The Prognostic Significance of Phenotypically ‘Normal’ Plasma Cells in Chemotherapy Treated AL Patients with Underlying MGUS and Multiple Myeloma

Abstract Background: Systemic AL amyloidosis is a rare complication of plasma cell dyscrasias. Much progress has occurred in treatment of AL amyloidosis but long term survival remains limited with advanced organ involvement, in particular, cardiac dysfunction determining outcomes. However, controlling the underlying plasma cell clone with chemotherapy or ASCT is the key to improving outcomes. Yet the role of plasma cell clones in determining prognosis remains to be fully explored and understood. The plasma cell burden in patient with AL amyloidosis is generally lower than that of multiple myeloma but reported degree of plasma cell infiltration has varied. A large study from the Mayo group reported markedly poor outcomes for patients with AL amyloidosis who have >10% BMPCs, even in the absence of symptomatic myeloma (Kourelis et al, JCO 2013). However, apart from just the number of BMPC, the composition appears to be of importance. Multiparameter flow cytometry (MFC) can identify proportion of normal and clonal plasma cells. Patients with >5% normal BMPC (defined as cells expressing CD38+CD138+CD19+) at diagnosis had a better prognosis (Paiva et al. Blood 2011). MFC underestimates the total proportion of BMPCs due to sample dilution effect. We report the impact of normal' plasma cells, as determined by MFC, on the outcome of AL patients in context of the total plasma cell burden as determined by standard morphological techniques in 104 patients with biopsy proven systemic AL amyloidosis, who had both bone marrow trephine and MFC performed at presentation between 2005-2013 assessed at UK National amyloidosis centre and St James's University Hospital. Methods: The bone marrow trephine biopsy (BMTB) plasma cell burden was estimated by morphology supplemented by CD138 immunohistochemistry as required. Patients with >10% CD138+ cells were classified as having AL-multiple myeloma (AL-MM) and those with <10% CD138+ cells as having AL-MGUS. Six or eight colour MFC was used to assess the proportion of CD38+CD138+ plasma cells expressing CD19 in the bone marrow aspirate samples. Results: The median age was 64.8 years (range: 38.5-83.3) with a male-female ratio of 1.7:1. 58 (56%) had cardiac involvement. All patients had treatment and the longest follow up was 8.3 years with 52 patients alive at the time of analysis. BMTB was inadequate for 3 patients, of the remaining 101 patients, 59 (57%) had >10% CD138+ PCs on trephine (classed as AL-MM) and 42 (40%) had <10% (classed as AL-MGUS). All patients had MFC and the median number of normal' PCs was 4.07% (range 0-72.57%). The median neoplastic PC% was 95.9 (range : 9.8-95.3). All patients had CD19 negative PC demonstrable, of which 61 (58%) had CD56 expression thereby confirming the diagnostic utility of MFC in this setting. ROC analysis gave 10% as the most significant cut-off for normal PC. 31 (30%) patients had greater than 10% normal' PCs; 22 (52%) and 8(14%) with underlying AL-MGUS and AL-MM respectively (p<0.001). There was a statistically significant negative correlation between the BMTB PC% and the normal' PC quantity on MFC (Spearman correlation -0.419, p=0.000). The median overall survival (OS) for the whole cohort was 26 months and that for those with AL-MGUS was 37.9months and AL-MM 18.1 months (p=0.140). Those patients with >10% normal PCs had a significantly superior survival (53.4months) compared to those with <10% normal PCs (16 months) (p = 0.019) on MFC (Figure 1). When outcome was assessed according to overall BM burden and MFC it was clear that the presence of >10% normal PCs conferred a favourable outcome regardless of the BM burden (Figure 2, p=0.075). Outcomes were similar for AL-MM and AL-MGUS in those patients with >10% normal PC (p=0.824) and those with <10% (p=0.755). Conclusion: In this study we have confirmed the value of MFC in patients with AL amyloid. Abnormal PC populations are demonstrable in all patients confirming the utility of the assay for diagnostic purposes. This is particularly relevant for those patients with low BM burden. Similarly the presence / absence of normal plasma cells by MFC had a significant effect on outcome which was demonstrable in patients with both AL-MGUS and AL-MM. MFC should be included in the diagnostic workup of all patients with AL. Further studies are required to determine how this additional prognostic data can be incorporated into existing prognostic models. Figure 1: Figure 1:. Figure 2: Figure 2:. Disclosures No relevant conflicts of interest to declare.

