Bone Marrow Biopsy May Be Required During the Initial Evaluation of Individuals with Asymptomatic Monoclonal Gammopathy

Abstract Abstract 5067 The incidental finding of a monoclonal gammopathy during workup for various conditions or in the context of a routine check-up is increasingly common. Several “patients” are then referred for diagnostic evaluation of their monoclonal gammopathy and additional workup is needed. It has been proposed that a bone marrow (BM) aspirate and biopsy is indicated when the monoclonal protein (M-protein) is ≥1.5 g/dL, when abnormalities are noted in the complete blood cell count, serum creatinine level, serum calcium level, or radiographic bone survey, in individuals with non-IgG monoclonal gammopathy and in those with an abnormal serum free light chain (FLC) ratio. The aim of this study was to identify factors that could aid in the evaluation of individuals presenting with asymptomatic monoclonal gammopathy and in whom invasive diagnostic testing with a bone marrow biopsy is considered. Thus, we analyzed our database and identified patients who were referred to the Department of Clinical Therapeutics of the University of Athens, Greece, for evaluation of asymptomatic monoclonal gammopathy and in whom a BM trephine biopsy, a serum and urine protein electrophoresis (SPEP) with immunofixation and quantitative immunoglobulins were performed. SPEPs were scanned and M-protein was measured using imaging analysis software. Patients with a monoclonal M-protein ≥ 3 g/dl (30 g/L), i.e. those diagnosed with asymptomatic/smoldering myeloma (SMM) or Waldenstrom's macorglobulinemia based on the standard criteria, were not included in the analysis. Clonality of BM plasma cells or lymphoplasmacytes was assessed by immunohistochemistry. Patients who eventually were diagnosed with plasma cell related conditions (i.e. amyloidosis, peripheral neuropathy, dermatoses, etc.) were also excluded from the analysis. Our analysis included 161 patients: 53% were females, median age was 64 year (range 33–89 years), 53% had a monoclonal IgG protein, 15.5% had a monoclonal IgA protein, 24% a monoclonal IgM protein and 2.5% had only a monoclonal light chain, while 4% had a biclonal protein. In 64% of patients the monoclonal light chain was kappa and in 37% was lambda. The median serum M-protein was 0.948 g/dl (range 0.1–2.99 g/dl); 52% of patients had an M-protein of <1 g/dl and 79% of <2 g/dl. Immunoparesis of at least one of the uninvolved immunoglobulins was present in 38% of cases and of both of the uninvolved immunoglobulins in 6%. Median BM infiltration by monoclonal plasma cells or lymphoplasmacytes was 15%. In 66.5% of individuals there was a BM infiltration of ≥10% by monoclonal plasma cells or lymphoplasmacytes, while in 10% of the studied cases the BM infiltration was ≥50%. A significant correlation of the size of M-protein and of the infiltration of the BM was found (R=0.592, p<0.001). However, 27% of patients with M-protein <0.5 g/dl had ≥10% clonal plasma cells or lymphoplasmacytes in their BM biopsies. The respective rates were 46% for those with M-protein <1 g/dl, 54% for those with M-protein 1.5 g/dl and 58% for those with M-protein <2 g/dl. Ninety per cent of those who had immunoparesis of at least one of the uninvolved immunoglobulins had ≥10% clonal plasma cells or lymphoplasmacytes. A BM infiltration of ≥10% was more frequent in individuals with a monoclonal IgG or IgA protein (72% and 80%, respectively) vs. 45% of those with a monoclonal IgM protein (p=0.015). Light chain isotype, age and gender were not predictive of the degree of BM plasma cell infiltration. In multivariate analysis, immunoparesis of at least one of the uninvolved immunoglobulins (OR: 6.45, 95% CI: 2.32–18, p<0.001), an IgG or IgA monoclonal protein (OR: 2.67, 95% CI: 1.1–6.4, p=0.028) and an M-protein of ≥1 g/dl (OR: 5.4, 95% CI: 2.23–13) were independently associated with the presence of ≥10% of clonal infiltration in BM biopsy. By combining the above risk factors we found that in those who had all three, 97% had ≥10% clonal cells in the BM biopsy, while in those with 0–1 of the above factors the probability to find ≥10% clonal cells was 43%. These findings indicate that even patients with low risk for BM infiltration by clonal plasma cells, may be diagnosed as SMM when a BM biopsy is performed. In conclusion, our data on a large number of individuals with asymptomatic monoclonal gammopathy who underwent a BM biopsy may indicate that the latter exam may provide useful information and could be included in the standard initial workup of these individuals. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v124.21.5688.5688 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5688-5688

Author(s):

Mona L Vekaria ◽

Bharat Rao ◽

Philip Kuriakose

Keyword(s):

