar performance to the original 2005 risk stratification model using the FreeLite assay.

Uncontrolled diabetes mellitus and the progression of monoclonal gammopathy of undetermined significance to multiple myeloma in US veterans.

7551 Background: Studies have shown that, independent of obesity, the metabolic effects of diabetes mellitus (DM) promote the progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM). However, it is unclear whether glycemic control is associated with MGUS progression in DM patients. We aimed to evaluate the association between poor glycemic control, measured by HbA1c >6.5%, and progression. Methods: Patients diagnosed with MGUS from 1999-2021 in the Veterans Health Administration (VHA) were identified using a published natural language processing (NLP)-based algorithm. We focused on patients whose MGUS subtype was IgG, IgA, or light chain. We excluded patients lacking body weight measurements from the time of MGUS diagnosis to the end of follow-up to ensure receiving care in the VHA. We further excluded patients with extended gaps >1 year between HbA1c measurements. Time-varying HbA1c measurements during the follow-up, evaluated at 1-day intervals and categorized into uncontrolled (HbA1c >6.5%) or controlled (≤6.5%) DM was the exposure variable. Progression of MGUS to MM was also confirmed by a published NLP algorithm. The association between the time-varying controlled/uncontrolled DM and progression was estimated by multivariable-adjusted hazard ratio (aHR) with death as a competing event. The covariates included sex, race, MGUS subtype as well as age, body mass index, monoclonal protein level, Charlson Comorbidity Index, DM medication, and DM type (type 1, type 2 with insulin-dependency status, type 2 without insulin-dependency status), all at MGUS diagnosis. Same analysis was conducted in a subgroup of patients with non-insulin dependent DM type 2 (NIDDMT2) without insulin use between MGUS diagnosis and the end of follow-up. Results: After applying inclusion and exclusion criteria, we identified 9,682 patients with both DM and MGUS. The multivariable analysis revealed a positive association between poor glycemic control and MM progression (see Table): (aHR 1.27, 95% CI 1.13-1.42). In NIDDMT2 without insulin use (n=3,498), poor glycemic control was associated with MM progression (aHR 1.81; 95% CI 1.57-2.10). Conclusions: For patients with DM and MGUS, the risk of MGUS progression to MM was 27% higher in uncontrolled DM and 81% higher in patients with NIDDMT2. This finding highlights a modifiable risk factor for MM progression in MGUS patients. Future studies should examine if interventions to enhance glycemic control could potentially reduce MGUS progression.

Population attributable fractions for risk factors for the progression of monoclonal gammopathy of undetermined significance to multiple myeloma in the Veteran population.

7552 Background: Multiple myeloma (MM) is the most common type of plasma cell cancer in the U.S. MM is consistently proceeded by monoclonal gammopathy of undetermined significance (MGUS). Studies have identified several risk factors for the progression of MGUS to MM. However, the contribution of each of these risk factors has not been quantified. We computed the population attributable fractions (PAFs) for selected risk factors in the U.S. Veterans Health Administration (VHA) health system. Methods: Veterans diagnosed with MGUS from 1999-2021 were identified and confirmed via a published natural language processing (NLP) model. We included Black and White patients whose immunoglobulin (Ig) subtype was IgA, IgG, or light chain. Patients who progressed to MM ≤6 months after MGUS diagnosis were excluded. We fit a multivariable time-to-event model controlling for sex, race (Black, White), Ig subtype (IgA, IgG, light chain), agent orange (AO) exposure, as well as M-protein level (≤, >1.5 g/dL), Charlson Comorbidity Index (CCI), obesity status (underweight, normal weight, overweight, obese), and age, all at MGUS diagnosis. The outcome was progression of MGUS to MM, which was also confirmed by a published NLP model. PAF for a risk factor is the fraction of all MM cases in the veteran population that is attributable to this specific risk factor. It accounts for both the prevalence and relative risk of this factor in the population. We calculated PAF for black race, IgA, AO exposure, and overweight/obesity. Results: The analysis included 24,917 patients with MGUS. Among them, 7.8% (n=1,944) progressed to MM (follow-up median 5.6, IQR 3.3-8.8 years). In the veteran population with MGUS, 17.9% of all MM cases was attributable to overweight or obesity (PAF 17.9%, 95% confidence interval [CI] 11.0-24.3%); 7.6% was attributable to black race (PAF 7.6%, 95% CI 4.3-10.9%), 5.7% was attributable to IgA (PAF 5.7%, 95% CI 4.0-7.4%), and 2.4% was attributable to AO exposure (PAF 2.4%, 95% CI 1.0-3.9%). Conclusions: In the veteran population with MGUS, overweight/obesity, the only modifiable factor, is the top contributor to progression to MM cases. In veterans with MGUS, had the overweight or obese MGUS patients to be reversed to normal weight, an estimated 17.9% of the progression cases could have been avoided.Our findings highlight the importance of maintaining a normal weight for reducing the risk of progression of MGUS to MM. [Table: see text]

Prior cancer and risk of monoclonal gammopathy of undetermined significance: a population-based study in Iceland and Sweden.

