Gammopathy Of Undetermined Significance Research Articles

Monoclonal gammapathies: Epidemiological, immunochemical and etiological analysis of a series of 50 cases

During the period from September 2022 to January 2023, 50 cases of monoclonal gammopathy (GM) were collected at the Avicenne military hospital in Marrakech. The average age of the patients was 62 years. Thirty patients were male and 20 were female. The etiological diagnosis could be established for the 50 observations: 5 were classified as GM of undetermined significance (GMSI), 42 were classified as myeloma, two case of Waldenström's disease and one case of AL amyloidosis. The clinical symptomatology was dominated by bone pain in 78% of patients with a deterioration in general condition in 43%. The most frequently found biological abnormalities were anemia in 62% of patients, renal failure in 48% of patients and 19% had hypercalcemia. A monoclonal peak was found in the electrophoreses of 45 patients (90%), of whom 6 migrated to the beta zone and 39 migrated to the gamma zone. The IgG Kappa isotype was the most frequent with a rate of 56%, followed by IgG Lambda (27%), IgA Kappa (8%), IgA Lambda (3%), IgM Lambda (3%) and lambda free light chains (3%).

Comparison of plasma cell bone marrow counts by different methods in patients diagnosed with plasma cell disorders

IntroductionPlasma cell quantification in bone marrow is important for diagnosis, prognosis, and treatment of plasma cell diseases. It can be performed by several methods such as aspiration, imprint and flow cytometry, and biopsy. ObjectivesTo compare plasma cell counts at diagnosis of plasma cell diseases using different methods. MethodsAn observational study was carried out of laboratory results of adult patients with plasma cell diseases, who underwent aspiration, imprint cytology, flow cytometry (CD38, C138) and biopsy in a single institution between January 2015 and May 2021. The intraclass correlation coefficient was used to assess agreement between different methods with results stratified into three groups: <10%; 10–59% and ≥60% of infiltration. ResultsSixty-seven cases were studied: 59.7% were men with a median age of 70 (range: 32–85) years. The diagnoses were multiple myeloma in 61%, gammopathy of undetermined significance in 25.4%, smoldering myeloma in 6% and other plasma cell dyscrasias in 7.6%. Less than 10% infiltration was found in 32 (47.7%), 35 (52.2%), 44 (65.7%) and 25 (37.3%) of patients, respectively by aspiration, imprint cytology, flow cytometry and biopsy. Infiltration ≥60% was detected in 7 (10.4%), 4 (6.0%), 2 (3.0%) and 21 (31.3%) cases, respectively. There was disagreement between the results in 37 (55.2%) of patients. Of these, 28 had greater infiltration in biopsies. The concordance (Kappa index) of biopsy with aspiration, imprint and flow cytometry was 0.501, 0.408 and 0.17; of aspiration with imprint and flow cytometry, it was 0.738 and 0.541 and between imprint and flow cytometry, it was 0.573%. ConclusionsOnly aspiration and imprint cytology results agreed. Biopsy showed greater infiltrations than the other methods, but aspiration, and imprint and flow cytometry provided additional data in the diagnosis and thus should also be performed.

Abstract 3491: New targets and new approaches for multiple myeloma: Extracellular vesicles as functional liquid biomarkers

Abstract Background: We have previously demonstrated that stromal cells (HS5) pre-treated with small extracellular vesicles (sEV) enriched from blood plasma of myeloma (MM) patients promoted adhesion of human MM cell lines (HMCL), with preliminary proteomic profiling of MM-sEV (vs healthy donors-HD) revealing enrichment of factors implicated in cell migration and adhesion. Aims: To demonstrate that plasma-derived MM-sEV induce a microenvironment favoring MM progression and identify the protein content of plasma-sEV that promotes this. Methods: sEV were enriched from plasma (1mL) using a commercial kit. Proteomic profiling (nLC and high-resolution mass spectrometry, Orbitrap HF-X) of plasma-sEV derived from HD (x10) and patients with MM (x8) or pre-malignant conditions (monoclonal gammopathy of undetermined significance - MGUS x10; smouldering/asymptomatic MM - SMM x4), and functional studies (co-culture system HS5:HMCL) were performed. Results: Stromal cells pre-treated with MM-sEV induced both HMCL proliferation (p &amp;lt; 0.05) and drug resistance (p &amp;lt; 0.0001) to anti-MM drugs (proteasome inhibitors) when compared to untreated stromal cells.The protein concentrations of MM-sEV positively correlated with tumor burden (r0.77; p=0.024).A total of 412 proteins were detected and quantified by proteomic profiling of plasma-sEV with 13 reported as highly enriched in EV marker databases (ExoCarta top 100) and 8/13 corresponding to universal cancer EV-markers proposed by Hoshino et al, Cell 2020. Gene ontology analysis of identified proteins (G:Profiler; p &amp;lt; 0.05) revealed enrichment for cellular component terms such as “extracellular vesicles/exosomes” and for several biological processes including “cell communication”, “endocytosis”, “cell migration”, “cellular response to stimulus”, “immune response”. Comparative analysis between our dataset and several publicly available datasets revealed sEV-markers with potential discriminatory specificity for MM, MGUS or SMM. Comparative analysis revealed 40, 40 and 41 proteins differentially regulated between HD-sEV and MM-sEV or MGUS-sEV or SMM-sEV (P &amp;lt; 0.05; log2 fold change ≥2). A specific protein signature identified in MM-sEV was found in ≥30% of MM-sEV but &amp;lt;30% HD-sEV. Specific protein signatures were also identified in MGUS-sEV (≥30% of MGUS-sEV but &amp;lt;30% HD-sEV or MM-sEV or SMM-sEV) and SMM-sEV (≥30% of SMM-sEV but &amp;lt;30% HD-sEV or MM-sEV or MGUS-sEV). These proteins were not found in human whole plasma (Lehallier et al, Nat medicine 2019) or solid tumors-derived sEV described by Hoshino et al (Cell 2020) and Vinik et al (Science Advances 2020). Conclusions: MM-sEV may play an important role in disease progression by re-programming the tumor microenvironment. The characterization and proteomic profiling of disease-specific circulating sEV as a biomarker discovery strategy may provide translational applications in MM. Citation Format: Antonia Reale, Tiffany Khong, Rong Xu, Irena Carmichael, Haoyun Fang, Nicholas Bingham, Sridurga Mithraprabhu, Maoshan Chen, Malarmathy Ramachandran, David W. Greening, Andrew Spencer. New targets and new approaches for multiple myeloma: Extracellular vesicles as functional liquid biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3491.