Risk Factors ◽

Bone Marrow ◽

Bone Marrow Biopsy ◽

Plasma Cell ◽

Monoclonal Gammopathy ◽

Plasma Cells ◽

Time To Progression ◽

Bone Marrow Biopsies ◽

Monoclonal Protein ◽

Cell Percentage

Abstract Introduction: Monoclonal gammopathies are characterized by the detection of a monoclonal immunoglobulin in the serum or urine and underlying proliferation of a plasma cell/B lymphoid clone. (1) Patients with monoclonal gammopathy of undetermined significance (MGUS) have a clonal plasma cell population in the marrow (<10%) and secrete a monoclonal protein in the serum (<3g/dL) and/or urine. However, they lack clinical features of overt Multiple Myeloma (MM) (lytic bone lesions, anemia, renal impairment and hypercalcemia). In a study from the Mayo Clinic, 59 of 241 patients with MGUS (24%) developed MM over a period of 22 years. (2) The interval from recognition of monoclonal protein to diagnosis of MM ranged from 2-29 years, indicating that patients with MGUS need to be followed indefinitely. Many risk factors have been looked at to identify those with MGUS who are at the highest risk to progress into MM. We hypothesize that a higher number of plasma cells would correlate with a greater risk of progression to MM and sought to find out if this could be documented by arbitrarily dividing patients between < or ≥5% plasma cells seen on initial bone marrow biopsy. Methods: We retrospectively reviewed patients diagnosed with MGUS at Henry Ford Hospital between 1999-2013 who underwent a bone marrow biopsy for documenting plasma cell percentage. In addition to this, we also recorded serum hemoglobin, calcium, creatinine, monoclonal protein type and amount, serum free light chains, beta-2 microglobulin and urine for monoclonal protein at the time of diagnosis of MGUS as well as last completed values. For patients that had skeletal surveys we noted if lytic lesions were present at diagnosis, as well as cytogenetics and karyotype evaluations on bone marrow biopsy samples, if completed. Results: 120 patients with bone marrow biopsies were reviewed. Out of this 17 patients were noted from initial bone marrow biopsy to have ≥10% plasma cells. The remaining 103 patients were categorized as having MGUS. While we were not able to complete full statistical analyses, we did note that 14 of these 103 (13.6%) patients went on to develop overt MM. Further evaluation of these patients revealed that 8 of 14 (57%) had bone marrow biopsies showing ≥5% plasma cells. Interestingly the average time to progression into MM in this subgroup was 1,879 days whereas in the 6 of 14 (43%) with bone marrow biopsy showing <5% plasma cells had average time to progression into MM of 1,965 days. Abnormal cytogenetics and karyotypes of the bone marrow biopsy were also seen in 37.5% of the subgroup of patients with ≥5% plasma cells whereas it was only seen in 16.7% of the subgroup of patients with <5% plasma cells. With statistical data analyses we hope to prove significance in the above collected data as well as make further correlations in regards to risk factors in patients with MGUS. Conclusion: While we have not been able to complete full statistical analyses of the collected data yet, basic review of the above patients with MGUS and ≥5% plasma cells in the bone marrow biopsy showed a trend to develop MM faster by an average of 86 days than those that had <5% plasma cells. These same patients also were more likely to have abnormal cytogenetics and karyotypes of their bone marrow biopsies. There is a need for further investigations to be done in patients with MGUS and higher risk features. It is important that hematologists be able to recognize a high risk MGUS patient as this would lead to closer monitoring and consideration for earlier aggressive treatment to potentially delay progression into overt MM. Disclosures No relevant conflicts of interest to declare.

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Prevalence of Monoclonal Gammopathy of Undetermined Significance in a Large Population with Annual Physical Examination in Beijing, China

Blood ◽

10.1182/blood-2019-124715 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5519-5519

Author(s):

Jinuo Wang ◽

Jian-Hua Han ◽

Yue-lun Zhang ◽

Xin-xin Cao ◽

Dao-Bin Zhou ◽

...

Keyword(s):

