Monoclonal Gammopathy Of Undetermined Significance Follow-up 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.

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.

Monoclonal gammopathy of undetermined significance (MGUS): where is the hidden danger? Definition and work-up

SummaryMonoclonal gammopathy of undetermined significance (MGUS) is a premalignant hematological condition arising from B‑cells, characterized by the presence of monoclonal immunoglobulin production, also known as paraprotein. It is found in up to 3% of individuals over the age of 50 years. The overall progression rate is low at around 1% per year, with most patients progressing to multiple myeloma (MM). Other diseases that may arise from MGUS include non-Hodgkin lymphomas, Waldenström macroglobulinemia, amyloid light-chain (AL) amyloidosis, POEMS (polyneuropathy, organomegaly, endocrinopathy, M‑protein, skin changes), cryoglobulinemia, monoclonal gammopathy of renal significance (MGRS), and additional paraprotein-driven diseases. Every case of monoclonal gammopathy warrants careful investigation to rule out the presence of a malignant form. In recent years, paraprotein-associated conditions such as MGRS have been increasingly recognized. Accurate diagnosis and work-up of these cases require a multidisciplinary approach, and it is paramount to accurately distinguish them from true MGUS in order to prevent end-organ damage. Follow-up of MGUS should be lifelong; however, a risk-adapted approach involving the primary care setting is recommended.

A Single-Center Retrospective Study to Investigate the Follow-Up of Patients with Monoclonal Proteinemia by Community Physicians in the UK.

BackgroundWe determined the detection rate of monoclonal gammopathy of undetermined significance (MGUS) and follow-up of MGUS patients in a center that uses reflex testing at globulin levels outside the reference range as part of its routine service to detect monoclonal protein (M-protein). We recorded the natural history and follow-up of these patients. This is one of the first reports on the diagnosis and follow-up of MGUS patients within the UK.Patients and MethodsA total of 163 patients diagnosed in 2006 and 393 patients with M-protein on long-term follow-up in 2006 were followed over a period of 10 years (y) by community physicians with laboratory support.ResultsIn 2006, newly diagnosed patients with an M-protein and total number of patients as a percentage of the Worcestershire population were, respectively, 0.025%, 0.045% (at 45–49y); 0.1%, 0.25% (at 60–64y); and 0.26%, 1.12% (at 75–79y). Patients with M-protein had a survival of 35.5% at 10 y and 43.5% at >10y follow-up. Kaplan–Meier analysis of patients with an M-protein showed that lymphoplasma-cell proliferative disorders (LPD)-free survival was 91% for both 10y and >10y follow-up. LPD-free survival decreased to approximately 73% when competing causes (death due to unrelated causes, transient M-protein, loss to follow-up) were censored. Progression to LPD occurred at initial M-protein values of 3g/L at diagnosis. During follow-up, 38.3% died without evidence of LPD, 12% were diagnosed with transient M-protein, 8.7% developed LPD, 10.9% had stable M-protein, 4.9% showed increasing M-protein, and 25.2% were lost to follow-up. Survival curves showed that M-protein isotype contributed to LPD-free survival in the order IgG=IgM>IgA>biclonal M-protein.ConclusionGeographical variations in the diagnosis and follow-up of MGUS patients in the UK need investigation. From public health viewpoint, it is essential to determine MGUS follow-up to improve clinical care and individualise risk-based follow-up of patients.

Diagnosis and Follow-Up of MGUS

Monoclonal gammopathy of undetermined significance (MGUS) usually is discovered as an incidental finding on serum protein electrophoresis (SPEP). In

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.

Monoclonal gammopathy of undetermined significance in medical hospital admissions - a new strategy for screening?

