Extensive Bone Marrow Infiltration and Abnormal Free Light Chain Ratio Identifies Patients with Smoldering Myeloma At High Risk for Progression to Symptomatic Disease,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3926-3926
Author(s):  
Efstathios Kastritis ◽  
Lia A Moulopoulos ◽  
Maria Gkotzamanidou ◽  
Dimitra Gika ◽  
Maria Roussou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Light Chain ◽  
Plasma Cells ◽  
Bone Lesions ◽  
Symptomatic Disease ◽  
Lytic Bone Lesions ◽  
Risk Of Progression ◽  
Bone Marrow Plasma ◽  
Substantial Risk

Abstract Abstract 3926 Asymptomatic/smoldering multiple myeloma (SMM) is a proliferative plasma cell disorder characterized by a substantial risk of progression to symptomatic myeloma. According to current recommendations, patients with SMM should be followed without treatment until they develop symptomatic disease. However, the risk of progression to symptomatic myeloma varies between different series and for individual patients; thus, significant effort is needed in order to identify factors that could discriminate those who are at high risk for progression. Such patients should be followed closer and should be considered candidates for clinical trials. In order to evaluate previously recognized risk factors and study patterns of progression we analyzed our series of patients with SMM, who have been diagnosed and followed in the Department of Clinical Therapeutics in Athens, Greece. SMM was defined as serum monoclonal (M) protein (IgG or IgA) level of ≥3 g/dL and/or bone marrow plasma cells ≥10%, absence of end-organ damage, such as lytic bone lesions, anemia, hypercalcemia, or renal failure, that can attributed to a plasma cell proliferative disorder (IMWG criteria, Br J Haematol 2003;121:749–57). Progression to symptomatic myeloma was defined as per the IMWG proposed criteria. We analyzed 95 patients with SMM, 53% of whom were females, 70% had IgG heavy chain, 22% had IgA, 5% had a biclonal SMM and 3% had light chain only SMM, while 65% had a kappa light chain and 35% a lambda light chain. Median infiltration by clonal plasma cells in BM trephine biopsy was 20% (range 10–90%), 10% of patients had ≥60% clonal plasma cells in BM biopsy. Fifty patients had MRI of the spine at the time of diagnosis of SMM and 19.5% had an abnormal pattern of BM infiltration (diffuse, focal or variegated pattern). In patients with available bone marrow immunohistochemistry data, 61% had clonal plasma positive for CD56, 17% for CD20 and 19% for cyclin D1. The median follow up of the cohort was 27 months (range 1–253 months) and 23 (24%) patients have progressed to symptomatic myeloma. The one-year, 2-year and 3-year cumulative probability of progression was 7%, 12% and 20% respectively. Nine patients (9.5%) progressed within the first two years from the diagnosis of SMM. All these patients had an M-protein of ≥1 g/dl (10 g/L), 67% had bone marrow plasma cells >60% and 80% had an abnormal MRI pattern of BM infiltration. The 3-year probability of progression to symptomatic myeloma was 4%, 18% and 87% for patients with <20%, 20–59% and ≥60% clonal plasma cells in bone marrow biopsy (P<0.001). The 2-year probability of progression to symptomatic myeloma was 0%, 13% and 60% for patients with <20%, 20–59% and ≥60% clonal plasma cells in BM biopsy (P<0.001). Patients with significantly abnormal free light chain ratio (either kappa/lambda ≥8 or kappa/lambda ≤0.125, according to Dispenzieri et al, Blood 2008;111:785–9) had a 3-year probability of progression to symptomatic MM of 41% vs. 15% (p=0.07). There was no significant difference in the risk of progression to symptomatic MM for patients with IgA vs. IgG myeloma. In multivariate analysis, abnormal FLC ratio less than 0.125 or more than 8 (HR: 6.4, 95% CI 1.3–34.5 p=0.032) and BM clonal plasma cells infiltration ≥60% (HR: 23, 95% CI 5–125, p<0.001) were independent risk factors for progression to symptomatic myeloma. Progression to symptomatic MM was manifested by the development of anemia in 52% of patients who progressed to symptomatic MM, development of lytic bone lesions or pathologic fracture in 48%, an increase of serum creatinine to ≥2 mg/dl in 13%, development of a soft tissue plasmacytoma in 4% and development of hypercalcemia in 4%. In conclusion, in our series of patients the 3-year probability of progression to symptomatic myeloma is about 20%, but there is a subgroup of patients with extensive bone marrow infiltration (≥60%) and highly abnormal FLC ratio, who have a substantial risk of progression to symptomatic disease within the first two years from the diagnosis of SMM. These high risk patients may also have other features such as abnormal MRI of the spine. Patients at high risk for progression should be considered for clinical trials evaluating the role of treatment before the development of symptomatic disease, which in most cases is manifested with anemia and/or lytic bone disease or pathologic fractures. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Bence Jones Proteinuria in Smoldering Multiple Myeloma As Predictor Marker of Progression to Symptomatic Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3369-3369 ◽  
Author(s):  
Veronica Gonzalez de la Calle ◽  
Ramon Garcia-Sanz ◽  
Eduardo Sobejano ◽  
Enrique M. Ocio ◽  
Noemi Puig ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Light Chain ◽  
Plasma Cells ◽  
Symptomatic Disease ◽  
Risk Of Progression ◽  
Bone Marrow Plasma ◽  
Active Disease ◽  
Bence Jones Proteinuria