Physical Examination ◽

Light Chain ◽

Chinese Population ◽

Monoclonal Gammopathy ◽

Conflicts Of Interest ◽

Large Population ◽

M Protein ◽

Monoclonal Protein ◽

Significant Difference ◽

Undetermined Significance

Introduction Monoclonal gammopathy of undetermined significance (MGUS) is a clinically asymptomatic premalignant plasma cell disorder. Previous studies in Western countries have described the prevalence of MGUS in Caucasians. However, data is limited in Chinese population. We therefore performed this study to ascertain the prevalence and characteristics of MGUS among Chinese population. Methods A total of 154597 consecutive healthy participants from Beijing who underwent annual physical examination between December 2013 and April 2019 at Peking Union Medical College Hospital were enrolled. Serum M protein was evaluated by capillary electrophoresis. Patients with a positive or suspicious serum M protein were suggested to be referred to the hematological clinic for immunofixation electrophoresis (IFE) and free light chain (FLC) assays. MGUS was defined in accordance with previous definitions. We calculated age-specific and sex-specific prevalence and described laboratory characteristics of patients with MGUS among those participants. Results MGUS were diagnosed in 843 patients (0.55%, 95%CI 0.51% to 0.59%). The median age at presentation was 58 years, with a range of 25-96 years. The overall prevalence of MGUS was 1.14% among participants aged 50 years or older and 2.6% among those aged 70 years or older. In both sexes, the prevalence increased with age: 0.1% (<40 years), 0.36% (40-49 years), 0.78% (50-59 years), 1.28% (60-69 years), 2.19% (70-79 years), and 3.77% (≥80 years) separately (Figure 1). The prevalence among men were higher than that among women (0.67% vs. 0.40%, OR =1.719, 95% CI 1.490 to 1.983, P<0.001) (Figure 1). The median concentration of serum Monoclonal protein was 1.4 g/L (0.1 -27.8 g/L). M protein level was less than 0.5g/L in 220 patients (26.1%), less than 5 g/L in 81.1% and more than 15 g/L in only 1.9% of 843 persons. There was no significant difference in the concentration of the monoclonal protein among the age groups. Of the 519 patients who were tested for IFE, the isotype of the monoclonal immunoglobulin was IgG in 344 (66.3%), IgA 112 (21.6%), IgM in 48 (9.2%), IgD in 2 (0.4%), light-chain in 3 (0.6%) and biclonal in 10 (1.9%). The serum light-chain type was kappa in 260 (50.1%), lambda in 255 (49.1%) patients, while 4 patients (0.8%) with biclonal M protein have both kappa and lambda light-chain. Of the 180 people who were tested for FLC, 42 (23.3%) had an abnormal FLC ratio. IgG isotype, M protein <15 g/L and normal FLC ratio were found in 102 patients (56.7%) and the remaining 78 people (43.4%) had 1(30.6%) or 2(12.8%) abnormal factors. Conclusions MGUS was found in 1.14% of persons 50 years of age or older and 2.6% among those 70 years of age or older among healthy Chinese population. The prevalence of MGUS increases with age. Males have a higher frequency of MGUS than Females. These observations offer the overall situation of MGUS epidemiology in a large Chinese population. Disclosures No relevant conflicts of interest to declare.

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The Natural History of Smoldering (Asymptomatic) Multiple Myeloma.

Blood ◽

10.1182/blood.v106.11.3396.3396 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3396-3396 ◽

Cited By ~ 4

Author(s):

Robert Kyle ◽

Ellen Remstein ◽

Terry Therneau ◽

Angela Dispenzieri ◽

Paul Kurtin ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Plasma Cell ◽

Light Chain ◽

Plasma Cells ◽

M Protein ◽

Cell Content ◽

Bone Marrow Plasma ◽

M Spike

Abstract Smoldering multiple myeloma (SMM) is characterized by a serum M protein ≥ 3g/dL and/or 10% or more of plasma cells in the bone marrow. However, the definition is not standardized, and it is not known whether both serum M protein levels and bone marrow plasma cell counts are necessary for diagnosis or if one parameter is sufficient. We reviewed the medical records and bone marrows of all patients from Mayo Clinic seen within 30 days of recognition of an IgG or IgA M protein ≥ 3g/dL or a bone marrow containing ≥ 10% plasma cells from 1970 to 1995. This allows for a minimum potential follow-up of 10 years. Patients with end-organ damage at baseline from plasma cell proliferation, including active multiple myeloma (MM) and primary amyloidosis (AL) and those who had received chemotherapy were excluded. A differential of the bone marrow aspirate coupled with the bone marrow biopsy morphology and immunohistochemistry using antibodies directed against CD138, MUM-1 and Cyclin D1 were evaluated in every case in order to estimate the plasma cell content. In all, 301 patients fulfilled either of the criteria for SMM. Their median age was 64 years and only 3% were less than 40 years of age; 60% were male. The median hemoglobin value was 12.9 g/dL; 7% were less than 10 g/dL, but the anemia was unrelated to plasma cell proliferation. IgG accounted for 75%, IgA 22%, and biclonal proteins were found in 3%. The serum light-chain was κ in 67% and λ in 33%. The median serum M spike was 2.9 g/dL; 11% were at least 4.0 g/dL. Uninvolved serum immunoglobulins were reduced in 81%; only 1 immunoglobulin was reduced in 31% and both were decreased in 50%. The urine contained a monoclonal κ protein in 36% and λ in 18% and 46% were negative. The median size of the urine M spike was 0.04 g/24h; only 5 (3%) were > 1 g/24h. The median bone marrow plasma cell content was 15 – 19%; 10% had less than 10% plasma cells, while 10% had at least 50% plasma cells in the bone marrow. Cyclin D-1 was expressed in 17%. Patients were categorized into 3 groups: Group 1, serum M protein ≥ 3g/dL and bone marrow containing ≥ 10% plasma cells (n= 113, 38%); Group 2, bone marrow plasma cells ≥ 10% but serum M protein < 3g/dL (n= 158, 52%); Group 3, serum M protein ≥ 3g/dL but bone marrow plasma cells < 10% (n= 30, 10%). During 2,204 cumulative years of follow-up 85% died (median follow-up of those still living 10.8 years), 155 (51%) developed MM, while 7 (2%) developed AL. The overall rate of progression at 10 years was 62%; median time to progression was 5.5 yrs. The median time to progression was 2.4, 9.2, and 19 years in groups 1, 2, and 3 respectively; correspondingly at 10 years, progression occurred in 76%, 59%, and 32% respectively. Significant risk factors for progression with univariate analysis were serum M spike ≥ 4g/dL (p < 0.001), presence of IgA (p = 0.003), presence of urine light chain (p = 0.006), presence of λ urinary light chain (p = 0.002), bone marrow plasma cells ≥ 20% (p < 0.001) and reduction of uninvolved immunoglobulins (p < 0.001). The hemoglobin value, gender, serum albumin, and expression of cyclin D-1 were not of prognostic importance. On multivariate analysis, the percentage of bone marrow plasma cells was the only significant factor predicting progression to MM or AL.

