Low-risk Monoclonal Gammopathy Of Undetermined Significance Research Articles

The China Monoclonal Gammopathy Screening Project in First-Degree Relatives of Patients with Multiple Myeloma (CHAPERONE) –a Multicenter Screening Study

Background and Significance: Multiple myeloma (MM) evolves from the precursor state monoclonal gammopathy of undetermined significance (MGUS). According to previous reports, the incidence of MM and its precancerous state MGUS was lower in Asian populations than in Western populations. However, with the aging of the population, we found that the incidence of MM in China has been on the rise in recent years, and the medical burden has continued to increase. Therefore, early recognition of MM and its precursor condition is even more critical. Our previous research has confirmed that monoclonal gammopathy (M-protein) screening and close follow-up of MGUS can increase the early diagnosis rate of MM and improve the prognosis of MM patients[1]. M-protein screening in healthy people at high risk for MM is a rational strategy. The risk of MM in the first-degree relatives of myeloma patients is 2-4 times that of the general population, constituting a high-risk group for MM. Although the screening of M-protein in high-risk populations has been explored in the US (the PROMISE study), little was known about the incidence, clinical features, and prognosis of MGUS in high-risk groups in China. Here, we describe the first prospective screening project to assess the potential benefits of M-protein screening and the prevalence and outcomes of MGUS in first-degree relatives of patients with multiple myeloma in the China population (NCT05965115). Study Design and Methods: The CHAPERONE study is a prospective, multicenter screening study for MGUS in first-degree relatives of MM patients, including a risk-stratified follow-up strategy(Figure). Clinical trial registry number: NCT05965115, actively recruiting. This study aims to assess the clinical significance of screening for monoclonal gammopathy in first-degree relatives of patients with multiple myeloma in China. The primary objective is to determine the prevalence and incidence rate of MGUS, the time to disease progression (TTP), and its influencing factors in first-degree relatives of MM patients in China. The secondary and exploratory study objective is to explore the clinical/genomic features, survival, and quality of life of the screened MGUS cases. The expected screening size is 10,000 healthy persons. To be eligible, participants must be over 18, with one or more first-degree relatives (including parents, children, and biological siblings) having multiple myeloma diagnosed by the International Myeloma Working Group (IMWG) Myeloma Diagnostic Criteria. Participants with a known diagnosis of plasma cell diseases, such as MGUS, smoldering myeloma (SMM), or MM, will be excluded. All eligible participants will receive M-protein screening by serum electrophoresis. Individuals with detected M-protein will undergo further diagnostic tests, including peripheral blood tests (immunofixation electrophoresis, serum free light chain, immunoglobulin quantification, blood routine, liver and kidney function, and blood calcium level) and X-ray bone assays. Patients with suspecting MM features will undergo further bone marrow surveys to ascertain the diagnosis. Patients with MGUS will be carefully assessed and stratified by the risk of progression to MM according to the IMWG MGUS consensus. Low-risk MGUS will be followed-up annually, while intermediate/high-risk MGUS will be biannual. Participants who progress to MM will be offered early treatment. Conclusions and Future Directions: One path to making MM a preventable cancer is better understanding its precursor condition (MGUS). This trial is positioned to provide epidemiology, clinical, and potential mechanistic data on MGUS at a high-risk group in China population that has yet to be thoroughly studied. Reference: [1] Li J, Wang Y, Liu P. The impact on early diagnosis and survival outcome of M-protein screening-driven diagnostic approach to multiple myeloma in China: a cohort study[J]. J Cancer, 2019, 10(20): 4807-4813.

Primary Care Management Pathways to Reduce Wait Times in Hematology: Monoclonal Gammopathy of Undetermined Significance