Abstract BACKGROUND Smoldering multiple myeloma (SMM) is a plasma cell proliferative disorder with no related organ or tissue impairment. It is associated with a risk of progression to symptomatic multiple myeloma (MM) of approximately 10% per year. Several prognostic factors for the progression to active disease have been identified, such as those defined by the Mayo Clinic including the proportion of bone marrow plasma cells, the serum monoclonal protein level at diagnosis and the serum immunoglobulin free light chain ratio (FLC); or those defined by the Spanish Group including the proportion of bone marrow aberrant plasma cells assessed by flow cytometry plus immunoparesis. The presence of Bence Jones (BJ) proteinuria is a myeloma feature associated with renal function and tumor burden as well. There is lack of evidence about the role of BJ proteinuria in SMM as predictor marker of progression to symptomatic disease. AIMS The goal of the present study was to investigate the role of the presence of Bence Jones proteinuria at diagnosis in SMM as predictor of progression to symptomatic disease. METHODS We reviewed 147 medical records of SMM patients from area of Castilla y León (Spain), diagnosed between 1983 and 2013, according to the criteria of the International Myeloma Working Group. The primary endpoint was time to progression to active multiple myeloma (hypercalcemia, renal insufficiency, anemia or bone lesions). RESULTS 147 patients with SMM were included in the analysis. The median age at diagnosis was 69 years-old (range: 34-90).The serum M-protein at diagnosis ranged from 1 to 26 g/l (median,25). 70% of SMM were Ig G subtype. The proportion of bone marrow plasma cells ranged from 1% to 55% (median, 14). In 64 % of SMM, the percentage of aberrant plasma cells assessed by flow cytometry was superior to 95% and 51% had immunoparesis. Bence Jones proteinuria was detected at diagnosis in 40 patients (27%) and the average amount of urinary monoclonal light chain was 236 mg per 24h. Of those patients, 58% had a monoclonal kappa light chain. The FLC ratio was assessed in 18 patients and it was abnormal (<0.26 or >1.65) in 83% of them. The median level of involved Immunoglobulin was 88.5 mg/l (range, 13-1200) and the median ratio of involved to uninvolved was 10.8 (range, 2.2-3360). In 4 patients, FLC ratio was greater than 100. At a median follow-up of 54 months, progression to active disease occurred in 49%. Anemia was the most common CRAB feature at the time of progression. Median time to progression (TTP) to symptomatic disease in the whole series was 63 months. SMM with BJ proteinuria had a significantly shorter median TTP to active disease as compared with patients without BJ proteinuria (21.7 months vs 82.9 months ;HR: 2.44, IC 95%: 1.48-4.02; p<0.001). The progression risk at 2 years in the BJ group of SMM was 53%. Multivariate analysis selected BJ proteinuria at diagnosis as an independent variable for progression to symptomatic MM (HR: 2.47, IC 95%: 1.32-4.63; P=0.005). Using this independent variable, we identified 4 risk categories according to amount of urinary monoclonal light chain: 0 mg per 24h; 1-250 mg/24h; 251-500 mg/24h ; or more than 500 mg/24h, with a median TTP of 83, 37, 16 and 7 months, respectively; p <0.001. CONCLUSIONS The presence of Bence Jones proteinuria at diagnosis in SMM patients is associated with significantly higher risk of progression to active MM (53% risk of progression at 2 years). Moreover, the presence of more than 500 mg of BJ proteinuria can be considered as a marker for the identification of ultra high risk SMM. Disclosures No relevant conflicts of interest to declare.