Abstract 3582: Single-cell RNA-sequencing for immune profiling of SARS-CoV2 vaccine response in healthy individuals and patients with precursor plasma cell malignancies

Abstract Introduction: Patients with hematological malignancies exhibit inferior response to SARS-CoV2 vaccination, compared to healthy individuals, however little is known about patients with precursor hematological malignancies and the cellular underpinnings of vaccination response. Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Myeloma (SMM) are plasma cell premalignancies that precede Multiple Myeloma (MM) and exhibit signs of immune dysregulation; they affect approximately 5% of the population over 50 years of age, who remain largely undiagnosed, due to lack of screening. In November 2019, we launched the IMPACT study to characterize the immune response to SARS-CoV2 vaccination in patients with plasma cell dyscrasias and healthy individuals. Methods: We performed single-cell RNA-sequencing on 224 peripheral blood mononuclear cell samples drawn from 118 IMPACT (IRB #20-332) participants with MGUS (n=20), SMM (n=48), or MM (n=24), as well as healthy individuals (n=26). Samples were collected before vaccination and after 2 doses of BNT162b2 (Pfizer-BioNtech) (n=123), mRNA-1273 (Moderna) (n=83) or 1 dose of Ad26.COV2.S (Janssen) (n=14). Results: Overall, we sequenced 2,025,611 cells from 224 samples of 118 patients with MGUS, SMM, MM and healthy individuals pre- and post-vaccination for SARS-CoV2, and profiled 553,082 T-cells, 95,392 B-cells, 74,394 NK cells, 195,371 Monocytes, and 35,236 Dendritic cells (DC). We identified activated clusters of B-cells, NK cells and DCs expressing genes such as CD83, CD69, CXCR4, and genes related to the NF-kB and AP-1 pathways. We compared cell type abundances pre- and post-vaccination within each participant population and found that activated CD83+ cells significantly increased post-vaccination in healthy individuals and patients with MGUS (paired t-test, q &amp;lt; 0.1), but not in patients with SMM or overt MM. At baseline, patients with SMM and MM had significantly fewer memory B-cells and significantly more cytotoxic T-cells and NK cells, compared to healthy individuals (Wilcoxon, q &amp;lt; 0.1), which could partly explain the differences observed post-vaccination. Patients with MM also had significantly higher levels of tolerogenic IL-10-expressing DCs (DC10) at baseline (Wilcoxon, q &amp;lt; 0.1), which could be dampening antigen-specific T-cell responses. Conclusion: We identified a significant expansion of activated B-cell, NK cell and DC subpopulations expressing CD83, CD69 and CXCR4, following vaccination in healthy individuals and patients with MGUS, but less so in patients with SMM and overt MM. Our results provide insight into the cellular mechanisms of immune response to SARS-CoV2 vaccination in healthy individuals and patients with precursor plasma cell malignancies and suggest that asymptomatic individuals with SMM may exhibit inferior response to vaccination. Citation Format: Romanos Sklavenitis-Pistofidis, Yoshinobu Konishi, Michelle Aranha, Mahshid Rahmat, Ting Wu, Michael Timonian, Shohreh Varmeh, Daniel Heilpern-Mallory, Michael P. Agius, Nang K. Su, Elizabeth D. Lightbody, Jacqueline Perry, Erica M. Horowitz, Anna V. Justis, Daniel Auclair, Catherine R. Marinac, Eric S. Fischer, Gad Getz, Irene M. Ghobrial. Single-cell RNA-sequencing for immune profiling of SARS-CoV2 vaccine response in healthy individuals and patients with precursor plasma cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3582.

Abstract 1729: Single-cell transcriptome profiling of multiple myeloma bone marrow samples suggests that disease progression interplays with tumor and tumor microenvironment in The MMRF CoMMpass Study

Abstract Multiple Myeloma (MM) is a hematologic malignancy marked by uncontrolled clonal expansion of plasma cells. Previous research has examined single-cell transcriptome profiles of Monoclonal gammopathy of undetermined significance (MGUS) and MM tumor microenvironment (TME) and found that natural killer (NK) cell abundance is elevated in the early stages and correlated with altered chemokine receptor expression. This study suggested the critical role of immune cells on myeloma progression from asymptomatic MGUS to symptomatic MM. Up to date, however, there are no published studies comprehensively comparing tumor and immune populations differences between MM NON-progressors (NPs) and FAST-progressors (FPs) and investigating how clonal plasma cells affect disease progression in a large cohort. Therefore, understanding how tumor and immune cells influence disease progression within symptomatic MM is of great interest.Here, we subjected CD138-negative Bone Marrow Mononuclear cells (BMMC) samples from 418 MM patients to scRNA-seq. From MMRF CoMMpass study (NCT01454297), we also have whole exome sequencing (WES) and bulk RNA-seq from CD138-positive fraction of BMMC samples. Based on time to progressive disease (TTPD), we classified patients into 2 categories. Patients with TTPD less than 18 months were classified as FAST-progressors (FPs), whereas patients with TTPD more than 5 years were classified as NON-progressors (NPs). By analyzing patient genomic alterations and its association with progression, we found that there was a significant association of slow MM progression with t(11;14) (p = 0.048), consistent with previous study. In our preliminary analysis, we profiled 83 CD138-sorted MM bone marrow samples using scRNA-seq. Interestingly, we found plasma cells from samples with the same genetic alterations tend to cluster together, highlighting the important role of genetic drivers in transcriptome profiles of plasma cells. Moreover, integrated analysis of bone marrow samples from 83 MM patients and 4 healthy donors revealed an atypical naïve-B cell subset with enrichment of cells from fast-progressors and partial expression of MS4A1. Differentially expressed genes for this naïve-B cell subset includes KLF9, BCL2L11, JOSD1, and IRS2, etc. Overall, as part of MMRF immune profiling research, this study will help to interrogate how genetic alterations and disease progression interplay MM tumor and TME and provide a sufficiently broad and valuable dataset for systematically characterizing MM at single-cell resolution. Hopefully, this study could identify novel targets for MM immunotherapies, and ultimately identify patients with high risk of fast progression for early intervention in the clinic. Citation Format: Lijun Yao, Tianjiao Wang, Kazuhiro Sato, Reyka Jayasinghe, I-Ling Chiang, Darwin D'souza, William Pilcher, Edgar Gonzalez-Kozlova, Yered Pita-Juarez, Taxiarchis Kourelis, Deon Bryant Doxie, Beena Thomas, Brian Lee, Swati Sharma Bhasin, Upadhyaya Bhaskar, Mark Fiala, Julie Fortier, Travis Dawson, John Leech, Shaji Kumar, Hearn Cho, Seunghee Kim-Schulze, Bee Raj, Stephen Oh, the MMRF Immune Profiling Research Team, John Dipersio, Ravi Vij, Adeeb Rahman, Ionnis Vlachos, Shaadi Mehr, Mark Hamilton, Daniel Auclair, Surendra Dasari, David Avigan, Madhav Dhodapkar, Sacha Gnjatic, Manoj Bhasin, Li Ding. Single-cell transcriptome profiling of multiple myeloma bone marrow samples suggests that disease progression interplays with tumor and tumor microenvironment in The MMRF CoMMpass Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1729.