Background:Prolonged wait times are a worsening barrier to accessing specialist care in Canada and other countries across the globe. The flow of patients between primary care and specialists has been a recognized area for improvement (Liddy et al., 2020; Moir & Barua, 2021). Kingston Health Sciences Centre (KHSC) has aimed to optimize referrals through the implementation of primary care management pathways (PCMPs). PCMPs are diagnostic and/or treatment algorithms, co-developed by local primary care physicians and specialists with input from patients. They are designed to support primary care providers in managing low risk medical conditions in the community while more quickly identifying patients with higher risk conditions to be seen by specialists. A PCMP was implemented in June 2021 for Monoclonal Gammopathy of Undetermined Significance (MGUS) (https://kingstonhsc.ca/refer/hematology). This asymptomatic condition with low levels of monoclonal protein in the blood or urine has an approximately 1% per year risk of transforming to a hematological malignancy such as multiple myeloma (Kyle et al., 2018). The MGUS PCMP outlines diagnostic criteria, management, and monitoring instructions for low-risk MGUS along with patient information. “Red flag” features, such as renal impairment, anemia or significantly increased monoclonal protein levels, are used to highlight those who need urgent referral. The aim of this study is to evaluate the impact of an MGUS PCMP on wait times in Hematology in Kingston, Ontario. Methods:All consecutive outpatient Hematology referrals received at KHSC from January 2021 to December 2022 were reviewed. Monthly outcome measures included the number of new referrals and median wait times for patients seen. Number of MGUS referrals deferred to the PCMP was included as a process measure. Monthly balancing measures included number of re-referrals of PCMP patients, number of deaths without being seen for MGUS, and number of new multiple myeloma diagnoses. To compare 6-month pre-PCMP implementation (January 2021 to June 2021) with 18-month post-PCMP implementation (July 2021 to December 2022), generalized linear regression analysis was conducted. p < 0.05 was considered statistically significant. A survey of primary care providers was distributed through the regional Primary Care Physicians' Council to assess primary care satisfaction with the PCMP. Results: Between January 2021 and December 2022, 4504 Hematology referrals were received, 278 (6%) of which were MGUS referrals. 76 (27%) of MGUS referrals were deferred to the PCMP. There was a significant increase in monthly Hematology referrals from a mean (± standard deviation (SD)) of 163.0 (± 13.9) pre-PCMP to 195.9 (± 27.3) post-PCMP (p<0.0001). There was no significant difference in mean monthly MGUS referrals pre-and post-PCMP (11.7 ± 4.7 versus 11.6 ± 3.5). Hematology's median wait time for those seen fell from a median (interquartile range (IQR)) of 51.3 days (13) pre-PCMP to 28.5 days (11) post-PCMP (p < 0.0001). The MGUS median wait time also fell from a median (IQR) of 40.5 days (59) to 37.0 days (32.5) (p < 0.0001). No significant difference was noted in the balancing measures. Pre-PCMP to post-PCMP, the mean number of deaths without being seen for MGUS (0.17 ± 0.41 versus 0.17 ± 0.38, p=0.36) and mean monthly new multiple myeloma diagnoses (5.17 ± 1.94 versus 5.17 ± 2.50, p = 0.54) remained stable. There were 7/76 (9.2%) re-referrals of patients deferred to the PCMP, with a median (IQR) time to re-referral of 64 days (348). A survey to assess primary care provider satisfaction with the PCMP included a total of 28 respondents; 19/28 (67.9%) reported using PCMPs. On a scale of 0 to 5, where 5 is the highest satisfaction, the median (IQR) overall experience was 4/5 (1.5) and impacts on supporting patient care and changing management were also 4/5 (1). The most common concern, raised by 7/28 respondents (25%), was the downloading of more work to primary care. Conclusion: The MGUS PCMP was associated with reduction in wait times for overall Hematology and MGUS despite an increase in referrals. Limitations of this study include concurrent changes in the program, including staffing and the COVID-19 pandemic. These results suggest that PCMPs may be an effective tool to address Hematology wait times, likely best complemented with other strategies to avoid overburdening primary care providers.

Risk of MGUS, a multiple myeloma precursor, in relation to food and beverage intake in the National Health and Nutrition Examination Survey (NHANES).

e20062 Background: Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder (PCD) with a prevalence of 3% in adults over age 50. The annual risk of progression to multiple myeloma (MM) is 1%. Although one cohort study in Caucasians reported that diets low in certain plant-based foods were associated with MGUS (Thordardottir et al. 2018), research on diet and MGUS in a more diverse population is scarce. Given that diet can vary greatly across ethnic/racial groups, we conducted a population-based study with multiple races and ethnicities. Methods: Using the National Health and Nutrition Examination Survey (NHANES), we conducted a case-control study in 373 individuals with MGUS and 1,406 controls frequency matched on age, body mass index, NHANES cycle, sex, and race. Diet was characterized by one 24-hour dietary recall, with gram intake of individual foods and beverages aggregated into groups. MGUS status was determined by blood screening. Unconditional multivariable logistic regressions were used to model associations between MGUS and intake, with odds ratios and 95% confidence intervals reported for the highest quantile of intake. Results: Daily intake of several food and beverage groups were significantly associated with MGUS, low-risk MGUS (LRMGUS) or intermediate/high-risk MGUS (IHRMGUS). Whole-grain bread, oats, and rice; fruits and vegetables; tomatoes; and cruciferous vegetables were associated with significantly lower risk (28-78%). Sugar- and artificially sweetened beverages were associated with significantly higher risk (34-113%). Interestingly, there were more significant findings for LRMGUS than IHRMGUS, suggesting potential contributing etiologic differences for LRMGUS and IHRMGUS. Conclusions: Our study shows that low intake of whole grains, fruits and vegetables and high intake of sweetened beverages are associated with MGUS. The identification of dietary risk factors for MGUS in a diverse population is of direct public health relevance. These findings also provide rationale for exploration of mechanistic links between diet and PCDs, such as the ongoing studies NCT04920084, NCT05640843, and NCT05312255. [Table: see text]

Association of Progression Patterns in Monoclonal Gammopathy of Undetermined Significance (MGUS) with Outcome in Multiple Myeloma: A Cohort Study of over 35 Years

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

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.

An evaluation of patient workflow in hematology clinics at a university hospital referred for the workup of monoclonal gammopathy of undetermined significance (MGUS).

207 Background: Monoclonal Gammopathy of Undetermined Significance (MGUS) is an asymptomatic premalignant condition that can be a precursor to multiple myeloma and lymphoproliferative disorders. There exists no best practice for the workup of MGUS, despite the number of patients diagnosed every year. We evaluated the workup of MGUS patients at a University Hospital Hematology clinic before and after implementation of an algorithm based on the Mayo Clinic Risk Stratification Model. Methods: This was a single-center IRB-approved retrospective study. Charts of 132 patients referred for MGUS were reviewed across two groups (A: June 2019 -May 2020 and B: June-Dec 2020). Use of the Mayo Clinic Risk Stratification Model for MGUS was implemented in May 2020. Data regarding initial work up, bone marrow studies and imaging were collected. Statistical analyses were performed using R software for computing (4.0.4). Results: Patient demographics and those who did not need further work up per the algorithm are summarized in table. All 86 new (100%) referrals had an initial CBC, creatinine, calcium, SPEP, and IFE while 7(8.1%) did not have an FLC assay. 43(50%) patients had a 24-hour urine protein electrophoresis. 65.1% (56/86) [group A: 26; group B: 30] met the criteria for no extended workup; 39.3% of these (22/56) underwent imaging while 7.1% (4/56) underwent bone marrow exam. After implementation of the algorithm, the number of patients who underwent imaging studies decreased from 50% (13/26) to 30% (9/30). Skeletal survey was the most ordered imaging modality (90.1%,20/22). Conclusions: Our study highlights the overutilization of imaging studies in low-risk MGUS patients. Approximately 50% of patients with MGUS are low risk with a lifetime risk of progression being less than 2%. In these patients avoiding extensive testing will minimize costs without adversely affecting clinical outcomes. We recommend a dedicated MGUS clinic to improve workup and monitoring of these patients. [Table: see text]