Bone Marrow Immunophenotypic Analysis Allows the Identification of High Risk of Progression and Immune Condition-Related Monoclonal Gammopathy of Undetermined Significance.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2804-2804
Author(s):  
AndrÉs Jerez ◽  
Francisco Ortuño ◽  
María del Mar Osma ◽  
Ignacio Español ◽  
Ana Gonzalez ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
High Risk ◽  
Plasma Cells ◽  
Plasma Cell Dyscrasia ◽  
Newly Diagnosed ◽  
Immune Disorders ◽  
Chronic Infections ◽  
Risk Of Progression ◽  
Bone Marrow Plasma

Abstract Abstract 2804 Poster Board II-780 Background: Monoclonal gammopathy of undetermined significance (MGUS) progresses to plasma cell dyscrasia, mainly multiple myeloma (MM), at a rate of approximately 1% per year. Moreover, recent studies have shown that MM is nearly always preceded by MGUS, encouraging investigators to find better predictors for MM development in order to implement strategies to prevent or delay progression. In addition, a high prevalence of MGUS has been noted in a series of patients with immune disorders or chronic infections. Multiparameter flow cytometry allows the identification and quantification of both monoclonal and polyclonal plasma cells. This study analyses the relationship between monoclonal and polyclonal bone marrow plasma cells (BMPC), studied by means of flow cytometry, and its association with either immune or infectious disorders, or the development of MM in newly diagnosed MGUS patients. Methods: We conducted a retrospective cohort study to analyse the prognostic value of the aberrant (CD38++ CD138+ CD19– CD45weak) to normal (CD38++ CD138+ CD19+ CD45+) phenotype bone marrow plasma cells ratio (A/N ratio) and another 13 variables at baseline for the development of a plasma cell dyscrasia. We also performed a cross-sectional study to evaluate the association of those variables at baseline with the presence of a chronic immune response disorder. In each patient, the following variables were examined: age, sex, hemoglobin, serum creatinine, serum calcium, B2-Microglobulin, type and size of the serum monoclonal component (MC), isotype of the MC immunoglobulin, presence of urine MC, quantification of serum immunoglobulin levels, erythrocyte sedimentation rate, BMPC percentage and presence of atypical plasma cells on light microscopy, and aberrant and normal phenotype BMPC percentages. The effect of variables on progression was calculated using a Cox proportional hazards regression model. To identify variables at baseline associated with immune or chronic infectious disorders. a series of univariate and multivariate analyses was fitted using a binary logistic regression strategy. Results: Between March 1997 and April 2008, flow cytometry analysis on bone-marrow samples was performed on 322 patients with newly diagnosed MGUS. Median patient age was 71 years (interquartile range (IQR) 63-78 years) with a slightly male predominance (51%). Median follow-up was 46 months (IQR 23-58 months). During the period of observation, in 23 (7.1%) patients a transformation was registered into: MM (n=22), and primary amyloidosis (n=1). A total of 24 (7.4%) patients had a diagnosis of autoimmune disorder, and 18 (5.6%) patients of a chronic infection. Multivariate analysis for progression to MM revealed an increased A/N ratio as the main independent prognostic variable. In addition, our study found a significant association between a reduced A/N ratio and the diagnosis of a chronic immune response related condition. Using receiver-operating characteristic analysis we created an A/N ratio range from 4 to 0.20. Values of 4 or higher define a group of MGUS patients at high risk of progression (OR, 10.7; 95% confidence interval 4.2-39), whereas A/N ratio values of 0.20 or lower are associated with immune disorders or chronic infections (OR, 20.9; 95% confidence interval 8.5-51.1). A total of 282 patients had an A/N ratio below 4, and 42 had values equal to or above the cut-off. Patients with an A/N ratio ≥ 4 had a cumulative probability of transformation of 35% at 5 years, compared with 3% for those with an A/N ratio < 4. Conclusions: Extreme values of the A/N ratio at diagnosis seem to be related with two different conditions: high risk MGUS, likely to progress to MM, and immune condition related MGUS. Our findings further support the routine use of phenotypic characterization of bone marrow plasma cells in patients with MGUS at diagnosis. Disclosures: No relevant conflicts of interest to declare.