There is some evidence that a prior cancer is a risk factor for the development of multiple myeloma (MM). If this is true, prior cancer should be associated with a higher prevalence or increased progression rate of monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM and related disorders. Those with a history of cancer might therefore constitute a target population for MGUS screening. This two-part study is the first study to evaluate a relationship between MGUS and prior cancers. First, we evaluated whether prior cancers were associated with having MGUS at the time of screening in the Iceland Screens Treats or Prevents Multiple Myeloma (iStopMM) study that includes 75,422 individuals screened for MGUS. Next, we evaluated the association of prior cancer and the progression of MGUS to MM and related disorders in a population-based cohort of 13,790 Swedish individuals with MGUS. A history of prior cancer was associated with a modest increase in the risk of MGUS (odds ratio=1.10; 95% confidence interval: 1.00-1.20). This excess risk was limited to prior cancers in the year preceding MGUS screening. A history of prior cancer was associated with progression of MGUS, except for myeloid malignancies which were associated with a lower risk of progression (hazard ratio=0.37; 95% confidence interval: 0.16-0.89; P=0.028). Our findings indicate that a prior cancer is not a significant etiological factor in plasma cell disorders. The findings do not warrant MGUS screening or different management of MGUS in those with a prior cancer.

Toward Precision Medicine for Patients with Multiple Myeloma

Multiple myeloma (MM), the second most common hematologic malignancy, is a plasma cell neoplasm that arises from a precursor, monoclonal gammopathy of undetermined significance (MGUS), which may or may not be previously diagnosed. Smoldering multiple myeloma (SMM), another precursor of MM, lacks myeloma-defining events and end-organ damage that are diagnostic of MM in the appropriate clinical settings. Newly diagnosed MM (NDMM) is highly heterogeneous genetically and clinically with very variable survival outcomes ranging from a few months to over a decade. Despite this heterogeneity, treatment outcomes have improved significantly in the last two decades, with overall survival improving continuously due to novel classes of drugs approved for treating MM. However, due to the immense heterogeneity, the quest for a cure will almost certainly require individualized patient evaluation and management at every level for every factor influencing patient quality of life and survival, including most importantly determining upfront the progression risks in the precursor states and prognostic risks for progression or relapse in NDMM. Toward that goal, this paper briefly describes, including a historical perspective, current concepts, and recent advances in NDMM for students, researchers, and clinical practitioners. The topics discussed include an overview of the epidemiology, current diagnostic criteria, including for distinguishing MGUS, SMM, and MM, refractory and relapsed MM, staging and prognosis of MM, treatment response criteria, including measurable residual disease evaluation, improvements in survival, current standards for treating NDMM, and disparities and inequities in receiving care in ethnic minority populations for treatment of MM, followed by progress in evaluating the risk of progression in MGUS and SMM, and finally, the genomics of MM, SMM, and MGUS since integrating disease biology in assessing and precisely managing all risk factors and achieving equity in treating all patients would help to achieve that precision medicine goal for a cure.

Racial Differences in the Association of Glucagon-like Peptide 1 Agonist Use and the Progression of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma in US Veterans with Diabetes Mellitus