Impact of Bone Marrow Biopsy on Risk Stratification of Low-Risk IgG MGUS Patients

▪Introduction: Multiple myeloma (MM) is a plasma cell malignancy accounting for 10% of all hematological malignancies and characterized by significant inter and intra-patient heterogeneity. MM usually progresses from asymptomatic precursor stages, namely monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Previous recommendation by the IMWG indicated that bone marrow evaluation should be deferred in patients with low levels of IgG M-protein (< 1.5g/dL). Here, we sought to examine the clinical characteristics and progression patterns of patients who are defined as low risk MGUS by IMWG criteria but who also had a bone marrow biopsy performed.Methods: A total of 244 patients with an IgG M-protein < 1.5 g/dL were identified from two cancer centers, Dana-Farber Cancer Institute, Boston, MA, USA and the Department of Clinical Therapeutics, Athens, Greece, in the period between 1998 to 2016. Patients who had undergone bone marrow biopsy immediately following the detection of M-protein in their serum were included in our cohort. Patients with IgA type or free light chain (FLC) disease were excluded because of their known high risk of progression. Continuous variables were summarized as median and interquartile range (IQR). Time-to-event endpoints were estimated using the method of Kaplan and Meier. The multivariate analysis was undertaken using Cox proportional-hazards regression, likelihood ratio model to identify independent predictors of progression among this group of patients. Subgroup analysis was performed according to the FLC ratio.Results: Median age at diagnosis was 63 years and male to female ratio was 1.31. IgG k was present in 62.3%, while IgG l in 46.3% of patients. Median FLC ratio was 1.7 (IQR 0.9-3.2) and 51% of patients had an abnormal FLC ratio. In 54.5% of the patients, bone marrow infiltration by clonal plasma cells was ≥ 10%, reclassifying these patients as having SMM rather than MGUS. The time to progression to MM was significantly different between the patients with and without BM infiltration ≥ 10% in the Kaplan-Meier estimate (log-rank p= 0.004) (Figure 1). Subgroup analysis showed that patients with abnormal FLC ratio had a higher percentage of BM involvement (12% vs. 6%, p < 0.001) and 67% had ≥10% BM plasma cells vs. 44% of those with normal FLC ratio (p= 0.002); M-spike was also higher in those with abnormal FLC ratio (0.9 vs. 0.6, p < 0.001), as well as the probability of disease progression (median time-to-event: 9.2 years vs. not reached, log-rank p= 0.015).Conclusion: Our findings indicate that over 50% of patients previously classified as low risk MGUS, based on the presence of an IgG monoclonal protein < 1.5 g/dL, would be reclassified as having SMM. Indeed, these patients had a higher risk of disease progression to symptomatic MM. Patients with less than 10% plasma cells and normal FLC had a negligible risk of progression. Thus, our data suggests that patients with M spike of < 1.5gm/dL should still undergo a bone marrow biopsy to complete their disease evaluation and help improve risk assessment for disease progression. Further validation of these results in other cohorts is warranted. [Display omitted] DisclosuresKastritis:Prothena: Honoraria; Janssen: Honoraria; Genesis pharma: Honoraria; Takeda: Honoraria; Amgen: Honoraria, Research Funding. Laubach:Novartis, Takeda, Celgene, Onyx: Research Funding; Novartis, Takeda, Celgene: Consultancy. Anderson:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; MedImmune: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees; Oncopep: Other: scientific founder; Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Other: scientific founder. Richardson:Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Oncopeptides AB: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dimopoulos:Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy, Honoraria, Other: Advisory Committee: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology; Genesis Pharma: Research Funding; Novartis: Consultancy, Honoraria.

Diagnosing and Managing Plasma Cell Disorders: Education Gaps in Primary Care Providers and Hematologist/Oncologists