Immunoglobulin Free Light Chain Ratio Is an Independent Risk Factor for Progression of Smoldering Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1487-1487 ◽  
Author(s):  
Angela Dispenzieri ◽  
Robert A. Kyle ◽  
Jerry A. Katzmann ◽  
Dirk Larson ◽  
Joanne Benson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Light Chain ◽  
Plasma Cells ◽  
Free Light Chain ◽  
M Protein ◽  
Baseline Serum ◽  
Smoldering Multiple Myeloma ◽  
Risk Of Progression ◽  
Bone Marrow Plasma

Abstract Background: Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell proliferative disorder with a high risk of progression to symptomatic multiple myeloma. Identification of risk factors that predict progression of SMM to symptomatic MM could identify higher risk patients who might benefit from chemoprevention or more intensive surveillance. We hypothesized that increased monoclonal free kappa or lambda immunoglobulin light chains in smoldering myeloma (SMM), as detected by the serum free light chain (FLC) assay, indicates an increased the risk of progression to active myeloma. Methods: Of 276 pathologically confirmed SMM patients seen at the Mayo Clinic from 1970 to 1995, baseline serum samples obtained within 30 days of diagnosis were available in 273. Results: At a median follow-up of surviving patients of 12.4 years, transformation to active disease has occurred in 161 (59%) patients. An abnormal FLC ratio was present at baseline in 90% of patients. The best break-point for predicting risk of progression was a FLC ratio less than or equal to 0.125 or greater than or equal to 8 (hazard ratio, 2.3; 95% CI, 1.6–3.2) [Figure 1]. The extent of abnormality of FLC ratio was independent of SMM risk categories defined by number of plasma cells in the bone marrow and size of serum M-proteins (bone marrow plasma cells ≥ 10% and serum M protein ≥ 3 g/dL; bone marrow plasma cells ≥ 10% but serum M protein &lt; 3 g/dL; and serum M protein ≥ 3 g/dL but bone marrow plasma cells &lt; 10%). Incorporating the FLC ratio into the risk model, the division of patients into high-, intermediate-, and low-risk groups is 28, 42, and 30% with 5 year progression rates of 76, 51, and 25%, respectively [Figure 2]. Conclusions: The serum immunoglobulin FLC ratio is an important additional determinant of clinical outcome in patients with SMM. Figure Figure Figure Figure

Prognostic Impact Of Serum Heavy/Light Chain Pairs In Patients With MGUS and Smoldering Myeloma: Long-Term Results From a Single Institution

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3132-3132
Author(s):  
Carlos Fernández de Larrea ◽  
Laura Magnano ◽  
Montserrat Elena ◽  
María Teresa Cibeira ◽  
Natalia Tovar ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Plasma Cell ◽  
Light Chain ◽  
M Protein ◽  
Cell Infiltration ◽  
Prognostic Impact ◽  
Plasma Cell Infiltration ◽  
Risk Of Progression ◽  
Bone Marrow Plasma

