High-risk Monoclonal Gammopathy Of Undetermined Significance Research Articles

Patient and provider-level drivers of healthcare utilization related to a diagnosis of a precancerous condition: monoclonal gammopathy of undetermined significance (MGUS).

Monoclonal gammopathy of undetermined significance (MGUS) is the precursor of multiple myeloma. This qualitative study described patient (n = 14) experiences and healthcare providers' (n = 8) opinions and practices concerning care for patients with MGUS in the US. Semi-structured, in-depth interviews were analyzed using thematic analysis. We identified six overarching themes related to the care pathway for patients with MGUS: (1) Process of MGUS diagnosis, (2) Providers' explanations, (3) Patients' understanding, (4) Impact of the diagnosis, (5) Follow-up/management, and (6) Factors influencing healthcare utilization. Patients demonstrated a basic understanding of MGUS. However, some patients felt anxiety around the diagnosis, which may affect other aspects of their lives. Non-hematologist providers report having less MGUS-specific knowledge. Older age, high-risk MGUS, and insurance coverage/healthcare costs influenced healthcare utilization. Patients with MGUS may have difficulty processing this premalignant diagnosis. Non-hematologist providers may have gaps in knowledge around specific care for patients with MGUS.

Predictive Immune Markers for Disease Progression in Multiple Myeloma and Monoclonal Gammopathy of Undetermined Significance

Multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM, are plasma cell neoplasms. The evolution of the treatment of MM in recent years has dramatically improved the outcome for these patients. Currently, multidisciplinary studies are being conducted to elucidate the etiopathogenesis of the disease and develop specific treatment agents and prognostic markers. The present study investigates the relationships between immunoexpression of CD138, Pan-Ras, CCL-3, DKK-1, and MUM-1 and disease progression in cases of MM and MGUS. Immunohistochemical staining for CD138, Pan-Ras, CCL-3, DKK-1, and MUM-1 were performed on bone marrow biopsy samples from 94 MM and 20 MGUS patients diagnosed between 2011 and 2018. Immunohistochemical results were examined semiquantitatively, and the associations between the immunohistochemical, clinical, and biochemical markers utilized for MM and MGUS patient staging were analyzed. Pan-Ras, DKK-1, and MUM-1 staining results were significantly higher in MM compared to MGUS (p=0.005, 0.001, and 0.001, respectively). The mean CCL-3 expression in patients with MGUS was 23.15%, while it was 18.68% in cases of MM (p=0.413). CCL-3 expression was significantly higher in high-risk MGUS cases compared to other risk groups according to the Mayo Clinic Risk Stratification for MGUS. According to the International Staging System and the Revised International Staging System, CD138 expression was higher among stage II and stage III patients than stage I patients. Differences in Pan-Ras, MUM-1, DKK-1, and CCL-3 expressions between MM and MGUS suggest that these molecules may play a role in the progression of MGUS to MM. CCL-3, an immunohistochemical marker, may be predictive of MGUS progression, while CD138 is associated with more advanced stages of MM.

A 12 Gene Signature Accurately Predicts Multiple Myeloma Progression from Monoclonal Gammopathy of Undetermined Significance

Introduction: More than 176,000 individuals are diagnosed with multiple myeloma (MM) worldwide per year. MM is always preceded by an asymptomatic phase, monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM). MGUS is found in 2.4% of individuals ≥ 50 years. The results of long-term retrospective follow-up studies have shown a 1.0% annual risk of MGUS progressing to MM. At present, using conventional serum markers, MGUS patients can be stratified into clinical risk groups. However, these models were based on retrospective analyses of cohorts tested for a limited set of clinical variables which did not incorporate genomic properties and are inconsistent as suggested by recent studies. Our previous work has established that the GEP70 signature can identify high-risk MM patients with median survival is about 2.5 years. A robust high-risk molecular signature predicting MGUS progression is still lacking. Methods: A total of 268 MGUS patients with gene expression profiles (GEPs) were included in this study. Twenty-six progressed to MM within 10 years and were considered the high-risk group, while 242 MGUS patients not progressing to MM within 10 years were referred to as the stable group. Plasma cells were enriched from bone marrow aspirates to >85% purity using anti-CD138 immunomagnetic beads. GEP was performed with the Affymetrix U133 Plus 2.0 microarray platform, using 54,613 gene probes. Affymetrix signals MAS5.0 normalized and transformed by log-base 2 for each sample. We used 3-fold cross-validation to identify the number of genes at the top of this list, probes were ranked by q-values, which collectively maximized the concordance between risk score and MGUS progression. Gene scores were computed by subtracting the average of the expression of down-regulated genes from the average of the expression of up-regulated genes. The overall accuracy of using a gene score to predict the outcome of progression was analyzed by a receiver operating characteristic curve (ROC) and its area under the curve (AUC). MGUS progression was assessed by Kaplan-Meier curves comparing the different groups. Cox proportional hazards regression analyses were applied to evaluate the significance of the gene signature for MGUS progression. Results: Of the 54,613 probes, using q statistics at <0.01, 81 probes were significantly associated with MGUS progression. After the 3-fold cross-validation analysis, the top twelve probes that appeared in each validation and maximized the concordance between risk score and MGUS progression were included in the gene signature 12 (GS12). The up-regulated genes were MTRR (5p15.31) and BAG1 (9p13.3). The down-regulated genes were ECHDC2(1p32.3), NLRP7(19q13.42), BIRC3(11q22.2), PLEKHF1(19q12), PTPN1(20q13.13), CKAP2(13q14.3), RNF5(6p21.32), LIMA1(12q13.12), CEACAM3(19q13.2) and LOC100128079(16p12.1). The ROC analysis showed that the GS12 could accurately predict the MGUS progression in all 268 MGUS patients (AUC = 0.920). An optimal cut-point for risk of progression by the GS12 score was found to be 2.73, which identified a subset of 23 (8.6%) patients with a 10-year progression probability of 73.9%. The remainder of the 245 patients (91.4%) had a probability of progression of only 3.7%. The sensitivity and specificity were 65.4% and 97.5% respectively. Multivariate analysis showed the GS12 to be an independent risk factor for the progression of MGUS to MM. Comparing GS12 with GEP70 showed that GS12 is better at predicting progression to MM than GEP70. GEP70-defined high-risk MGUS predicted risk of progression to MM of 18% while GS12-defined high-risk MGUS raised that estimate to 73.9%. Conclusion: A gene score based upon twelve highly differentiating genes showed excellent accuracy in predicting 10-year MM progression from MGUS. Integration of gene signatures into the routine management of MGUS patients may improve the application of risk-adapted approaches to prevent progression to overt MM. We are in the process of collecting more samples and incorporating RNA-seq data to determine whether this model can be adapted to predict MGUS progression on a larger scale with current state-of-the-art technologies.

