IgG4-related diseases (IgG-RDs) are a group of fibroinflammatory diseases that affect a variety of tissues, resulting in tumour-like effects and/or organ dysfunction. Monoclonal gammopathies (MGPs) are a group of disorders characterized by clonal proliferation of plasma cells or lymphoid cells resulting in the secretion of a monoclonal immunoglobulin. Cases of MGPs in IgG4-RDs coexisting with plasma cell dyscrasias and lymphoid neoplasms have been reported over the past few years. Therefore, the results of examinations of M protein in IgG4-RD patients should be interpreted with caution. Herein, we report the case of a 58-year-old male with a history of type 2 diabetes who presented with submandibular masses, anosmia, swollen lymph nodes, proteinuria, and renal impairment. Laboratory tests revealed hyperglobulinemia and elevated levels of IgG4 (124 g/L) and serum-free light chains (sFLCs). Serum protein electrophoresis (SPEP) revealed an M spike of 5.6 g/dL, and immunofixation electrophoresis (IPE) revealed biclonal IgG-κ and IgG-λ. The patient underwent bone marrow, lymph node, and kidney biopsy, which ruled out plasma cell disorders and lymphoma. He was finally diagnosed with an IgG4-RD comorbid with diabetic nephropathy. The findings in this case highlight that significant activation of B cells in IgG4-RD patients, especially those with multiorgan involvement can lead to significant hyperglobulinemia and high sFLC and IgG4 levels, which are more pronounced in the setting of renal impairment. Relatively high concentrations of polyclonal IgG4 can give rise to a focal band bridging the β and γ fractions, which may mimic the appearance of a monoclonal band on SPEP and monoclonal gammaglobulinemia in IFE. The patient experienced considerable improvement in his symptoms after rituximab combined with glucocorticoid therapy, and a monoclonal immunoglobulin was not detected.

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BACKGROUND: Multiple myeloma (MM) is a common hematologic malignancy that originates from a malignant clone of plasma cells. Solitary plasmacytoma, history of diabetes, and platelet count are considered as prognostic factors for MM. But some patients are still associated with much worse outcomes without any prognostic predictors. This study aimed to observe the reduction rate of monoclonal protein (M protein) after the first and fourth chemotherapy cycles, which is considered as a new prognostic factor for progression-free survival (PFS) in standard-risk group of newly diagnosed MM patients.
OBJECTIVE: To investigate the reduction rate of M protein after first and fourth cycle chemotherapy as a useful prognostic factor.
METHODS: A total of 316 patients diagnosed with MM for the first time between 2010 and 2019 at the Lishui Municipal Central Hospital were included. All patients were diagnosed according to the National Comprehensive Cancer Network (NCCN) 2020.V1 diagnostic criteria. The risk assessment was performed by the Mayo Stratification for Macroglobulinemia and Risk-Adapted Therapy guidelines. After diagnosis, 164 patients were evaluated and underwent treatment with four to eight courses of continuous induction chemotherapy. The patients with no response after induction treatment were administered additional therapy following the NCCN 2020.V1 criteria. The following baseline data from the patients were collected: Gender, age at diagnosis, Durie-Salmon stage, glutamic-pyruvic transaminase, glutamic-oxaloacetic transaminase, catabolite activator protein, albumin/globulin ratio, lactate dehydrogenase, translocation (t)(6;14), t(11;14), maintenance regimen, total cholesterol (TC), triglyceride, and phosphorous. All baseline data and the reduction rate of M protein after each chemotherapy cycle from the first to fourth were assessed by univariate analysis. The factors influencing the overall survival and PFS were then assessed by multivariate analysis. We found the first cycle (C1) reduction rate and the fourth cycle (C4) reduction rate as predictors of PFS. Then, PFS was compared between patients with a C1 reduction rate of M protein of ≥ 25% vs < 25% and ≥ 50% vs < 50%, and between patients with a C4 reduction rate of ≥ 25% vs < 25%, ≥ 50% vs < 50%, and ≥ 75% vs < 75%.
RESULTS: Multivariate analysis revealed age [hazard ratio (HR): 1.059, 95% confidence interval (95%CI): 1.033-1.085, P ≤ 0.001], International Staging System stage (HR: 2.136, 95%CI: 1.500-3.041, P ≤ 0.001), autotransplantion (HR: 0.201, 95%CI: 0.069-0.583, P = 0.019), TC (HR: 0.689, 95%CI: 0.533-0.891, P = 0.019), C1 reduction rate (HR: 0474, 95%CI: 0.293-0.767, P = 0.019), and C4 reduction rate (HR: 0.254, 95%CI: 0.139-0.463, P = 0.019) as predictors of PFS. The Kaplan-Meier survival analysis and the log-rank tests revealed that a higher reduction rate of M protein after first cycle (≥ 50%) and fourth cycle (≥ 75%) chemotherapy was associated with a longer PFS than the lower one.
CONCLUSIONS: Higher reduction rates of M protein after the first and fourth chemotherapy cycles can act as advantageous prognostic factors for PFS in standard-risk group of MM patients during initial diagnosis.