Abstract Background Asymptomatic monoclonal gammopathies, such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM), are clinical conditions that usually precede symptomatic multiple myeloma (MM). However, risk stratification is crucial due to the heterogeneous progression rate among patients with these entities, particularly nowadays when chemoprevention trials are encouraged in high risk patients. In this sense, biomarkers and prognostic index based on tumoral load, M-protein behaviour (evolving vs. non-evolving) and/or immunological status have been developed. In MGUS, serum heavy/light chain (HLC) pairs have allowed the identification of abnormal ratios of involved and non-involved immunoglobins for each specific heavy-chain isotype (IgG-kappa/IgG-lambda, IgA-kappa/IgA-lambda and IgM-kappa/IgM-lambda). The aim of the present study was to investigate the prognostic impact on progression of the isotype-specific suppression of the uninvolved HLC-pair in a series of patients with MGUS and SMM with long follow up. Patients and Methods We retrospectively evaluated 114 patients (median age 61 years; 44M/70F) with SMM (35) and MGUS (79). Median follow up for alive patients was 13 years (range 3 to 27 years). Only 12 patients with SMM accomplished both diagnostic criteria for high risk (bone marrow plasma cell infiltration ≥10% and M-protein ≥30 g/L). Heavy isotype distribution was mainly IgG (71%), IgA (15.8%) and IgM (11.4%); only two patients (1.8%; 1 MGUS and 1 SMM) had only light-chain M-protein. Median bone marrow plasma cell infiltration was 4% and 15% in MGUS and SMM, respectively. 13 patients (11.4%) showed an “evolving” pattern of their serum M-protein. All patients had an available initial frozen serum sample. Three serum HLC pairs (IgG, IgM and IgA) were evaluated by immunonephelometry (Hevylite; gently provided by The Binding Site, Ltd); HLC kappa/lambda ratio were calculated for each one. Normal values were obtained from 95% normal values reported in healthy donors. Results Progression to malignant symptomatic gammopathies was observed in 15 patients (13.2%; 9 SMM and 6 MGUS), mainly to MM (13) with exception of AL amyloidosis and Waldenström's macroglobulinemia in one case each. Risk of progression was 4 times higher in patients with SMM than in those with MGUS (p=0.009), being 8 times higher for high risk SMM (p<0.001). An “evolving” pattern of serum M-protein (p=0.004; HR 4.93, IC 95% 1.7 to 14.8) and a serum M-protein greater than 15 g/L (p=0.01; HR 5.2, IC 95% 1.5 to 18.5) were also associated with higher risk of progression. Patients with SMM had lower IgG-lambda, IgA-lambda and HLC IgM ratio (p<0.05) than patients with MGUS. IgG HLC ratio was positively associated with bone marrow plasma cell infiltration (r=0.555; p<0.0001). Normal or lower than normal HLC ratios for IgG and IgM were associated with longer time to progression to symptomatic disease (TTP) than higher values (p=0.008 and p=0.013, respectively) (Figure 1). This difference in HLC IgG ratio were even more evident in SMM patients (p=0.002), where only 1 patient with normal or low HLC IgG ratio has progressed. There was also a trend for HLC IgM ratio in this sense (p=0.08). In a multivariate analysis taking into account SMM vs. MGUS diagnosis, “evolving” pattern and HLC IgM and IgG ratio, only the first three variables remained statistically significant for predicting TTP. Suppression of uninvolved HLC pair was more evident in IgG patients, both MGUS and SMM. Hence, any reduction in IgA-kappa or IgA-lambda isotypes was associated with higher risk of progression (p=0.04) (Figure 2). Conclusion HLC ratios seem to be a valuable tool in the risk stratification of patients with SMM and MGUS. Suppression of the uninvolved isotype (i.e. uninvolved IgA or HLC IgM ratio in IgG MGUS or SMM) is particularly interesting since this phenomenon has not been previously recognized. The picture of differential clonal suppression of heavy-chain isotypes across risk groups is an issue to be prospectively explored. Disclosures: Fernández de Larrea: The Binding Site Ltd: Consultancy, Honoraria.

Neoplastic Plasma Cells Are Demonstrable at Bone Marrow Sites Distant to Solitary Plasmacytoma of Bone and Predict for Progression to Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3512-3512 ◽  
Author(s):  
Quentin A. Hill ◽  
Ruth M. de Tute ◽  
J. Anthony Child ◽  
Andy C. Rawstron ◽  
Roger G. Owen
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Plasma Cells ◽  
Autologous Transplantation ◽  
Solitary Plasmacytoma ◽  
Aberrant Expression ◽  
Risk Of Progression ◽  
Bone Marrow Plasma ◽  
Chi Square Analysis

Abstract Solitary plasmacytoma of bone (SPB) typically present as single destructive lesions within the spinal column or long bones. Local radiotherapy is the treatment of choice but approximately 50% of patients progress to myeloma. Many patients have a monoclonal protein detectable in their serum and/or urine at diagnosis and persistence of this for greater than 1 year after radiotherapy predicts for progression to myeloma. Identification of high risk patients at the time of diagnosis is clearly desirable as it would enable risk stratification and more careful monitoring of patients. Although prophylactic adjunctive chemotherapy has not definitively been shown to benefit unselected patients with SPB, future therapeutic advances might be targeted on patients with a high risk of progression. Interestingly it has recently been shown that patients positive for serum free light chains are at greater risk of progression to myeloma. We and others have previously demonstrated that neoplastic bone marrow plasma cells are distinguishable from their normal counterparts by virtue of their lack of CD19 expression and/or their aberrant expression of CD56. We have developed a multiparameter flow cytometry assay which predicts outcome following autologous transplantation in myeloma patients and risk of progression in patients with MGUS. In this study we have applied this assay to assess the staging bone marrow specimens from patients with biopsy proven SPB for the presence of occult disease at sites distant to the primary lesion. 52 patients were included in this analysis (31 male, 21 female; median age 65) and in each case the staging bone marrow aspirate and trephine biopsy (obtained from a site distant from the SPB, typically the right iliac crest) was not indicative of myeloma (<10% plasma cells). Plasma cells comprised a median of 0.6% (0.05–6.2%) of bone marrow leucocytes while distinct populations with a neoplastic immunophenotype (>30% CD19− and/or CD56+ as per convention) were demonstrable in 35/52 (67%). Neoplastic plasma cells when present comprised a median of 70% (35–100%) of bone marrow plasma cells. 21 patients (40%) developed myeloma with a median time to progression of 476 days (range 18–1632). Progression occurred in 18 of the 35 (51%) patients with neoplastic plasma cells in their staging marrows and in 3/17 (18%) patients with a normal phenotypic profile. The difference was significant using Chi-square analysis with Yates’ correction for continuity (p=0.04). The overall risk of progression was similar in patients with a “myeloma pattern” in which >90% of bone marrow plasma cells had a neoplastic phenotype (5/12, 42%) and those with an MGUS or mixed pattern in which distinct populations of both normal and neoplastic cells are demonstrable (13/23, 57%). We would conclude that neoplastic plasma cells are frequently found at bone marrow sites distant to SPB and that their presence predicts for progression to multiple myeloma. Trials of adjuvant systemic therapy are warranted in this group.

