Identifying monoclonal gammopathy of undetermined significance in electronic health data.

PURPOSE: Monoclonal gammopathy of undetermined significance (MGUS) is a prevalent yet largely asymptomatic precursor to multiple myeloma. Patients with MGUS must undergo regular surveillance and testing, with few known predictors of progression. We developed an algorithm to identify MGUS patients in electronic health data to facilitate large-scale, population-based studies of this premalignant condition. METHODS: We developed a four-step algorithm using electronic health record and health claims data from men and women aged 50 years or older receiving care from a large, multispecialty medical group between 2007 and 2015. The case definition required patients to have at least two MGUS ICD-9 diagnosis codes within 12 months, at least one serum and/or urine protein electrophoresis and one immunofixation test, and at least one in-office hematology/oncology visit. Medical charts for selected cases were abstracted then adjudicated independently by two physicians. We assessed algorithm validity by positive predictive value (PPV). RESULTS: We identified 833 people with at least two MGUS diagnosis codes; 429 (52%) met all four algorithm criteria. We randomly selected 252 charts for review, including 206 from patients meeting all four algorithm criteria. The PPV for the 206 algorithm-identified charts was 76% (95% CI, 70%-82%). Among the 49 cases deemed to be false positives (24%), 33 were judged to have multiple myeloma or another lymphoproliferative condition, such as lymphoma. CONCLUSIONS: We developed a simple algorithm that identified MGUS cases in electronic health data with reasonable accuracy. Inclusion of additional steps to eliminate cases with malignant disease may improve algorithm performance.

Multiple Myeloma and Its Precursor Disease Among Firefighters Exposed to the World Trade Center Disaster.

Importance: The World Trade Center (WTC) attacks on September 11, 2001, created an unprecedented environmental exposure to known and suspected carcinogens suggested to increase the risk of multiple myeloma. Multiple myeloma is consistently preceded by the precursor states of monoclonal gammopathy of undetermined significance (MGUS) and light-chain MGUS, detectable in peripheral blood. Objective: To characterize WTC-exposed firefighters with a diagnosis of multiple myeloma and to conduct a screening study for MGUS and light-chain MGUS. Design, Setting, and Participants: Case series of multiple myeloma in firefighters diagnosed between September 11, 2001, and July 1, 2017, together with a seroprevalence study of MGUS in serum samples collected from Fire Department of the City of New York (FDNY) firefighters between December 2013 and October 2015. Participants included all WTC-exposed FDNY white, male firefighters with a confirmed physician diagnosis of multiple myeloma (n = 16) and WTC-exposed FDNY white male firefighters older than 50 years with available serum samples (n = 781). Exposures: WTC exposure defined as rescue and/or recovery work at the WTC site between September 11, 2001, and July 25, 2002. Main Outcomes and Measures: Multiple myeloma case information, and age-adjusted and age-specific prevalence rates for overall MGUS (ie, MGUS and light-chain MGUS), MGUS, and light-chain MGUS. Results: Sixteen WTC-exposed white male firefighters received a diagnosis of multiple myeloma after September 11, 2001; median age at diagnosis was 57 years (interquartile range, 50-68 years). Serum/urine monoclonal protein isotype/free light-chain data were available for 14 cases; 7 (50%) had light-chain multiple myeloma. In a subset of 7 patients, myeloma cells were assessed for CD20 expression; 5 (71%) were CD20 positive. In the screening study, we assayed peripheral blood from 781 WTC-exposed firefighters. The age-standardized prevalence rate of MGUS and light-chain MGUS combined was 7.63 per 100 persons (95% CI, 5.45-9.81), 1.8-fold higher than rates from the Olmsted County, Minnesota, white male reference population (relative rate, 1.76; 95% CI, 1.34-2.29). The age-standardized prevalence rate of light-chain MGUS was more than 3-fold higher than in the same reference population (relative rate, 3.13; 95% CI, 1.99-4.93). Conclusions and Relevance: Environmental exposure to the WTC disaster site is associated with myeloma precursor disease (MGUS and light-chain MGUS) and may be a risk factor for the development of multiple myeloma at an earlier age, particularly the light-chain subtype.