Background: Diagnosis of plasma cell disorders (PCD) may be delayed due to generalized symptoms in patients. In fact, a recent analysis demonstrated that 2 years prior to diagnosis, 58% of patients with multiple myeloma (MM) indicated they had back pain and 34% had fatigue or weight loss [Goldschmidt N et al, JABFM 2016]. Furthermore, diagnostic criteria, staging, monitoring and management of PCD has vastly changed over the past decade allowing better methods for assessment and treatment options for patients with these disorders [Rajkumar SV et al, Lancet 2014, Palumbo A et al, JCO 2015]. To elucidate the clinical practice gaps in PCD, a study was undertaken to assess the ability of primary care providers (PCPs) and hematologists/oncologists (hem/onc) to appropriately diagnose, monitor, refer, stage and manage patients with PCD.Methods: A continuing medical education-accredited clinical practice assessment survey was developed utilizing current evidence-based consensus guidelines and best practices in plasma cell disorders (http://www.medscape.org/viewarticle/866138 ). The assessment consisted of 20 multiple-choice, knowledge- and case -based questions that clinicians completed confidentially on-line starting on August 18, 2016. The questions assessed: diagnosis, risk stratification, and criteria to initiate therapy, monitoring, and management of patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and MM. Responses from physicians were de-identified and aggregated prior to analysis.Results: As of July 11, 2017, 161 PCP and 281 hem/oncs participated in the assessment. Of the PCPs and hem/onc respondents, 45% and 38%, respectively, saw 1 to 5 patients with PCD per month. PCPs indicated that knowledge of appropriate tests was the biggest barrier in accurately diagnosing PCD (50%); whereas, hem/oncs indicated accessibility to tests was the biggest barrier (33%). Key findings included the following:Diagnosis of PCDMost clinicians were able to identify serum protein electrophoresis (SPEP) and immunofixation as necessary tests to order for diagnosing MGUS in a patient with elevated protein and mild anemia (79% PCPs and 94% hem/oncs). However, when presented with the outcome of laboratory tests, only 45% of PCPs were able to recognize that a patient may have a PCD and should be referred to a hem/onc. Based on the results of laboratory tests, less than half (42%) of PCPs were able to recognize that the patient had SMM or symptomatic myeloma and required referral. Only 24% of PCPs indicated that bone morrow examination, serum free light chain (sFLC), and testing for Bence Jones protein in urine were necessary to diagnose MM in a patient. Only 23% of PCPs and 50% of hem/oncs were aware of the new diagnostic criteria for myeloma that included sFLCs of involved/uninvolved ratio > 100.Monitoring and StagingBoth PCP and hem/oncs struggled with the frequency of assessing a patient with MGUS for progression to SMM (32% and 30% of PCPs and hem/oncs, respectively, answering the patient should be seen at 6 months). 51% of PCPs and 74% of hem/oncs were able to identify the parameters of a patient with low-risk MGUS. Based on the results of test parameters only 29% of hem/oncs were able to identify the patient had revised ISS stage III SMM, and only 40% were able to assess that the patient had high risk SMM according to the Mayo criteria.Conclusions: This educational research yielded important insights into clinical knowledge gaps for both the PCP and hem/onc. Both groups demonstrated education gaps in the areas of ordering and interpretation of tests, monitoring requirements, timing of referral, staging/risk assessment. Given the critical role that PCPs and hem/oncs play in the management of PCD, increased clinician awareness of gaps and tailored education is warranted in order to improve outcomes in patients with PCD. DisclosuresOrlowski:BioTheryX: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mikhael:Celgene Corp: Research Funding; sanofi-aventis: Research Funding; Abbvie: Research Funding.

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.

Monoclonal Gammopathy of Undetermined Significance: Indications for Prediagnostic Testing, Subsequent Diagnoses, and Follow-up Practice at Mayo Clinic

ObjectivesTo determine the indications for prediagnostic testing, subsequent diagnoses found, and follow-up practices in patients who were incidentally diagnosed with monoclonal gammopathy of undetermined significance (MGUS). Patients and MethodsFrom our prospective MGUS database, we identified 329 patients residing in southeastern Minnesota who were diagnosed from January 1, 2011, through December 31, 2014, and followed up at Mayo Clinic. ResultsMost test orders came from nonhematologists (n=310, 94.2%). The top 5 indications were neuropathy (n=65, 19.8%), renal disease (n=45, 13.7%), anemia (n=42, 12.8%), bone disorder or connective tissue pain (n=42, 12.8%), and cutaneous disease (n=19, 5.8%). Hypercalcemia was an infrequent indication (n=9, 2.7%). The final diagnosis for all neuropathy evaluations was sensory/motor neuropathy—not otherwise specified, with 18.7% having IgM MGUS. Chronic kidney disease—not otherwise specified, iron deficiency, and osteoporosis/osteopenia were the most common subsequent diagnoses for test indications of renal disease, anemia, and bone disorder or connective tissue pain, respectively. Most patients (n=213, 64.7%) had 1 or more follow-up visit during the study period. A minority were followed by hematologists (43.5%, n=143). Patients with low-risk MGUS comprised 45.0% (n=148) of the cohort. Male patients and younger patients were more likely to be followed up than their counterparts (P<.01). About one-third (n=27, 32.1%) of patients 80 years or older (n=84) continued to have regular follow-up visits. Hematologists were more likely to follow patients with MGUS more closely than nonhematologists (P<.001). However, the intensity of follow-up was not based on MGUS risk. ConclusionMonoclonal protein testing is commonly performed for signs and symptoms not typically associated with lymphoplasmacytic malignancies. There is a significant variation in MGUS follow-up between hematologists and nonhematologists (P<.001) that is not based on risk factors or clinical practice guidelines.