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An Intact Immunoglobulin IgAλ Multiple Myeloma Patient Exhibiting Light Chain Escape

Blood ◽

10.1182/blood.v120.21.5008.5008 ◽

2012 ◽

Vol 120 (21) ◽

pp. 5008-5008

Author(s):

Maria Kraj ◽

Barbara Kruk ◽

Krzysztof Warzocha ◽

Andrzej Szczepinski ◽

Kelly Endean ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Bone Marrow Biopsy ◽

Light Chain ◽

Plasma Cells ◽

Induction Treatment ◽

Mild Renal Impairment ◽

Multiple Myeloma Patient ◽

Monoclonal Protein ◽

Serum And Urine

Abstract Abstract 5008 A 48 year old man was referred to the Institute of Hematology and Transfusion Medicine, Warsaw, Poland in April 2008 with anemia (Hemoglobin; 10. 4 g/dl) and mild renal impairment (eGFR; 75. 4 mL/min/1. 73m2). An initial diagnostic monoclonal protein screen (serum protein electrophoresis (SPE), serum immunofixation electrophoresis (IFE) and serum free light chain (FLC) analysis) revealed an IgAλ monoclonal protein (0. 8g/dL) with monoclonal serum FLC and an abnormal serum FLC κ/λ ratio (0. 0001; RI, 0. 26–1. 65). A bone marrow biopsy at that time confirmed 60% involvement of monoclonal λ - restricted plasma cells; a bone survey did not detect any osteolysis. The patient was diagnosed with multiple myeloma (MM) (ISS stage I, Durie and Salmon stage IA) and was initially treated with 6 cycles of vincristin, doxorubicin and dexamethasone (VAD). The patient responded well to the induction treatment and subsequently underwent a successful autologous stem cell transplantation (ASCT). The patient was monitored for 3 years subsequent to the ASCT with both serum and urine electrophoresis, serum FLC analysis (Freelite) and heavy chain/light chain (HLC) immunoassays (Hevylite). Sixteen months following the ASCT the dFLC (involved λ FLC– uninvolved κ FLC) concentration began to increase, the FLC κ/λ ratio became abnormal with a trace of λ Bence Jones protein (BJP) detected by urine IFE. However, both SPE and IFE were normal and the HLC ratio (IgAλ/IgAκ) was within the normal range. During the next 9 months the dFLC continued to increase and a λ BJP could now be clearly detected on the urine IFE. 27 months following the ASCT the patient sustained a pathological fracture of the tibiae and was referred to our centre 4 months later. At this point, the dFLC concentration was highly elevated (3168 mg/L) with a λ BJP detectable by both serum and urine IFE. However, there was no detectable monoclonal intact immunoglobulin by serum IFE or HLC analysis, indicating disease relapse by a separate FLC clone; referred to as light chain escape (LCE). A bone marrow biopsy revealed 15% involvement of λ restricted plasma cells; this time a bone survey identified osteolysis. The patient was diagnosed with progression of multiple myeloma and received 6 cycles of bortezomib, cyclophosphamide and dexamethasone (VCD regimen). He responded well to treatment and 3 years following the ASCT achieved a CR as indicated by a normalized κ/λ FLC ratio, negative immunofixation with 1–3% bone marrow plasma cells. The patient is now well and able to continue with normal life. In this case study the increase in the dFLC levels was the first indication of disease progression and highlights the importance of monitoring intact immunoglobulin MM patients with serum FLC immunoassays for early detection of LCE. Disclosures: Endean: The Binding Site Group Ltd: Employment. Harding:Binding Site: Employment.