[Spectrum of monoclonal gammopathies].

The monoclonal gammopathies are defined as heterogenous group of diseases characterized by proliferation of a single clone of plasma cells, producing immunoglobulin or light (rarely heavy) chains, which can be detected in blood or urine as monoclonal (M) protein. The most common among them is monoclonal gammopathy of undetermined significance (MGUS), the asymptomatic benign disorder, present in ~ 3% of the population aged ≥50 years. However MGUS is a pre malignant condition and may progress to symptomatic multiple myeloma or related malignancies, with annual rate of approximately 1%. The clone may also produce kidney damage, resulting from just the protein M, with different patterns of renal disease. Since the lesions are progressive and may be severe leading to a significant morbidity the term "monoclonal gammopathy of renal significance (MGRS)" has been recently introduced.

Unexpected migration of free light chains in urinary protein electrophoresis.

Urinary protein electrophoresis analysis (UPE) is an essential investigation for the study of abnormal proteins in urines. The interpretation of this analysis must be comprehensive and relevant. Indeed, UPE is often requested by clinicians and may have an important impact in patient's management. This paper presents two cases with free light chains showing unexpected electrophoretic migration which can lead to the misinterpretation of results. This article helps biologists to keep in mind the interest of UPE among the several analyses useful in the laboratory.

Neutrophil Gelatinase--Associated Lipocalin and Cystatin C Are Sensitive Markers of Renal Injury in Patients With Multiple Myeloma.

BACKGROUND: Renal impairment is a common complication of patients with multiple myeloma (MM). We aimed to evaluate the clinical significance of 2 newly discovered biomarkers of renal injury, cystatin C (CysC), a protein reflecting glomerular filtration rate, and neutrophil gelatinase-associated lipocalin (NGAL), a protein reflecting tubular injuries. PATIENTS AND METHODS: We studied 64 patients with newly diagnosed myeloma: 16 with asymptomatic (smoldering) MM and 48 with symptomatic myeloma; 8 patients with monoclonal gammopathy of undetermined significance (MGUS); and 20 healthy control subjects. Along with common blood and urine chemistry determinations, measurements of CysC, NGAL, ß2-microglobulin, high-sensitivity C-reactive protein, and interleukin 6 were performed. RESULTS: We found that only patients with symptomatic MM had increased levels of CysC compared to controls (P < .01); that serum NGAL levels were elevated in all patients compared to controls P < .001; that NGAL strongly correlated with both estimation of glomerular filtration rate (eGFR) (CysC) and eGFR (Modification of Diet in Renal Disease [MDRD] formula) (r = 0.616, P < .0001; and r = -0.371, P < .01, respectively); that CysC showed strong correlation with eGFR (r = -0.782, P < .001) and with the International Scoring System (ISS) (more pronounced in patients with ISS-3); and that receiver operating characteristic curve analysis showed that NGAL values of > 50.5 µg/L have a 80.8% sensitivity and 86.4% specificity for eGFR < 60 mL/min (area under the curve = 0.764). CONCLUSION: These findings suggest that both NGAL and CysC are very sensitive markers that reflect renal impairment in newly diagnosed patients with MM. The high levels of NGAL in asymptomatic patients and in MGUS patients support the hypothesis of the presence of renal damage in these patients early in the course of their disease and may reveal NGAL to be an early marker that predicts the presence of renal impairment in MM.

Serum cystatin C and serum and urine NGAL in the kidney function assessment of patients with MGUS.

