High rate of profound clonal and renal responses with daratumumab treatment in heavily pre‐treated patients with
            light chain (AL)
            amyloidosis and high bone marrow plasma cell infiltrate

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.

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Systemic AL amyloidosis with high bone marrow plasma cells (BMPCs) infiltration: a case report and literature review

Journal of Xiangya Medicine ◽

10.21037/jxym.2019.07.01 ◽

2019 ◽

Vol 4 ◽

pp. I 30-30

Author(s):

Hui-Wen Wang ◽

Rong Tang ◽

Xiang-Cheng Xiao ◽

Wei Liu ◽

Morie A. Gertz ◽

...

Keyword(s):

Bone Marrow ◽

Case Report ◽

Literature Review ◽

Plasma Cells ◽

Al Amyloidosis ◽

Bone Marrow Plasma ◽

High Bone

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The Value of the Bone Marrow Plasma Cell Cytoplasmic Light Chain Ratio in Differentiating Between Multiple Myeloma and Monoclonal Gammopathy of Undetermined Significance

Leukemia & Lymphoma ◽

10.3109/10428199209051032 ◽

1992 ◽

Vol 8 (6) ◽

pp. 491-493 ◽

Cited By ~ 3

Author(s):

G. Majumdar ◽

R. J. Grace ◽

A. K. Singh ◽

N. G. P. Slater

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Plasma Cell ◽

Light Chain ◽

Monoclonal Gammopathy ◽

Bone Marrow Plasma ◽

Undetermined Significance

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Clinical Characteristics and Outcome of Patients with Wild-Type Transthyretin and AL Cardiac Amyloidosis Confirmed By Mass Spectrometry

Blood ◽

10.1182/blood-2018-99-115317 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3126-3126

Author(s):

Stephen Parkin ◽

Michael A. Seidman ◽

Margot Davis ◽

Kevin Song

Keyword(s):

Mass Spectrometry ◽

Bone Marrow ◽

Light Chain ◽

Nyha Class ◽

Complete Response ◽

Al Amyloidosis ◽

Cell Percentage ◽

Bone Marrow Plasma ◽

Kappa Light Chains ◽

Al Amyloid

Abstract INTRODUCTION: Cardiac involvement is common in both wild-type transthyretin (wATTR) and AL amyloidosis and these entities can have overlapping clinical features (Banypersad et al, JAHA 2012). Accurate diagnosis is vital given differences in spectrum of disease, management, and prognosis. We examined the presenting clinical features and survival outcome of patients diagnosed with cardiac wATTR and AL amyloidosis confirmed by mass spectrometry. MATERIALS & METHODS: Patients diagnosed between January 2014 and September 2017 with biopsy proven wATTR or AL amyloidosis and cardiac involvement by consensus criteria (Gertz et al, Amyloid 2010) were included. Mass spectrometry testing was performed at the Mayo Clinic Laboratories to confirm amyloid subtype in all cases. Patient records were retrospectively reviewed to identify clinical characteristics as well as details regarding treatment and survival. RESULTS: Forty-three patients were identified (wATTR n=27, AL n=16) with site of biopsy: 41 cardiac (95%); 1 gastric (2%); 1 skin (2%). Two (13%) patients with AL amyloid had coexisting multiple myeloma. Thirty-five (81%) patients were male, with a strong male predominance in wATTR patients (100% vs 50% for AL patients, p=<0.01). Median age at diagnosis was 73 years (range 45-86), with a trend towards older age in wATTR patients (median 75 vs 62 years for AL patients, p=0.09). No difference was seen in presenting NYHA class or levels of troponin and ntProBNP between amyloid subtypes. BNP trended towards higher values in AL patients (median 514 vs 249 ng/L for wATTR, p=0.09). wATTR amyloid patients had lower median presenting left ventricular ejection fraction (43 vs 53%, p=0.05). Two (7%) patients with wATTR amyloid had an M-protein on SPEP compared to 7 (44%) with AL amyloid. Only 2 patients with AL amyloid had M-protein greater than 5 g/L while both wATTR patients had less than 5 g/L. In those with serum free light chain testing available (wATTR n=24, AL n=16), median lambda light chain level was higher in AL patients (176.0 vs 16.9 mg/L for wtATTR, p=<0.01). No difference was seen in kappa light chains (16.5 vs 23.8 mg/L for wATTR, p=0.60), though the only patient with kappa AL amyloid had kappa light chains significantly elevated at 1640 mg/L. The kappa/lambda ratio was abnormal in 15% of wATTR patients (all kappa predominant) compared to 100% in AL amyloid patients (94% lambda predominant) (p=<0.01). The median difference between involved and uninvolved light chain (dFLC) was 22 mg/L for wtATTR patients compared to 249 mg/L for AL patients. In patients with bone marrow biopsy results available (AL n=15, wATTR n=7), bone marrow plasma cell percentage was higher in patients with AL amyloid (median 7% vs 2%, p=0.01). No monoclonal plasma cells were seen on bone marrow in wATTR patients by immunophenotype. Treatment for patients with AL amyloid was: bortezomib, cyclophosphamide, and dexamethasone (VCD) in 11 (69%); VCD followed by melphalan 200 mg/m2 autologous transplantation in 1 (6%); melphalan/dexamethasone in 1 (6%); no treatment in 2 (13%); unknown in 1 (6%). In evaluable patients, hematologic response rate was 54% (complete response n=4, very good partial response n=2, partial response n=1, no response n=6). With a median follow-up of 1.8 years for surviving patients, 1 year overall survival (OS) was 76% for the entire cohort. Patients with AL amyloidosis had significantly poorer 1 year OS (41% vs 92% for wATTR patients, p=<0.01). Patients with NYHA class 3-4 had significantly worse 1 year OS (54% vs 96% for those 1-2, p=<0.01), and this held true for both AL and wATTR patients. In AL patients, revised Mayo stage (Kumar et al, JCO 2012) of III-IV predicted for poor 1 year OS (19% vs 75% for stages I-II, p=0.03), as did not achieving complete response to primary treatment (1 year OS 33% vs 67% for CR patients, p=0.06). DISCUSSION & CONCLUSIONS: Male sex, older age, and lower LVEF were more common in patients with wATTR compared to AL amyloidosis. Higher levels of BNP, larger dFLC with lambda predilection, and higher bone marrow plasma cell percentage were more common in AL amyloid patients. Overall survival was significantly worse for patients with AL amyloidosis, particularly those with high NHYA class, advanced revised Mayo stage, and suboptimal response to primary therapy. These results highlight the importance of accurate amyloid sub-typing in patients with suspected cardiac amyloidosis. Disclosures No relevant conflicts of interest to declare.