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Comparison Of Hevylite™ Assay and Plasma Cell Immunophenotyping For Response Evaluation and Residual Disease Characterisation In IgA Myeloma

Blood ◽

10.1182/blood.v122.21.5319.5319 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5319-5319

Author(s):

Daniela Lakomy ◽

Stephanie Lemaire-Ewing ◽

Cedric Rossi ◽

Jessica Borgeot ◽

Jean-Noël Bastie ◽

...

Keyword(s):

Bone Marrow ◽

Binding Site ◽

Plasma Cell ◽

Light Chain ◽

Plasma Cells ◽

Conflicts Of Interest ◽

Residual Disease ◽

Response To Treatment ◽

Response Evaluation ◽

Bone Marrow Plasma

Abstract Introduction The evaluation of multiple myeloma response to treatment as defined by international guidelines is currently based on morphologic examination of bone marrow plasma cells, serum protein electrophoresis (SPEP), immunofixation electrophoresis (IFE) and serum free light chain assay. For several years new tools are available as bone marrow plasma cell immunophenotyping and the HevyliteTM assay. HevyliteTM IgA assay provides an automated evaluation of serum heavy/light chain ratio (HLC) of the involved and uninvolved immunoglobulin (Ig) (i.e. IgAΚ/IgAλ). This is particularly interesting in IgA myeloma where the use of SPEP is limited due to a frequent comigration of monoclonal IgA with other proteins. We therefore compared the IgA quantification by Hevylite™ assay and the bone marrow plasma cell immunophenotyping for response evaluation and residual disease characterisation in IgA myeloma. Methods Hevylite™ assay, SPEP, IFE were performed in eleven IgA myeloma patients at different times: after induction chemotherapy, after the consolidation phase and after autologous stem-cell transplantation (ASCT). In the same time, minimal residual disease (MRD) assessment was performed on bone marrrow by multiparameter flow cytometry (MFC). Hevylite™ assay was performed on a Binding Site SPAplus analyser (Hevylite, Binding Site, Birmingham, UK) following the manufacturer recommendations. SPE and IFE were realized on Sebia Hydrasys analyser (Sebia, Evry, France) and results were read by two experienced biologists. Results 1. We found a perfect agreement between the IFE and immunophenotyping results at each time of evaluation, for positive results as for negative results. 2. The SPEP was contributive only in two patients and in these cases it was less sensitive than IFE. In the other patients, the monoclonal IgA migrated in beta region and/or as multiple bands, making the quantitative estimation difficult. 3. In all patients, when MRD by MFC was undetectable and IFE was negative, the HLC ratio was normal. 4. In 3 patients, HLC ratio was consistent with the IFE and MRD by MFC at each time of evaluation. Nevertheless, in 8 patients out of 11, while HLC ratio became normal, MRD by MFC and IFE were still positive. In all cases, the normalization of HLC ratio was followed, at the next step of evaluation, by the normalization of MFC and IFE. 5. In 5 patients, the normalization of HLC ratio occurred before ASCT, while IFE and MRD by MFC were still positive. Nevertheless, after ASCT, IFE and MRD by MFC became also negative, in accordance with the HLC ratio (Table 1). Conclusions During the evaluation of response to treatment of IgA myeloma, we observed a normalization of HLC ratio (Hevylite™ IgA assay) preceding the normalization of MRD by MFC and IFE. This could be explained by the fact that IFE and immunophenotyping provide very sensitive information but only on the monoclonal component. HLC ratio reflects the balance between the monoclonal and polyclonal Igs of involved and uninvolved isotype. A normalization of HLC ratio can be interpreted as an increasing polyclonal Ig proportion parallel with a decreasing monoclonal Ig proportion and may reflect the reconstitution of polyclonal plasma cells. If confirmed by other studies and long term follow-up, HLC ratio could be a non-invasive predictive marker of a good response in IgA myeloma. Disclosures: No relevant conflicts of interest to declare.

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Pure Red Cell Aplasia Associated with Plasma Cell Myeloma: Does Monoclonal Protein Inhibit Erythropoiesis?

Blood ◽

10.1182/blood.v116.21.642.642 ◽

2010 ◽

Vol 116 (21) ◽

pp. 642-642

Author(s):

Neha Korde ◽

Kelsey Loeliger ◽

Olga Simakova ◽

Adriana Zingone ◽

Richard Childs ◽

...