OBJECTIVES: Monoclonal gammopathy of undetermined significance (MGUS) occurs without other symptoms, although monoclonal proteins can cause kidney injuries. Here, we assessed kidney function and identified the best follow-up parameters in patients with MGUS without kidney damage symptoms. METHODOLOGY: Forty-six patients with MGUS were included in the study group. The control group (CRT, n = 23) consisted of healthy subjects matched for age and sex. Serum cystatin C was determined using an immunonephelometric method, serum and urine neutrophil gelatinase-associated lipocalin (NGAL) was measured with an immunoenzymatic method, and cathepsin B activity was determined fluorometrically. RESULTS: Serum cystatin C and urine NGAL were higher, and serum NGAL was lower in MGUS patients compared with CRT. Neither serum cystatin C, nor serum or urine NGAL, correlated with the biomarkers of MGUS. The serum activity of cathepsin B did not differ between groups and did not correlate with serum cystatin C. Serum cystatin C correlated with serum creatinine, while serum NGAL did not correlate with serum creatinine or cystatin C. The estimated glomerular filtration rates (eGFRs) in MGUS were within normal range and correlated with serum cystatin C. The strongest correlation was observed for CKD-EPI. Seven patients presented with albuminuria >30 mg/day. There was a correlation between albuminuria in this group and λ free light chains. CONCLUSIONS: The kidney function in MGUS patients is impaired, although there are no clinical and standard laboratory test manifestations. Cystatin C and urine, but not serum, NGAL should be considered markers for kidney injury. CKD-EPI is recommended for eGFR assessment.

[Monoclonal gammopathy of undetermined significance and asymptomatic multiple myelom in the year 2014 ]. / Monoklonální gamapatie nejistého významu a asymptomatický mnohocetný myelom z pohledu roku 2014.

Presence of monoclonal immunoglobulin in serum or urine is a relatively common event affecting about 3.2 % of people over 50. Isolated increase of only one type of free light chain, either κ or λ, is detected in 0.7-0.8 % of people over 50. Most people with monoclonal immunoglobulin meet the criteria of the so-called "mono-clonal gammopathy of undetermined significance (MGUS)". MGUS is defined by concentration of monoclonal immunoglobulin in serum < 30 g/l, number of plasma cells in the bone marrow < 10 % and the absence of symptoms of multiple myeloma and other lymphoproliferative diseases. A proportion of people with MGUS gradually progresses from asymptomatic into symptomatic myeloma or other malignant lymphoproliferative disease requiring treatment. Therefore, MGUS is considered to be one of the most common premalignant conditions with an average risk of transformation into malignant disease of 1 % per year. Monoclonal gammopathy of IgG and IgA subtype can develop into multiple myeloma. Light chain monoclonal gammopathy can develop not only into light chain multiple myeloma but also into AL-amyloidosis and light chain deposition disease (amorphous deposits of light chains damaging organs). IgM monoclonal gammopathy may develop into Waldenstrom macroglobulinemia or other lymphoproliferative disorder, or into rare IgM subtype of multiple myeloma. Unfortunately, people with MGUS are threatened by more than an increased risk of transformation into multiple myeloma or other severe hematologic disease. Pre-malignant clone of plasma cells in the bone marrow causes changes in the bone marrow that directly affect the person. For people with MGUS, there is an increased incidence of osteoporosis and increased fracture risk when compared to the general population. People with MGUS also have an increased risk of bacterial infections and thromboembolic complications compared with the same age population without MGUS. Clonal plasma cells, which are the basis of MGUS, may in some cases produce toxic monoclonal immunoglobulin which can damage the body's own antibody activity by binding to specific antigens (such as cold agglutinin disease), or their deposits in organs (e.g. kidney damage) or physical properties (e.g. cryoglobulinemia). Therefore, it is recommended that this group of people is regularly checked with the aim to capture not only transformation into symptomatic multiple myeloma or another malignant disease, but also the formation of the above-mentioned complications. Moreover, it is recommended to monitor patients with asymptomatic myeloma and to initiate treatment only after symptoms of multiple myeloma are observed. In 2014, discussion of subdivision of subgroups of patients with asymptomatic myeloma with high ( 80 %) probability of early (within 2 years) transformation in multiple myeloma which would be beneficial for early initiation of treatment is ongoing. According to first proposals, patients with asymptomatic myeloma that meet at least one of the three conditions: more than 60 % of plasma cells in the bone marrow, ratio of free light kappa and lambda chains is greater than 100 or less than 0.01, or multiple focal lesions on whole-body MRI of the skelet. The review contains current opinions on prognostic classification and appropriate intervals and extent of control examinations.

Monoclonal gammopathy of undetermined significance: an update for nephrologists.