Monoclonal gammopathy of undetermined significance (MGUS), is a common clonal plasma cell disorder with a prevalence that increases with age up to 3·2% in those aged >50 years in population-based screening studies (Kyle et al., 2006). It is a precursor of myeloma and certain other lymphoproliferative diseases, with a risk of progression of about 1% per year. Also, in the absence of malignant transformation MGUS may be associated with complications that motivate further examination and treatment (Go & Rajkunar, 2018). Most studies on MGUS, including risk factors for progression and association with comorbidities, have been done in patients where serum protein electrophoresis was performed during the medical evaluation of various symptoms and constitute a selected population. In this journal, Catherine Atkins and coworkers present data on the prevalence of MGUS in unselected emergency medical hospital admissions. After obtaining informed consent, serum samples were collected and M protein identified by protein electrophoresis and immunofixation. The study by Atkins et al. has produced some interesting data (Atkins et al., 2020). First, they show that the prevalence of MGUS is considerably higher in this group than reported in a large study based on population screening (Kyle et al., 2006). There is a debate on the pros and cons of population screening for MGUS, considering on one hand the need for early diagnosis of myeloma, and on the other hand the overall low risk of progression, the impact on healthcare resources and concern that the diagnosis of MGUS might cause unneccessary anxiety (Go & Rajkunar, 2018). The present study suggests that patients admitted to an emergency unit might represent a select population for screening with a favourable health economy compared to screening of the general population. The authors have also attempted to find explanations for the increased prevalence by studying reasons for admission and comorbidity. Unfortunately, the number of cases is too low to draw any definite conclusions. However, some interesting associations are reported including comorbidities such as heart failure and chronic kidney disease. Although no cases of light-chain (AL)-amyloidosis or light-chain deposition disease were identified in the study, the follow-up is limited and the observation highlights the need to consider clinical characteristics to identify patients who should be further examined for M protein-related diseases. An interesting observation is that some patients had a previously detected M protein that was unknown to the patients and evidently was not acted upon. This indicates an unmet need for education about follow-up of MGUS. Although several clinical practice guidelines for risk stratification and follow-up have been published, the adherence to these is often low (Go et al., 2017). Current practical guidelines do not recommend population screening for MGUS or treatment of MGUS, but this can change. Ten years ago, only patients with symptomatic myeloma defined by CRAB criteria (C, hypercalcaemia; R, Renal insufficiency; A, Anaemia; B, Bone lesions) were treated, but now a number of studies indicate that patients with smouldering (asymptomatic) myeloma may benefit from treatment (Landgren, 2017). In the future, treatment of selected patients with MGUS with a high risk of progression may be considered. There is limited information on the effect of routine follow-up of MGUS on early diagnosis of multiple myeloma and on survival (Go et al., 2015; Sigurdardottir et al., 2015). A randomised controlled trial (iSTOPMM [Iceland Screens Treats or Prevents Multiple Myelom] study) is ongoing in Iceland, with the aim to assess the benefits and harms of population screening and follow-up of MGUS. Efforts to identify patient groups where screening for MGUS may be recommended are important.

Monoclonal Gammopathy of Undetermined Significance: Follow-up Patterns in the United States and Concordance With Clinical Practice Guidelines.

ObjectiveTo determine follow-up practice patterns of US patients with monoclonal gammopathy of undetermined significance (MGUS) and their concordance with 4 clinical practice guidelines.Patients and MethodsIn a retrospective analysis of adult patients using the OptumLabs Data Warehouse database, we identified those who had an incident diagnosis of MGUS from January 1, 2006, through December 31, 2013, no history or subsequent diagnosis of lymphoplasmacytic malignancy, and at least 2 years of follow-up.ResultsA total of 11,676 patients with MGUS were included in the study. During the first 2 years after MGUS diagnosis, the distribution of patients by mean interval between visits was as follows: less than 6 months, 12.7%; every 6 to 12 months, 25.2%; every 13 to 24 months, 17.7%; and longer than 24 months, 44.4%. A higher proportion of patients were followed up at intervals of less than 13 months over time, from 32.7% to 41.1% (P<.001). Patients 60 years or older were more likely to be followed up at intervals of less than 13 months; those from the Northeast or younger than 50 years were more likely to be followed up at intervals longer than 24 months compared with their counterparts (P<.001). More than half of the patients 80 years or older were followed up at intervals of less than 6 months (12.3%), 6 to 12 months (27.8%), or 13 to 24 months (18.2%). Only approximately half of the patients (41.1%-58.8%) with MGUS diagnosed in 2013 were concordant with any of the 4 clinical guidelines.ConclusionThe MGUS follow-up practice patterns varied geographically and demographically and were frequently discordant with guideline recommendations. A large proportion of patients with limited life expectancy had frequent follow-up visits.