Keyword(s):

Bone Marrow ◽

Plasma Cell ◽

Light Chain ◽

Plasma Cells ◽

Pure Red Cell Aplasia ◽

M Protein ◽

Normal Donor ◽

Red Cell ◽

Plasma Cell Myeloma ◽

M Proteins

Abstract Abstract 642 Pure red cell aplasia (PRCA) is a rare hematologic disorder characterized by selective inhibition of red cell precursors in the bone marrow. The pathogenesis of PRCA is unclear. Reported secondary causes of PRCA include thymoma, lymphoproliferative disorders (large granular lymphocyte leukemia, chronic lymphocytic leukemia), and viral infection such as human B19 parvovirus; however, in a large portion of patients the cause of PRCA is not able to be elucidated. In this study, we report a series of PRCA patients with unusual histopathological features and associated increase in clonal plasma cells that appear to represent a previously unrecognized PRCA variant associated with MGUS/plasma cell myeloma. We performed a retrospective analysis of bone marrow biopsies and aspirates from 50 patients diagnosed with idiopathic PRCA at the National Institutes of Health between 2001 and 2009. All samples underwent morphological, immunohistochemical and molecular analysis. Serum protein assays were performed on a cohort of patients that demonstrated increased plasma cells and/or light chain restricted plasma cells. In addition to the classical PRCA finding of marked erythroid hypoplasia with maturation arrest, we found 11/50 (22%) PRCA patients with the following atypical bone marrow features: hypercellularity with increased fibrosis and variable degree of plasmacytosis with light chain restriction and frequent aberrant CD56 or cyclin D1 expression, indicating clonality. Based on CD138 staining, 10 of the 11 (91%) patients had 10–20% plasma cells on marrow biopsies, while 1 patient demonstrated 5% plasma cells. Light chain restriction of plasma cells was morphologically demonstrated in 7/11 (64%) patients. 8/11 (72%) patients demonstrated M-proteins on serum protein electrophoresis (SPEP) and/or immunofixation; 6 of the 7 evaluable patients with M-proteins had a skewed serum free light chain (FLC) kappa/lambda (K/L) ratio. There were 7 IgG M-proteins, and the isotype of the M-protein was not defined for one patient. Mean M-protein concentration was 1.18 g/dL (0.6-2.5 gm/dL). Among the 3/11 (27%) patients without M-protein, 2 patients had a skewed FLC K/L-ratio (normal range 0.26–1.65), and 1 patient had a K/L ratio of 1.57. Based on these findings, 9/11 (82%) patients were diagnosed with plasma cell myeloma, 1 patient with MGUS, and clonality of plasma cells could not be demonstrated in 1 patient. In order to better understand underlying mechanisms, we performed an erythroid colony forming assay by co-culturing normal donor hematopoietic stem cells (HSCs) with serum from a PRCA patient containing M-protein versus serum from a normal donor. Compared to normal serum, colony cultures containing M-protein had a 43% reduction in CFU-E and BFU-E suggesting inhibition of erythroid colonies by the monoclonal protein. Clinically, response rates to daclizumab are increased in idiopathic PRCA compared to PRCA variant associated with MGUS/plasma cell myeloma, 10/23 (43%) vs. 0/6 (0%), respectively, (p=0.04). Among 3/11 patients receiving anti-myeloma therapy, 1 patient had resolution of PRCA and later became transfusion independent after bortezomib and 2 patients were lost to follow-up. Over 20% of patients originally diagnosed with idiopathic PRCA were shown to harbor clonal plasma cells and exhibit atypical histopathological marrow features. CFU-E and BFU-E colony growth from normal donor HSCs was inhibited by patient serum containin M-protein. Resolution of PRCA with transfusion independence was achieved in a patient treated with bortezomib based therapy. These findings point to a novel, previously not recognized pathogenetic mechanism of PRCA associated with relatively low plasma cell burden and demonstrate that these patients may benefit from myeloma based treatment strategies rather than standard immunosuppression. Disclosures: No relevant conflicts of interest to declare.

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Monoclonal Gammopathy of Undertermined Significance (MGUS): Clinical Predictors of Malignant Transformation in 434 Patients with a Long Follow-Up from a Single Institution.

Blood ◽

10.1182/blood.v104.11.4838.4838 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4838-4838

Author(s):

L. Rosiñol ◽

S. Montoto ◽

J. Bladé ◽

M.T. Cibeira ◽

M. Rozman ◽

...