A Randomized Placebo-Controlled Phase 2 Study of Metformin for the Prevention of Progression of Monoclonal Gammopathy of Undetermined Significance and Low Risk Smoldering Multiple Myeloma

Background: Multiple Myeloma (MM) is thought to evolve from the precursor conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), which are common premalignant disorders that progress to overt MM in a subset of individuals for reasons that are poorly understood. Despite increasing interest in preventing disease progression in this patient population, the standard of care still consists of close surveillance until progression to MM; however, once MM develops it cannot be cured. Therefore, the identification of prevention and interception strategies for patients with MGUS and SMM is of considerable importance.A promising pharmacologic intervention to reduce the risk of progression of MGUS/SMM to MM is metformin, a drug commonly used to treat type 2 diabetes but that is also considered safe for use in non-diabetic populations. In vivo and in vitro studies have revealed that metformin has direct antitumor effects across a variety of cancers including MM, and recent epidemiological data suggests it may reduce the risk of MM in diabetic patients with MGUS. Here, we describe the first randomized controlled trial testing the efficacy of metformin in reducing clinical signs of disease progression in patients with MGUS and SMM (NCT04850846).Study Design and Methods: This is a phase II single center, randomized controlled trial of metformin vs. placebo in patients with high-risk MGUS and low-risk SMM. The primary objective of the study is to determine whether metformin can reduce or stabilize serum monoclonal (M-)protein concentrations from baseline to 6-months. Exploratory objectives include mass spectrometry quantification of M-protein, examination of molecular evolution of tumor cells in response to metformin, as well as changes in other clinical laboratory parameters in response to metformin.To be eligible, patients must have high-risk MGUS or low-risk SMM. High-risk MGUS is defined as bone marrow plasma cell concentration <10% with one or more of the following higher-risk features: serum M-protein level ≥1.5 g/dL to <3 g/dL or abnormal free light-chain (FLC) ratio (<0.26 or>1.65); a forthcoming amendment will include non-IgG subtype as an additional high-risk feature. Low-risk SMM is defined as bone marrow plasma cells ≥10%with the absence of any features of high-risk SMM.Metformin and its corresponding placebo are the pharmacological treatments. The metformin dose is 1500 milligrams/day, provided in 500 milligram pills. To minimize gastrointestinal symptoms, metformin is started at a low dose of 500 milligram (1 pill) per day and participants gradually increase the dosage over the course of the first month of treatment until the full 1500 milligram (3 pill) per day regimen is achieved. The study treatment period is 6 months, with primary outcomes assessed at the end of the 6-month treatment period.Conclusions and Future Directions: While the cornerstone of clinical management in MGUS and SMM is to delay therapy until progression to symptomatic MM, patients and oncologists continually seek new ways to prevent end organ damage and incurable malignancy. This trial is positioned to provide preliminary but robust mechanistic data to support the development of novel prevention strategies for MGUS and SMM patients. DisclosuresMarinac: GRAIL Inc: Research Funding; JBF Legal: Consultancy. Sperling: Adaptive: Consultancy. Parnes: Sigilon: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; UniQure: Membership on an entity's Board of Directors or advisory committees; Sunovion: Consultancy; I-mAb: Consultancy; Aspa: Consultancy; Genentech/Hoffman LaRoche: Research Funding; Shire/Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Richardson: Protocol Intelligence: Consultancy; Regeneron: Consultancy; Sanofi: Consultancy; Secura Bio: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; AstraZeneca: Consultancy; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy. Nadeem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure:metformin, which is an anti-diabetic medication

Screening for Monoclonal Gammopathy of Undetermined Significance: A Population-Based Randomized Clinical Trial. First Results from the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) Study