UNASSIGNED: Dual hematological malignancies, asynchronous or synchronous, are underrecognized entities and are usually suspected when clinical, hematological, or biochemical features cannot be explained by the primary malignancy alone. We present a case of synchronous dual hematological malignancies (SDHMs), where the patient was diagnosed with symptomatic multiple myeloma (MM) and essential thrombocythemia (ET), when excessive thrombocytosis occurred following initiation of MPV (melphalan-prednisone-bortezomib) antimyeloma therapy.
UNASSIGNED: An 86-year-old woman presented to the emergency in May 2016 with confusion, hypercalcemia, and acute kidney injury. She was diagnosed with free light chain (FLC) lambda and Immunoglobulin G (IgG) lambda MM and started MPV (standard of care at that time) treatment with darbopoietin support. At diagnosis, she had normal platelet count since the ET was likely masked by bone marrow suppression due to active MM. After she reached stringent complete remission with no MP detected on serum protein electrophoresis or immunofixation, we noticed that her platelet counts increased to 1,518,000 × 109/L. She was tested positive for mutation in exon 9 of calreticulin (CALR). We concluded that she had concomitant CALR-positive ET. After bone marrow recovery from MM, the ET became clinically apparent. We started hydroxyurea for ET. Treatment for MM with MPV did not affect the course of ET. Presence of concomitant ET did not decrease the efficacy of sequential antimyeloma therapies in our elderly and frail patient.
UNASSIGNED: The possible mechanism underlying the occurrence of SDHMs is unclear but is likely due to stem cell differentiation defects. SDHMs can be challenging to treat and warrant several considerations. In the absence of clear guidelines on how to manage SDHMs, management decisions depend on several factors including disease aggressiveness, age, frailty, and comorbidities.

Several studies have demonstrated the analytical sensitivity of MALDI-TOF mass spectrometry (MALDI-TOF MS) by immunoenrichment for M-protein analysis. We report the results of a novel, low-cost, reagent-based extraction process using acetonitrile (ACN) precipitation to enrich for κ and λ light chains which can be analysed by MALDI-TOF MS.
Institutional Ethics committee approval was obtained. Serum samples from patients with monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), plasmacytoma, AL amyloidosis and Waldenström macroglobulinemia (WM) underwent ACN precipitation. The images obtained were overlaid on apparently healthy donor serum samples to confirm the presence of M-protein. A sample was considered positive for M-protein if there was a sharp or broad peak within the κ or λ mass/charge (m/z) range: m/z- [M + 2H]2+: 11,550-12,300 Da and λ m/z- [M + 2H]2+: 11,100-11,500 Da. Images were acquired at a m/z range of 10,000-29,000 Da. Corresponding serum protein electrophoresis (SPEP), serum immunofixation electrophoresis (IFE) and serum free light chain (sFLC) assay by nephelometry were performed for all the samples.
Two-hundred-and-two serum samples were included in the study: MM- 184 (91%); AL amyloidosis- 2 (1%); plasmacytoma- 8 (4%); MGUS- 6 (3%) and WM- 2 (1%). All the SPEP positive samples were identified by MALDI-TOF MS. Out of 179 samples positive for M-protein by IFE, MALDI-TOF MS was positive in 176 samples (98%). Compared to IFE, the sensitivity and specificity of M-protein identification by MALDI-TOF MS were 98.3% and 52.2%, respectively.
This study demonstrates the feasibility of qualitatively identifying M-protein without the need for antibody-based immunoenrichment, making the technique cost-effective.