Background: Glucagon-like peptide 1 (GLP-1) agonists are antidiabetic medications that exert cardiac and renal benefits in addition to their well-established antihyperglycemic effects. A prior analysis has shown that GLP-1 agonist use is associated with a 65% reduction in the risk of progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) in US Veterans with diabetes mellitus (DM). However, it is unknown whether there are racial differences to this effect of GLP-1 agonists. We aimed to assess the racial differences in the association between GLP-1 agonist use and the progression risk in diabetic patients with MGUS. Methods: Patients diagnosed with MGUS in the Veterans Health Administration (VHA) database from 10/1/99-12/31/21 were identified using ICD codes. A natural language processing algorithm was used to confirm MGUS diagnosis and progression to smoldering MM or MM. Patients diagnosed with MGUS before DM and those who experienced progression within 1 year of MGUS diagnosis or within 2 years of DM diagnosis were excluded. For each race, we performed 1:2 matching for patients with and without GLP-1 agonist use based on follow-up time. The outcome was progression to smoldering MM or MM. Cumulative incidence functions stratified by GLP-1 agonist use (ever vs. never use) were plotted and a Gray's test was performed to detect the difference between the functions. The association between time-varying GLP-1 agonist use and MGUS progression was estimated using a multivariable Fine-Gray subdistribution hazard model with death as a competing event. Results: Our NLP algorithm confirmed 20,832 patients with DM and MGUS. After applying our inclusion and exclusion criteria, we had 9,294 white patients and 4,981 black patients, of which 909 and 403, respectively, were GLP-1 agonist users. After matching, our analytic cohort included 2,718 white patients (33.3% with GLP-1 agonist use) and 1,191 black patients (33.3% with GLP-1 agonist use). GLP-1 agonist use was associated with a dramatically significant reduction in progression rate in white patients (aHR 0.25; 95% CI 0.09-0.68), while the association was not shown in black patients (aHR 1.01; 95% CI 0.36-2.90). Conclusion: For patients with MGUS and DM, GLP-1 agonist use is associated with a 75% reduction in progression risk in white patients and no significant reduction in black patients. This highlights a racial disparity in the potential role of GLP-1 agonist for chemoprevention in the management of MGUS.

Sars-Cov-2 Infection Does Not Lead to Progression of Monoclonal Gammopathy of Undetermined Significance: Results from the Population-Based Istopmm Screening Study

Background The mechanisms that lead to the progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) and related disorders are largely unclear. Infections have been hypothesized to play a role in the onset of MM through dysregulation of the immune response or chronic immune stimulation. Therefore, the effect of concurrent viral infection, for example SARS-CoV-2 infection, might increase the risk of MGUS progression to MM. In Iceland, widespread and easy access to PCR testing for SARS-CoV-2 was implemented early in the COVID-19 pandemic, leading to very high testing rates. This provides a unique opportunity to evaluate whether PCR-proven SARS-CoV-2 infection has an impact on the risk of MGUS progression. To study this relationship, we performed a prospective nationwide study based on data from the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study. Methods A total of 75,422 individuals were screened for M protein and free light chains (FLC) between September 2016 and December 2020, and 3,358 individuals were diagnosed with MGUS and randomized to one of three study arms, two of which (n=2,037) are followed longitudinally with repeated serum protein electrophoresis (SPEP) and FLC analysis. These two arms comprised the study population. Iceland enforced a strict COVID-19 screening policy at the beginning of the pandemic where individuals suspected of having SARS-CoV-2 infection, exposed to SARS-CoV-2, or as part of a screening program underwent PCR testing. This screening policy ended on February 23 rd, 2022. All PCR test results in Iceland (positive or negative) and SARS-CoV-2 vaccinations were centrally registered, providing complete nationwide information on SARS-CoV-2 infections and vaccination coverage. By cross linking this data to the iStopMM database, individuals with MGUS who underwent PCR testing for SARS-CoV-2 in Iceland were identified. As M protein levels change over time, a linear mixed model with random intercept and slope was used to estimate changes in M protein concentration as a function of age, before and after SARS-CoV-2 infection. The slope of the evolution of M protein level over age was modelled using a restricted cubic spline to determine the effects of a proven infection on changes in M protein levels. Results A total of 1,305 individuals (53% males) with MGUS who had undergone at least one PCR test for SARS-CoV-2 were identified. Median age was 66 years (range: 41-97) and median M protein concentration at study inclusion was 2.0 g/L (range: 0-26.0). 5,401 PCR tests were performed in this group, with a median of two PCR tests (range: 1-68) per individual. 188 individuals tested positive for SARS-CoV-2 (14.4%), and 19 individuals (10.1%) had not received SARS-CoV-2 vaccination at the time of infection. In all, 5,473 serum samples were analyzed for M protein concentration, of which 347 (6.4%) were obtained a median 107 days (interquartile range: 45-213) after a confirmed SARS-CoV-2 infection (Table 1). After adjusting for age, sex, calendar year, and SARS-CoV-2 vaccination status, no difference in M protein concentration was observed when comparing samples obtained before or after a positive test result (exponentiated beta coefficient (Exp(β)): 1.01; 95% confidence interval [CI], 0.91-1.12). The same was true when analyzed for each sex separately (Figure A). Analysis of the effect of SARS-CoV-2 infection on M protein development in a subset of unvaccinated individuals (n=19) demonstrated a 40% increase in M protein concentration following SARS-CoV-2 infection when compared to those who were vaccinated at time of infection (Exp(β): 1.4; 95% CI, 1.1-1.8). Summary In this large population-based screening study that included 1,305 individuals with MGUS who had undergone PCR testing and were observed before and after SARS-CoV-2 infection, we found no evidence of SARS-CoV-2 infection being associated with progression from MGUS to MM. A small subset of unvaccinated individuals had a significant increase in M protein concentration after SARS-CoV-2 infection compared to vaccinated individuals who were infected. Compared to the remainder of the iStopMM cohort, the subset of unvaccinated individuals had higher M protein concentration at baseline which implied a higher baseline risk of progression. Overall, our study shows that infection with SARS-CoV-2 is not associated with an increased risk of progression from MGUS to MM.