Abstract CT550: Phase II study of acalabrutinib and an anti-CD20 monoclonal antibody in patients with anti-MAG mediated neuropathy

Abstract Background: Peripheral neuropathy occurs in 20-25% of patients with an IgM paraprotein and 40-50% of patients with an IgM monoclonal gammopathy have a detectable anti-myelin associated glycoprotein (MAG) antibody. The presence of an anti-MAG antibody is often associated with a chronic, progressive symmetric demyelinating polyneuropathy that can lead to sensory deficits and gait dysfunction, significantly altering a patient’s quality of life. Prior clinical trials have failed to demonstrate an effective long-term therapy for anti-MAG neuropathy. Additionally, the best manner to assess the evolution of this type of neuropathy has not been elucidated. We designed this clinical trial to evaluate a potential therapy for anti-MAG related neuropathy based on previous reports of subjective improvement in patients with anti-MAG neuropathy treated with rituximab or Bruton’s tyrosine kinase inhibitors. We included multiple neurologic outcome measures so their responsiveness and performance could be assessed in a clinical trial setting. Methods: This is a single-arm open-label phase II trial investigating the use of acalabrutinib and an anti-CD20 monoclonal antibody for the treatment of an IgM-associated anti-MAG mediated neuropathy. Eligible patients must have positive anti-MAG antibody titers with an IgM monoclonal gammopathy of undetermined significance (MGUS) or Waldenström macroglobulinemia (WM). Patients must have a predominantly sensory neuropathy characterized by demyelinating features in nerve conduction studies with a modified Rankin score of ≥1 with progressive symptoms or a modified Rankin score of ≥2. The ECOG performance status must be ≤2. Acceptable organ and marrow function are required. Prior exposure to chemotherapy, Bruton Tyrosine Kinase inhibitors, or other therapies for WM are not permitted except for steroids, IVIg, or an anti-CD20 monoclonal antibody given at least 90 days before study drug initiation. Approximately 33 patients will be enrolled in this study. Patients will be treated with acalabrutinib 100 mg orally twice daily on days 1-28 of each cycle and treatment will be administered until disease progression or unacceptable toxicity. Rituximab (or a biosimilar) will be administered on days 1, 8, 15, and 22 of cycles 1 and 4. The primary endpoint of this trial is to evaluate the overall hematologic response rate (defined as ≥25% reduction in serum IgM) associated with the treatment. The key secondary endpoint is to evaluate the proportion of patients that achieve improvement or stability in neuropathic symptoms based on the Inflammatory Rasch-built Overall Disability Scale (I-RODS) patient-reported disability scale. Additional secondary neurologic endpoints include the INCAT disability score, exam-based outcomes (the MRC distal sum score and INCAT-ISS), measures of function (10-meter walk test, 9-hole peg test), a pain scale, a fatigue scale (FSS), and a neuropathy-specific quality of life scale (IN-QOL). Additional secondary endpoints include time to next treatment, overall survival, hematologic response based on MYD88 and CXCR4 mutational status, change in bone marrow disease burden, and proportion of adverse events associated with treatment. This study is currently open and accruing patients. Clinical trial information: NCT05065554 Sponsor: AstraZeneca Citation Format: Shayna Sarosiek, Christopher T. Doughty, Andrew Branagan, Catherine A. Flynn, Kirsten Meid, Timothy P. White, Megan Little, Carly Leventoff, Steven P. Treon, Jorge J. Castillo. Phase II study of acalabrutinib and an anti-CD20 monoclonal antibody in patients with anti-MAG mediated neuropathy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT550.

Abstract 640: Genome sequencing of circulating multiple myeloma cells for minimally invasive molecular characterization of precursor disease pathology