Monoclonal Gammopathy of Undetermined Significance (MGUS) Follow-up Practice Patterns in the US: Frequency of Visits, Types of Tests and Concordance with Clinical Practice Guidelines

Background: The optimal follow-up of MGUS patients, including frequency of visits and type of tests to order, is unknown because there are no evidence-based data available for guidance. Nevertheless, there are currently 4 clinical practice guidelines that are based on expert-consensus: UK-Nordic (2009), International Myeloma Working Group (IMWG; 2010), International Expert Consensus (IEC; 2010) and European Myeloma Network (EMN; 2014). Most guidelines recommend annual follow-up with laboratory tests until life expectancy becomes limited. How MGUS patients are followed in the US and whether clinical practice guidelines are being followed remain largely unknown.Methods: We conducted a retrospective analysis of adult (age >18 years) patients from 2006-2012 using theOptum Labs Data Warehouse,a large database including administrative claims information on >150 million privately insured and Medicare Advantage enrollees throughout the US. We identified patients with an incident diagnosis of MGUS (ICD9: 273.1) who had enrollment periods of>1 year pre- and>2 years post-diagnosis in order to exclude patients with a prior history or subsequent diagnosis of lymphoplasmacytic malignancy. We determined the overall outpatient follow-up practice patterns (visits or tests performed for MGUS), their variations over time and by geo-demographic subgroups, and concordance with current clinical practice guidelinesResults: There were 10,349 MGUS patients who met the study criteria. The mean interval per MGUS follow-up visit was 13.1 months. The distribution of patients by mean interval between visits was: q<6 months (39.9%), q6-12 months (10.7%), q13-24 months (2.6%) and q>24 months (46.8%). There was a significant trend towards a higher proportion of patients being followed q<6 over time from 36.2% in 2006 to 43.7% in 2013 (P=0.01). Patients ≥70 years were more likely followed q<6 months, while those from the Northeast or ≤50 years were more likely followed q>24 months compared to their counterparts (P<0.01). Over half of patients≥80 years were being followed either q<6 (44.7%) or q6-12 (11.6%) months (Figure 1). Only about half of the patients diagnosed in 2013 were concordant with any of the available guidelines regardless of whether the guidelines were more aggressive (UK-Nordic/IEC) or more conservative (IMWG/EMN) in their follow-up recommendations (54.6% and 56.5%, respectively). The tests ordered during follow-up are shown in Figure 2. The most common tests were complete blood count, calcium, and creatinine as they were ordered in over half of the follow-up visits (56.5% to 68.4%). In 11.6% of the follow-up, a face-to-face visit was not associated with any ancillary test, while in 31.5%, the follow-up was comprised of ancillary tests only without a face-to-face visit. The test combination of complete blood count, calcium, creatinine, and serum protein electrophoresis with or without free light chain was ordered in 25.0% of the visits.Conclusions: In the US, the MGUS follow-up practice patterns varied demographically and geographically. Only half of the patients were followed according to current guideline recommendations. A large proportion of patients with limited life expectancy continued to undergo close follow-ups. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Estimating the Risk of Progression of Monoclonal Gammopathy of Undetermined Significance into Lymphoplasmacytic Malignancies in the United States: Determining Demographic Differences Using a National Dataset