Background:Cancer screening is performed worldwide for several malignancies. Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM) and related lymphoproliferative disorders (LP). However, less than 5% of all MM patients are diagnosed during their precursor state and individuals who develop MM while being monitored for MGUS have better overall survival and fewer complications, compared to MM patients diagnosed without knowledge of MGUS. Thus, population-based screening for MGUS could identify candidates for early treatment of MM/LPs. To evaluate whether systematic screening is beneficial, we performed the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study, the first population-based screening study for MGUS that includes a randomized clinical trial (RCT) of follow-up and treatment strategies.Methods:All living residents of Iceland on September 9th, 2016 who were born before 1976 (N=148,708) were invited to participate. Of those, 80,759 (54.3%) provided informed consent for screening. Serum samples were collected from participants alongside clinical blood sampling in the Icelandic health service between September 2016 and the end of 2020. All samples were shipped to the Binding Site in Birmingham, UK, for screening. Samples were tested for M-proteins by capillary zone electrophoresis and immunofixation electrophoresis performed to confirm and characterize suspected M-proteins. Free light chains (FLCs) were measured using the FreeLite® assay. Individuals with a previous diagnosis of MM/LPs/MGUS (N=237) were excluded. Per protocol and informed consent, participants with MGUS were randomized to one of the three study arms: Arm 1 where participants are not contacted; Arm 2 where individuals are followed based on current guidelines; and Arm 3 where individuals are followed with a more intensive diagnostic and monitoring strategy. Participants who progress are offered early treatment. All participants repeatedly answered questionnaires on quality of life and mental health.Results:A total of 75,422 participants (93.4%) provided a serum sample for screening. Of those, 3,725 (4.9%) had MGUS. The prevalence of MGUS was dependent on age with 2.3%, 6.2%, and 12.9% diagnosed in age groups 40-59, 60-79, and 80-103 years, respectively. The prevalence of MGUS was higher in males, 5.9% vs 4.1% (p<0.0001). Most individuals with MGUS had either low-risk (38%) or low-intermediate (36%) risk MGUS, followed by high-intermediate (26%) risk MGUS. High-risk MGUS was only present in 0.2% of MGUS cases (n=9).The RCT includes 3,487 newly diagnosed MGUS individuals with 1164, 1159, and 1164 individuals in arms 1, 2 and 3, respectively (Table). The median age at diagnosis was 69 years in arms 1 and 2, and 70 years in arm 3. Females constituted 45.9% and the isotypes were IgG (50%), IgA (10%), IgM (18%) and biclonal (8%). The median M-protein concentration was 0.34 g/dL. A total of 428 light-chain MGUS cases were randomized. The demographic distribution was well balanced between the three arms.After a median follow-up of 3 years, 194 patients in the RCT have been diagnosed with any LP: 9 in arm 1, 92 in arm 2, and 133 in arm 3 (p<0.001). The participants in arm 1 were diagnosed with smoldering Waldenström's macroglobulinemia (SWM)(N=2), WM (N=2), chronic lymphocytic leukemia (CLL) (N=1), and MM (N=4). Participants in arm 2 were diagnosed with amyloidosis (N=1), SWM (N=18), WM (N=2), CLL (N=2), non-Hodgkin lymphoma (NHL) (N=1), smoldering MM (SMM) (N=56), and MM (N=12). Participants in arm 3 were diagnosed with amyloidosis (N=2), SWM (N=22), CLL (N=5), NHL (N=6), SMM (N=82), and MM (N=16). The difference between study arms was statistically significant for all LPs combined, and for SWM, SMM, and MM (Table).Conclusion:In this large prospective population-based screening study including >75,000 screened persons, we have identified 3,725 individuals with monoclonal gammopathy. In the RCT, after 3 years of follow-up, we show that active screening identifies significantly higher number of individuals with full-blown malignancy and smoldering disease, illustrating the fact that early detection and intervention is achievable. Although our findings are encouraging, until final results of the iStopMM study become available, including data on survival and quality of life, we advise against systematic MGUS screening in healthy individuals. [Display omitted] DisclosuresKristinsson: Amgen: Research Funding; Celgene: Research Funding. Kampanis: The Binding Site: Current Employment. Hultcrantz: Curio Science LLC: Consultancy; Daiichi Sankyo: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Intellisphere LLC: Consultancy. Durie: Amgen: Other: fees from non-CME/CE services ; Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy. Harding: The Binding Site: Current Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Landgren: Janssen: Research Funding; Celgene: Research Funding; Janssen: Honoraria; Janssen: Other: IDMC; Amgen: Honoraria; Takeda: Other: IDMC; Amgen: Research Funding; GSK: Honoraria.

NS-62: The Importance of regular disease monitoring for patients with low or low intermediate risk Monoclonal Gammopathy of Undetermined Significance (MGUS)

<h3>Background</h3> Monoclonal gammopathies encompass a number of disorders characterized by a clone of a normal protein. Although biologically heterogeneous, monoclonal gammopathy of undetermined significance (MGUS) represents the most common of these disorders with the production of a monoclonal protein (Mprotein). This abnormal clone of plasma or other lymphoid cells carries a variable risk of progression to a plasma cell disorders (PCDs) requiring treatment. Few studies report real-world incidence of progression from low risk MGUS to PCDs requiring therapy and with newer risk models. Purpose: To describe characteristics of patients who progress from MGUS to PCD requiring plasma cell directed therapy. <h3>Methods</h3> A list of all patients with MGUS seen at the Cleveland Clinic from 1/1998 to 6/2021 was obtained from an internal IRB approved data base. Demographic information, the date of antecedent MGUS diagnosis, and disease characteristics were confirmed. Patients were categorized as having low, low-intermediate, high intermediate, or high risk MGUS by assigning a point system as follows: Mprotein with IgA isotype (1point), Mprotein concentration of 1.5g/dL or more (1point), serum FLC ratio less than 0.1 or more than 10 (1point), and immunoparesis (≥1 uninvolved immunoglobulins below lower level of normal; 1-2 points).In the scoring system for light-chain MGUS, serum FLC ratio less than 0.1 or more than 10 (1 point) and immunoparesis (1, 2, or 3 points) were identified as risk factors. Patients were excluded if MGUS was diagnosed prior to 2004, missing sFLC, or MGUS <1 year. <h3>Results</h3> Included in this study were 3,188 charts of patients with confirmed MGUS. Of these, 209 were excluded as did not meet criteria for analysis. An additional 102 patient charts were excluded due to incomplete baseline disease evaluation, or a diagnosis of MGUS prior to 2004 (when light chain assay was commercially available). A total of 2,853 patients remained without evidence of disease progression according to 2014 IMWG diagnostic criteria. 23 patients (12M;11F) progressed from MGUS:14 progressed to MM, 6 progressed to amyloidosis, 2 progressed to WM and 1 progressed to MGRS. The median days from MGUS diagnosis to PCD diagnosis requiring therapy was 2,018 days (5.53y). Interestingly, 5 patients had 0 risk factors for progression but still progressed (3 MM, 2 Amyloidosis); 11 had 1 risk factor/low intermediate risk (7 MM,4 Amyloidosis); 6 had 2 risk factors (4 MM, 2 WM) while 1 had 3 risk factors (to MM). <h3>Conclusions</h3> Despite this small sample from a single institution, our findings are consistent with other studies in that the number of patients who progress from MGUS to other PCDs remains low. Routine monitoring can improve the time to diagnosis and minimize the risk of organ damage. Advanced practice providers and nurses are well-suited to monitor and mangage patients with MGUS.These findings support regular blood and urine testing for MGUS and ongoing risk assessment.