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Automated digital enumeration of plasma cells in bone marrow trephine biopsies of multiple myeloma

Journal of Clinical Pathology ◽

10.1136/jclinpath-2020-207066 ◽

2020 ◽

pp. jclinpath-2020-207066

Author(s):

Jacques A J Malherbe ◽

Kathryn A Fuller ◽

Bob Mirzai ◽

Bradley M Augustson ◽

Wendy N Erber

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Plasma Cell ◽

Plasma Cells ◽

Intraclass Correlation ◽

Antigen Expression ◽

Bone Marrow Biopsies ◽

Bone Marrow Trephine ◽

Bone Marrow Trephine Biopsy ◽

Plasma Cell Neoplasms

AimsDetermination of the number of plasma cells in bone marrow biopsies is required for the diagnosis and ongoing evaluation of plasma cell neoplasms. We developed an automated digital enumeration platform to assess plasma cells identified by antigen expression in whole bone marrow sections in multiple myeloma, and compared it with manual assessments.MethodsBone marrow trephine biopsy specimens from 91 patients with multiple myeloma at diagnosis, remission and relapse were stained for CD138 and multiple myeloma oncogene 1 (MUM1). Manual assessment and digital quantification were performed for plasma cells in the entire trephine section. Concordance rates between manual and digital methods were evaluated for each antigen by intraclass correlation analyses (ICC) with associated Spearman’s correlations.ResultsThe digital platform counted 16 484–1 118 868 cells and the per cent CD138 and MUM1-positive plasma cells ranged from 0.05% to 93.5%. Overall concordance between digital and manual methods was 0.63 for CD138 and 0.89 for MUM1. Concordance was highest with diffuse plasma cell infiltrates (MUM1: ICC=0.90) and lowest when in microaggregates (CD138: ICC=0.13). Manual counts exceeded digital quantifications for both antigens (CD138: mean=26.4%; MUM1: mean=9.7%). Diagnostic or relapse threshold counts, as determined by CD138 manual assessments, were not reached with digital counting for 16 cases (18%).ConclusionsAutomated digital enumeration of the entire, immunohistochemically stained bone marrow biopsy section can accurately determine plasma cell burden, irrespective of pattern and extent of disease (as low as 0.05%). This increases precision over manual visual assessments which tend to overestimate plasma burden, especially for CD138, and when plasma cells are in clusters.

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Use Of Plasma Cell Immunophenotype As Prognostic Markers In Patients With Systemic AL Amyloidosis

Blood ◽

10.1182/blood.v122.21.3120.3120 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3120-3120 ◽

Cited By ~ 3

Author(s):

Sajitha Sachchithanantham ◽

Anna Baginska ◽

Dorota Rowczenio ◽

Shameem Mahmood ◽

Rabya Sayed ◽

...

Keyword(s):