The Utilization of Screening Tests for Plasma Cell Dyscrasias By Internal Medicine Physicians at a Teaching Hospital

Background. Plasma cell Dyscrasias (PCD) are a spectrum of monoclonal gammopathies which result from proliferation of plasma cells that produce an immunologically homogeneous protein known as M-protein. PCDs include monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), multiple myeloma (MM), Waldenstrom's macroglobulinemia (WM), primary amyloidosis (AL), plasmacytoma, light chain deposition disease (LCDD) and POEMS syndrome. Screening for gammopathy is usually done by serum protein electrophoresis (SPEP) with immunofixation (IFE), serum free light chains (FLC) and urine protein electrophoresis (UPEP) with immunofixation. Except for low risk MGUS, early diagnosis can have a significant impact on the clinical outcome of PCD. Thus, accurate and timely screening for early diagnosis is crucial. In this study, we aim to evaluate the screening process for plasma cell dyscrasias in a teaching hospital by targeting internal medicine physicians including primary care physicians. Methods: We retrospectively reviewed charts of 2532 patients who had undergone PCD screening tests at Truman Medical Center (TMC), the primary teaching hospital for University of Missouri-Kansas City (UMKC). The studied data was from two blocks of time: 2011-2012 and 2017-2018. Only patients who were &gt;18 years of age and who had any of these screening tests done for the very first time during the study period were included. Patients who had tests done outside of the study period or had prior similar testing or known diagnosis of PCD were excluded. Data was collected to assess if screening tests had been ordered appropriately by internal medicine physicians. Appropriate screening was defined as a screening that had SPEP along with IFE and FLC. We compared internal medicine physicians' utilization of these tests between two different time frames 1/1/2011-12/31/2012 versus 1/1/2017-12/31/2018. Results: A total of 2532 patients were reviewed. 1076 were included with a mean age of 57.4 years. Population demographic is detailed in Table 1. Most of the PCD screening tests were ordered in the outpatient setting (67%). The three most common indications for testing were workup of chronic kidney disease, abnormal serum protein levels and neuropathy (Figure 1). Outcomes of screening tests are shown in Figure 2. Majority of these tests were ordered by internal medicine physicians (42%) followed by nephrology (19%) and hematology-oncology services (10%). Internal medicine ordered 448 tests overall. During 2011-2012 they screened 211 patients. Out of these, 199 had SPEP, 19 had IFE, 68 had UPEP and 23 patients had FLC ordered on initial screening. Only 18 patients (8.5%) were screened appropriately. Between 2017-2018, a total of 237 patients were screened by internal medicine physicians. Among them 231 had SPEP, IFE was checked by automatic reflex (a new feature added by our lab in 2013) in 138 patients, UPEP was ordered 67 times and 48 patients had FLC checked with 45 patients (19%) screened appropriately. Conclusion : Screening for plasma cell dyscrasias is frequently done by physicians from specialties other than hematology-oncology. Ordering an appropriate set of tests including FLC in addition to SPEP with IFE is imperative at time of initial screening. Our study showed that internal medicine physicians order most of the intial testing for PCD, however they often miss incorporating FLC as part of their screening for PCD. This could potentially lead to missing some cases and delay in timely diagnosis. Although there has been improvement in ordering appropriate screening, but proper measures should be undertaken to increase the efficacy of screening for PCD. Disclosures No relevant conflicts of interest to declare.

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): Indications for Pre-Diagnostic Testing, Subsequent Diagnoses, and Follow-up Practice

Introduction: MGUS is generally an incidental finding in the diagnostic work-up for clinical signs and symptoms suggestive of lymphoplasmacytic malignancies (multiple myeloma, light chain amyloidosis, and Waldenström macroglobulinemia), which are relatively rare (<35,000 annual new cases in the US). While much is known about the natural history of MGUS, information regarding the pre- and post-diagnostic part of MGUS patient care is lacking. Our study objectives were to determine the following: 1) indications for monoclonal protein testing; 2) subsequent diagnoses found for those indications; 3) specialty of ordering clinicians; 4) follow-up patterns after MGUS diagnosis.Methods: We identified MGUS patients residing in southeastern Minnesota who were diagnosed from 2011-2014 and followed at the Mayo Clinic. Medical records were reviewed to confirm the diagnosis and obtain relevant clinical data. Laboratory tests and visits were identified using Current Procedural Terminology-4th edition (CPT-4) codes from billing data. We defined a follow-up visit as: 1) any face-to-face encounter linked to MGUS diagnosis 30 days after the date of MGUS diagnosis regardless of whether ancillary test was performed or not; and 2) MGUS-specific tests or laboratory tests linked to an MGUS diagnosis claim performed without a face-to-face encounter. Based on the Mayo Clinic MGUS risk stratification model, we classified our cohort into either low-risk or non-low risk. Criteria for low-risk used were: serum monoclonal protein <1.5 g/dL, IgG subtype, and normal serum free light chain ratio. Follow-up patterns were analyzed according to year of diagnosis, demographics, and the specialty of clinicians performing the follow-up.Results: 330 MGUS patients were included in the study. The median age at diagnosis was 73 years (range, 21-98) and most were males (59.7%). The common indications for monoclonal protein studies were neuropathy (19.6%), kidney disease (13.6%), anemia (12.7%), bone symptoms/signs (12.7%), cutaneous disorders (5.8%), congestive heart failure (4.8%), and hypercalcemia (2.7%). The most common subsequent diagnoses for these indications were neuropathy not otherwise specified (NOS;100%), chronic kidney disease NOS (35.5%), anemia of chronic kidney disease (19%), osteopenia/osteoporosis (45.2%), congestive heart failure NOS (57.1%), and dermatitis NOS (100%), respectively. The practice specialties that most commonly diagnosed MGUS were internal medicine (31.3%), neurology (13.7%), nephrology (10.3%), family medicine (6.1%), and hematology (5.8%).Low risk MGUS comprised 44.8% of the cohort. After a median follow-up of 53.5 months (range, 13.0-77.4; IQR, 40.8-77.4), the total number of follow-up visits was 937. Majority (85.5%) of the visits were a combination of office visit with laboratory testing, while the rest were either office visit (11.2%) or laboratory tests (3.3%) only. The distribution of patients by mean interval between visits was: every <6 months (7.9%); every 6-12 months (19.4%); every 13-24 months (15.2%), and every >24 months or no follow-up at all (57.6%). The follow-up patterns did not change significantly (Kruskal Wallis; P=0.6759) over time (Figure 1) and were similar when age groups were compared (Figure 2; P=0.1328). However, males were followed more frequently than females (P=0.0365). Among patients 80 years and older, 32.1% continued to be followed at least once every 2 years (Figure 2). Hematologists were more likely than non-hematologists to follow MGUS patients regardless of the risk category (Figures 3-4). Among low risk patients, 31.1%, 22.2%, 20.7%, and 19.1% had at least one follow-up during years 2, 3, 4, and 5, after MGUS diagnosis (Figure 3).Conclusions: Approximately 1/3 of MGUS diagnoses were made during the evaluation of signs and symptoms not related to lymphoplasmacytic malignancies. The subsequent diagnoses found were a wide variety of common diseases. Most MGUS diagnoses were made by general internists, neurologists, and nephrologists. Follow-up practices varied between hematologists and non-hematologists. Nearly 1/3 of the oldest old patients continued to have follow-up, despite limited life expectancy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