Background: Prior studies on the risk of progression of monoclonal gammopathy of undetermined significance (MGUS) into lymphoplasmacytic malignancies (LPMs) were almost exclusively in the White populations, comprised of limited number of patients residing in relatively small geographic areas, or included patients mostly detected by serologic screening as part of clinical study (as opposed to detected clinically during evaluation of symptoms suspicious for LPMs). Similar epidemiologic studies in a large, racially diverse population are lacking.Methods: We conducted a retrospective analysis of incident MGUS patients diagnosed from 2006-2013 using theOptum Labs Data Warehouse, a large database including administrative claims information on >110 million privately insured and Medicare Advantage enrollees throughout the United States. We identified patients with a diagnosis of MGUS (ICD9: 273.1) with 1-5 years of continuous enrollment. Each enrollment cohort based on the duration of follow-up (1-, 2-, 3-, 4-, or 5-year) was analyzed individually to help estimate the progression to cancer. We excluded patients who were diagnosed with LPMs within three months of MGUS diagnosis. We calculated the rate of progression into LPMs (chronic lymphocytic leukemia [CLL], light chain amyloidosis [AL], multiple myeloma [MM], non-Hodgkin lymphoma [NHL], and Waldenström macroglobulinemia [WM]) expressed as number per 100 person-years.Results: There were 14,728 MGUS patients for a total of 21,288 person-years of follow-up. The distributions of the number of patients and events according to the cohorts classified by duration of follow-up were: 1-year (14,728 patients; 243 events), 2-year (10,644 patients; 307 events), 3-year (7,333 patients; 299 events), 4-year (4,497 patients; 237 events), and 5-year (2,960 patients; 191 events). The rates of progression to LPMs were consistently highest during the first year after MGUS diagnosis (~2.00), generally declined by half during the second year and remained fairly stable thereafter (~1.00; Table 1). The rates of progression into LPMs overall as well as by demographics are shown in Table 2. The risk of progression was significantly higher among men (P < 0.01) and older patients (>50 years; P = 0.03) compared to their counterparts but similar among races (P = 0.15). Of the 243 patients who progressed, the distribution of LPMs was MM (70.0%), NHL (13.2%), WM (12.3%), AL (4.1%), and CLL (0.4%).Conclusions: Among patients withMGUS, the risk of transformation into LPMs is continuous although twice as high during the first year after MGUS diagnosis compared to subsequent years. The risk of transformation was higher among men and those who were older but did not differ among the racial subgroups. Our findings can be used to develop an optimal risk-based MGUS follow-up strategy that incorporates not only serum biomarkers but also demographic factors. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Role of Diagnosis and Clinical Follow-up of Monoclonal Gammopathy of Undetermined Significance on Survival in Multiple Myeloma.

Multiple myeloma (MM) is consistently preceded by the precursor state, monoclonal gammopathy of undetermined significance (MGUS). The average annual risk of progression from MGUS to multiple myeloma is 0.5% to 1.0%. Current guidelines suggest life-long clinical follow-up of individuals diagnosed as having MGUS depending on risk stratification. The impact of diagnosing and conducting clinical follow-up of MGUS on MM survival is unclear. To estimate the impact of prior knowledge of MGUS diagnosis and comorbidities on MM survival. We conducted a population-based study including all patients with MM (MM patients) diagnosed in Sweden (n = 14,798) from 1976 to 2005 (with follow-up until 2007); 394 (2.7%) had previously been diagnosed as having MGUS. Information on comorbidities was gathered for all patients. We calculated survival rates from the time of MM diagnosis, comparing patients with vs those without prior knowledge of MGUS. Using Cox proportional hazards models, we calculated hazard ratios (HRs) and 95% CIs for risk factors for death. χ2 Tests were used to evaluate differences in comorbidities. Prior knowledge of MGUS among MM patients. In a subanalysis, monoclonal (M)-protein concentration and type were used as exposure. Risk of death and comorbidities. Patients with MM with prior knowledge of MGUS had significantly (HR, 0.86; 95% CI, 0.77-0.96; P < .01) better overall survival (median survival, 2.8 years) than MM patients without prior knowledge of MGUS (median survival, 2.1 years), although MM patients with (vs without) prior knowledge of MGUS had more comorbidities (P < .001). Among MM patients with prior knowledge of MGUS, low M-protein concentration (<0.5 g/dL) at MGUS diagnosis was associated with poorer MM survival (HR, 1.86; 95% CI, 1.13-3.04; P = .01). Patients with MM with prior knowledge of MGUS had better MM survival, suggesting that earlier treatment of MM leads to better survival. The observation that a low M-protein concentration at MGUS diagnosis was associated with poorer MM survival may reflect less frequent clinical follow-up. Our observations stress the importance of clinical follow-up in patients with MGUS, regardless of risk stratification.