Abstract Introduction: Multiple myeloma (MM) develops from indolent stages monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Precursor conditions are incidentally diagnosed and require invasive bone marrow (BM) biopsies for complete characterization, highlighting the urgent need for improved early detection methods. Minimally invasive blood biopsies to measure circulating multiple myeloma cells (CMMCs) as markers of MM disease development are a promising solution to this unmet need. Here, we present our novel method CatchTheFISH, for whole genome sequencing (WGS) of CMMCs that enables genomic profiling and WGS based cytogenetic analyses from enriched liquid biopsy samples. Application of WGS in a cohort of 20 patients, revealed CMMCs were of tumor origin and able to faithfully match BM sequencing results and detect 100% of clinically reported events. Methods: Peripheral blood from 110 SMM patients from the PCROWD observational study (Dana-Farber Cancer Institute IRB #14-174) was collected and processed on CellSearch system (Menarini Silicon Biosystems), with enrichment and enumeration of CMMCs based on CD138+38+CD45-19- immunophenotype. In 20 patients, CMMCs and white blood cells were sorted for library construction, quantification and WGS on Illumina NovaSeq6000. Mutation analyses were performed with the cancer genome analysis pipelines of the Broad Institute. Results: CMMCs were detected in 84% of SMM patients enrolled in the study, with a median count of 13 CMMCs (range 0 to 43836). We first demonstrated the concordance of WGS results obtained from CMMCs with BM. In 100% of patients tested with paired BM and CMMCs (n = 8), we observed full agreement in structural event calling between our samples and clinical reports, including translocations and CNAs (trisomies, tetrasomy, monosomy 13 and 1q gain/amplification). Next, we showed WGS of CMMCs provided increased diagnostic yield compared to BM biopsy for the detection of structural events and MM-associated driver mutations. In 7 patients (88%) we detected additional aberrations not found by FISH. Unknown translocation events of IGH-MYC and t(14;20) were distinguished in two patients. Additionally, our method enabled detection of MM driver mutations. Three patients (38%) were found to harbor RAS mutations (KRAS and NRAS) in BM samples, which were also validated in matched CMMCs. Finally, we assessed a validation cohort of 12 SMM patients with CMMCs only. WGS detected comprehensive mutation data across all scales including clinically relevant translocations, trisomies, CNAs and mutations. Conclusion: Our findings provide proof of principle that capture and genomic profiling of CMMCs could be a robust surrogate to BM biopsy, allowing minimally invasive detection and monitoring of disease, unlocking the clinical potential of liquid biopsies for MM diagnostics. Citation Format: Ankit K. Dutta, Jean-Baptiste Alberge, Elizabeth D. Lightbody, Romanos Sklavenitis-Pistofidis, Cody J. Boehner, Tarek H. Mouhieddine, Anna Cowan, Nang Kham Su, Erica M. Horowitz, Andrew Dunford, Chip Stewart, Ziao Lin, Laura Hevenor, Hadley Barr, Amanda Cao, Ornkleaw Zepp, Thai Bui, Steve Gross, Daniel Auclair, Gad Getz, Irene M. Ghobrial. Genome sequencing of circulating multiple myeloma cells for minimally invasive molecular characterization of precursor disease pathology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 640.

Abstract 5277: Humoral SARS-CoV-2 response in asymptomatic precursor plasma cell dyscrasia patients: IMPACT study results

Abstract Introduction: Patients with hematologic malignancies, including multiple myeloma (MM), experience worse SARS-CoV-2 infection outcomes and sub-optimal vaccine responses. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) precede MM and affect ~5% of individuals age &amp;gt;=50. We previously showed that individuals with MGUS and SMM exhibit immune dysregulation. Here, we investigate the immune response to SARS-CoV-2 vaccination in these asymptomatic but potentially immunocompromised individuals. Methods: The IMPACT study (IRB #20-332) is a prospective study at Dana-Farber Cancer Institute in collaboration with MMRF, which enrolled individuals nationwide with a diagnosed plasma cell dyscrasia and healthy individuals. As of October 2021, 3,005 individuals completed a questionnaire regarding prior infection or vaccination. We obtained 1,350 blood samples from 628 participants and analyzed anti-SARS-CoV-2 IgG antibody titer by ELISA. Results: 2,771 (92%) participants were fully vaccinated (2 doses BNT162b2 or mRNA-1273; 1 dose Ad26.COV2.s), 269 (9%) had received a 3rd mRNA vaccine dose, and 234 (8%) were unvaccinated. 1,387 (46%) and 1,093 (36%) participants received mRNA vaccines (BNT162b2 and mRNA-1273), and 139 (5%) participants received an adenovirus vector vaccine (Ad26.COV2.S). 34 (1%) individuals reported SARS-CoV-2 infection after full vaccination. We measured antibody titers in 201 MGUS, 223 SMM, 40 smoldering Waldenstrom macroglobulinemia (SWM), 64 MM, and 100 healthy controls. Multiple linear regression model estimated the association between various clinical variables and post-vaccination antibody titers. As previously reported, having MM was associated with low antibody titer (p &amp;lt; 0.001). Of note, having SMM, regardless of risk stratification by 2/20/20 criteria, was also associated with low antibody titers, indicating that even low-risk SMM patients have a poor response to vaccination. MGUS and SWM diagnoses were not significantly associated with antibody titers. Additionally, male sex (p &amp;lt; 0.010), elapsed time after vaccination (p &amp;lt; 0.001), and BNT162b2 vaccine (p &amp;lt; 0.001) were associated with low antibody titers. SARS-CoV-2 infection prior to vaccination was associated with high antibody titers. We identified 25 patients (6 MGUS, 10 SMM, 2 SWM, 7 MM) who submitted blood samples after both the 2nd and 3rd dose. In these patients we observed a significant increase in antibody titer after a 3rd dose (p = 0.002). We also observed that antibody titers of patients after a 3rd dose (13 MGUS, 12 SMM, 2 SWM, 31 MM) were comparable to that of healthy individuals after a 2nd dose (p = 0.833). Conclusion: Our data indicates that suboptimal response to SARS-CoV-2 does not only occur with MM and cancer patients receiving therapy but also in precursor asymptomatic patients including low-risk SMM. Citation Format: Yoshinobu Konishi, Romanos Sklavenitis-Pistofidis, Hong Yue, Federico Ferrari, Massimiliano Russo, Robert A. Redd, Jacqueline Perry, Erica Horowitz, Anna V. Justis, Nader A. Shayegh, Elizabeth D. Lightbody, Shohreh Varmeh, Radoslaw P. Nowak, Mark Hamilton, Daniel Auclair, Catherine R. Marinac, Lorenzo Trippa, Eric S. Fischer, Irene M. Ghobrial. Humoral SARS-CoV-2 response in asymptomatic precursor plasma cell dyscrasia patients: IMPACT study results [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5277.