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.

Monoclonal gammopathy of undetermined significance as viewed by haematology healthcare professionals.

To investigate the words and descriptions used by haematology healthcare professionals (HCPs) to describe monoclonal gammopathy of undetermined significance (MGUS) to their patients. A cross-sectional survey of haematology HCPs attending an annual haematology conference was undertaken. Content analysis was applied to the returned qualitative responses. In total, 55 people, many of whom were doctors (n=32; 58.2%), responded. The majority of respondents reported using simple terminology such as "abnormal protein" to describe MGUS to their patients. Some reported using analogies that the patient was more likely to be familiar with, such as comparing a paraprotein to the finding of a mole or lump. Education level, age and cognitive ability were cited as important factors in deciding how and whether information was relayed to patients. Many respondents supported frequent follow-up and the transfer of low-risk MGUS patients to primary care. However, several highlighted a lack of awareness and understanding of MGUS outside of haematology, particularly within primary care. Only 41.8% of respondents reported providing all of their patients with an information leaflet. With an ageing population, it is important to consider management strategies for MGUS patients. Our findings will assist those in making these arrangements.

Cost Effectiveness in Low Risk MGUS Patients

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant disorder characterized by the asymptomatic presence of a monoclonal protein. It is defined by an M protein < 3 gm/dl, less than 10% clonal plasma cells in the bone marrow, and the absence of anemia, hypercalcemia, renal insufficiency and bone lesions. In 2010 the International Myeloma Working Group (IMWG) advocated for MGUS patients to be stratified into low risk disease, which carries a 5% risk of progression to multiple myeloma at 20 years, and high risk disease, which represents a 20% risk at 20 years. This stratification model categorizes patients as low risk if they have an IgG paraprotein with an M-component < 1.5 g/dl and a normal free light chain (FLC) ratio. As such, it is suggested that the initial workup be comprised of a serum protein electrophoresis (SPEP), an immunofixation (IFE), and a FLC ratio. A bone marrow biopsy (BM) and bone survey should only be performed if anemia, hypercalcemia or an elevated creatinine of unclear etiology is noted. If these studies place a patient into the low risk, it is suggested the patient follow up at 6-months with only an SPEP. If the SPEP is stable, the next follow-up is recommended to occur at 2 to 3 year intervals unless symptoms arise suggestive of a plasma cell dyscrasia.The risk stratification of MGUS patients was validated in 2013 by Turesson et al. in a Swedish cohort (Blood, 2014; 123:338-345). Nevertheless, the risk model is not universally accepted and unnecessary office visits along with laboratory studies are performed on low risk patients.The purpose of this study was to perform an internal retrospective review of our patients diagnosed with low risk MGUS, evaluating excess medical costs incurred when patients were not risk stratified by the IMWG recommendations.Methods:MGUS patients seen in the Hematology Oncology Division of Drexel University between 2014 and 2016 were retrospectively categorized into high and low risk based on the IMWG criteria. Those determined to be low risk were evaluated over two years for extra costs incurred outside the IMWG recommendations. Extra cost was tallied based on initial workup and surveillance studies performed up to two years from diagnosis.Costs per test and follow up visits were based on our office appointment pricing and BM biopsy charges. Laboratory costs were obtained based on pricing from ACCU reference lab.Cost per test (varies by lab/provider)SPEP $67UPEP $130Serum IFE $200Urine IFE $72IgA $27IgG $27IgM $27K/L ratio $120B2 microglobulin $42Office Visit $40 - $100Bone Survey $500 - $1200BM biopsy $500- $1000Results:Sixty patients seen between 2014 and 2016 met the criteria for MGUS. Twenty-eight patients were determined to have low risk disease. Of the 28 patients, five were diagnosed prior to 2010 and were excluded. In the remaining 23 patients, four followed up at exactly six months from diagnosis and only one had an SPEP. The most common test ordered was quantitative immunoglobulins (QI) aside from a CBC and CMP. The total number of excess office visits was 49. Three patients had unnecessary BM biopsies (total cost $1,000 - $2,000), and 11 had unnecessary bone surveys (Total $5,500 - $13,200). The total cost of unnecessary lab tests within 2 years was $6,024 and the total cost of unnecessary office visits within 2 years was $1960 - $4900. Thus, the average excess spent per patient was $630 - $1135, for a total excess cost for the 23 patients of $14,484 - $26,124.Conclusion:This internal review highlights the excess medical costs incurred when patients are not risk stratified by the IMWG recommendations. Ideally, no further health care dollars should be spent for low risk MGUS patients who have a stable SPEP at the 6-month visit until the 2 or 3 year follow up visit. The actual excess amount spent in our office in 2 years for these patients was $14,484 - $26,124 beyond the cost of the standard of care recommended by the IMWG guidelines. Additionally, these values did not include excess basic labs such as a CBC or CMP and it did not include extension of our investigation out to three years which would result in further unnecessary costs. One patient was noted to accumulate excess cost due to his co-morbid condition of prostate cancer, which led to increased surveillance for his low risk MGUS. The risk stratification model allows physicians to offer patients a better understanding of their disease, decrease the patient's burden and reduce the cost on healthcare. DisclosuresNo relevant conflicts of interest to declare.