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Clinical presentation and outcome of patients with AL amyloidosis requiring salvage therapy.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e20043 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e20043-e20043

Author(s):

Chen Wang ◽

Yumeng Zhang ◽

Lauren Duncanson ◽

Jason B. Brayer ◽

Doris K. Hansen ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Light Chain ◽

Salvage Therapy ◽

Plasma Cells ◽

Al Amyloidosis ◽

Comparison Results ◽

Bone Marrow Plasma ◽

Organ Response ◽

Upfront Therapy

e20043 Background: The diagnosis and upfront management of immunoglobulin light chain (AL) amyloidosis have greatly improved in recent years. However, little is known about the presentation, treatment, and outcome of these patients at first relapse/progression (R/P). Methods: All patients with AL amyloidosis who received salvage therapy for first R/P disease at Moffitt Cancer Center between 2008 and 2020 were included in this retrospective review. Definitions of hematologic and organ R/P were based on 2012 consensus. Overall survival was measured from the time of salvage to last follow up/death. Survival was assessed by Kaplan-Meier with log-rank comparison. Results: Sixty-nine patients were included. The median age at diagnosis was 62 years and 61% were male. Upfront therapy included high dose melphalan with autologous transplant in 36% and bortezomib in 52%. At salvage, 19% had disease refractory to upfront therapy and 40% had not achieved an organ response. The median time from upfront to salvage therapy was 22 months. Salvage regimens included proteasome inhibitors, daratumumab and immunomodulatory drugs in 55%, 13% and 22%, respectively. At least a very good partial response and organ response were achieved in 35% (22/62) and 39% (21/54) with measurable disease. The median overall survival was 60 months. Based on salvage indication, patients were classified into hematologic (n = 29) and organ R/P (n = 40), and the latter showed more frequent lambda-light chain disease (59% vs. 83%, p = 0.028) and low difference of involved-uninvolved free light chain at diagnosis (< 50 mg/L, 8% vs. 44%, p = 0.002). Negative prognostic markers for survival included bone marrow plasma cells ≥20% at diagnosis (median 17 months vs. not reached; p < 0.001) and organ, particularly cardiac R/P (median, 31 months vs. not reached; p = 0.003). Salvage ( p = 0.48) or prior regimens ( p = 0.11) did not impact post-salvage survival. Conclusions: Our study highlights the unmet need of salvage in R/P AL amyloidosis in a real-world setting, given the low rate of deep responses regardless of current salvage options. Patients with bone marrow plasma cells ≥20% at diagnosis and organ R/P at salvage had inferior survival, supporting use of intensive upfront regimens for the former and adjustment of therapy if deep response is not achieved.[Table: see text]

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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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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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Novel Analysis of Clonal Diversification in Blood B Cell and Bone Marrow Plasma Cell Clones in Immunoglobulin Light Chain Amyloidosis

Journal of Clinical Immunology ◽

10.1007/s10875-006-9056-9 ◽

2006 ◽

Vol 27 (1) ◽

pp. 69-87 ◽

Cited By ~ 16

Author(s):

ROSHINI S. ABRAHAM ◽

MICHELLE K. MANSKE ◽

NETA S. ZUCKERMAN ◽

ABHISHEK SOHNI ◽

HANNA EDELMAN ◽

...

Keyword(s):

Bone Marrow ◽

B Cell ◽

Plasma Cell ◽

Light Chain ◽

Immunoglobulin Light Chain ◽

Light Chain Amyloidosis ◽

Cell Clones ◽

Bone Marrow Plasma ◽

Immunoglobulin Light Chain Amyloidosis

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

Blood ◽

10.1182/blood.v122.21.3132.3132 ◽

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.

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