Abstract 3651: Obesity, metabolic comorbidities, and lifestyle factors and their association with monoclonal gammopathies in a high-risk screened population: Results of the PROMISE study

Abstract Background: Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant condition of multiple myeloma (MM) traditionally identified by serum protein electrophoresis (SPEP) and immunofixation (IFX). Recently, novel, ultra-sensitive mass spectrometry (MS)-based approaches have allowed for monoclonal (M)-protein detection at concentrations below SPEP levels. MGUS has only few known risk factors implicated in its development and progression. Thus, we analyze MS results of the PROMISE nationwide U.S. screening study to evaluate risk factors for (1) MGUS at traditional SPEP/IFX levels of detection and (2) low-level monoclonal gammopathies, which bear uncertain etiology and clinical significance. Methods: PROMISE enrolled individuals age ≥40 who are Black and/or have a first-degree relative with a blood cancer or MM precursor condition. Those with ≥2 first-degree relatives were eligible at age ≥18. Participants were screened for monoclonal gammopathy by MALDI-TOF MS and provided a survey querying metabolic comorbidities and lifestyle. M-protein concentrations ≥0.02 g/dL were considered traditionally-defined MGUS, whereas M-proteins &amp;lt;0.02 g/dL are hereafter referred to as monoclonal gammopathy of indeterminate potential (MGIP). Multivariable logistic regression models estimated odds ratios (OR) and 95% confidence intervals (CI) for exposure and MGUS/MGIP associations. Results: 1,893 screened participants completed the survey. MGUS and MGIP were detected in 13.4% and 22.0% of Blacks and 8.6% and 26.7% of individuals with family history. Adjusting for sex, age at screening, income, and education, obesity or BMI of ≥30 was associated with MGUS (OR, 1.55; 95% CI, 1.08-2.21), compared to BMI &amp;lt;30. Clinician-diagnosed hypertension (yes/no) and diabetes mellitus (yes/no) were associated with MGUS with ORs 1.44 (95% CI, 1.01-2.04) and 1.88 (95% CI, 1.004-3.51). There were no significant associations between MGUS and high cholesterol, high triglycerides, heart disease, myocardial infarction, or stroke. Short sleep of ≤6 hours/day was associated with MGUS (OR, 1.43; 95% CI, 1.01-2.03), compared to &amp;gt;6 hours/day. Physical activity (metabolic equivalents/week), smoking status (current, past, never), alcohol consumption (g/day) had no associations with MGUS. No risk factor associations were found for MGIP. Conclusion: In screening a high-risk population by mass spectrometry, we found associations of both traditionally established (obesity) and novel risk factors (diabetes, hypertension, short sleep) with MGUS. None of these exposures were associated with MGIP despite finding a high prevalence of MGIP in Blacks and individuals with family history, suggesting that these risk factors may not be etiologically involved in MGIP development but possibly its clonal expansion to more advanced stages. Citation Format: David J. Lee, Habib El-Khoury, Jean-Baptiste Alberge, D.J. Sakrikar, David Barnidge, Mark C. Perkins, Stephen Harding, Jacqueline Perry, Maya I. Davis, Julia Amstutz, Erica Horowitz, Timothy R. Rebbeck, Irene M. Ghobrial, Catherine R. Marinac. Obesity, metabolic comorbidities, and lifestyle factors and their association with monoclonal gammopathies in a high-risk screened population: Results of the PROMISE study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3651.

Abstract 2259: Predictive modeling of smoldering multiple myeloma progression to multiple myeloma by continuous variable analysis

Abstract Introduction: Multiple myeloma (MM) is consistently preceded by two precursor conditions, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). The distinctions between MGUS, SMM, and MM rely on clinical values with inherent variation relating to tumor burden quantified from bone marrow biopsies, a measure subject to inconsistencies in location, timing, and pathologist interpretation. These challenges limit the potential of current standardized risk criteria and advocate for models that examine precursor disease kinetics. We thus developed a risk model that leverages dynamic changes in markers of precursor disease to improve clinical ability to predict time to disease progression. Methods: To model the evolution of progression risk, we built PANGEA, an international retrospective cohort of precursor patients with baseline and serial time points of clinical and biological variables. This cohort comprises 1095 SMM patients, 254 (23%) of which progressed to MM. Using this cohort, we modeled progression to MM with Cox regression using time-dependent and continuous clinical variables. The model was trained on a subset of data restricted to patients of the Dana-Farber Cancer Institute (DFCI) and validated its performance by computing the c-statistic in a sub-cohort independent from the DFCI training cohort. Results: The PANGEA cohort was first used to validate current models of SMM disease progression. We validated the 20/2/20 International Myeloma Working Group criteria for SMM patients using binary cutoffs of initial measurements (baseline model), and then extended this model, allowing for re-stratification by the 20/2/20 criteria over time (dynamic model). We then assessed whether rates of change in a set of myeloma-specific clinical variables unrestricted to those of the 20/2/20 criteria improved the predictive ability of the model. This improved our progression prediction as indicated by a c-statistic increase of more than 10% with respect to both 20/2/20 models (baseline and dynamic). Specifically, changes in disease indicators such as age and creatinine are highly predictive of imminent disease progression (p-value &amp;lt; 0.01). Finally, we clustered patients based on latent trajectories of these time-varying clinical variables and included the trajectory classes in the Cox regression. The resulting multivariable, dynamic algorithm is a dramatic improvement over current clinical standards in predicting progression from SMM to MM disease. Conclusion: The PANGEA multivariable algorithm’s use of continuous clinical variables enhances progression risk predictions in SMM. These findings demonstrate that disease progression from SMM to MM, which likely occurs by the acquisition of sequential changes to the plasma cell clone, can be tracked by trends in clinical values, thus improving prognostication for precursor patients. Citation Format: Annie Cowan, Habib El-Khoury, Federico Ferrari, Samuel S. Freeman, Robert Redd, Jacqueline Perry, Vidhi Patel, Priya Kaur, Hadley Barr, Katelyn Downey, David Argyelan, Anna V. Justis, David J. Lee, Elizabeth D. Lightbody, Foteini Theodorakakou, Despina Fotiou, Nikolaos Kanellias, Christine Liacos, Gad Getz, Lorenzo Trippa, Catherine Marinac, Efstathios Kastritis, Dimopoulos Meletios, Irene Ghobrial. Predictive modeling of smoldering multiple myeloma progression to multiple myeloma by continuous variable analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2259.