The role of bone marrow biopsy in patients with plasma cell disorders: should all patients with a monoclonal protein be biopsied?

We conducted a retrospective review of multiple myeloma (MM), smoldering multiple myeloma (SMM), and monoclonal gammopathy of undetermined significance (MGUS) patients seen at Mayo Clinic to determine whether a bone marrow biopsy (BM) is necessary in all patients diagnosed with a monoclonal protein. A total of 2254 MM, 397 SMM, and 5836 MGUS patients were included in the study. A total of 29 (1.3%) MM patients “without CRAB/FLC” were identified where BM or advanced imaging was critical for diagnosis, 8 (0.3% MM cohort) of whom were diagnosed with MM solely on BM findings (plasma cells > 60%). Without BM or advanced imaging none of these patients would be classified low-risk MGUS. A total of 314 (79%) MGUS-like SMM patients were identified where classification of SMM was based on BM findings. Without BM 97 would be classified as low/low-intermediate-risk MGUS and 151 intermediate or high-risk MGUS; 66 had missing information precluding classification. Only three (<1% SMM cohort) were low-risk MGUS without abnormalities in hemoglobin, calcium, and renal function. In patients presenting with low-risk MGUS and normal hemoglobin, calcium, and renal function, the risk of missing a diagnosis of SMM and MM by omitting BM is <1%. BM should be deferred in these patients in preference to clinical and laboratory monitoring.

Imaging of Monoclonal Gammapathy of Undetermined Significance and Smoldering Multiple Myeloma.

Multiple myeloma (MM) is always preceded by an initial monoclonal gammopathy of undetermined significance (MGUS) that then develops into asymptomatic or smoldering multiple myeloma (SMM), which constitutes an intermediate clinical stage between MGUS and MM. According to a recent study, risk factors for faster MGUS to MM progression include an M protein of 1.5 g/dL or more and an abnormal free light chain ratio in patients with non-IgM MGUS. Therefore, the International Myeloma Working Group (IMWG) decided to recommend whole-body computed tomography (WBCT) for patients with high-risk MGUS in order to exclude early bone destruction. Studies evaluating magnetic resonance imaging (MRI) in SMM found an optimal cutoff of two or more focal lesions to be of prognostic significance for fast progression into symptomatic disease and considered this biomarker as a myeloma-defining event (MDE) needing to start therapy with the aim to avoid progression to harmful bone lesions. Moreover, studies assessing positron emission tomography (PET) with computed tomography (CT) using 18F-deoxyglucose (FDG) (FDG-PET/CT) in SMM showed that presence of focal bone lesion without underlying osteolysis is associated with a rapid progression to symptomatic MM. Latest IMWG guidelines recommended to perform WBCT (either CT alone or as part of an FDG-PET/CT protocol) as the first imaging technique at suspected SMM and, if these images are negative or inconclusive, to perform whole-body MRI. The goal of this paper is to clarify the role of different imaging modalities in MGUS and SMM workups.

Association of Immune Marker Changes With Progression of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma

Multiple myeloma is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS). Risk models that estimate the risk of progression from MGUS to multiple myeloma use data from a single time point, usually the initial workup. To longitudinally investigate the alterations of serum immune markers with stable vs progressive MGUS. This prospective cross-sectional cohort study included 77 469 adult participants aged 55 to 74 years in the screening arm of the National Cancer Institute Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who had a diagnosis of progressing MGUS (n = 187) or stable MGUS (n = 498), including light-chain subtype, from November 1993, through December 2011. For each participant, all available serially stored prediagnostic serum samples (N = 3266) were obtained. Data analysis was performed from April 2018, to December 2018. Serum protein and monoclonal immunoglobulin levels, serum free light chains, and serum light chains within each immunoglobulin class were measured. Of 685 individuals included in the study, 461 (67.3%) were men; the mean (SD) age was 69.1 (5.6) years. In cross-sectional modeling, risk factors associated with progressive MGUS were IgA isotype (adjusted odds ratio [OR], 1.80; 95% CI, 1.03-3.13; P = .04), 15 g/L or more monoclonal spike (adjusted OR, 23.5; 95% CI, 8.9-61.9; P < .001), skewed (<0.1 or >10) serum free light chains ratio (adjusted OR, 46.4; 95% CI, 18.4-117.0; P < .001), and severe immunoparesis (≥2 suppressed uninvolved immunoglobulins) (adjusted OR, 19.1; 95% Cl, 7.5-48.3; P < .001). Risk factors associated with progressive light-chain MGUS were skewed serum free light chains ratio (adjusted OR, 44.0; 95% CI, 14.2-136.3; P < .001) and severe immunoparesis (adjusted OR, 48.6; 95% CI, 9.5-248.2; P < .001). In longitudinal analysis of participants with serial samples prior to progression, 23 of 43 participants (53%) had high-risk MGUS before progression; 16 of these 23 (70%) experienced conversion from low-risk or intermediate-risk MGUS within 5 years. Similar results were found for light-chain MGUS. The findings of evolving risk patterns support annual blood testing and risk assessment for patients with MGUS or light-chain MGUS.

Monoclonal Gammopathy of Undetermined Significance (MGUS)Monoclonal Gammopathy of Undetermined Significance (MGUS).