Clinical and Diagnostic Challenges in Patients with Concomitant Plasma Cell Disorders and Myeloproliferative Neoplasms

Background: Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell precursor disease that regularly precedes the development of multiple myeloma (MM). It accounts for about 4.5% in the entire population, however patients with myeloproliferative neoplasms (MPN) seem at a higher risk for MGUS with a reported rate of concomitant disease at 3-14%. The reason for this co-occurrence of MGUS and MPN remains unclear, and a common cell of origin has not yet been defined. Inversely, constant MPN-driven inflammation in the bone marrow microenvironment (BM) may stimulate the expansion of a pre-existing plasma cell clone thereby promoting the transition from MGUS to active MM. Here, we investigated the clinical and molecular characteristics of a comprehensive series of cases treated for MGUS/MPN overlap at our center. Methods: Patients who were diagnosed with concomitant MGUS/MM and MPN between 2006 and 2023 were identified by retrospective chart review, yielding a total of 13 cases. Results: We identified 5/13 patients with a confirmed diagnosis of MGUS and 8/13 cases with active MM, all coinciding with a diagnosis of MPN (5 polycythemia vera (PV), 4 chronic myelomonocytic leukemia (CMMol), 3 primary myelofibrosis (PMF), 1 chronic myelogeneous leukemia (CML)). Median age at diagnosis was 66 (range 44-78) years for MGUS/MM and 64 (range 43-81) years for MPN. Overall survival in our cohort was rather short at a median of 8.2 (range 0-16) years. For clinical management, anti-MM therapy was prioritized over MPN treatment in the majority of patients, with the exception of CMMol. MPN-related organ restrictions significantly limited treatment options for MM, including bleeding disorders, infectious complications and impaired hematopoiesis (in PMF). High-dose concepts were performed in transplant-eligible cases, including autologous in 4 and allogenic stem cell transplantation in 2 patients. Two out of 6 patients died under transplant (1 autologous graft failure), indicating a comparably high transplant-related mortality. Another patient died from MM progression as PMF-induced anemia did not allow for more intense treatment. To examine the evolutionary path from MGUS to MM and the potential impact on this transformation by a concomitant MPN, we next examined the clinical course of disease in each patient. Six out of 13 patients had secondary MPN after prior MGUS/MM diagnosis, 5/13 patients were diagnosed with MPN first, and for 2/13 cases BM assessment revealed coincidental findings of MPN/ MM at the same time. For the cases of secondary MPN after initial diagnosis of MM/MGUS, latency between both diseases was shorter, than vice versa (40.2 vs. 73.6 months, P=0.19). No association was observed between secondary MPN and prior treatment for MM, as only 1/6 patients was diagnosed with PV following high-dose melphalan chemotherapy, potentially pointing towards a negligible role of treatment-induced secondary primary malignancies the context of MM/MPN overlap. In contrast, MGUS progression to active MM was observed in 1 patient with hyperdiploid IgG kappa MM (including trisomy 9) and long-term coexistent JAK2-mutated PV. Another patient was diagnosed with IgG kappa MM and 9p gain along with concomitant JAK2-mutated PMF. Whole-genome sequencing (WGS) is currently ongoing for these patients to decipher the temporal relationship of MM/MGUS and JAK2-mutated MPN. Conclusions: The prevalence of MGUS/MM in MPN patients seems modestly increased as compared to the entire population. From a clinical viewpoint, overlap of both diseases poses significant challenges to healthcare providers as treatment-related mortality tends to be higher than in patients with mutually exclusive MPN/ MM. Improved understanding of the molecular interplay of both diseases will inform risk-adjusted treatment decisions and will lead to improved outcomes in this highly challenging subgroup of patients.

Monoclonal Protein Concentration and Risk of Multiple Myeloma: Is 0.5 g/DL the New 1.5?