scholarly journals Coexistent Multiple Myeloma or Increased Bone Marrow Plasma Cells Define Equally High-Risk Populations in Patients With Immunoglobulin Light Chain Amyloidosis

2013 ◽  
Vol 31 (34) ◽  
pp. 4319-4324 ◽  
Author(s):  
Taxiarchis V. Kourelis ◽  
Shaji K. Kumar ◽  
Morie A. Gertz ◽  
Martha Q. Lacy ◽  
Francis K. Buadi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Light Chain ◽  
Plasma Cells ◽  
Survival Rates ◽  
Bone Lesions ◽  
Al Amyloidosis ◽  
Characteristic Analysis ◽  
Bone Marrow Plasma

Purpose There is consensus that patients with light chain (AL) amyloidosis with hypercalcemia, renal failure, anemia, and lytic bone lesions attributable to clonal expansion of plasma cells (CRAB criteria) also have multiple myeloma (MM). The aim of this study was to examine the spectrum of immunoglobulin AL amyloidosis with and without MM, with a goal of defining the optimal bone marrow plasma cell (BMPC) number to qualify as AL amyloidosis with MM. Patients and Methods We identified 1,255 patients with AL amyloidosis seen within 90 days of diagnosis between January 1, 2000, and December 31, 2010. We defined a population of patients with coexisting MM on the basis of the existence of CRAB criteria (AL-CRAB). Receiver operating characteristic analysis determined the optimal BMPC cut point to predict for 1-year mortality in patients with AL amyloidosis without CRAB to produce two additional groups: AL only (≤ 10% BMPCs) and AL plasma cell MM (AL-PCMM; > 10% BMPCs). Results Among the 1,255 patients, 100 (8%) had AL-CRAB, 476 (38%) had AL-PCMM, and 679 (54%) had AL only. Their respective median overall survival rates were 10.6, 16.2, and 46 months (P < .001). Because the outcomes of AL-CRAB and AL-PCMM were similar, they were pooled for univariate and multivariate analyses. On multivariate analysis, pooled AL-CRAB and AL-PCMM retained negative prognostic value independent of age, Mayo Clinic AL amyloidosis stage, prior autologous stem-cell transplantation, and difference between the involved and uninvolved free light chain. Conclusion Patients with AL amyloidosis who have more than 10% BMPCs have a poor prognosis, similar to that of patients with AL-CRAB, and should therefore be considered together as AL amyloidosis with MM.

scholarly journals An Unprecedented Case of p190 BCR-ABL Chronic Myeloid Leukemia Diagnosed during Treatment for Multiple Myeloma: A Case Report and Review of the Literature

2018 ◽  
Vol 2018 ◽  
pp. 1-5
Author(s):  
Kosuke Miki ◽  
Naoshi Obara ◽  
Kenichi Makishima ◽  
Tatsuhiro Sakamoto ◽  
Manabu Kusakabe ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Plasma Cells ◽  
Bone Marrow Examination ◽  
Bone Lesions ◽  
Dexamethasone Treatment ◽  
Lytic Bone Lesions

We report the case of a 76-year-old man who was diagnosed as having chronic myeloid leukemia (CML) with p190 BCR-ABL while receiving treatment for symptomatic multiple myeloma (MM). The diagnosis of MM was based on the presence of serum M-protein, abnormal plasma cells in the bone marrow, and lytic bone lesions. The patient achieved a partial response to lenalidomide and dexamethasone treatment. However, 2 years after the diagnosis of MM, the patient developed leukocytosis with granulocytosis, anemia, and thrombocytopenia. Bone marrow examination revealed Philadelphia chromosomes and chimeric p190 BCR-ABL mRNA. Fluorescence in situ hybridization also revealed BCR-ABL-positive neutrophils in the peripheral blood, which suggested the emergence of CML with p190 BCR-ABL. The codevelopment of MM and CML is very rare, and this is the first report describing p190 BCR-ABL-type CML coexisting with MM. Moreover, we have reviewed the literature regarding the coexistence of these diseases.

