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.

Bone Marrow Plasma Cell Infiltration in Light-Chain Amyloidosis

2018 ◽  
Vol 18 ◽  
pp. S236
Author(s):  
Luis Gerardo Rodríguez-Lobato ◽  
Natalia Tovar ◽  
Ma. Teresa Cibeira ◽  
Laura Magnano ◽  
Ignacio Isola ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Plasma Cell ◽  
Light Chain ◽  
Cell Infiltration ◽  
Light Chain Amyloidosis ◽  
Plasma Cell Infiltration ◽  
Bone Marrow Plasma

Bone marrow plasma cell infiltration in light chain amyloidosis: impact on organ involvement and outcome

Amyloid ◽  
2018 ◽  
Vol 25 (2) ◽  
pp. 79-85 ◽  
Author(s):  
Natalia Tovar ◽  
Luis Gerardo Rodríguez-Lobato ◽  
Maria Teresa Cibeira ◽  
Laura Magnano ◽  
Ignacio Isola ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Plasma Cell ◽  
Light Chain ◽  
Organ Involvement ◽  
Cell Infiltration ◽  
Light Chain Amyloidosis ◽  
Plasma Cell Infiltration ◽  
Bone Marrow Plasma

BONE MARROW PLASMA CELL INFILTRATION IN MULTIPLE MYELOMA

1984 ◽  
Vol 57 (2) ◽  
pp. 351-352 ◽  
Author(s):  
Aimery De Gramon ◽  
Oscar Benitez ◽  
Nicole Smadja ◽  
Philippe Brissaud ◽  
Agnés Sirinelli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Cell Infiltration ◽  
Plasma Cell Infiltration ◽  
Bone Marrow Plasma

Quantification of bone marrow plasma cell infiltration in multiple myeloma: usefulness of bone marrow aspirate clot with CD138 immunohistochemistry

2016 ◽  
Vol 35 (3) ◽  
pp. 323-328 ◽  
Author(s):  
Kosei Matsue ◽  
Yuya Matsue ◽  
Kaoru Kumata ◽  
Yoshiaki Usui ◽  
Yasuhito Suehara ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Bone Marrow Aspirate ◽  
Cell Infiltration ◽  
Plasma Cell Infiltration ◽  
Bone Marrow Plasma

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.

The Natural History of Smoldering (Asymptomatic) Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3396-3396 ◽  
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 &gt; 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 &lt; 3g/dL (n= 158, 52%); Group 3, serum M protein ≥ 3g/dL but bone marrow plasma cells &lt; 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 &lt; 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 &lt; 0.001) and reduction of uninvolved immunoglobulins (p &lt; 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.

BONE MARROW PLASMA CELL INFILTRATION IN MULTIPLE MYELOMA

1984 ◽  
Vol 57 (2) ◽  
pp. 352-353 ◽  
Author(s):  
M. Cavo ◽  
M. Baccarani ◽  
M. Gobbi ◽  
A. Lipizer ◽  
S. Tura
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Cell Infiltration ◽  
Plasma Cell Infiltration ◽  
Bone Marrow Plasma

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

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