Introduction : Monoclonal Gammopathy of Undetermined Significance (MGUS) is an asymptomatic clonal plasma cell disorder with a risk of progression to multiple myeloma (MM). To provide an accurate prognosis, monoclonal protein (M-protein) concentration has been used to assess risk of progression to myeloma. Current risk models developed from stored serum samples in a predominately white population of patients indicated a low risk of progression (less than 1% per year) in patients with M-protein of <1.5 g/dL. Little is known about M-protein concentration and risk of progression in patients tested during routine clinical care in a more diverse population. We assessed the outcomes of MGUS five years after diagnosis, and determined the association between baseline characteristics and the rate of progression to MM. Methods: We used data from national Veterans Health Administration system to identify patients diagnosed with MGUS from 1999-2021 and were followed from MGUS diagnosis until progression, death, or the date 7/11/2023 was reached. MGUS diagnosis and progression to MM was confirmed utilizing a natural language processing algorithm. We included patients of black and white race and those with IgG, IgA, or light chain MGUS. The exposure was M-protein concentration at MGUS diagnosis, stratified by ≤0.5, >0.5-≤1.0, >1.0-≤1.5, >1.5 g/dL. We plotted the cumulative incidence function curve and used a multivariable Fine-Gray sub distribution hazard model with progression at 5 years as the event of interest, and death as a competing event. Covariates included sex, race, MGUS type, age, body mass index (BMI), diabetes, renal disease, and other comorbidities summarized by Charlson Comorbidity Index at MGUS diagnosis. Results: We included 15,520 patients with MGUS. The mean age at the diagnosis was 71.1. IgG subtype was more common (83.2%) than IgA (12.7%), and light chain (4.1%). 19.6% and 39.5% of patients had renal disease and diabetes, respectively. Black veterans represented 5600 (36.1%) of the cohort. At 5 years, 26.6% of veterans with an M-protein of >1.5 g/dL were diagnosed with myeloma, compared to 11.7% with 1.1-1.5 g/dL, 6.9% with 0.6-1.0 g/dL, and 3.3% with ≤0.5 g/dL. In multivariable models an M-protein >1.5 was associated with a greater risk of progression compared to ≤0.5 (multivariable-adjusted Hazard Ratio [aHR] 9.76, 95% Confidence Interval [CI] 8.37-11.40). Overall, increasing age was shown to have lower risk of transitioning to MM at 5 years with aHR of 0.983 (95% CI 0.978-0.988). Conclusion: In this modern cohort, only an M-protein of ≤0.5 g/dL was associated with a less 1% per year risk of developing MM. Conversely, 26.6% of veterans with an M-protein level >1.5 g/dL developed MM at 5 years. Risk of MM in patients clinically evaluated for MGUS may be higher than previously thought and new models of MM progression should be developed.

Characterization of monoclonal gammopathy of undetermined significance progression to multiple myeloma through meta-analysis of GEO data

The etiology of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) is still obscure as are the processes that enable the progression of MGUS to MM. Understanding the unique vs. shared transcriptomes can potentially elucidate why individuals develop one or the other. Furthermore, highlighting key pathways and genes involved in the pathogenesis of MM or the development of MGUS to MM may allow the discovery of novel drug targets and therapies.We employed STARGEO platform to perform three separate meta-analysis to compare MGUS and MM transcriptomes. For these analyses we tagged (1) 101 MGUS patient plasma cells from bone marrow samples and 64 plasma cells from healthy controls (2) 383 MM patient CD138+ cells from bone marrow and the 101 MGUS samples in the first analysis as controls (3) 517 MM patient peripheral blood samples and 97 peripheral blood samples from healthy controls. We then utilized Ingenuity Pathway Analysis (IPA) to analyze the unique genomic signatures within and across these samples.Our study identified genes that may have unique roles in MGUS (GADD45RA and COMMD3), but also newly identified signaling pathways (EIF2, JAK/STAT, and MYC) and gene activity (NRG3, RBFOX2, and PARP15) in MGUS that have previously been shown to be involved in MM suggesting a spectrum of molecular overlap. On the other hand, genes such as DUSP4, RN14, LAMP5, differentially upregulated in MM, may be seen as tipping the scales from benignity to malignancy and could serve as drug targets or novel biomarkers for risk of progression. Furthermore, our analysis of MM identified newly associated gene/pathway activity such as inhibition of Wnt-signaling and defective B cell development. Finally, IPA analysis, suggests the multifactorial, oncogenic qualities of IFNγ signaling in MM may be a unifying pathway for these diverse mechanisms and prompts the need for further studies.

The force awakens, but questions remain: The future of MGUS.

The force awakens, but questions remain: The future of MGUS.

Association between excess body mass index trajectory and change in monoclonal protein level in patients diagnosed with monoclonal gammopathy of undetermined significance.