New Criteria To Identify Risk of Progression in Monoclonal Gammopathy of Uncertain Significance: Multiparametric Flow Cytometry Analysis of Bone Marrow Plasma Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3517-3517
Author(s):  
Ernesto Perez-Persona ◽  
María-Belén Vidriales ◽  
Gema Mateo ◽  
Ramón Garcia Sanz ◽  
Marivi Mateos ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Monoclonal Gammopathy ◽  
Plasma Cells ◽  
Flow Cytometry Analysis ◽  
Dna Index ◽  
Multiparametric Flow Cytometry ◽  
Uncertain Significance ◽  
Risk Of Progression ◽  
Bone Marrow Plasma

Abstract Monoclonal Gammopathy of Uncertain Significance (MGUS) is a monoclonal disorder defined by the presence of a serum monoclonal protein <3g/dL, bone marrow plasma cells < 10% and absence of end-organ damage. The risk of progression to multiple myeloma (MM) is about 1% per year, and therefore these patients require long follow-up. Accordingly, the definition of new parameters that could be used for the identification of patients at risk of progression could be of great value. The aim of the present study is to evaluate the utility of multiparameter flow cytometry analysis of bone marrow (BM) plasma cells (PC) for predicting the risk of progression of MGUS patients. From January 1996 to September 2004, bone marrow aspirate samples from 350 patients, who fulfil the criteria of MGUS according to the International Myeloma Working Group criteria, were analysed by multiparametric flow cytometry. A specific gate on PC was performed based on CD138/CD38 expression and FSC/SSC characteristics and PC were immunophenotypically classified as normal (polyclonal) or aberrant (clonal) according to the expression of CD138, CD38, CD45, CD19 and CD56 antigens. Twenty seven patients (8 %) progressed to MM, with a median time to progression (TTP) of 46 months (range 9 to 109 months). Interestingly, the percentage of aberrant PC within the total BM PC compartment (aPC/BMPCc) clearly identify patients at different risk of progression. Thus, TTP in patients with ≥ 95% aPC/BMPCc was 85 months vs not reached cases with <95% aPC/BMPCc (p=0.0000). Other parameters with a significant influence on progression in the univariate analysis were: paraprotein level (higher vs lower of 2 mg/dl; p= 0.0004), the presence of immunoparesis (no paresis vs. decreased levels in one or two Ig. p= 0.0005), Bence-Jones proteinuria (p= 0.0003), PC BM infiltration assessed both by morphology and flow cytometry (p=0.0074; and p= 0.001, respectively), and DNA index assessed by flow cytometry (diploid vs aneuploid; p=0.0064). Moreover, the cut off level of 95% aPC/BMPCc, also allows the discrimination of two risk categories upon considering only patients at low risk of progression, based on a low paraprotein level or absence of inmunoparesis (p= 0.0000 and p= 0.0000, respectively). On multivariate analysis only the percentage of aPC/BMPCc (≥95%) (p=0.000), the DNA index (p=0.007), and the Bence-Jones proteinuria (p=0.000) showed independent prognostic value. In summary, our results show that multiparameter FC evaluation of BMPC at diagnosis is a simple, cost-effective and valuable tool for predicting the risk of progression of MGUS patients.

Predictive Significance of Serum Beta 2-Microglobulin Levels and M-Protein Velocity for Symptomatic Progression of Smoldering Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3379-3379 ◽  
Author(s):  
Tsuyoshi Muta ◽  
Shinsuke Iida ◽  
Kosei Matsue ◽  
Kazutaka Sunami ◽  
Jun Isoda ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cumulative Incidence ◽  
Plasma Cells ◽  
M Protein ◽  
Bone Lesions ◽  
Landmark Point ◽  
Protein Levels ◽  
Lytic Bone Lesions ◽  
Bone Marrow Plasma ◽  
Beta 2 Microglobulin