OBJECTIVE: The value of monoclonal protein (M-protein) in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patients with renal involvement has not been investigated.
METHODS: We analyzed AAV patients with renal involvement from 2013 to 2019 in our center. Patients with immunofixation electrophoresis were divided into M-protein positive group and M-protein negative group. The clinicopathological features and outcomes of the two groups were compared.
RESULTS: Ninety-one AAV patients with renal involvement were enrolled for analysis, and 16 patients (17.6%) had a positive test for M-protein. Compared with M-protein negative patients, M-protein positive patients had lower hemoglobin (77.6 vs 88.4 g/L, p = 0.016), mean corpuscular hemoglobin concentration (313 vs 323 g/L, p = 0.002),serum albumin (29.4 vs 32.5 g/L, p = 0.026) and complement 3 (C3) (0.66 vs 0.81 g/L, p = 0.047), while higher platelets (252 vs 201 109/L, p = 0.048) and incidence of pulmonary infection (62.5% vs 33.3%, p = 0.029). However, renal pathological features between the two groups had no significant difference. In addition, during a median follow-up of 33 months, Kaplan-Meier survival analysis showed that, compared with M-protein negative patients, M-protein positive patients had a higher risk of all-cause mortality (log-rank test, p = 0.028), especially for patients who were not dialysis-dependent at the time of admission (log-rank test, p = 0.012).
CONCLUSIONS: Our results indicate that M-protein is associated with different clinicopathological features and increased all-cause mortality in AAV patients with renal involvement. Testing M-protein and rigorous diagnosing of the significance of the presence of M-protein may be helpful for assessing the survival of AAV patients with renal involvement.

Monoclonal gammopathies are a group of disorders associated with clonal proliferation of plasma cells that produces a monoclonal protein.
The main objective of this study was to describe the epidemiological and immunochemical characteristics of monoclonal gammopathies diagnosed during 19 years in a Moroccan teaching hospital.
This retrospective study enrolled 443 Moroccan patients with monoclonal gammopathy, patients meeting the inclusion and exclusion criteria in at the biochemistry department of Military Hospital in Rabat, the capital of Morocco, from January 2000 to August 2019. Of the 443 enrolled patients, 320 (72.23%) were men and 123 (27.77%) were women. All patients were of Caucasian origin, from 12 Moroccan regions. The patient\'s samples were collected and subjected to serum protein electrophoresis and serum immunofixation electrophoresis to further characterize the monoclonal protein. The mean ± SD age of the 443 participants was 62.24 ± 13.14 years. Reasons for being admitted to the hospital were as follows, bone pain (41.60%), renal failure (19.08%), alteration of the general condition (12.21%), and anemia (10.69). Plasma cell proliferative disorders in our study were as follows, multiple myeloma (MM) (45.65%), Monoclonal gammopathies of undetermined significance (MGUS) (39.05%), Waldenstrom\'s macroglobulinemia (5.58%), Lymphoma (2.27% + 1.2%), Chronic Lymphocytic Leukemia (2.48%), Plasma cell leukemia (1.86%), Plasmacytoma (0.62%), POEMS syndrome (0.41%), and Amyloidosis (0.84%). The most frequent isotypes in MM were the IgGκ (62) 36.5%, IgGλ (52) 30.6%, IgAκ (27) 15.9%, and the IgAλ (19) 11.2%. It is also worth noting that Free light chain MM represents 20% of all cases of MM.
We found that monoclonal gammopathies are age-related and affects men more than women, also the results of this study point to the delayed diagnosis of monoclonal gammopathies, since most of our patients were diagnosed at the MM stage. The most frequent isotypes were the IgGκ and IgGλ in MM and MGUS, in Waldenström macroglobulinemia were IgMκ and IgMλ and the oligoclonal profile represented only 3.70%.