Prevalence of monoclonal gammopathy of undetermined significance in black South African men.

e20032 Background: Monoclonal gammopathy of undetermined significance (MGUS) is the precursor to multiple myeloma (MM). MM disproportionately affects black individuals, but the cumulative risk of progression from MGUS to malignancy does not differ by race. Hence, the racial disparities in MM incidence appear to arise from differences in the occurrence of MGUS. Nonetheless, MGUS has been studied mainly in white populations; the study that first described the natural history of MGUS was conducted by Kyle, et al. (2006) in 97.3% white Olmsted County, Minnesota. Methods: We determined the prevalence of MGUS among black South African men &gt;30 years of age at the Chris Hani Baragwanath Academic Hospital in Johannesburg. We conducted serum protein electrophoresis (SPEP) and free light chain (FLC) quantification and used the same criteria for MGUS as the Olmsted County studies: a monoclonal protein on SPEP or an abnormal FLC-ratio plus elevation in the appropriate FLC. We also investigated the association between MGUS and various clinical and behavioral factors. Results: The prevalence of MGUS in our cohort (n=386) was 8.03% (95%CI 5.32-10.74), nearly 1.6-fold higher than in Olmsted County males. In a univariable logistic regression model, MGUS was associated with HIV status (odds ratio (OR) 2.39, 95%CI 0.95-5.51), but in the adjusted model that also included body mass index (BMI) and cigarette use, the magnitude of the association decreased to an OR of 2.17 and was not statistically significant. MGUS was associated with current (vs. never) cigarette smoking in both univariable (OR 5.2, 95%CI 1.53-24.0) and multivariable (OR 4.11, 95%CI 1.08-20.4) models. Conclusions: Not only did we find the prevalence of MGUS in black South African men to be substantially higher than in white populations, but we also report that MGUS cases are associated with potentially modifiable risk factors. Building on this pilot study, a larger study is currently underway powered to confirm the relationship between MGUS and HIV, as well as between MGUS and cigarette smoking, in a black African population inclusive of both genders. Future studies designed to evaluate genetic and matched-environmental contributions may elucidate racial disparities and facilitate the development of strategies to prevent plasma cell malignancies.[Table: see text]

Retrospective analysis of vaccine antibody titers in patients with different stages of monoclonal plasma cell disorders.

e20031 Background: Infections occur with up to twofold increased risk in patients with monoclonal gammopathy of undetermined significance (MGUS) and tenfold increased risk in multiple myeloma (MM). To reduce risk, revaccination following autologous hematopoietic cell transplantation (AHCT) is recommended to restore humoral immunity. We have previously shown that vaccine titers after AHCT have prognostic significance. In the COVID era, reliable clinical data about antibody titers is relevant yet scarce. We investigated the significance of different vaccine titers in newly diagnosed patients in different stages of the disease. Methods: The study population comprised of 77 patients with MGUS, smoldering multiple myeloma (SMM) and MM who were seen at a tertiary cancer center from 2018-2022. All patients had antibody titers (B. pertussis, Diptheria, H. Influenzae B, Hepatitis, Influenza, Meningitis, Mumps, Rubeola, Rubella, Poliovirus, S. pneumoniae, Varicella Zoster and Tetanus) tested at the time of diagnosis, prior to start of treatment if indicated. Titers were interpreted in accordance with the manufacturers’ recommendations. Patient characteristics were compared using the Kruskal-Wallis and Fisher’s exact tests. Associations with % titer positivity were evaluated using the Kruskal-Wallis test. Results: There was significant difference in antibody titer positivity between the different patient groups (51.4% in MGUS, 40.5% in SMM and 34.2% in MM) (p &lt; 0.001). There was no difference in antibody titer positivity depending on age, sex or race. Among individual pathogens, there was a significant difference between the three groups in regards to titers for Diphtheria, Mumps, Poliovirus 3, Strep pneumoniae 19, Strep pneumoniae 56 and Varicella Zoster. Conclusions: Antibody titers for vaccine preventable diseases are significantly different between patients with MGUS, SMM and MM at the time of diagnosis, with MGUS having the highest and MM having the lowest positivity. Patient related factors such as age, sex or race were not associated with antibody titer positivity. Current guidelines for revaccination are not extended to patients with MGUS and SMM and can be considered in prospective trials.[Table: see text]

Natural language processing of Veterans’ electronic health records to confirm diagnoses of monoclonal gammopathy of undetermined significance.

1557 Background: The Veterans Health Administration (VHA) provides extensive electronic health records (EHRs) on Veterans nationwide. Our prior studies utilized VHA data to study the risk of progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma. These studies relied on International Classification of Disease (ICD) codes and manual abstraction on clinical notes to both identify and verify MGUS patients. Diagnosis confirmation is necessary because many providers place a diagnosis on the clinical notes to order lab tests, which is often left in the EHR despite a negative test result. However, manual abstraction is labor intensive and time consuming. With the advancement in natural language processing (NLP), we developed a model to make MGUS confirmation more efficient. Methods: We randomly selected 700 patients within patients diagnosed with MGUS from 1999-2021 in the VHA identified via ICD codes. A random sample of 500 patients were selected and split into the training (80%) and the testing (20%) sets. The remainder (n = 200) served as the validation set. There were 32,708 unstructured hematology/oncology Text Integration Utility reports and 9,237 lab reports (including 2,322 discrete results and 6,915 unstructured comments). All reports were manually reviewed to confirm MGUS diagnoses and served as the reference standard. We compiled three lists of keywords suggestive of MGUS diagnosis, subtypes of immunoglobulins, and negation modifiers. We trained a symbolic NLP model to identify diagnoses using combinations of the lists along with M-protein levels from lab reports. The optimized combination that gave the highest recall and precision from the training set was used and evaluated on the testing and validation sets. Results: Among patients with ICD codes for MGUS, manual abstraction confirmed 84% MGUS diagnoses in the testing set and 80% in the validation set. Our NLP model in the training set confirmed 75% and achieved recall, precision, accuracy, and F1 score of 88.1, 98.7, 89.0, and 93.1%, respectively; in the validation set, our rule confirmed 76% patients and the recall, precision, accuracy, and F1 score were 89.4, 94.7, 87.5, and 92.0%, respectively. On average data abstraction took five minutes per patient (excluding data loading time), whereas NLP model completed 13 patients per minute. Conclusions: The developed NLP model to confirm MGUS diagnosis improves accuracy in diagnosis, compared to ICD codes alone. While the performance is similar to that of manual abstraction, our NLP model is an efficient and viable method in MGUS diagnosis confirmation. [Table: see text]

The association of agent orange (AO) exposure with monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) progression: A population-based study.