Monoclonal gammopathy of undetermined significance (MGUS) is one of the most prevalent premalignant conditions associated with a risk of malignant transformation to multiple myeloma (MM) or other forms of lymphoproliferative disorders with risk of progression of approximately 1% per year. IgG and IgA MGUS are precursor conditions of multiple myeloma (MM), whereas light-chain MGUS is a precursor condition of light chain MM. IgM MGUS is a precursor condition of Waldenström macroglobulinemia (MW) or other lymphoproliferative diseases. Assessment of the risk of progression of patients with asymptomatic monoclonal gammopathies (MG) is based on various factors, including the serum paraprotein (M protein) concentration, isotype of M protein, serum free light chain ratio, infiltration of bone marrow plasmocytes, reduction of one or two noninvolved immunoglobulin subtype levels (immunoparesis), evolving and non-evolving subtype of MGUS, ratio of normal/abnormal plasma cells in bone marrow identified by multiparametric flow cytometry techniques and number of circulating plasma cells in peripheral blood. Three risk stratification models have been constructed that are useful in daily practice for predicting risk of progression of MGUS into malignant forms of monoclonal gammopathy - MAYO, PETHEMA and CMG model. The goal of all three models is to identify correctly prognostic markers that can divide patients into low-risk MGUS and high-risk MGUS groups. This review provides a look at the definition, pathogenesis, diagnostic algorithm, clinical significance and stratification of MGUS patients, followed by recommendations for patient risk dispensarisation intervals.

Psychosocial effects of the relaxation response resiliency program (SMART-3RP) in patients with MGUS and smoldering multiple myeloma: A waitlist controlled randomized clinical trial.

10051 Background: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic clonal precursors to multiple myeloma, a hematological malignancy. Because observation is currently the standard of care, a diagnosis of MGUS or SMM can be associated with stress and worry about progression. We evaluated the efficacy of the evidence-based mind-body intervention, the Stress Management and Resiliency Training: Relaxation Response Resiliency Program (SMART-3RP) in reducing distress and stress reactivity in patients with MGUS and SMM. Methods: In participants diagnosed with intermediate or high risk MGUS or SMM, this randomized, waitlist controlled trial (Oct 2013 – Sep 2016) assessed distress (10-point scale) as the primary outcome and perceived stress (PSS-10), stress reactivity (MOCS-A), and mindfulness (FFMQ) as secondary outcomes and hypothesized mediators of distress reduction. We collected self-report measures at enrollment (T1), 3 months (T2), and 6 months (T3). The immediate treatment arm received the 8-session, 1.5 hour/week SMART-3RP group intervention from T1 to T2 and continued practicing skills from T2 to T3; the waitlist arm received the intervention from T2 to T3. Results: 93 participants (59% women) diagnosed with MGUS (n = 49) or SMM (n = 44) were randomized to immediate treatment (n = 45) or waitlist (n = 48). In an ITT analysis of immediate SMART-3RP vs. waitlist (T1-T2), we found significantly greater improvement in distress (-1.4 vs. -0.3, p = .04) and stress reactivity (0.39 vs. 0.02, p &lt; .001), but not perceived stress (-3.9 vs. -2.2, p = .12) or mindfulness (2.4 vs. -0.1, p = .17). Improvements in stress reactivity were maintained for the immediate treatment group (T2-T3), but only partially for distress. Conclusions: The SMART-3RP, compared to waitlist, reduced distress in participants with intermediate or high-risk MGUS and SMM, with improvements in stress reactivity as a primary mediator of distress reduction. Participants strongly endorsed the intervention’s ability to enhance coping and reduce distress. Clinical trial information: NCT01955395.

Significance of Bone Marrow Plasma Cell Percentage in Patients with Monoclonal Gammopathy of Unknown Significance Developing Multiple Myeloma

Introduction: Monoclonal gammopathies are characterized by the detection of a monoclonal immunoglobulin in the serum or urine and underlying proliferation of a plasma cell/B lymphoid clone. (1) Patients with monoclonal gammopathy of undetermined significance (MGUS) have a clonal plasma cell population in the marrow (<10%) and secrete a monoclonal protein in the serum (<3g/dL) and/or urine. However, they lack clinical features of overt Multiple Myeloma (MM) (lytic bone lesions, anemia, renal impairment and hypercalcemia). In a study from the Mayo Clinic, 59 of 241 patients with MGUS (24%) developed MM over a period of 22 years. (2) The interval from recognition of monoclonal protein to diagnosis of MM ranged from 2-29 years, indicating that patients with MGUS need to be followed indefinitely. Many risk factors have been looked at to identify those with MGUS who are at the highest risk to progress into MM. We hypothesize that a higher number of plasma cells would correlate with a greater risk of progression to MM and sought to find out if this could be documented by arbitrarily dividing patients between < or ≥5% plasma cells seen on initial bone marrow biopsy.Methods: We retrospectively reviewed patients diagnosed with MGUS at Henry Ford Hospital between 1999-2013 who underwent a bone marrow biopsy for documenting plasma cell percentage. In addition to this, we also recorded serum hemoglobin, calcium, creatinine, monoclonal protein type and amount, serum free light chains, beta-2 microglobulin and urine for monoclonal protein at the time of diagnosis of MGUS as well as last completed values. For patients that had skeletal surveys we noted if lytic lesions were present at diagnosis, as well as cytogenetics and karyotype evaluations on bone marrow biopsy samples, if completed.Results: 120 patients with bone marrow biopsies were reviewed. Out of this 17 patients were noted from initial bone marrow biopsy to have ≥10% plasma cells. The remaining 103 patients were categorized as having MGUS. While we were not able to complete full statistical analyses, we did note that 14 of these 103 (13.6%) patients went on to develop overt MM. Further evaluation of these patients revealed that 8 of 14 (57%) had bone marrow biopsies showing ≥5% plasma cells. Interestingly the average time to progression into MM in this subgroup was 1,879 days whereas in the 6 of 14 (43%) with bone marrow biopsy showing <5% plasma cells had average time to progression into MM of 1,965 days. Abnormal cytogenetics and karyotypes of the bone marrow biopsy were also seen in 37.5% of the subgroup of patients with ≥5% plasma cells whereas it was only seen in 16.7% of the subgroup of patients with <5% plasma cells. With statistical data analyses we hope to prove significance in the above collected data as well as make further correlations in regards to risk factors in patients with MGUS.Conclusion: While we have not been able to complete full statistical analyses of the collected data yet, basic review of the above patients with MGUS and ≥5% plasma cells in the bone marrow biopsy showed a trend to develop MM faster by an average of 86 days than those that had <5% plasma cells. These same patients also were more likely to have abnormal cytogenetics and karyotypes of their bone marrow biopsies. There is a need for further investigations to be done in patients with MGUS and higher risk features. It is important that hematologists be able to recognize a high risk MGUS patient as this would lead to closer monitoring and consideration for earlier aggressive treatment to potentially delay progression into overt MM. DisclosuresNo relevant conflicts of interest to declare.