Monoclonal gammopathy of renal significance (MGRS) is a hemato-nephrological term referring to a heterogeneous group of kidney disorders characterized by direct or indirect kidney injury caused by a monoclonal immunoglobulin (MIg) produced by a B cell or plasma cell clone that does not meet current hematologic criteria for therapy. MGRS-associated kidney diseases are diverse and can result in the development of end stage kidney disease (ESKD). The diagnosis is typically made by nephrologists through a kidney biopsy. Many distinct pathologies have been identified and they are classified based on the site or composition of the deposited Mig, or according to histological and ultrastructural findings. Therapy is directed towards the identified underlying clonal population and treatment decisions should be coordinated between hematologists and nephrologists in a multidisciplinary fashion, depend on the type of MGRS, the degree of kidney function impairment and the risk of progression to ESKD.

Serum protein electrophoresis (SPEP) is a method by which proteins present in serum are separated into different fractions based on their molecular weight and electric charge. Presence of M spike, composed of monoclonal protein, on electrophoretogram is a characteristic finding that can be seen in monoclonal gammopathies like multiple myeloma. M spike is most commonly seen in the gamma region however, the M-spike can be observed in fraction other than the Y fraction as well i.e. in the beta region and rarely alpha region. Here we have enumerated few cases where M protein has been seen in fractions other than the gamma region. Thus one needs to be cautious about the variable appearance of M-spike during interpretation of SPEP as some physiological proteins if elevated can also give rise to similar spike sometimes referred as pseudo monoclonal pattern.

UNASSIGNED: Monoclonal gammopathy of undetermined significance (MGUS) is associated with renal dysfunction, inflammation, and increased cardiovascular mortality, but the cardiovascular risks are not fully understood.
UNASSIGNED: The authors explored the association of MGUS with a spectrum of cardiovascular diseases using the Danish nationwide databases.
UNASSIGNED: Between 1995 and 2018, patients 18 years and older with MGUS were age- and sex-matched (1:10) with control patients and followed prospectively until December 31, 2018, for the occurrence of cardiovascular diseases. Patients diagnosed with multiple myeloma, lymphoma, or amyloidosis were excluded. Multivariable adjusted hazard ratios (HRs) for cardiovascular outcomes were estimated using Cox proportional hazard regression.
UNASSIGNED: Patients with MGUS (n = 8,189; mean age 69.8 ± 11.7 years; 51.2% male) had higher prevalence of cardiovascular risk factors at baseline, including hypertension (48.0% vs 38.5%) and type 2 diabetes (13.0% vs 9.3%), compared with control patients. Outcomes included an increased risk of heart failure (HR: 1.55; 95% CI: 1.41-1.69), acute myocardial infarction (HR: 1.22; 95% CI: 1.06-1.40), ischemic stroke (HR: 1.16; 95% CI: 1.03-1.30), atrial fibrillation (HR: 1.32; 95% CI: 1.23-1.42), aortic aneurysm (HR: 1.55; 95% CI: 1.28-1.89), aortic stenosis (HR: 1.60; 95% CI: 1.41-1.82), aortic regurgitation (HR: 1.67; 95% CI: 1.34-2.07), heart block (HR: 1.32; 95% CI: 1.08-1.61), peripheral artery disease (HR: 1.69; 95% CI: 1.47-1.95), cor pulmonale (HR: 2.06; 95% CI: 1.55-2.73), and venous thromboembolism (HR: 1.43; 95% CI: 1.24-1.65). A sensitivity analysis including only patients without certain comorbidities (type 2 diabetes, hypertension, acute myocardial infarction, and chronic kidney disease) yielded similar results.
UNASSIGNED: MGUS is associated with a broad spectrum of cardiovascular diseases, with greater relative risks observed for diseases previously associated with infiltrative and inflammatory disorders. Further studies are warranted to explore the underlying mechanisms.