8050 Background: With limited evidence from a single center study [n=211 (11 with AO exposure)] reporting AO exposure as a risk factor for transformation, whether or not AO exposure increases the rate of transformation from MGUS to MM is unclear. Thus, we aimed to conduct a nation-wide study to determine the association between AO exposure and the risk of MGUS to MM progression. Methods: A retrospective, matched cohort study using data from the U.S. Veterans Health Administration system was conducted. Based on a power calculation, a random sample of MGUS patients with AO exposure was selected and 1:1 matched to those with MGUS without AO exposure (matching factors: age at MGUS diagnosis, race, body mass index categories). Data abstraction confirmed MGUS and MM diagnoses. In addition, information on date of diagnosis, MGUS subtype, and monoclonal protein (M-protein) values was performed. Patients were considered to have MGUS if they had M-protein detected on serum protein electrophoresis (SPEP) with immunofixation confirmation. The association of AO exposure with progression from MGUS to MM was examined using a multivariable Fine-Gray subdistribution hazard model with death as the competing event. The covariates included M-protein at MGUS diagnosis (&gt;1.5, ≤1.5 g/dL [reference]), MGUS subtype (Immunoglobulin A, light chain, and Immunoglobulin G [reference]), and Charlson comorbidity score at MGUS diagnosis. A sensitivity analysis was conducted using inverse probability treatment weighted survival analysis to evaluate the robustness of the conclusion. Results: After excluding individuals with no confirmed MGUS or M MGUS subtype, a total of 563 MGUS patients with AO exposure and 563 matched controls were included. No statistically significant difference was observed in the progression of MGUS to MM between the AO exposed group and control group (adjusted hazard ratio (aHR) 0.78, 95% confidence interval (CI) 0.53 to 1.17). The sensitivity analysis demonstrated consistent results. Conclusions: Our carefully designed study does not show an association between AO exposure and progression of MGUS to MM in a national cohort of Veterans. [Table: see text]

A systematic review of the literature on gastrointestinal tract amyloidomas: Presentation, management and outcomes.

e16220 Background: Gastrointestinal tract amyloidomas are uncommon malignancies, and little is known regarding this entity. AL amyloidosis and Amyloidomas mostly occurs in association to plasma cell dyscrasias such as multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), and Waldenstrom’s macroglobulinemia (WM), although it has been also described in the absence of plasma cell dyscrasias. In general, plasma cell dyscrasias and systemic amyloidosis either AL or AA are typically treated with systemic therapy followed by Hematopoietic Stem Cell Transplant (HSCT) if patient is eligible. Nowadays, there are several systemic approaches that may or may not include autologous stem cell transplant. 56 On the contrary, localized amyloidomas have been mostly managed surgically and for the most part local amyloidomas are considered to have excellent prognosis. To this date there is no standard of care to guide clinicians in the management of local gastrointestinal amyloidomas. To the best of our knowledge this is the largest systematic review of gastrointestinal amyloidomas. The objective of this study was to evaluate the characteristics, treatments available, outcomes and surveillance these patients. Methods: We conducted a systematic review of cases reported in the literature from 1962-2021 that included a total of 62 cases reported in the literature. Patients with Gastrointestinal Amyloidomas reported in English literature were included in the analysis. We described and summarized the patient’s characteristics, treatments, clinical presentations, outcomes, and surveillance. Results: The systematic review of reported clinical cases included 62 patients. In these patients, the most common site of amyloid deposition was the stomach (45%). The median age of diagnosis is 64.4 years old, has a 2:1 prevalence among males (63%) to females (37%), abdominal pain is the most common type of presentation (41%) although patients could also be asymptomatic. There is a high curative rate (100%) with resection alone. Among patients treated with a type of systemic therapy, an 80% achieved a complete response. The minority of cases reported a type of surveillance post treatment and among those, the 62% pursued serial clinical evaluations alone. Conclusions: To our knowledge, this is the first and largest systematic review of the literature in Gastrointestinal Tract Amyloidomas. This is more common among males, and seems to have an excellent curative rate (100%) with surgery alone. Systemic therapy is an option for those with non-resectable amyloidomas. Serial clinical evaluations should be part of the standard surveillance care in these patients.

Fibrillary Glomerulonephritis and Monoclonal Gammopathy: Potential Diagnostic Challenges.

Fibrillary glomerulonephritis (FGN) is a rare glomerular disease featured by the randomly arranged 12- to 24-nm fibrils under electron microscopy (EM). Up to 10% of FGN patients have monoclonal gammopathy. However, distinguishing between FGN as monoclonal gammopathy of renal significance (MGRS) and FGN from other causes with incidental monoclonal gammopathy of undetermined significance (MGUS) can be challenging, as the current way of demonstrating monoclonality is flawed due to (1) the suboptimal sensitivity of kappa staining by immunofluorescence in frozen tissue (IF-F) as compared to pronase-digested paraffin sections (IF-P), causing incorrect labeling of light chain restriction; (2) the unavailability of immunoglobulin G (IgG) subtyping in some centers; and (3) the unavailability of tests demonstrating the monoclonality of highly variable VH or VL domains in immunoglobulin structures in clinical use. The discovery of DnaJ homolog subfamily B member 9 (DNAJB9) allows diagnosis for FGN with less reliance on EM, and the summary of recent studies revealed that genuine MGRS is extremely rare among FGN. Further research integrating IF-P, IgG subtyping, VH or VL domain monoclonality confirmation, and DNAJB9 as diagnostic modalities, with corresponding clinical data including treatment response and prognosis, is required for a better understanding of this subject.

Waldenstrom's macroglobulinemia in geriatric practice

Using the clinical case of Waldenstrom's macroglobulinemia in an older patient, a research was carried out to find an algorithm for diagnosing the disease in patients of advance age, whose frequent polymorbid pathology makes it difficult to diagnose and detect the disease at an early stage. The study of Waldenstrom's macroglobulinemia has great relevance due to the dim clinical picture and high prevalence among the older population. This condition is relatively rare, but its timely detection is very important to prevent the development of complications. We analyzed the literature dedicated to study Waldenstrom's macroglobulinemia, as well as pathways of transformation a monoclonal gammopathy of undetermined significance into Waldenstrom's macroglobulinemia.