Bone Marrow ◽

Plasma Cell ◽

Cardiac Involvement ◽

Plasma Cells ◽

Cell Clone ◽

Cell Phenotype ◽

Al Amyloidosis ◽

Haematological Response ◽

Normal Plasma ◽

Spearman’S Correlation

Abstract The prognosis of patients with systemic AL amyloidosis is mainly driven by advanced organ dysfunction, mainly heart involvement. The contribution of the underlying plasma cell clone to prognosis has not been much studied – lately the serum free light chain load has been shown to impact survival. Detailed analysis of plasma cell immunophenotype by multiparameter flow cytometry has been reported to be prognostic in myeloma as well as MGUS. We report that the plasma cell phenotype may allow us to refine prognostic assessment in patients with systemic AL amyloidosis. 48 serial patients with biopsy proven systemic AL amyloidosis had bone marrow as part of a prospective bone marrow study. Flow cytometry was done using previously published protocols (Paiva et al Blood 2010) using fluorescent labelled monoclonal antibodies to the following markers (maximum eight in one tube): CD138, CD38, CD56, CD117, CD28, CD20, CD27, CD19, CD81 and kappa and lambda light chains. Organ involvement, survival and haematological response were analysed in the context of plasma cell phenotypes. Abnormal plasma cell phenotype was defined as cells expressing CD38+CD138+CD19- and further markers were analysed on this population. Cardiac, renal and liver involvement in the cohort was 69%, 75% and 29% respectively. The median follow up was 7 months (range 0.7-18.7months). Results Cardiac involvement was significantly higher in patients co-expressing CD56 (spearman’s correlation coefficient = 0.342 and p=0.021) and a non-significantly greater in those with CD27 expression. 77% had achieved a haematological response on an intention to treat analysis with 65% achieving a VGPR or better. Patients with plasma cells lacking expression of CD27 or CD81 achieved a significantly higher rate of VGPR or better compared to those expressing these markers, (spearman’s correlation coefficient = -.565 and -0.394, p=0.001 and p=0.021 respectively) (Table 1). Median OS was not reached for the whole cohort and the 2 year OS in patients with >5% normal plasma cells (defined as CD38+CD138+CD19+ plasma cells) was 74% compared to 45% in those with <5% normal plasma cells (median OS not reached (NR) vs 4.3 months respectively). Patients with cardiac involvement had a median OS of 5.2 months compared to not reached (NR) for those without cardiac involvement (p=0.017). Within the former group, those with >5% normal plasma cells had a better median OS compared to those with <5% normal plasma cells (NR vs 3.7 months, p=0.564). The median OS was not reached for those achieving a clonal response vs. 3.2 months for non responders (p<0.000). Of the patients who achieved VGPR, those with >5% normal plasma cells appear to have a better OS than those with <5% normal plasma cells with a 2 year survival of 100% and 76%, respectively. Patients with abnormal plasma cell clone expressing CD27 phenotype had a significantly worse OS than those without CD27 (2.6 months vs median OS NR, p=0.010, figure 1). Similarly, expression of CD56 by the abnormal clones had a significantly worse OS, than CD56- plasma cells (4.3 months vs Median OS NR, p=0.052). Patients with abnormal clones expressing CD27+CD56+ had an OS of 1.5 months compared to median OS not reached in the CD27+CD56- group (p=0.003). Median OS was not reached in either CD27-CD56- or CD27-CD56+ patients, but the former group appear to have a better outcome with a 2 year survival of 90% and 67% respectively (figure 2). On a multivariate analysis, expression of CD27 and CD56 on abnormal plasma cells remained significant prognostic factors when analysed along with different variables of cardiac involvement including Mayo staging. Conclusion In summary, presence of >5% normal plasma cells is associated with better OS. Expression of CD56 correlated with cardiac involvement and of CD27 with a poorer haematological response. Expressions of CD27 or CD56 on CD38+CD138+CD19- plasma cells appear to be independent markers of poorer prognosis. Patients expressing both having even worse outcomes with a median OS <2 months. In summary, defining the plasma cell immunophenotype may help to refine the current staging of AL amyloidosis and response to treatment. This observation requires further validation in larger studies. Disclosures: No relevant conflicts of interest to declare.

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CD28 Supports Normal Plasma Cell Survival and Interactions with Microenvironment

Blood ◽

10.1182/blood.v112.11.2713.2713 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2713-2713

Author(s):