Keyword(s):

Bone Marrow ◽

Malignant Transformation ◽

Light Chain ◽

Monoclonal Gammopathy ◽

Plasma Cells ◽

M Protein ◽

Single Institution ◽

Protein Size ◽

Bone Marrow Plasma

Abstract Background: MGUS is a common disorder characterized by the presence of a small serum M-protein in individuals with no evidence of multiple myeloma (MM), Waldenström’s macroglobulinemia (WM) or primary amyloidosis (AL). Although about one fourth of these individuals will evolve into a malignant disease with a transformation rate of 1% per year, there are not well-established predictors of outcome. Aim: To identify predictor features of malignant transformation in a large series of patients with MGUS and prolonged follow-up. Patients and methods: Four hundred and thirty-four patients (200 M/234 F; median age 66 years) diagnosed with MGUS in a single institution from September 1970 to January 2001 with a minimum follow-up of one year were included in the study. All patients had an M-protein size < 30g/L. Bone marrow aspirates were reviewed independently by two of the authors and the proportion of bone marrow plasma cells (BMPC) were estimated from a 500 cell-count by each observer. The median follow-up was 5.2 years (range: 1–28.8 years) with 84 patients followed for more than 10 years. Results: The type of M-protein was IgG in 67.2% of the cases, IgA in 18.8%, IgM in 11.9%, light chain in 1% and biclonal in 1%. The light chain was kappa type in 56.4% of the patients. The median M-protein size was 15.6 g/L (<10 g/L in 10.8%, 10–20 g/L in 61.7%, and > 20g/L in 27.4%). The median percentage of BMPC in 305 reviewed samples was 4.6% (range: 0.4–25). After a median follow-up of 5.2 years, 50 patients (11.5%) have evolved into a malignant monoclonal gammopathy (44 MM, 5 WM and 1 AL). The median time to progression was 5.4 yrs (range: 1.4 – 16.9). The risk of transformation was 15.4% (95% CI: 10.5–20.3) and 34% (95% CI 22.6–45.3) and 34% (95% CI: 22.6–45.3) at 10 and 20 years, respectively. The variables associated with a higher risk of transformation were IgA-type (p=0.003), kappa light chain (p=0.009), the amount of M-protein (<15 vs >15 g/L, p=0.005) and the percentage of BMPC (<5% vs >5%, p=0.007). Conclusions: In this series of patients with MGUS, the type (i.e. IgA or kappa) and size of M-protein (>15g/L) as well as the percentage of bone marrow plasma cells (>5%) significantly predicted malignance transformation.

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Multiple Myeloma Variant with Ascites and Cytoplasmic Crystalline Granules in Plasma Cells

Blood ◽

10.1182/blood.v118.21.5088.5088 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5088-5088

Author(s):

Cesar Rodriguez ◽

Anthony Janckila ◽

Sylvia Potenziani ◽

Vivek R. Sharma

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Monoclonal Gammopathy ◽

Plasma Cells ◽

Conflicts Of Interest ◽

Clinical Work ◽

Cytoplasmic Inclusions ◽

Monoclonal Protein ◽

Crystalline Inclusions ◽

Work Up

Abstract Abstract 5088 CASE REPORT: CLINICAL HISTORY: A 62-year-old male patient who presented with anemia and findings of monoclonal gammopathy of IgA type was referred to the Hematology clinic for work-up and management of possible multiple myeloma. At the same time, the patient was being managed by the Gastroenterology service with diuretics and recurrent paracentesis for an ongoing significant ascites of unclear etiology. These interventions had been performed for a year on a biweekly basis. CLINICAL WORK-UP: The patient had IgA gammopathy with a monoclonal protein level of 1.2 Gm/dL and findings on skeletal survey consistent with lytic lesions in the pelvic bones. PROCEDURE: A bone marrow biopsy obtained from the patient revealed a plasmacytosis of 15% with atypical crystalline cytoplasmic inclusions seen in the majority of plasma cells and some histiocytes as well. The transudative ascitic fluid was analyzed for crystalline deposits, but these could not be conclusively detected even though there were inclusions seen in some macrophages that may represent remnants of the crystals. TREATMENT: The patient was diagnosed with IgA myeloma given the above findings and was treated with a combination of Revlemid, Velcade and Dexamethazone with good response in terms of his IgA monoclonal protein as well as in significant improvement in his ascites, which essentially resolved. He no longer required therapeutic paracentesis upon initiation of chemotherapy and was able to get weaned off of diuretics as part of his treatment. CONCLUSION: This case represents what we believe to be a rare variant of multiple myeloma that presented with monoclonal gammopathy in the blood as well as concomitant ascites. The bone marrow showed plasma cells containing crystalline inclusions. The precise nature of these inclusions is presently unknown, however it is felt most likely to be precipitated immunoglobulins. We plan to investigate this further. For reasons that are not entirely clear, this particular biology appears to induce a reactive process in the peritoneum causing a development of ascites. The resolution of such ascites with treatment directed toward the myeloma seems to indicate that the two are related. A case similar to this was reported by Doctors Martin, et al in 1987 with a patient presenting with similar type of crystalline inclusions in plasma cells with clinically associated ascites.1 There was no information available on treatment effect and so it was not possible to tie the clinical presentation of the myeloma and ascites together. Disclosures: No relevant conflicts of interest to declare.