Screening for a monoclonal protein is a common part of the assessment of patients presenting with a renal injury. While in the settings of acute kidney injury, chronic kidney disease and proteinuria monoclonal proteins can be associated with significant pathologies such as cast nephropathy, amyloidosis, and light chain deposition disease, they can also be an unrelated finding. The purpose of this review is to provide the nephrologist with an update to the diagnostic assessment and risk stratification of monoclonal proteins to avoid unnecessary investigation and monitoring of those patients with low-risk monoclonal gammopathies.

Monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and curcumin: a randomized, double-blind placebo-controlled cross-over 4g study and an open-label 8g extension study.

Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) represent useful models for studying multiple myeloma precursor disease, and for developing early intervention strategies. Administering a 4g dose of curcumin, we performed a randomised, double-blind placebo-controlled cross-over study, followed by an open-label extension study using an 8g dose to assess the effect of curcumin on FLC response and bone turnover in patients with MGUS and SMM. 36 patients (19 MGUS and 17 SMM) were randomised into two groups: one received 4g curcumin and the other 4g placebo, crossing over at 3 months. At completion of the 4g arm, all patients were given the option of entering an open-label, 8g dose extension study. Blood and urine samples were collected at specified intervals for specific marker analyses. Group values are expressed as mean ± 1 SD. Data from different time intervals within groups were compared using Student's paired t-test. 25 patients completed the 4g cross-over study and 18 the 8g extension study. Curcumin therapy decreased the free light-chain ratio (rFLC), reduced the difference between clonal and nonclonal light-chain (dFLC) and involved free light-chain (iFLC). uDPYD, a marker of bone resorption, decreased in the curcumin arm and increased on the placebo arm. Serum creatinine levels tended to diminish on curcumin therapy. These findings suggest that curcumin might have the potential to slow the disease process in patients with MGUS and SMM.

Monoclonal gammopathies in a Moroccan military hospital.

The aim of this study was to describe biological features and aetiology of monoclonal gammopathy diagnosed during a 10-year period in the biochemistry department of the Moroccan Military Hospital Mohamed V in Rabat. The study was performed from 1 January 2000 to 31 December 2009. The records of 261 patients living in the Rabat area in which either serum protein electrophoresis and serum and/or urine immunofixation were performed at the biochemistry department of Military Instruction Hospital in Rabat were analysed. A cohort of 182 (70%) men and 79 (30%) women, the mean ± SD (range) ages were 60.21 ± 12.56 years. All patients were Caucasian. Electrophoresis found that 211 (80.84%) of the patients had a monoclonal gammopathy. Immunofixation confirmed that 251 (96.17%) patients had a monoclonal band in serum. In our cohort, MM was the most frequent diagnosis, our patients were late diagnosed.

Long-term biological variation of serum protein electrophoresis M-spike, urine M-spike, and monoclonal serum free light chain quantification: implications for monitoring monoclonal gammopathies.

BACKGROUND: We analyzed serial data in patients with clinically stable monoclonal gammopathy to determine the total variation of serum M-spikes [measured with serum protein electrophoresis (SPEP)], urine M-spikes [measured with urine protein electrophoresis (UPEP)], and monoclonal serum free light chain (FLC) concentrations measured with immunoassay. METHODS: Patients to be studied were identified by (a) no treatment during the study interval, (b) no change in diagnosis and <5 g/L change in serum M-spike over the course of observation; (c) performance of all 3 tests (SPEP, UPEP, FLC immunoassay) in at least 3 serial samples that were obtained 9 months to 5 years apart; (d) serum M-spike ≥10 g/L, urine M-spike ≥200 mg/24 h, or clonal FLC ≥100 mg/L. The total CV was calculated for each method. RESULTS: Among the cohort of 158 patients, 90 had measurable serum M-spikes, 25 had urine M-spikes, and 52 had measurable serum FLC abnormalities. The CVs were calculated for serial SPEP M-spikes (8.1%), UPEP M-spikes (35.8%), and serum FLC concentrations (28.4%). Combining these CVs and the interassay analytical CVs, we calculated the biological CV for the serum M-spike (7.8%), urine M-spike (35.5%), and serum FLC concentration (27.8%). CONCLUSIONS: The variations in urine M-spike and serum FLC measurements during patient monitoring are similar and are larger than those for serum M-spikes. In addition, in this group of stable patients, a measurable serum FLC concentration was available twice as often as a measurable urine M-spike.