Cheryl H Rozanski ◽

Jayakumar Nair ◽

Louise Carlson ◽

Kelvin P. Lee

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Dendritic Cells ◽

Cell Survival ◽

Plasma Cell ◽

Plasma Cells ◽

Bone Marrow Biopsies ◽

Myeloma Cells ◽

Normal Plasma

Abstract The long term generation of protective antibodies (Abs) requires the continuous survival of long-lived plasma cells that are maintained within specialized bone marrow niches by complex interactions that remain largely uncharacterized. Previous studies have shown that the T cell costimulatory receptor CD28 is expressed on normal and transformed (murine plasmacytoma, human multiple myeloma) plasma cells – however, its role in the B cell lineage remained unclear. We have recently shown that CD28 expressed on transformed human plasma cells (multiple myeloma cells) directly delivers pro-survival signals to the myeloma cells and protects them against intrinsically and extrinsically induced death (Bahlis et al, 2007). Furthermore, myeloma cells directly interact with dendritic cells (DC, both in vitro and in patient bone marrow biopsies), and the DC provide the ligands (i.e. CD80 and CD86) for myeloma-CD28. Others studies utilizing competitive bone marrow reconstitution have indirectly suggest a role for CD28 in the function and/or survival of normal murine plasma cells (Delogu et al, 2006). These observations led us to directly investigate the role of CD28 in normal plasma cell survival as well as cell-cell interactions with CD80/CD86+ bone marrow derived dendritic cells (BMDC). In vitro serum starvation experiments, direct activation of CD28 by an agonistic anti-CD28 mAb increased survival of serum-starved PC by 63% (p<0.001). Addition of BMDC improved the survival of PC by 20% over that seen with media alone, and resulted in a significant increase in IgG production (p<0.01). We and others have shown that CD28 binding to CD80/CD86 on DC also “backsignals” to the DC to produce the PC survival factor IL-6. We found that co-culture with the murine plasmacytoma cell line S194 induced 155 pg/ml of IL-6 from BMDC (p<0.01 vs. BMDC alone and S194 alone), and primary plasma cells isolated from bone marrow induced 290 pg/ml of IL-6 from BMDC (p<0.001 vs. BMDC alone). Induction of BMDC production of IL-6 by both primary and transformed PC was significantly inhibited (p<0.05) by antibody blockade of CD80 and CD86. Our data demonstrates that signaling through CD28 directly supports the survival of normal bone marrow plasma cells, and that “backsignaling” through PC-CD28 engagement of DC-CD80/CD86 induces DC to secrete the pro-survival cytokine IL-6. These findings suggest that CD28 is a key molecular bridge that connect normal plasma cells to the supportive microenvironment.

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

Journal of Clinical Oncology ◽

10.1200/jco.2013.50.8499 ◽

2013 ◽

Vol 31 (34) ◽

pp. 4319-4324 ◽

Cited By ~ 119

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.

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Bone disease as the first manifestation of systemic AL-amyloidosis

Terapevticheskii arkhiv ◽

10.26442/00403660.2020.07.000775 ◽

2020 ◽

Vol 92 (7) ◽

pp. 85-89

Author(s):

L. P. Mendeleeva ◽

I. G. Rekhtina ◽

A. M. Kovrigina ◽

I. E. Kostina ◽

V. A. Khyshova ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Bone Disease ◽

Plasma Cells ◽

Interventricular Septum ◽

Bone Destruction ◽

Amyloid Deposition ◽

Bone Lesions ◽

Al Amyloidosis ◽

Linear Type

Our case demonstrates severe bone disease in primary AL-amyloidosis without concomitant multiple myeloma. A 30-year-old man had spontaneous vertebral fracture Th8. A computed tomography scan suggested multiple foci of lesions in all the bones. In bone marrow and resected rib werent detected any tumor cells. After 15 years from the beginning of the disease, nephrotic syndrome developed. Based on the kidney biopsy, AL-amyloidosis was confirmed. Amyloid was also detected in the bowel and bone marrow. On the indirect signs (thickening of the interventricular septum 16 mm and increased NT-proBNP 2200 pg/ml), a cardial involvement was confirmed. In the bone marrow (from three sites) was found 2.85% clonal plasma cells with immunophenotype СD138+, СD38dim, СD19-, СD117+, СD81-, СD27-, СD56-. FISH method revealed polysomy 5,9,15 in 3% of the nuclei. Serum free light chain Kappa 575 mg/l (/44.9) was detected. Multiple foci of destruction with increased metabolic activity (SUVmax 3.6) were visualized on PET-CT, and an surgical intervention biopsy was performed from two foci. The number of plasma cells from the destruction foci was 2.5%, and massive amyloid deposition was detected. On CT scan foci of lesions differed from bone lesions at multiple myeloma. Bone fragments of point and linear type (button sequestration) were visualized in most of the destruction foci. The content of the lesion was low density. There was no extraossal spread from large zones of destruction. There was also spontaneous scarring of the some lesions (without therapy). Thus, the diagnosis of multiple myeloma was excluded on the basis based on x-ray signs, of the duration of osteodestructive syndrome (15 years), the absence of plasma infiltration in the bone marrow, including from foci of bone destruction by open biopsy. This observation proves the possibility of damage to the skeleton due to amyloid deposition and justifies the need to include AL-amyloidosis in the spectrum of differential diagnosis of diseases that occur with osteodestructive syndrome.