Mesangial proliferative glomerulonephritis with monoclonal immunoglobulin deposits: why nephrobiopsy is crucial

Proliferative glomerulonephritis (GN) with monoclonal immunoglobulin deposits (PGNMIDs) is a recently described entity among the spectrum of monoclonal gammopathy of renal significance (MGRS). The disease is renal limited and manifests in chronic glomerular disease, altered renal function and albuminuria, sometimes in the nephrotic range. Acute nephritic syndrome is rare. Until recently, in the absence of criteria for symptomatic haematological disease, patients with monoclonal Ig-related nephropathies often experienced difficulties in getting appropriate chemotherapy. Noticeable progress in management was achieved with the introduction of the concept of monoclonal gammopathy of renal significance, which distinguishes the situation of nephropathies induced by dangerous small B-cell clones from that of monoclonal gammopathy of undetermined significance (MGUS) that does not feature any end-organ damage. Monoclonal gammapathy of renal significance is not an independent kidney disease, not “chronic glomerulonephritis”, but a condition in which kidney damage is secondary to clonal B-cell proliferation. In other words, MGRS is a precancerous disease combined with chronic kidney disease that requires immediate treatment. Renal prognosis is poor, with progression to end stage renal disease in 25 % of patients within 30 months and frequent early recurrence on the renal allograft. However, recent studies indicate that clone-targeted chemotherapy may significantly improve renal outcomes, opening future perspectives for the management of this rare disease.

MO371: Should We Systematically Look for Urine Alterations in all Patients With Monoclonal Gammopathy of Undetermined Significance?

Abstract BACKGROUND AND AIMS Monoclonal gammopathy of undetermined significance (MGUS) has a high prevalence in the elderly population, being as high as 9% in subjects over 85 years. Population aging leads to an increase in the number of patients with MGUS. In 2012, monoclonal gammopathy of renal significance (MGRS) was described to identify MGUS patients with renal alterations but without overt hematological disorders. Despite an increasing number of cases and case series being reported, the prevalence and natural history of MGRS are not known with precision, in part because a systematic search for kidney damage is not standardized in all patients in whom MGUS is diagnosed. Our objective was to analyze in how many MGUS patients urine has been systematically analyzed and in how many of them any alterations suggestive of MGRS were detected. METHOD A retrospective observational study was carried out in our center of all patients in whom a paraprotein had been detected in the blood during the first trimester of 2018 and who did not present a known underlying hematological disorder. Glomerular filtration rate (GFR) was estimated using the CKD-EPI equation. The percentage of patients with a urine test using dipstick and urine sediment was analyzed, as well as the presence or any alteration suggestive of MGRS in them. RESULTS Three hundred and sixty patients were recorded, 44% females and with a mean age of 74 ± 12 years. Mean GFR was 69 ± 22 mL/min/1.73 m2 being 32% below 60 mL/min/1.73 m2. Urine dipstick and urine sediment were performed in only 42% and 24% of patients, respectively. Urine dipstick was more frequently performed in patients with worse GFR (72 ± 20 versus 64 ± 24 mL/min/1.73 m2P = 0.001) and in older patients (73 ± 13 versus 76 ± 11, P = 0.027). Similarly, urine sediment was more frequently performed in patients with worse GFR (72 ± 20 versus 59 ± 25 mL/min/1.73 m2 P &amp;lt; 0.001). Significant hemoglobinuria was found in 38% and dipstick albuminuria in 29% of them. Among those patients with urine sediment analysis, significant hematuria was detected in 56% and leukocyturia in 52%. Patients with significant dipstick hemoglobinuria (70 ± 21 versus 55 ± 26 mL/min/1.73 m2 P &amp;lt; 0.001) and albuminuria (68 ± 21 versus 54 ± 28 mL/min/1.73 m2 P = 0.005) showed worse GFR (figure 1). CONCLUSION Despite the risk of suffering some pathologic renal conditions included in the term MGRS, in most of our patients with MGUS, a urine dipstick or sediment analysis is not performed. MGUS patients with urine alterations show worse renal function. We advocate that all MGUS patients should have a dipstick and sediment urinalysis to rule out any possible associated kidney damage.

Body mass index associated with monoclonal gammopathy of undetermined significance (MGUS) progression in Olmsted County, Minnesota

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal disorder that progresses to multiple myeloma (MM), or other plasma-cell or lymphoid disorders at a rate of 1%/year. We evaluate the contribution of body mass index (BMI) to MGUS progression beyond established clinical factors in a population-based study. We identified 594 MGUS through a population-based screening study in Olmsted County, Minnesota, between 1995 and 2003. Follow-up time was calculated from the date of MGUS to last follow-up, death, or progression to MM/another plasma-cell/lymphoid disorder. BMI (kg/m2 < 25/≥25) was measured close to screening date. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of BMI ≥ 25 versus BMI < 25 with MGUS progression and also evaluated the corresponding c-statistic and 95% CI to describe discrimination of the model for MGUS progression. Median follow-up was 10.5 years (range:0–25), while 465 patients died and 57 progressed and developed MM (N = 39), AL amyloidosis (N = 8), lymphoma (N = 5), or Waldenstrom-macroglobulinemia (N = 5). In univariate analyses, BMI ≥ 25 (HR = 2.14,CI:1.05–4.36, P = 0.04), non-IgG (HR = 2.84, CI:1.68–4.80, P = 0.0001), high monoclonal (M) protein (HR = 2.57, CI:1.50–4.42, P = 0.001), and abnormal free light chain ratio (FLCr) (HR = 3.39, CI:1.98–5.82, P < 0.0001) were associated with increased risk of MGUS progression, and were independently associated in a multivariable model (c-statistic = 0.75, CI:0.68–0.82). The BMI association was stronger among females (HR = 3.55, CI:1.06–11.9, P = 0.04) vs. males (HR = 1.39, CI:0.57–3.36, P = 0.47), although the interaction between BMI and sex was not significant (P = 0.15). In conclusion, high BMI is a prognostic factor for MGUS progression, independent of isotype, M protein, and FLCr. This association may be stronger among females.