Comment on: Monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and curcumin: A randomized, double‐blind placebo‐controlled crossover 4g study and an open‐label 8g extension study

To the Editor: We read with interest the results of this clinical study by Golombick et al. [1]. This and two previous articles from the same authors show that in some, but not all patients with monoclonal gammopathies, the paraprotein load, urinary bone turnover, and the free light chain ratio (FLCr), prognostic factors for progression of disease, did moderately improve. Although the results are hopeful and the medico-scientific world looked forward to the recent follow-up of the previous studies, they also indicate that it is still unclear which criteria would allow to preselect responsive patients so that trials could become more meaningful. Curcumin had been chosen by the authors because of its capacity to down-regulate interleukin-6 (IL-6), an inflammatory cytokine, known to be associated to indicators of systemic inflammation such as C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR). Curcumin has been known for centuries in India as an anti-inflammatory compound and long-term curcumin intake significantly reduces CRP levels [2]. There is consequently reason to speculate that the observed response to curcumin might be associated to the presence of inflammation. This is especially true as inflammation-related microenvironmental factors may locally sustain ongoing lymphoproliferation and B cell transformation [3]. Regrettably, however, neither IL-6 nor CRP or ESR levels, associated to an unfavorable prognosis, have been reported. In case the authors are in the possession of data on IL-6, CRP, or ESR, it would be very easy to verify whether or not their results gain in statistical significance when the presence of inflammation at baseline is used as a patient selection criterion. Even if for none of these indicators data would be available, it might still be tempted to gain insight on the basis of existing results. Absolute levels of FLCs rather than their ratio have recently been suggested as potential biomarkers of immune stimulation and inflammation. CRP appears to be a most relevant indicator in acute illnesses. However, in cases where the CRP response is limited it appears associated to FLC levels [4]. Stratification of the available data according to the absolute levels of uninvolved FLCs (uFLCs) might, therefore, be used in an attempt to verify whether there is an association between the response of the three prognostic factors used to curcumin and the baseline level of uFLCs. If such an association is found and if the response of the three markers is coherent, uFLCs levels might serve as a criterion for patient selection in future trials on curcumin for monoclonal gammopathy of undetermined significance (MGUS) and thereby improve their statistical significance. Curcumin has given some hope to doctors and patients because it is relatively nontoxic in healthy people. Nevertheless, there are reasons for concern about safety in patients with monoclonal gammopathies [5]. As stated by the authors, curcumin may benefit some but not all patients with high risk MGUS. A rapid identification of the subgroup of patients who could benefit from curcumin treatment would be appreciated by all concerned. We, therefore, eagerly look forward to the above suggested further elaboration by the authors on the interesting results of their study [1]. Alphons J. M. Vermorken*, Jingjing Zhu*, Willem J. M. Van de Ven*, Emmanuel Andrès , * Department of Human Genetics, Laboratory for Molecular Oncology, KU Leuven, Belgium, Department of Internal Medicine, Diabetes and Metabolic Disorders, University Hospital of Strasbourg, Strasbourg, France.

Can Whole-body Low-dose Multidetector CT Exclude the Presence of Myeloma Bone Disease in Patients with Monoclonal Gammopathy of Undetermined Significance (MGUS)?

To determine the benefit of using whole-body low-dose computed tomography (WBLD-CT) in patients with monoclonal gammopathy of undetermined significance (MGUS) for exclusion of multiple myeloma (MM) bone disease. Seventy-one consecutive patients with confirmed MGUS (as defined by the latest criteria of the International Myeloma Working Group) who underwent WBLD-CT for diagnosis were identified retrospectively by a search of our institution's electronic medical record database (2002-2009). Patients were classified as low-risk or intermediate/high-risk and followed over a ≥2-year period with additional CT imaging and/or laboratory parameters. Presence of osteolysis, medullary, or extramedullary abnormalities compatible with involvement by MM was recorded. A diffuse or focal increase in medullary density to Hounsfield unit (HU) values >20 HU/>0 HU was considered suspicious for bone marrow infiltration if no other causes identifiable. The presence of osteolysis was excluded in all 71 patients with MGUS at initial diagnosis and patients were surveilled for ≥2 years. Lytic changes were observed at follow-up in 1/71 patients that progressed to MM and were detectable via WBLD-CT at an early stage (even before a significant rise in M-protein was recorded). In 3/71 patients with MGUS (4%) suspicious bone marrow attenuation values were measured, disclosing disease progression to smoldering myeloma in another patient and false-positive results in 2/71 patients. Bone marrow attenuation assessment resulted in a specificity and negative predictive value of 97%, respectively. No significant difference with respect to bone marrow attenuation was observed in patients with low-risk MGUS versus intermediate- to high-risk MGUS. One of 71 patients showed serologic disease progression to active MM without bone abnormalities detectable. WBLD-CT reliably excludes findings compatible with myeloma in MGUS and thereby complements hematologic laboratory analysis.