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Multiple myeloma: circulating lymphocytes that express plasma cell antigens

Blood ◽

10.1182/blood.v64.2.352.bloodjournal642352 ◽

1984 ◽

Vol 64 (2) ◽

pp. 352-356

Author(s):

GJ Ruiz-Arguelles ◽

JA Katzmann ◽

PR Greipp ◽

NJ Gonchoroff ◽

JP Garton ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Plasma Cell ◽

Peripheral Blood ◽

Plasma Cells ◽

Peripheral Blood Lymphocytes ◽

Tumor Burden ◽

B Cell Differentiation ◽

Blood Lymphocytes ◽

Bone Marrow Plasma

The bone marrow and peripheral blood of 14 patients with multiple myeloma were studied with murine monoclonal antibodies that identify antigens on plasma cells (R1–3 and OKT10). Peripheral blood lymphocytes expressing plasma cell antigens were found in six cases. Five of these cases expressed the same antigens that were present on the plasma cells in the bone marrow. Patients that showed such peripheral blood involvement were found to have a larger tumor burden and higher bone marrow plasma cell proliferative activity. In some patients, antigens normally found at earlier stages of B cell differentiation (B1, B2, and J5) were expressed by peripheral blood lymphocytes and/or bone marrow plasma cells.

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Myeloma Cell Associated Therapeutic Protein Discovery Using Single Cell RNA-Seq Data

Blood ◽

10.1182/blood-2020-142205 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 4-5

Author(s):