10538 Background: Obesity is a known risk factor for the development of multiple myeloma (MM) and for progression of its asymptomatic premalignant state, monoclonal gammopathy of undetermined significance (MGUS) to MM. Prior studies have demonstrated that monoclonal protein (M-spike) at MGUS diagnosis as well as high M-spike velocity within a year following MGUS diagnosis predict progression of MGUS to MM, making M-spike a useful, readily available, and less invasive (compared to bone marrow biopsy) marker to assess progression risk. However, no studies have evaluated to what extent exposure to high body mass index (BMI) over time influences M-spike trajectory. Methods: Patients diagnosed with MGUS from 1999-2021 in the Veterans Health Administration were identified. We used a natural language processing-based algorithm to confirm MGUS diagnosis and progression to smoldering MM or MM. MGUS patients without IgM or IgD subtype or Diabetes Mellitus and were black or white were included in the analysis. Other exclusion criteria were progression within 5 years of MGUS diagnosis, patients without M-spike level within a year before or after MGUS diagnosis, and patients without BMI data 3 years or more after MGUS diagnosis. The exposure was the trajectory of excess BMI (defined as BMI > 25 kg/m2), defined by an area under the curve (AUC) of excess BMI during the 5 years following MGUS diagnosis. The outcome was continuous M-spike trajectory post-MGUS diagnosis since a prior study demonstrated that this was a reliable marker for progression risk A multivariable mixed model was used to estimate the association of excess BMI trajectory AUC with M-spike trajectory to control for correlation between M-spike values overtime. The covariates included BMI at MGUS diagnosis, M-spike level ( > = 1.5g/dL) at MGUS diagnosis, age at MGUS diagnosis, sex, race, MGUS heavy chain subtype, and light-chain MGUS. Results: After applying the inclusion and exclusion criteria, the analytic cohort consisted of 6757 MGUS patients. Our multivariable analysis demonstrated a positive association between excess BMI trajectory and increasing M-spike trajectory (β = 0.005, p = 0.007). Conclusions: In patients diagnosed with MGUS, increasing BMI over time following MGUS diagnosis was associated with increasing M-spike level. This further supports the relationship between obesity and weight gain in the pathway of MGUS to MM progression.

Significance of bone marrow immunohistochemical analysis in patients with plasma cell neoplasms

Background. The group of plasma cell neoplasms includes benign and malignant diseases. Sometimes there are difficulties in making a diagnosis. The study of the diagnostic and prognostic significance of immunohistochemical (IHC) markers is of current interest.Aim. To study the significance of IHC markers and histological features of the bone marrow in primary diagnosis in patients with multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS).Materials and methods. The study included 287 patients with plasma cell neoplasms: MGUS (n = 148), MM (n = 139). The observation period was 50 months. All patients have performed an aspiration biopsy and histological examination of the bone marrow with IHC analysis of CD138+, CD56+, CD34+, κ- and λ-chains expression.Results. During the observation period the progression of MGUS to MM was recorded in 8.8 % (n = 13) of cases, the progression of MM was determined in 38.1 % (n = 53) of cases.In patients with MGUS and MM the determined percentage of plasma cells at aspiration biopsy was somewhat lower than at histological examination (p >0.001). Statistically significant differences were determined between the groups MGUS and MM by the type of infiltration (р <0.001). With an increase in the percentage of bone marrow lesions by IHC (<20 % vs. 20–50 % and 20–50 % vs. >50 %), in our study interstitial and diffuse type of lesion with large accumulations was more common compared to the nodular type (p = 0.001).The CD138+ expression (IHC) more than 10 % was associated with a decrease of progression-free survival in patients with MGUS.In MM patients with an interstitial type of bone marrow infiltration and CD138+ over 10 % osteodestructive syndrome was detected by X-ray methods in 82.9 % of cases.Determination of CD56+ and immunoglobulin light chains expression in patients with MM and MGUS indicated an unfavorable prognosis.Resistance to chemotherapy or disease progression in MM patients most often occurred with a combination of IgG and immunoglobulin light chains secretion, with CD138+ plasma cells more than 50 % according to IHC, with a diffuse type of bone marrow lesion with accumulations of plasma cells. MGUS patients progressed more frequently with more than 20 % CD138+ plasma cells according to IHC, interstitial type and diffuse plasma cells accumulation type of bone marrow lesion, secretion of IgG or two immunoglobulins.Conclusion. The significance of the IHC study in the diagnosis of plasma cell neoplasms was confirmed. Markers associated with the disease progression and chemotherapy resistance in patients with MGUS and MM were identified.