Evaluation of Current Clinical Models for Risk of Progression from Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma or Related Malignancies in 2028 Persons Followed in the Czech Republic

Introduction:Monoclonal gammopathy of undetermined significance (MGUS) is a non-malignant condition associated with a risk of progression to multiple myeloma (MM) or related disorders. There are currently 2 clinical models predicting progression from MGUS to MM. The Mayo Clinic model uses levels and type of serum monoclonal protein (M-protein) and serum free light chain ratio (sFLC). The Spanish PETHEMA model uses flow cytometry of bone marrow plasmocytes (BMPC) and the presence of DNA aneuploidy.Purpose:The primary end point was to estimate the cumulative risk of hematologic disorders occurring during the follow-up of our cohort. The secondary end points were: to validate known clinical models suggested by the Mayo Clinic group and the Spanish PETHEMA group for the risk of progression from MGUS to MM or related malignancies and to establish a new risk model by the Czech Myeloma Group (CMG model) with better prediction of low-risk MGUS group.Group:Data for this study were obtained from the Registry of Monoclonal Gammopathies (RMG) acquired from hematologic centers of the Czech Republic. MGUS diagnosis was made according to IMWG criteria. In total, 2028 persons with MGUS were enrolled in the RMG study from May 2007 to June 2013. A total of 93% (1887/2028) of persons were evaluated.Results:1887 MGUS persons were followed with median 4 years. Malignancies developed in 8.6% (162/1887) cases; MM occurred in 77.2% (125/162) of persons. The risk of progression was 1.5% at 1 year, 7.6% at 5 years and 16.5% at 10 years after diagnosis. The key predictors factors of progression were as follows: age ≥ 69 years, serum M- protein concentration ≥ 1.5 g/dL, BMPC > 5%, pathological sFLC ratio (< 0.26 or >1.65), immunoparesis of polyclonal immunoglobulins, levels of serum hemoglobin at baseline < 12.0 g/dL and the presence of normal plasma cells (nPC) in bone marrow ≤ 5 % identified by multiparametric flow cytometry techniques. Distribution of MGUS persons according to risk groups based on the Mayo Clinic model confirmed predictive power of Mayo Clinic model based on our data although isotype of M- protein was not found as independent predictor. At 10 years, no-risk group had 4.9% risk of progression compared to 16.3%, 24.6%, and 54.9% in groups with 1, 2 or 3 risk factors, respectively (p< 0.001). MGUS group with 1, 2 and 3 risk factors in comparison to the reference group without any risk factor had HR( 2.59 [95% CI: 1.39- 4.84]; p= 0.003, HR 4.79 [95% CI: 2.56-8.93]; p< 0.001, HR 12.97 [95% CI: 5.52-30.48];p< 0.001), retrospectively. Immunoparesis instead of DNA aneuploidy was used together with the presence of abnormal plasma cells (aPCs) to validate the modified PETHEMA model. The rates of progression at 3 years were 2.5%, 8.1% and 28.0% for groups with neither, one or both risk factors, respectively (p< 0.001). MGUS group with 1 and 2 risk factors in comparison to the reference group without any risk factor had HR (3.98 [95% CI: 1.60-9.91]; p= 0.003, HR 14.23 [95% CI: 2.86-70.76]; p< 0.001), retrospectively. Based on the 5 parameters with independent predictive value in the univariate analysis (immunoparesis, serum M-protein quantity ≥ 1.5 g/dL, BMPC > 5%, abnormal sFLC ratio and serum level of hemoglobin < 12.0 g/dL) we proposed a new CMG model. The created CMG model clearly detected MGUS persons at low risk 86.6% (828/956) with the risk of progression 5.6% at 5 years better than previously described models. As expected, the number of MGUS persons with the highest risk of progression was limited to 3.7% only (35/956), with the risk of progression 31.9% at 5 years. The MGUS group with 5 risk factors had 63 times higher hazard of progression compared to reference MGUS group (HR 63.17 [95% CI: 13.99-285.36]; p< 0.001).Conclusion:In the large cohort of MGUS persons, we confirmed validity of previously considered clinical models for the risk of progression from MGUS to MM by the Mayo Clinic group and the Spanish PETHEMA group (model used for SMM). New CMG model for the risk of progression from MGUS to MM or related malignancies was established with an advantage for better identification of MGUS persons at low risk (87% of persons with risk of progression below 10% in 5 years) as well as few persons at the highest risk of progression. As a consequence, limited evaluation and visits can be planned in majority of MGUS persons in follow-up.Acknowledgments: This work was supported by grants NT13492-4, NT14575-3 and by EU FP7/2007-2013; grant n° 278570. DisclosuresNo relevant conflicts of interest to declare.