Monoclonal gammopathy of undetermined significance in patients with psoriasis: is it really a side effect of biological therapy?

Moderate-to-severe psoriasis is treated using biological drugs targeting cytokines involved in the pathogenesis of the disease, such as tumor necrosis factor alpha (TNF-α) (adalimumab, infliximab, etanercept) and interleukin 12/23 (IL 12/23) (ustekinumab). There is a slight risk of developing hematological malignancies, such as monoclonal gammopathy of undetermined significance (MGUS) with anti TNF-α agents. There are no data available on anti-IL12/23 drugs. This retrospective study of data from 191 patients describes the appearance and follow-up of MGUS in three patients with psoriasis receiving long-term biological therapy. Since the appearance of MGUS occurred after about 6 years of anti-TNFα treatment in only three subjects, it was deemed unlikely to be due to the biological treatment. The decision not to suspend biological therapy after the appearance of MGUS was taken after careful assessment of the possible risks and benefits.

Determining the clinical significance of monoclonal gammopathy of undetermined significance: a SEER-Medicare population analysis.

Clinical guidelines have recommended annual follow-up examinations of most patients with monoclonal gammopathy of undetermined significance (MGUS); however, evidence supporting this practice is lacking. We performed a population-based study to examine the patterns of disease presentation and outcomes of patients with multiple myeloma, Waldenström macroglobulinemia, and lymphoplasmacytic lymphoma (monoclonal gammopathy-associated malignancies) comparing those with or without a previous MGUS follow-up examination. Patients with monoclonal gammopathy-associated malignancy from 1994 through 2007 were identified using the Surveillance, Epidemiology, and End Results-Medicare linked database and divided into 2 cohorts: those with follow-up (MGUS follow-up examination preceding the diagnosis) and those with no follow-up (no such follow-up examination). We compared the outcomes, including the rates of major complications at cancer diagnosis (acute kidney injury, cord compression, dialysis use, fracture, and hypercalcemia) and survival using propensity score adjustment and Cox proportional hazard models. All statistical tests were 2-sided. Of the 17,457 study patients, 6% had undergone MGUS follow-up. After multivariable modeling, the follow-up group had significantly fewer major complications at diagnosis (odds ratio 0.68; 95% confidence interval [CI], 0.57-0.80) and better disease-specific (median, 38 vs. 29 months, P < .001; hazard ratio [HR] 0.85; 95% CI, 0.76-0.94) and overall (median, 23 vs. 19 months, P < .001; HR 0.87; 95% CI, 0.80-0.95) survival. Patients with MGUS follow-up preceding the diagnosis of a monoclonal gammopathy-associated malignancy can experience fewer major complications and have longer survival than those without such follow-up examinations. Future studies replicating our findings in the non-Medicare population and determining the optimal schedule and cost-effectiveness of MGUS follow-up are warranted.