Abstract 1960: Racial differences in the association of metformin use with progression of monoclonal gammopathy of undetermined significance to multiple myeloma in US veterans with diabetes mellitus

Abstract Background: Metformin is an oral antihyperglycemic with possible antineoplastic properties based on preclinical and retrospective studies. A retrospective study of Veterans demonstrated a reduction in monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) progression in patients with diabetes mellitus (DM) treated with metformin for ≥4 years. However, it is unclear whether there are racial differences to this effect of metformin. Methods: Patients diagnosed with MGUS from 1999-2021 in the Veterans Health Administration were identified. We used a natural language processing-based algorithm to confirm MGUS diagnosis and progression, including smoldering MM and MM. Only patients with DM, IgG, IgA, or light chain MGUS, and black and white patients were included in the analyses. We excluded patients who experienced progression within 6 months of MGUS diagnosis, patients who were diagnosed with MGUS before DM diagnosis, and patients who died, progressed to MM, or were lost to follow up within four years of MGUS diagnosis. We defined metformin users as those who had metformin use for ≥4 years after DM diagnosis and before MM development. Cumulative incidence functions (CIF) were stratified by metformin use status. Gray’s test was performed to detect the difference between the two functions. The association between metformin use and progression was estimated by multivariable-adjusted hazard ratio (aHR) using Fine-Gray distribution hazard model with death as a competing event. The covariates included age, BMI, monoclonal protein (M-spike) level (≥1.5g/dL), creatinine, and glycated hemoglobin (HbA1c) at MGUS diagnosis, as well as sex, race, MGUS heavy chain subtype, light-chain MGUS, and Charlson Comorbidity Index. Results: Our NLP algorithm confirmed 19,551 patients with DM and MGUS. After applying our inclusion and exclusion criteria, we had 13,068 (35% black and 65% white) patients of which, 4,268 (26.2% black and 36.2% white) were metformin users. Cumulative incidence function was stratified by metformin use status were statistically significant different (p=0.04) with a lower progression rate for metformin users (see Fig). The multivariable analysis demonstrated a statistically significant reduction in progression with metformin use in the overall cohort (aHR 0.79; 95% CI 0.67-0.95). Further multivariable analyses showed that metformin use was associated with a significant reduction in progression rate in white patients (aHR 0.73; 95% CI 0.58-0.91) but not in black patients (aHR 0.90; 95% CI 0.69-1.17). Conclusions: For patients with DM and MGUS, ≥4 years of metformin use was associated with a reduced risk of progression of MGUS to MM in white patients but not in black patients. Citation Format: Lawrence W. Liu, Nikhil Grandhi, Mei Wang, Theodore Thomas, Akhil Kumar, Kristin Vargo, Kristen M. Sanfilippo, Graham Colditz, Su-Hsin Chang. Racial differences in the association of metformin use with progression of monoclonal gammopathy of undetermined significance to multiple myeloma in US veterans with diabetes mellitus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1960.

Relationship between Monoclonal Gammopathy of undetermined significance and multiple myeloma via online database analysis.

To explore the relationship between Monoclonal Gammopathy of undetermined significance (MGUS) and Multiple Myeloma (MM) based on bioinformatics methods. In this study, we conducted bioinformatics to identify genes associated with MGUS and MM using the PubMed pubmed2ensemble (http://pubmed2ensembl.ls.manchester. ac.uk/) until 2021. Gene ontology function was used to label overlapping genes, and Kyoto Encyclopedia of Genes and Genomes analysis was used to identify enriched pathways. The cluster-1 genes obtained from Cytoscape were analyzed by Comparative Toxicogenomics Database (CTD, http://ctdbase.org/) and then used to screen candidate drugs using the DSigDB database (https://amp.pharm.mssm.edu/Enrichr/). In total, 227 genes were common to both MGUS and MM. These genes were significantly associated with cytokine-cytokine receptor interaction and the PI3K-Akt signaling pathway. The protein-protein interaction network revealed that TNF, IL-1B, IL-6, CSF2, CXCL8, and IL-10 were among the core genes of MM. Finally, eight candidate drugs showed maximum interaction with core genes, which could potentially prevent MGUS from progressing to MM. The progression of MGUS to MM is driven by aberrant cytokine secretion, which leads to inflammation immune dysfunction, and dysregulation of the PI3K/AKT/mTOR signaling pathway.