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Bone Marrow Plasma Cell Burden in Gaucher Disease Correlates with Local Macrophage Infiltration and May be Altered By Disease Treatment

Blood ◽

10.1182/blood-2019-131343 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3593-3593

Author(s):

Monika Klimkowska ◽

Maciej J. Machaczka

Keyword(s):

Bone Marrow ◽

Plasma Cell ◽

Gaucher Disease ◽

Plasma Cells ◽

Conflicts Of Interest ◽

M Protein ◽

Specific Therapy ◽

Increased Risk ◽

Disease Specific

Introduction Gaucher disease (GD), caused by deficient activity of lysosomal glucocerebrosidase, results in tissue infiltration by transformed macrophages (Gaucher cells, GC), loaded with undigested glycolipids. Ensuing clinical signs and symptoms include skeletal lesions and cytopenias, and seem to be due to both local tissue replacement by pathological infiltrates but also to accompanying inflammatory response, elicited by engorged macrophages. Bone marrow GC infiltration coincides with increased microvascular density and skewed angiogenic profiles. The basis for increased risk of plasma cell (PC) dyscrasia in GD remains however still unexplained. The presented study aimed to investigate patterns of PC distribution in bone marrow of untreated GD patients, potential their clinical correlates and evolution during treatment. Methods Study material includes BM samples from 11 previously untreated GD1 patients (7 males, 4 females), followed at the Hematology Center, Karolinska University Hospital, Stockholm, Sweden. Diagnosis of GD was previously confirmed with proven deficient glucocerebrosidase activity in PB, and demonstrated GBA1 mutation. The study was performed in accordance with Declaration of Helsinki, and institutional ethical permit was obtained. Clinical data were retrieved from patient journals. After BM sampling, 10 patients began disease specific therapy, with 9 subjects receiving enzyme replacement therapy (ERT), and one treated with substrate reduction therapy (SRT). Bone marrow samples (trephine biopsies or fine needle aspirates) were taken as part of routine hematologic work-up, at baseline and, if needed, during follow-up. Samples were routinely processed at the Department of Clinical Pathology and Cytology at the same hospital. Plasma cell burden and distribution were studied in immunohistochemically stained sections (CD138), scanned at 40x magnification using the NanoZoomer S360 Digital slide scanner (Hamamatsu Photonics, Hamamatsu, Japan). NDPI.view2 Viewing software was used for scan evaluation, and image saving (JPEG format, 461 nm/pix resolution). For each sample, 5 fields with prominent Gaucher cell infiltrates (≥50% field area; GC-rich areas ), and 5 with <50% GC infiltration (non-GC-rich areas) were registered. In the obtained pictures (442x 248 μm) all plasma cells were manually counted. Results At baseline, the patients were 21-86 years old (mean 58.8, median 42 yrs). All but one patient carried at least one N370S mutated GBA1 allele. Four were previously splenectomized; only one of the remainder group had no splenomegaly. Three patients had anemia, and 10 thrombocytopenia; one patient was not cytopenic. Ten patients had hyperferritinemia but only 2 had mildly increased IL-6 levels (Tab. 1). Proteinogram studies identified M-protein in only 2 subjects, with oligoclonal Ig increase in 2, and polyclonal Ig in 3 patients. Decreased Ig levels were found in 2 patients. Morphological analysis revealed multifocal, compact to dispersed Gaucher cell infiltrates, in all patients, with markedly varying GC burden. Notably, plasma cells were found in higher frequency in GC-rich areas (range 26.2-174.2/HPF), where their usual perivascular distribution pattern was only partially preserved (Fig. 1). Areas dominated by normal hematopoietic tissue demonstrated a significantly lower plasma cell infiltration (range: 2-128.2/HPF; Fig. 2). In patient 5, PC infiltration level was consistent with myeloma, M-protein was at 32 g/L, and difference in PB burden between GC-rich and non-GC areas was in his BM lower than in other patients. Follow up BM samples were obtained in 5 patients, 12-14 months from treatment onset. In 4 of those, PC burden decreased in GC-rich areas but increased in areas with dominant normal hematopoiesis (Fig. 3). The longest documented follow-up was in the SRT subject (over 6 years, patient 1), where similar trends could be observed. Patient 4 initially increased PC burden in BM, and patient 5 succumbed to myeloma and MDS shortly after study onset. Conclusion Bone marrow in GD1 demonstrates increased plasma cell density, particularly in areas affected by the disease. This phenomenon seems to be at least partly modified by disease specific therapy, albeit at a slow pace. N370S mutation was associated with dysimmunoglobulinemia but did not coincide with MGUS in most patients; unexpectedly, the myeloma patient was N370S heterozygous. Disclosures No relevant conflicts of interest to declare.

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