Natural History Of Smoldering Monoclonal Gammopathy-Associated Malignancies: A Population-Based Study

BackgroundWe performed a population-based study to determine the natural history of monoclonal gammopathy-associated malignancies (MGAM) including multiple myeloma, lymphoplasmacytic lymphoma, and Waldenstrom's macroglobulinemia that were considered smoldering at the time of cancer diagnosis. We compared the clinical outcomes among those with and without a prior monoclonal gammopathy of undetermined significance (MGUS) follow-up. MethodsData were obtained from the Surveillance Epidemiology and End Results (SEER) database linked to Medicare claims. We considered patients age ≥ 67 years with MGAM diagnosed from 1994-2005. We excluded those who were diagnosed by autopsy or death certificate only, had invasive cancers within 5 years prior to MGAM diagnosis, prior diagnosis of MGAM, lacked date of either diagnosis or death, lacked complete Medicare parts A/B coverage 15 months prior to or 3 months after MGAM diagnosis (or to date of death, if death was within 3 months), and receiving dialysis more than 3 months before MGAM diagnosis. Major complications including acute kidney injury, cord compression, dialysis-requirement, fracture, and hypercalcemia at time of disease progression were obtained from diagnosis and procedure claims. MGUS follow-up was defined as having a diagnosis claim 4-15 months prior to smoldering MGAM diagnosis. Smoldering MGAM was defined as absence of all of the following criteria: any major complication claims, any treatment claims, and death because of MGAM within 12 months of MGAM diagnosis, while progression to active MGAM was defined by the presence of any of these criteria. ResultsAt the time of MGAM diagnosis 2,189 had smoldering disease. Of these, 1,753 (80.1%) progressed to active MGAM with a median time-to-progression of 17 months. Progression to active MGAM were identified by claims reflecting the development of major cancer complications (34.9%), administration of cancer therapy (59.5%), both (0.7%), or report of death from MGAM without major complication or treatment claims (4.9%). The cumulative probability of progression by Kaplan-Meier analysis was 40.2%, 72.9%, 85.7%, and 96.1%, at years 1, 3, 5, and 10, respectively. Among those who progressed, 35.6% developed one or more major complications including acute kidney injury (13.0%), cord compression (1.8%), dialysis-requirement (2.0%), fracture (15.6%), and hypercalcemia (5.6%). A prior MGUS follow-up occurred in 199 (9.1%) smoldering MGAM patients. The time to progression for smoldering MGAM patients with a prior MGUS follow-up was similar to those without MGUS follow-up (P = 0.52). Multivariable analysis factoring in year of smoldering MGAM diagnosis, type of cancer, age, sex, race, place of residence, SEER site, median annual household income, Charlson co-morbidity index, and prior MGUS follow-up showed that older age, higher Charlson co-morbidity scores, and diagnosis of multiple myeloma as independent predictors of progression (Table). ConclusionsOur population-based study shows that most patients with smoldering MGAM diagnosed at age ≥ 67 years progress to active disease within the first three years. Those with a prior history of MGUS follow-up progress at a similar rate compared to those without such a history. The determinants of progression at diagnosis are age, number of co-morbidities, and type of MGAM.VariablesHazard Ratio (95% CI)PAge (years)------67-75Reference---76-851.132 (1.020-1.256)0.020≥ 861.394 (1.207-1.611)< 0.001Charlson Co-Morbidity Index (score)------0Reference---11.058 (0.917-1.221)0.44020.971 (0.788-1.196)0.783≥ 31.497 (0.788-1.196)0.002Diagnosis------Waldenstrom's macroglobulinemiaReference---Lymphoplasmacytic lymphoma1.103 (0.882-1.378)0.391Multiple myeloma1.505 (1.296-1.748)< 0.001 Disclosures:No relevant conflicts of interest to declare.