Gammopathy interference in clinical chemistry assays: mechanisms, detection and prevention.

Monoclonal gammopathy is characterized by the presence of an M-protein in serum or urine that has homogeneous structural and functional properties. It can occur in very high concentrations and may cause significant interference in clinical chemistry assays. Examples of gammopathy interference for the analytes glucose, bilirubin, gamma-glutamyltransferase, urea and ferritin are presented. Various mechanisms of interference are described, such as the production of turbidity by the M-protein and the binding of the M-protein to a component of the test system or analyte. In immunoglobulin tests, the M-protein is the analyte itself and may not be completely bound by the test antibody owing to its structural properties. Modern analyzers can detect unusual changes in absorption during the course of a reaction, and thus the formation of turbidity due to M-proteins. This interference may be prevented by optimizing the buffering conditions of the reagents to avoid the formation of turbidity or by removal of the M-protein prior to analysis of the sample. Owing to the unique properties of each M-protein, it is impossible to protect common clinical chemistry test systems completely from gammopathy interference. Therefore, efficient ways for the detection of such interference are needed.

Acromegaly associated with monoclonal gammopathy of undetermined significance (MGUS).

Here we report the case of a 65-year-old woman with acromegaly complicated with monoclonal gammopathy of undetermined significance (MGUS). The patient visited Shimane University Hospital for treatment of spinal canal stenosis, and was diagnosed as acromegaly with GH 43.1 ng/ml, insulin-like growth factor (IGF)-I 510 ng/ml and the detection of a pituitary adenoma by MRI. She was also diagnosed as MGUS with IgG 2208 mg/dl, the existence of IgG-kappa type monoclonal protein, and 5.6% plasma cells in bone marrow. After a pituitary adenoma was operatively removed by transsphenoidal approach, IgG levels, as well as GH and IGF-I levels, decreased spontaneously and simultaneously. We suspect a pathogenetic link between acromegaly and MGUS in this case, because both GH and IGF-I are known to directly promote immunoglobulin production from plasma cells, thus inducing the proliferation of the cells in vitro.

Guidelines for the analysis of Bence Jones protein.

The detection and quantification of monoclonal free light chains in urine (Bence Jones protein, BJP) are thorny issues for the laboratorian. Immunoelectrophoretic techniques (immunofixation) allow the characterization of the two pathognomonic features of light chains: monoclonality and absence of heavy chains. Immunochemical methods such as nephelometry and turbidimetry are widely used in clinical practice to exclude the presence of BJP. However, these methods are limited by several metabolic and analytical problems. The accuracy of quantitative immunochemical methods is hampered by the heterogeneous molecular forms (fragments and polymers) of BJP and by the lack of reference materials, and the precision of the methods in clinically relevant regions of the dynamic range is poorly defined. Immunoelectrophoretic methods, especially immunofixation, are recommended because of their ability to demonstrate monoclonality and the absence of heavy chains. Immunofixation is also considered the best method to document the disappearance of the monoclonal protein (complete remission). The physiology of immunoglobulins and the clinical relevance of BJP are illustrated in the two appendices to this paper.

[A case of monoclonal gammapathy type IgD]. / Un caso de gammapatía monoclonal del tipo IgD.

We refer in the present article, the first case found in our laboratory of Monoclonal gammapathy of the IgD type. A 47-year-old man presented at the emergency department with a history of malaise, lethargy, tiredness, thirstiness and obscure depositions. Clinical examination revealed a normocytic anaemia. The plasma urea was 423 mg/dl and the plasma creatinine was 15, 3 mg/dl. He was admitted to hospital with a diagnosis of acute renal failure. The later electrophoresis in serum revealed a little monoclonal band that was identified as IgD-lambda type by immunofixation electrophoresis. In urine electrophoresis was observed a beta-band. Bone marrow biopsy revealed a 20% of plasmocytic cells. Renal biopsy was compatible with myelomatose lesions. Osteolytic lesions were observed.