Lijun Yao ◽

Reyka G Jayasinghe ◽

Tianjiao Wang ◽

Julie O'Neal ◽

Ruiyang Liu ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Cell Surface ◽

B Cell ◽

Tumor Cells ◽

Plasma Cell ◽

Tissue Specificity ◽

Plasma Cells ◽

Expression Data ◽

Intracellular Proteins

Multiple myeloma (MM) is a hematological cancer of the antibody-secreting plasma cells. Despite therapeutic advancements, MM remains incurable due to high incidence of drug-resistant relapse. In recent years, targeted immunotherapies, which take advantage of the immune system's cytotoxic defenses to specifically eliminate tumor cells expressing certain cell surface and intracellular proteins have shown promise in combating this and other B cell hematologic malignancies. A major limitation in the development of these therapies lies in the discovery of optimal candidate targets, which require both high expression in tumor cells as well as stringent tissue specificity. In an effort to identify potential myeloma-specific target antigens, we performed an unbiased search for genes with specific expression in plasma and/or B cells using single-cell RNA-sequencing (scRNAseq) of 53 bone marrow samples taken from 42 patients. By comparing >40K plasma cells to >97K immune cells across our cohort, we were able to identify a total of 181 plasma cell-associated genes, including 65 that encode cell-surface proteins and 116 encoding intracellular proteins. Of particular interest is that the plasma cells from each patient were shown to be transcriptionally distinct with unique sets of genes expressed defining each patient's malignant plasma cells. Using pathway enrichment analysis, we found significant overrepresentation of cellular processes related to B-Cell receptor (BCR) signaling, protein transport, and endoplasmic reticulum (ER) stress, involving genes such as DERL3, HERPUD1, PDIA4, PDIA6, RRBP1, SSR3, SSR4, TXNDC5, and UBE2J1. To note, our strategy successfully captured several of the most promising MM therapeutic targets currently under pre-clinical and clinical trials, including TNFRSF17(BCMA), SLAMF7, and SDC1 (CD138). Among these, TNFRSF17 showed very high plasma cell expression, with concomitant sharp exclusion of other immune cell types. To ascertain tissue specificity of candidate genes outside of the bone marrow, we analyzed gene and protein expression data from the Genotype-Tissue Expression (GTEx) portal and Human Protein Atlas (HPA). We found further support for several candidates (incl. TNFRSF17,SLAMF7, TNFRSF13B (TACI), and TNFRSF13C) as being both exclusively and highly expressed in lymphoid tissues. While several surface candidates were not found to be lymphocyte-restricted at the protein level, they remain relevant considerations as secondary targets for bi-specific immunotherapy approaches currently under development. To further investigate potential combinatorial targeting, we examine sample-level patterns of candidate co-expression and mutually-exclusive expression using correlation analysis. As the majority of our detected plasma cell-specific genes encode intracellular proteins, we investigated the potential utility of these epitopes as therapeutic targets via MHC presentation. Highly expressed candidates include MZB1, SEC11C, HLA-DOB, POU2AF1, and EAF2. We analyzed protein sequences using NetMHC and NETMHCII to predict high-affinity peptides for common class-I and class-II HLA alleles. To correlate MHC allelic preference with candidate expression in our cohort, we performed HLA-typing for 29 samples using Optitype. To support our scRNAseq-driven findings, we cross-referenced gene expression data with 907 bulk RNA-sequencing samples, including 15 from internal studies and 892 from the Multiple Myeloma Research Foundation (MMRF), as well as bulk global proteomics data from 4 MM cell lines (TIB.U266, RPMI8226, OPM2, MM1ST) and 4 patients. We see consistent trends across both cohorts, with high positive correlation (Pearson R ranging between 0.60 and 0.99) for a majority of genes when comparing scRNA and bulk RNA expression in the same samples. Our experimental design and analysis strategies enabled the efficient discovery of myeloma-associated therapeutic target candidates. In conclusion, this study identified a set of promising myeloma CAR-T targets, providing novel treatment options for myeloma patients. Disclosures Goldsmith: Wugen Inc.: Consultancy. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees.

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THE BONE MARROW ON STERNAL ASPIRATION IN MULTIPLE MYELOMA

Blood ◽

10.1182/blood.v3.9.987.987 ◽

1948 ◽

Vol 3 (9) ◽

pp. 987-1018 ◽

Cited By ~ 52

Author(s):

EDWIN D. BAYRD

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Plasma Cell ◽

Plasma Cells ◽

Myeloma Cell ◽

Multinucleated Cells ◽

Cytoplasmic Bodies ◽

Plasma Cell Type ◽

Well Differentiated ◽

Diagnostic Pitfalls

Abstract Generalizing, it can be said that the pathologic cells seen in smears of the bone marrow in multiple myeloma resemble the plasma cell and vary from the very anaplastic and immature cell to the well-differentiated and almost characteristic plasma cell. The feature which the "myeloma" cell shares with the plasma cell is the abundant, granular, basophilic cytoplasm which tends to be fragile and undergo the same degenerative changes in each; namely, the formation of Russell bodies and vacuolization. Fairly frequently a perinuclear clear area or Hof is present and the nucleus tends to be eccentrically placed. Cytoplasmic extensions or pseudopodia may also be seen in either case, but they occur more often and more dramatically in instances of multiple myeloma. Multinucleated cells are commonly seen. In addition, myeloma-plasma cells will often have a large clear nucleolus and a leptochromatic nucleus and will exhibit a tendency to the formation of isolated areas of condensed chromatin. Cytoplasmic extrusions, free cytoplasmic bodies, occasionally complete with Russell bodies and vacuoles are almost universally present. All cases were of the plasma cell type; there was no exception. In these cases, the myeloma-plasma cell constituted from 2.5 to 96 per cent of the leukocytic elements present. The opinion was expressed that all so-called types of multiple myeloma are merely variations in differentiation of this same cell. It was noted that anaplasia, hypernucleation and lack of plasma cell predominance in certain cases were diagnostic pitfalls. Additional evidence was adduced to confirm the reticulo-endothelial origin of the myeloma-plasma cell. It was further observed that certain prognostically valuable information could be gleaned from a careful review of the cytologic characteristics in these cases.