Cancer Complications At the Time of Multiple Myeloma Diagnosis and the Impact of Monoclonal Gammopathy of Undetermined Significance (MGUS) Follow-up: A Population-Based Study

AbstractAbstract 3996 Background:We performed a population-based study to determine the rates of major complications related to multiple myeloma, lymphoplasmacytic lymphoma, and Waldenstrom's macroglobulinemia (hence abbreviated as MM) at the time of cancer diagnosis in the US, their trends over time, disparities among demographic subsets, and the impact of preceding follow-up for MGUS. Methods:Data were obtained from the Surveillance Epidemiology and End Results (SEER) database linked to Medicare claims. We considered patients age >/= 67 years with MM diagnosed from 1994–2007 (N = 28,879). We excluded those who were diagnosed by autopsy or death certificate only, had invasive cancers within 5 years prior to MM diagnosis, lacked date of either diagnosis or death, lacked complete Medicare parts A/B coverage 15 months prior to or 3 months after MM diagnosis date (or to date of death, if death was within 3 months), and receiving dialysis for other conditions (n = 11,450). Major complications including acute kidney injury (AKI), dialysis requirement, cord compression, fracture, and hypercalcemia presenting within 3 months before or after MM diagnosis were obtained from diagnosis and procedure claims. MGUS follow-up was defined as having a diagnosis claim 3–15 months prior to MM diagnosis. Results:Of the 17,429 MM patients included in our study, 50.6% were males and the median age was 77 years. Major complications were present at diagnosis in 31.9% of the patients in the following order of frequency: fracture (16.6%), acute kidney injury (13.5%), hypercalcemia (5.5%), dialysis (5.3%), and cord compression (2.4%). There was a significant increase in most complication rates (unadjusted) over time (P <.001) except for hypercalcemia and cord compression. Females were more likely to have hypercalcemia (6.0% vs 5.1%; P = .005) or fracture (19.4% vs 13.9%; P <.001), but men were more likely to have AKI (14.6% vs 12.3%; P <.001) and to require dialysis (5.8% vs 4.8%; P = .002). Blacks were more likely to have hypercalcemia (7.1%; P <.001), AKI (18.3%; P <.001), cord compression (3.1%; P = .009), or require dialysis (7.8%; P <.001), but were less likely to have fracture (14.6%; P <.001) compared to whites (5.4%, 12.9%, 2.3%, 5.0%, and 17.1%, respectively) or other races (4.6%, 12.5%, 1.0 %, 4.8%, and 16.0%, respectively). Overall, 6% of the patients had MGUS follow-up (n = 1,037) preceding MM diagnosis with an increasing trend from 2.6% in 1994 to 6.9% in 2007 (P <.001). Complication rates were lower in the group with MGUS follow-up compared to those without follow-up: any complication (20.8% vs 32.6%; P <.001), AKI (10.1% vs 13.7%; P <.001), cord compression (1.4% vs 2.4%; P <.001), dialysis (3.4% vs 5.4%; P = .004), fracture (11.0% vs 17.0%; P <.001), and hypercalcemia (2.4% vs 5.7%; P <.001). Conclusions:At the time of MM diagnosis, major cancer-related complications were present in a third of patients with increasing trends from 1994–2007 for fracture, AKI, and requirement for dialysis. Complication rates varied among gender and race. Patients being followed for MGUS had significantly lower complications rates compared to those who were not. Disclosures:No relevant conflicts of interest to declare.

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

Determining Why and Which Clinicians Order Serum Protein Electrophoresis (SPEP), Subsequent Diagnoses Based On Indications, and Clinical Significance of Routine Follow-up: a Study of Patients with Monoclonal Gammopathy of Undetermined Significance (MGUS).