Monoclonal gammopathy of undetermined significance: to screen or not to screen for multiple myeloma? – response

Monoclonal gammopathy of undetermined significance: to screen or not to screen for multiple myeloma? – response

Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management

Monoclonal gammopathy of undetermined significance (MGUS) was identified in 3.2% of 21 463 residents of Olmsted County, Minnesota, 50 years of age or older. The risk of progression to multiple myeloma, Waldenstrom's macroglobulinemia, AL amyloidosis or a lymphoproliferative disorder is approximately 1% per year. Low-risk MGUS is characterized by having an M protein <15 g/l, IgG type and a normal free light chain (FLC) ratio. Patients should be followed with serum protein electrophoresis at six months and, if stable, can be followed every 2-3 years or when symptoms suggestive of a plasma cell malignancy arise. Patients with intermediate and high-risk MGUS should be followed in 6 months and then annually for life. The risk of smoldering (asymptomatic) multiple myeloma (SMM) progressing to multiple myeloma or a related disorder is 10% per year for the first 5 years, 3% per year for the next 5 years and 1-2% per year for the next 10 years. Testing should be done 2-3 months after the initial recognition of SMM. If the results are stable, the patient should be followed every 4-6 months for 1 year and, if stable, every 6-12 months.

Bone Marrow Immunophenotypic Analysis Allows the Identification of High Risk of Progression and Immune Condition-Related Monoclonal Gammopathy of Undetermined Significance.

Abstract 2804Poster Board II-780 Background:Monoclonal gammopathy of undetermined significance (MGUS) progresses to plasma cell dyscrasia, mainly multiple myeloma (MM), at a rate of approximately 1% per year. Moreover, recent studies have shown that MM is nearly always preceded by MGUS, encouraging investigators to find better predictors for MM development in order to implement strategies to prevent or delay progression. In addition, a high prevalence of MGUS has been noted in a series of patients with immune disorders or chronic infections. Multiparameter flow cytometry allows the identification and quantification of both monoclonal and polyclonal plasma cells. This study analyses the relationship between monoclonal and polyclonal bone marrow plasma cells (BMPC), studied by means of flow cytometry, and its association with either immune or infectious disorders, or the development of MM in newly diagnosed MGUS patients. Methods:We conducted a retrospective cohort study to analyse the prognostic value of the aberrant (CD38++ CD138+ CD19– CD45weak) to normal (CD38++ CD138+ CD19+ CD45+) phenotype bone marrow plasma cells ratio (A/N ratio) and another 13 variables at baseline for the development of a plasma cell dyscrasia. We also performed a cross-sectional study to evaluate the association of those variables at baseline with the presence of a chronic immune response disorder. In each patient, the following variables were examined: age, sex, hemoglobin, serum creatinine, serum calcium, B2-Microglobulin, type and size of the serum monoclonal component (MC), isotype of the MC immunoglobulin, presence of urine MC, quantification of serum immunoglobulin levels, erythrocyte sedimentation rate, BMPC percentage and presence of atypical plasma cells on light microscopy, and aberrant and normal phenotype BMPC percentages. The effect of variables on progression was calculated using a Cox proportional hazards regression model. To identify variables at baseline associated with immune or chronic infectious disorders. a series of univariate and multivariate analyses was fitted using a binary logistic regression strategy. Results:Between March 1997 and April 2008, flow cytometry analysis on bone-marrow samples was performed on 322 patients with newly diagnosed MGUS. Median patient age was 71 years (interquartile range (IQR) 63-78 years) with a slightly male predominance (51%). Median follow-up was 46 months (IQR 23-58 months). During the period of observation, in 23 (7.1%) patients a transformation was registered into: MM (n=22), and primary amyloidosis (n=1). A total of 24 (7.4%) patients had a diagnosis of autoimmune disorder, and 18 (5.6%) patients of a chronic infection. Multivariate analysis for progression to MM revealed an increased A/N ratio as the main independent prognostic variable. In addition, our study found a significant association between a reduced A/N ratio and the diagnosis of a chronic immune response related condition. Using receiver-operating characteristic analysis we created an A/N ratio range from 4 to 0.20. Values of 4 or higher define a group of MGUS patients at high risk of progression (OR, 10.7; 95% confidence interval 4.2-39), whereas A/N ratio values of 0.20 or lower are associated with immune disorders or chronic infections (OR, 20.9; 95% confidence interval 8.5-51.1). A total of 282 patients had an A/N ratio below 4, and 42 had values equal to or above the cut-off. Patients with an A/N ratio ≥ 4 had a cumulative probability of transformation of 35% at 5 years, compared with 3% for those with an A/N ratio < 4. Conclusions:Extreme values of the A/N ratio at diagnosis seem to be related with two different conditions: high risk MGUS, likely to progress to MM, and immune condition related MGUS. Our findings further support the routine use of phenotypic characterization of bone marrow plasma cells in patients with MGUS at diagnosis. Disclosures:No relevant conflicts of interest to declare.

Gene Expression Profiles of Tumor Biology Provide a Novel Approach to Prognosis and May Guide the Selection of Therapeutic Targets in Multiple Myeloma

Monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) comprise heterogeneous disorders with incompletely understood molecular defects and variable clinical features. We performed gene expression profiling (GEP) with microarray data to better dissect the molecular phenotypes, sensitivity to particular chemotherapeutic agents, and prognoses of these diseases. Using gene expression and clinical data from 877 patients ranging from normal plasma cells (NPC) to relapsed MM (RMM), we applied gene expression signatures reflecting deregulation of oncogenic pathways and tumor microenvironment to highlight molecular changes that occur as NPCs transition to MM, create a high-risk MGUS gene signature, and subgroup International Staging System (ISS) stages into more prognostically accurate clusters of patients. Lastly, we used gene signatures to predict sensitivity to conventional cytotoxic chemotherapies among identified clusters of patients. Myc upregulation and increasing chromosomal instability (CIN) characterized the evolution from NPC to RMM (P < .0001 for both). Studies of MGUS revealed that some samples shared biologic features with RMM, which comprised the basis for a high-risk MGUS signature. Regarding MM, we subclassified ISS stages into clusters based on shared features of tumor biology. These clusters differentiated themselves based on predictions for prognosis and chemotherapy sensitivity (eg, in ISS stage I, one cluster was characterized by increased CIN, cyclophosphamide resistance, and a poor prognosis). GEP provides insight into the molecular defects underlying plasma cell dyscrasias that may explain their clinical heterogeneity. GEP also may also refine current prognostic and therapeutic models for MGUS and MM.