Abstract Background: Smoldering multiple myeloma (SMM) has been defined as precursor state to symptomatic multiple myeloma (MM). Mayo Clinic demonstrated that the presence of bone marrow plasma cells (BMPC) ≥ 10% and M protein levels ≥ 3 g/dL significantly associated with early progression to symptomatic MM and the serum free-light chain (FLC) ratio of < 0.125 or 8 < was an important additional predictors of progression. PETHEMA showed that the proportion of aberrant plasma cells (aPCs) within the BMPC > 95% as assessed by flow cytometry was another important variable for progression. However, NIH demonstrated the discordance of these two risk models. The aim of this project is to develop the method to predict the symptomatic progression more definitely by simple parameters, usually available at medical practice. Methods: We employed the nation-wide retrospective study. The clinical data of SMM patients were collected from 61 medical centers in Japan and risk predictors of progression to symptomatic MM were analyzed. The diagnosis of SMM is made by the presence of the ratio of bone marrow plasma cells (BMPCs) ≥ 10% or serum M-protein levels ≥ 3 g/dL, and the absence of any myeloma derived end-organ damage. Eligible patients were aged 18 to 90 years, previously untreated, and diagnosed between 2000 and 2012. This study was approved by the institutional review board at all participating institutions. Results: Total 301 patients fulfilled the inclusion criteria. The median age was 67 years (rang 27 to 90). IgG is the major (80%) compared to IgA (15%) or Bence Jones protein (3%). Total 145 patients developed to symptomatic MM. The symptoms consisted of anemia in 66%, lytic bone lesions in 43%, and renal impairment in 10%. Both anemia and lytic bone lesions were seen in 16%. The median time to progression was 4.3 years. The cumulative incidence of progression was 30.7% at 2 years, 50.0% at 4 years, 59.8% at 6 years, and 68.6% at 8 years. Based on multivariate analysis, we firstly identify the serum beta 2-microglobulin (B2MG) levels ≥ 2.5 mg/L as a predictor for the early progression (HR 1.59; 95% CI, 1.11 to 2.29, p = 0.01), as well as the known factors: presence of both BMPC ≥ 10% and M protein levels ≥ 3 g/dL (HR 1.89; 95% CI, 1.31 to 2.73, p = 0.0007), IgA or Bence Jones type (HR:1.61; 95%CI, 1.04 to 2.49, p = 0.03), and immunoparesis (HR:1.88; 95%CI, 1.14 to 3.08, p = 0.01). FLC ratio was examined in 52 patients. A significant association with high risk of progression was observed in patients with FLC ratio of < 0.0625 or 16 < (P = 0.04), but not in those with the ratio of < 0.125 or 8 < (P = 0.09). Cytogenetic abnormality was examined with FISH in 82 patients. The cumulative incidence of progression in patients with either t(4;14), t(14;16), or del(17p) was not significantly different from those without such chromosomal aberration (P = 0.4). Notably, we firstly focused on the rate of rise of the M-protein levels over time which is referred to as the "M-protein velocity". We employed the linear regression analysis to estimate the gradient to assess the M-protein velocity of each patient. The receiver operating characteristics curve analysis showed that the M-protein velocity of 1.035 mg/dL/day was a risk-stratification cut-off point with a high specificity of 0.96 and with a moderate sensitivity of 0.60. Based on the landmark analysis, the serum B2MG levels ≥ 2.5 mg/L at diagnosis (HR 2.76; 95% CI, 1.69 to 4.51, P = 5 x 10–5) and the M-protein velocity > 1 mg/dL/day before the 18-month landmark point (HR 2.27; 95% CI, 1.30 to 3.95, P = 4 x 10–3) had independently correlated with subsequent progression to symptomatic MM. The cumulative incidence of progression of the patients with both the serum B2MG levels ≥ 2.5 mg/L at diagnosis and the M-protein velocity > 1 mg/dL/day showed 67.5% at 2 years, 75.6% at 3 years and 100% at 6.3 years after the landmark point. Conclusions: We identify the novel risk factors consisted of serum B2MG levels ≥ 2.5 mg/L and the M-protein velocity > 1 mg/dL/day for subsequent symptomatic progression. Theoretically, it is possible to emphasis that the serum B2MG levels represent the initial tumor burden of SMM and the M-protein velocity reflects the the growth rate of tumor cells. These results also suggest that the quantification of time-dependent change of measured values should be taken into consideration for the precise prediction of symptomatic progression. This study is supported by the National Cancer Center Research and Development Fund in Japan. Disclosures No relevant conflicts of interest to declare.

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