Abstract 4883 BackgroundMGUS is considered an incidental finding in the diagnostic work-up for multiple myeloma (MM) and related malignancies. Biologically, MGUS precedes all MM; however, its clinical significance and the utility of annual follow-up of these patients remain unknown. We studied a large series of MGUS patients to determine why clinicians ordered serum protein electrophoresis (SPEP) that resulted in an MGUS diagnosis, the subsequent diagnoses found based on test indications, and how malignant transformations are found. MethodsUsing our electronic medical database, we identified all MGUS patients diagnosed from January 1995-May 2009 at our institution. We excluded those who developed malignant transformation within 2 years of MGUS diagnosis. We reviewed the medical records to confirm the diagnosis and obtained relevant clinical data. To determine the likelihood of clinicians diagnosing a malignancy as a result of ordering SPEP, in recent years, we retrieved the number of patients with SPEP performed from 2004-2008 for indications other than follow-up of previously diagnosed MGUS, MM, and related malignancies. ResultsWe found 361 MGUS patients with a median age at diagnosis of 74 years (range, 27-96). Fifty four percent were men and the median follow up time was 3 years (range, 0-37). The most common indications for monoclonal gammopathy testing were anemia (44%), bone symptoms/signs (20%), high creatinine (19%), elevated erythrocyte sedimentation rate (13%), and neuropathy (12%). Fifty-nine percent of patients had only 1 indication, 31% had 2 indications, and 10% had 3 or more indications. The departments that most commonly diagnosed MGUS were internal medicine (30%), hematology (19%), nephrology (11%), family practice (10%), and neurology (9%). The most common subsequent diagnoses were etiology unknown (22%), kidney disease (21%), chronic inflammation (12%), autoimmune conditions (9%), and iron deficiency (7%). The indications associated with an unknown diagnosis were anemia (38%), neuropathy (20%), and bone symptoms/signs (18%). Fifteen (4%) MGUS patients developed MM or a related malignancy at a median time of 4 years (range, 2-28). Of the transformations, 60% were detected because of symptoms and 40% were detected at scheduled MGUS follow-up. Of the 6 patients with malignant transformations detected at follow-up, 2 required treatment within a month of diagnosis, while 4 patients were observed for at least 6 months before initiating treatment. In 2004-2008, 7,090 patients had SPEP's performed to look for conditions associated with monoclonal gammopathy. This resulted in the diagnoses of 179 (3%) MGUS's and 89 (1%) malignancies. ConclusionsAt our institution, clinicians have a low threshold looking for malignancies associated with monoclonal gammopathy when evaluating elderly patients presenting with symptoms or signs seen in these conditions. This is despite the extremely low likelihood of finding one. For patients incidentally found to have MGUS, the rate of malignant transformation was low as expected; however, majority of transformations were found due to symptomatic presentations outside of scheduled follow-up visits. Our study calls into question the utility of the current practice of routinely following patients with MGUS. DisclosuresNo relevant conflicts of interest to declare.

CHRONIC NEUTROPHILIC LEUKAEMIA: A DISTINCT CLINICAL ENTITY?

CHRONIC NEUTROPHILIC LEUKAEMIA: A DISTINCT CLINICAL ENTITY?

Long-Term Follow-Up of Monoclonal Gammopathy of Undetermined Significance in Transplant Patients

We report the long-term follow-up of 5 patients (4 kidney, 1 heart recipients) having a pretransplant monoclonal gammopathy of undetermined significance (MGUS). The follow-up of MGUS before transplantation was 41.2 +/- 40.7 months (range 2-108). The monoclonal component isotype was IgG-kappa in 3 cases and IgA-lambda in 2. The pretransplant level of the monoclonal component was 11.1 +/- 4.8 g/l (range 4-15.6). The transplant recipients who had MGUS were older than our other transplant patients. All but one of them received ciclosporine A. They did not experience more rejection or infectious complications than the others. Their posttransplant follow-up ranged from 3 to 9 years. The monoclonal component level remained stable in 2 patients but increased in 3 (33-225%). This was not correlated with bone marrow plasmocytosis. Two patients developed smoldering myeloma indicated by bone marrow immunochemistry studies which showed monomorph monoclonal plasma cells; nevertheless, they did not have cytopenia or bone lytic lesions. This percentage is higher than in the Kyle study but we cannot assume that it is due to ciclosporine A since our study sample is too small. In conclusion, MGUS is not a contraindication to organ transplantation.