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CD43 Expression Is an Adverse Prognostic Factor in Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2021-146754 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4753-4753

Author(s):

Xueqin Ning ◽

Yongqiang Wei ◽

Xiaolei Wei ◽

Ru Feng ◽

Bingyuan Chen ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Prognostic Factor ◽

Plasma Cells ◽

Newly Diagnosed ◽

Negative Group ◽

Hematopoietic Stem ◽

Female Ratio ◽

Positive Group ◽

Adverse Prognostic Factor

Abstract CD43 expression is an adverse prognostic factor in newly diagnosed multiple myeloma Introduction CD43 is an abundant, heavily-glycosylated, cell surface protein expressed on bone marrow hematopoietic stem cells and most white blood cells. Previous studies have found that CD43 also expressed in some types of lymphoma cells and associated with adverse outcomes. However, the prognosis value of CD43 expression in multiple myeloma (MM) remain unknown. Patients and Methods A total of 109 MM patients, newly diagnosed in Nanfang Hospital of Southern Medical University from January 2017 to December 2019, were included in the study. CD43 was detected by flow cytometre as follows: 2 ml of heparin anticoagulated bone marrow was collected from the patients at the time of diagnosis，1×10 6 cells were detected, and a gate was set for identifying abnormal plasma cells characterized by CD138 expression and CD38. CD43 positive was defined as more than 20% of the plasma cells expressed CD43. Results A total of 109 patients with newly diagnosed MM were enrolled in the study, including 77 patients (70.6%) for CD43 positive and 32 patients (29.4%) for CD43 negative . The median age was 58 years, and the male-female ratio was 1.7:1. Patients in the CD43 positive group were more likely to have international staging system (ISS) stage III (67.5% VS 46.9%, P= 0.044), hemoglobin < 85g/L (64.9% VS 37.5%, P= 0.008), 13q deletion (31.4% VS 10.4%), and higher percentage of bone marrow monoclonal plasma cells detected by flow cytometry (5.5% VS 1.4%, P=0.003). Most patients enrolled in the study received bortezomib-based treatment. The very good partial response (VGPR) or better rate after 4 induction cycles was significantly lower in the CD43 positive group than CD43 negative group (35.1% VS 56.3%, P=0.041), and the overall response rate (ORR) in the CD43 positive group was lower than that in CD43 negative group (75.3% VS 84.4%, P=0.299), but no significantly difference. The median follow-up time was 22 months. Patients with CD43 positive had significantly lower PFS (median PFS 24 months VS not reached, P =0.012), and OS (median OS not reached, P = 0.023) than those with CD43 negative. Multivariate analysis indicated that CD43 positive expression was an independent poor risk factor for PFS (HR 2.517 95%CI 1.178-5.376, P = 0.017) and OS (HR 3.664 95%CI 1.100-12.075, P = 0.034). Conclusion Our study showed that CD43 expression was an adverse prognosis for multiple myeloma. Disclosures No relevant conflicts of interest to declare.

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The role of bone marrow microenvironment in the progression of multiple myeloma from monoclonal gammopathy of undetermined significance

Oncohematology ◽

10.17650/1818-8346-2021-16-3-26-32 ◽

2021 ◽

Vol 16 (3) ◽

pp. 26-32

Author(s):

A. S. Khudovekova ◽

Ya. A. Rudenko ◽

A. E. Dorosevich

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Monoclonal Gammopathy ◽

Plasma Cells ◽

Bone Marrow Microenvironment ◽

Genetic Mutations ◽

Microbiome Composition ◽

The Impact ◽

Undetermined Significance

Multiple myeloma is a tumor of plasma cells, one of the most common malignant blood diseases. It is preceded by a stage called monoclonal gammopathy of undetermined significance, from which true multiple myeloma develops in only a small percentage of cases. It was assumed that this process is associated with the accumulation of genetic mutations, but in recent years there is increasing evidence that the bone marrow microenvironment plays a key role in progression and that it can become a target for therapy that prevents the myeloma development. The review considers the role of mesenchymal stem cells, immune system cells, endotheliocytes, fibroblasts, adipocytes, osteoclasts and osteoblasts in multiple myeloma progression, as well as the impact of the sympathetic nervous system and microbiome composition.

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