Multiple Myeloma Patients With Prior Knowledge Of MGUS Have a Better Survival Compared To Multiple Myeloma Patients Without Prior Knowledge Of MGUS

BackgroundA recent prospective cancer screening trial including over 77,000 individuals followed-up for over 10 years shows that multiple myeloma (MM) is consistently preceded by a precursor state, monoclonal gammopathy of undetermined significance (MGUS). Clinically, most newly diagnosed MM patients are unaware of their prior MGUS state. Importantly, among individuals diagnosed with MGUS, only a small proportion will develop MM or a related malignancy during their lifespan. Current clinical guidelines suggest lifelong, annual monitoring of individuals diagnosed with MGUSto detect progression to MM or related disorders. At this time, the impact of annual monitoring on the outcome of patients who eventually develop MM is unknown. In addition, as MGUS is usually diagnosed during work-up for another disorder, the impact of comorbidity in MM patients with prior knowledge of MGUS is unknown. We assessed the impact of prior knowledge of MGUS in relation to MM survival. Patients and MethodsThe study cohort consisted of 14,798 individuals diagnosed with MM in Sweden 1976-2005, with follow-up until 2007. A total of 394 patients had previously been diagnosed with MGUS. Patients diagnosed with MM were identified through the Swedish Cancer Register. MM patients with prior knowledge of MGUS were identified from a nationwide MGUS cohort which was established from in and out-patient units from major hospital-based hematology/oncology centers in Sweden. Details of sex, date of birth, date of diagnosis, type and concentration of M-protein at MGUS diagnosis, and comorbidities (autoimmune diseases, infections, other malignant diseases, ischemic heart diseases, heart failure, cerebrovascular diseases, chronic lung diseases and renal diseases) were gathered for all patients. Survival rate from time of MM diagnosis comparing patients with and without prior knowledge of MGUS was calculated with a Kaplan Meier method. Risk factors for death were analysed in a Cox proportional hazards model where relative risks (RR) and 95% confidence intervals (CIs) were calculated. A Chi-square test was used to evaluate whether there was a significant difference in comorbidities. ResultsMM patients with prior knowledge of MGUS had significantly (RR = 0.86; CI = 0.77-0.96) better survival (median = 2.8 years; 95% CI = 2.6-3.3) than MM patients without prior knowledge of MGUS (median = 2.1 years; 95% CI = 2.1-2.2; Figure). Older age at diagnosis (RR = 1.04; 95% CI = 1.04-1.05) was associated with an inferior survival, whereas female sex and recent year at diagnosis were related to improved survival: RR = 0.86 (CI = 0.83-0.89) and 0.95 (CI = 0.95-0.95), respectively. There was no difference in survival comparing MGUS patients with high (>1.5 g/dL) versus low (<1.5 g/dL) M-protein concentration (RR = 1.01; 95% CI 0.72-1.41). Unexpectedly, M-protein concentration ≤0.5 g/dL at MGUS diagnosis was associated with poored survival than M-protein concentration greater than 0.5 g/dL (RR = 1.86; 95% CI = 1.13-3.04, p=0.014). [Display omitted] Autoimmune diseases (p<0.001), infections (p<0.001), other malignant diseases (p<0.001), ischemic heart diseases (p<0.001), heart failure (p<0.001), cerebrovascular diseases (p<0.001), and renal diseases (p<0.001) at diagnosis of MM were significantly more common in MM patients with prior knowledge of MGUS than in MM patients without. ConclusionsBased almost 15,000 MM patients diagnosed in Sweden between 1976 and 2005, for the first time, we found that prior knowledge of MGUS is associated with better survival (median overall survival 2.8 versus 2.1 years). Given patterns of co-morbidities, the observed survival difference is likely a reflection of the fact that MGUS patients are evaluated more often for signs of MM progression and may be diagnosed/treated at an earlier stage. The finding that low-risk MGUS patients that develop MM had a shorter survival rate is interesting and may be due to less intense monitoring and needs to be studied further. Our observations raise the question whether screening for MGUS, e.g., above the age of 50, could translate into earlier detection/treatment of MM (“early myeloma“) and lead to better survival. Future prospective studies are needed to explore these findings further. Disclosures:Turesson:Celgene Corp: Honoraria.

Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma: A Review of the Current Understanding of Epidemiology, Biology, Risk Stratification, and Management of Myeloma Precursor Disease

The term monoclonal gammopathy of undetermined significance (MGUS) was coined in 1978. The recent advances in our knowledge about MGUS and smoldering multiple myeloma (SMM) have helped us better understand the pathogenesis of myeloma. It seems that myeloma evolves from a precursor state in almost all cases. We do not completely understand the multistep process from the precursor state to myeloma, but studies like whole genome sequencing continue to improve our understanding of this process. The process of transformation may not be linear acquisition of changes, but rather a branched heterogeneous process. Clinical features that are prognostic of rapid transformation have been identified, but no specific molecular markers have been identified. Even with recent advances, multiple myeloma remains an incurable disease in the vast majority, and intervening at the precursor state provides a unique opportunity to alter the natural history of the disease. A limitation is that a vast majority of patients with precursor disease, especially low-risk MGUS, will never progress to myeloma in their lifetime, and treating these patients is not only unnecessary but may be potentially harmful. The challenge is to identify a subset of patients with the precursor state that would definitely progress to myeloma and in whom interventions will have a meaningful impact. As our understanding of the molecular and genetic processes improves, these studies will guide the selection of high-risk patients more appropriately and ultimately direct a tailored management strategy to either delay progression to symptomatic myeloma or even "cure" a person at this premalignant stage.