A Pre-Existing Plasma Cell Disorder Occurs in Most Patients with Multiple Myeloma.

Background. A pre-existing plasma cell disorder (PPCD), such as monoclonal gammopathy of undetermined significance (MGUS), is thought to be present in at least one-third of patients presenting with symptomatic multiple myeloma (MM). However, no study has comprehensively evaluated the proportion of patients with MM that had a PPCD by laboratory testing on pre-diagnostic sera.Methods. The Walter Reed Army Medical Center autologous stem cell transplant database was cross-referenced with the Department of Defense Serum Repository (DoDSR) database, which catalogs serum samples collected every 2 years on over 4 million active-duty service members. All samples 32 years prior to the diagnosis of MM were retrieved. Serum protein electrophoresis (SPEP), immunofixation electrophoresis (IFE) and serum free light chain analysis (sFLC) (The Binding Site, San Diego, CA) were performed on all samples. A PPCD was defined as a positive SPEP, IFE or abnormal sFLC ratio.Results. Serum samples prior to the diagnosis of MM were available for 30/90 patients, and the median number of samples per patient was 3.5 (range, 1–14). The median age at diagnosis of MM was 48.1 yrs (29–67), with 96% male, 53% Caucasian, and 47% African-American. The Ig isotype of MM was IgG 76%, IgD 10%, light-chain 7%, and non-secretory 7%. A PPCD was detected in 27/30 patients (90%, 95% CI 74–97%). The initial PPCD was detected by sFLC alone in 6/27 (22.2%), IFE alone 2/27 (7.4%), SPEP+IFE 5/27 (18.5%), SPEP+IFE+sFLC 13/27 (48.1%) and IFE+sFLC 1/27 (3.7%). There were 4 patients whose only positive sera was 2.5–3.5 years prior to diagnosis, with all preceding sera negative.Conclusions. First, a pre-existing plasma cell disorder is present in most MM patients at least 2.5 years prior to diagnosis. Second, consistent with published evidence for a small fraction of patients with high risk MGUS, 4/30 patients were documented to progress rapidly through an MGUS phase to MM. Third, 4/4 patients with light chain only or non-secretory MM had a PPCD that was detected only by sFLC, thereby indicating that all these tumors are preceded by a light chain only or non-secretory PPCD.

Increased Risk of Monoclonal Gammopathy in First-Degree Relatives of Patients with Multiple Myeloma or Monoclonal Gammopathy of Undetermined Significance.

Background: Monoclonal gammopathy of undetermined significance (MGUS) is a common pre-malignant plasma cell disorder associated with a 1% per year risk of progression to multiple myeloma or related malignancy. Since the risk factors for MGUS are poorly defined, the goal of the present study was to determine if the risk of MGUS is increased in first degree relatives of patients with known multiple myeloma (MM) or MGUS.Methods: MGUS probands (index cases) were recruited from a population-based prevalence study of MGUS in Olmsted County, MN while MM probands were recruited through the Mayo Clinic practice. Consenting probands were asked to provide contact information on all first-degree relatives ages 40 years and older. Serum samples were then collected from first-degree relatives with informed consent and subjected to agaraose-gel electrophoresis and immunofixation. The prevalence of MGUS in first-degree relatives of MM and MGUS probands was compared to population-based rates from Olmsted County using risk ratios (RR). For comparisons to the reference population, only cases detected by protein electrophoresis and confirmed by immunofixation were included so that the diagnostic strategy was identical in the two groups being compared.Results: Serum samples were obtained from 911 relatives of 329 unique families, including 493 siblings, 324 children and 94 parents of patients with MGUS or MM. Using protein electrophoresis, monoclonal protein was detected in the serum of 55 (6%) while immunofixation identified 28 additional relatives (3%), for an age- and sex-adjusted prevalence rate of 8.1% (95%CI: 6.3, 9.8). The age-specific prevalence of MGUS in first-degree relatives increased with age (1.9%, 6.9%, 11.6%, 14.6%, and 21.0% for ages 40–49, 50–59, 60–69, 70–79 and ≥80, respectively; P<0.001). Based on similar MGUS detection methodology as the reference population, there was a significantly higher risk of MGUS in first-degree relatives (age-adjusted RR, 2.6, 95%CI: 1.9, 3.4) compared to the reference population. The increased risk (P<0.001) was seen both in relatives of MM probands (RR, 2.0, 95%CI: 1.4, 2.8), as well as MGUS probands (RR, 3.3, 95%CI: 2.1, 4.8). This association was similar across age of proband, age and gender of relative, and relationship of the first-degree relative. When examining whether the increased risk of MGUS in relatives was specific to probands with a large monoclonal protein concentration or specific monoclonal immunoglobulin isotype (i.e. high-risk MGUS phenotype), there was suggestion of a greater risk for relatives of probands with a high (3 1.5 g/dL) M-protein (RR, 2.8, 95%CI: 2.0,3.8) compared to lower M-protein levels (RR, 1.8, 95%CI: 1.1,2.8) although the difference did not reach statistical significance (P=0.12). The risk of MGUS in relatives did not differ by proband's isotype (IgG vs. other).Conclusions: First-degree relatives of patients with MM or MGUS have a greater than two-fold risk of MGUS compared to the general population, implying underlying genetic predisposition for these diseases and providing rationale for identifying genetic determinants of MGUS. This study also provides important baseline rates of MGUS in first-degree relatives that impact the clinical care of these patients.