Artificial intelligence-enabled screening strategy for drug repurposing in monoclonal gammopathy of undetermined significance

Monoclonal gammopathy of undetermined significance (MGUS) is a benign hematological condition with the potential to progress to malignant conditions including multiple myeloma and Waldenstrom macroglobulinemia. Medications that modify progression risk have yet to be identified. To investigate, we leveraged machine-learning and electronic health record (EHR) data to screen for drug repurposing candidates. We extracted clinical and laboratory data from a manually curated MGUS database, containing 16,752 MGUS patients diagnosed from January 1, 2000 through December 31, 2021, prospectively maintained at Mayo Clinic. We merged this with comorbidity and medication data from the EHR. Medications were mapped to 21 drug classes of interest. The XGBoost module was then used to train a primary Cox survival model; sensitivity analyses were also performed limiting the study group to those with non-IgM MGUS and those with M-spikes >0.3 g/dl. The impact of explanatory features was quantified as hazard ratios after generating distributions using bootstrapping. Medication data were available for 12,253 patients; those without medications data were excluded. Our model achieved a good fit of the data with inverse probability of censoring weights concordance index of 0.883. The presence of multivitamins, immunosuppression, non-coronary NSAIDS, proton pump inhibitors, vitamin D supplementation, opioids, statins and beta-blockers were associated with significantly lower hazard ratio for MGUS progression in our primary model; multivitamins and non-coronary NSAIDs remained significant across both sensitivity analyses. This work could inform subsequent prospective studies, or similar studies in other disease states.

Evaluation of Genes and Molecular Pathways Involved in the Progression of Monoclonal Gammopathy of Undetermined Significance (MGUS) to Multiple Myeloma: A Systems Biology Approach.

Today, Monoclonal Gammopathy of Undetermined Significance (MGUS) is known as a plasma cell malignancy susceptible to evolving into the life-threatening stage, multiple myeloma (MM), without prominent clinical manifestations. Despite the discovery of advanced therapies and multiple pathogenic markers, the complexity of MM development has made it an incurable malignancy. In this study, the microarray dataset was downloaded from the Gene Expression Omnibus (GEO) database and analyzed using the LIMMA package of R-software to determine differentially expressed genes (DEGs) in MGUS and MM compared to the control samples. Enrichment analysis of DEGs was evaluated using the GeneCodis4 software. Protein-protein interaction (PPI) networks were constructed via the GeneMANIA database, and Cytoscape visualized them. The Molecular Complex Detection (MCODE) plugin from Cytoscape was used to identify the key modules from the PPI network. Afterward, the hub genes were recognized using the cytoHubba plug-in in Cytoscape. Eventually, the correlation between hub-DEGs and MM-specific survival was evaluated via the PrognoScan database. A total of 138 (MM-normal) and 136 (MGUS-normal) DEGs were obtained from the datasets, and 62 common DEGs between MGUS and MM diseases (26 up-regulated and 36 down-regulated genes) were screened out for subsequent analyses. Following enrichment analyses and the PPI network's evaluation, FOS, FOSB, JUN, MAFF, and PPP1R15A involved in the progression of MGUS to MM were detected as the hub genes. The survival analysis revealed that FOS, FOSB, and JUN among hub genes were significantly associated with disease-specific survival (DSS) in MM. Identifying the genes involved in the progression of MGUS to MM can help in the design of preventive strategies as well as the treatment of patients. In addition, their evaluation can be effective in the survival of patients.

Assessing the frequency of CD163+ tumor-associated macrophages and CD3+ T lymphocytes between MGUS and plasma cell myeloma

Plasma cell dyscrasias (PCDs) are a heterogeneous group of diseases, and the most common is monoclonal gammopathy of undetermined significance (MGUS). This premalignant PCD consistently precedes multiple myeloma (MM), with a 1% risk of progression per year. Evading and suppressing the host immune system is an important step in the progression of MGUS to MM. This pilot study was designed to assess whether MGUS and MM have a distinct microenvironment, characterized by a unique distribution of immune cells, including tumor-associated macrophages. Evaluation of bone marrow (BM) tumor microenvironment was performed using immunohistochemical quantification of T cells (CD3), macrophages (CD68), and a macrophage subtype (CD163). The findings were compared between MGUS and MM to determine whether differences existed. The results suggest that there is a significantly lower percentage of CD3-positive, CD68-positive and CD163-positive immune effector cells in BM trephine biopsy samples from patients with MGUS than in those from patients with untreated MM (p < 0.001). Interestingly, in a patient treated for MM, the percentages of CD3+ and CD68+ cells were the same as those in other patients with untreated MM; however, the percentage of CD163+ cells reduced and correlated with low plasma cell count. Future studies are required to investigate whether the percentage of CD163+ cells is correlated with disease burden in patients with MM. If this is the case, then the level of soluble CD163 in plasma could be a potential biomarker of disease burden in patients with nonsecretory myelomas, in whom measurements of levels of paraprotein and free light chains are inconclusive.