Urinary alpha 1- and beta 2-microglobulin in light chain proteinuria.

Thirteen patients with light chain (LC) proteinuria (11 with multiple myeloma and two with monoclonal gammopathy of undetermined significance) were followed up for one to 3.5 (median 2.5) years and studied for urinary excretion of LCs, alpha 1-microglobulin (alpha 1 M), beta 2-microglobulin (beta 2M), albumin, and serum creatinine concentration at intervals of 6 +/- 2 months. At the beginning of the follow-up, urinary alpha 1M excretion correlated with that of beta 2M (r = 0.81, p = 0.0007) and LCs (0.69, p = 0.0084), and with the serum creatinine level (r = 0.56, p = 0.047). During the follow-up period, renal function remained stable in eight patients despite high or fluctuating LC excretion. In seven of them, urinary alpha 1M was repeatedly below 150 mg/24 h and in one it transiently exceeded that level. The remaining five patients had an unstable renal function (deterioration in four, improvement in one) although their urinary LC and albumin excretion during the study period was comparable to those in patients with stable renal function. In the five patients with unstable renal function, high (> 150 mg/24 h) urinary alpha 1M excretion was associated with a rise in the serum creatinine level. alpha 1M excretion was thus found to be a useful indicator of renal damage caused by LCs.

IgD monoclonal gammopathy with long-term follow-up.

The presence of a serum IgD monoclonal protein (M-protein) is usually indicative of a malignant plasma cell disorder. However, one case of well-documented benign monoclonal gammopathy (BMG) of IgD type has been reported. We describe another patient with IgD monoclonal gammopathy of undetermined significance (MGUS) with long-term follow-up. In this patient an IgD lambda M-protein was found on routine serum electrophoresis. She is alive and has no evidence of multiple myeloma or amyloidosis after 8 years of follow-up. Although IgD MGUS is exceedingly rare, this case demonstrates that the presence of a serum IgD M-protein is not necessarily synonymous with a malignant plasma cell process.

Immunoglobulin D benign monoclonal gammopathy. A case report.

The authors report a case, perhaps the first, of immunoglobulin D (IgD) benign monoclonal gammopathy. The patient, a 48-year-old black woman, initially had a 500 mg/dl IgD-lambda M-spike, hypercalcemia, and anemia. There was no bone pain, lytic bone lesions, or evidence of renal failure. The bone marrow showed 2.8% plasma cells with a diffuse (not nodular) IgD plasmacytosis and strong lambda predominance. Only trace amounts of free lambda light chains could be demonstrated by immunoelectrophoresis in serum and concentrated urine. The anemia responded quickly to iron therapy. Chemotherapy was not initiated. Over the 6+ years of follow-up, the patient has had no progression of clinical disease attributable to her IgD monoclonal gammopathy. The IgD M-spike has steadily decreased.

Monoclonal free light chains in urine and their significance in clinical diagnostics: are they really tumor markers?

Bence Jones proteins (monoclonal free light chains of immunoglobulins) are the earliest known biological markers of malignant cell dyscrasia; Bence Jones proteinuria is also present in many types of B cell-related neoplasms. Sometimes, it may also occur in Hodgkin's disease. In some cases, benign monoclonal gammapathy was found to be associated nontumorous diseases as well. The type of monoclonal light chain, the degree of polymerization, and the isoelectric point of the molecule may affect the course of the disease. Urine samples from 637 patients with true or suspected lymphoproliferative diseases were investigated over a 2-yr period by different immunochemical methods. Bence Jones proteinuria was identified in 71 cases by isoelectric focusing combined with immunofixation, while the pathological protein was detected only in 63 cases by conventional methods. Bence Jones proteins can be detected by this new method at a level below the sensitivity of conventional procedures. Bence Jones proteins in the urine may signal a malignant tumor or malignant transformation of an earlier disease. The early detection of monoclonal immunoglobulin light chains in the urine may be important in clinical diagnosis, therapy, and follow-up.