Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
  • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
  • A61K38/1716—Amyloid plaque core protein
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/02—Bacterial antigens
  • A61K39/025—Enterobacteriales, e.g. Enterobacter
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/02—Bacterial antigens
  • A61K39/09—Lactobacillales, e.g. aerococcus, enterococcus, lactobacillus, lactococcus, streptococcus
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
  • G01N15/10—Investigating individual particles
  • G01N15/14—Optical investigation techniques, e.g. flow cytometry
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
  • G01N33/575—Immunoassay; Biospecific binding assay; Materials therefor for cancer
  • G01N33/57505—Immunoassay; Biospecific binding assay; Materials therefor for cancer of the blood, e.g. leukaemia
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
  • G01N33/575—Immunoassay; Biospecific binding assay; Materials therefor for cancer
  • G01N33/5758—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
  • G01N15/10—Investigating individual particles
  • G01N2015/1006—Investigating individual particles for cytology

Definitions

• the invention relates to the field of cancer diagnosis, more specifically to means and method for the monitoring of disease development during and after treatment or for the detection of minimal disseminated disease.
• Cytostatic or cytotoxic treatment induces remission in the majority of patients with lymphoid malignancies. Nevertheless many of these patients relapse.
• the current cytostatic or cytotoxic treatment protocols are not capable of killing all malignant cells in these relapsing patients, although they reached so-called complete remission according to cytomorphological criteria. Since the detection limit of cytomorphological techniques is not lower than 1-5% malignant cells, it is obvious that such techniques can only provide superficial information about the effectiveness of treatment, up to 10 10 tumor cells still potentially remaining in the body
• MRD minimal disease
• the present inventors set out to identify additional markers which could be used to obtain a more sensitive and reliable assay for detecting MRD, particularly based on a fully integrated approach, in which information of multiple markers is combined via multivariate analysis.
• this new approach is not anymore limited to individual patients, but is applicable to every patient of a specific disease category, such B-cell precursor acute lymphoblastic leukemia (BCP-ALL), B-cell chronic lymphocytic leukemia (B- CLL) and multiple myeloma (MM).
• BCP-ALL B-cell precursor acute lymphoblastic leukemia
• B- CLL B-cell chronic lymphocytic leukemia
• MM multiple myeloma
• fluorochromes (based on need for brightness, compensation, stability, etc.), a set of antibody reagents was developed. The studies were complemented with extensive multicentric evaluation of the consensus panels in order to reshape and achieve an optimal efficiency.
• the inventors designed novel > 8-color stainings with carefully selected and thoroughly tested combinations of antibodies, which can reach sensitivities of 10 -4 to 10 -5 Based on design-testing-redesign-retesting-redesign (etc.), specific combinations of fluorochrome-conjugated antibodies have been developed per disease category, such as BCP-ALL, B-CLL and MM.
• the provided 10-color and 12-color antibody combinations can even better discriminate between normal cells and their malignant counterparts, thereby allowing for MRD detection with sensitivities down to 10 5 .
• BCP-ALL BCP - B-cell precursor acute lymphoblastic leukemia
• B-CLL B-cell chronic lymphocytic leukemia
• MM Multiple myeloma
• PCD plasma cell disorders
• the invention provides unique reagent compositions for flow cytometric detection of MRD, comprising a combination of at least eight distinct fluorochrome- conjugated antibodies.
• the reagent compositions are of use for detecting MRD in patients with BCP-ALL, B-CLL or MM/PCD.
• the composition comprises monoclonal antibodies against a given CD antigen.
• CD stands for cluster designation and is a nomenclature for the identification of specific cell surface antigens or intracellular antigens defined by monoclonal antibodies.
• the invention provides a reagent composition for flow cytometric detection of BCP-ALL cells in a human subject, comprising a panel of at least eight distinct fluorochrome-conjugated antibodies.
• the BCP-ALL panel comprises antibodies against the four "core markers" CD 10, CD 19, CD20, CD34 and CD45.
• the panel further comprises one or more antibodies selected from the group of antibodies against CD38, CD81, Cylgp, and deoxynucleotidyl transferase (NuTdT).
• the panel further comprises one or more sets of antibodies selected from (a) set of antibodies against CD66c and CD123; (b) set of antibodies against CD304 and CD73; and (c) set of antibodies against SmlgK and SmlgA, wherein the antibodies within each set are conjugated to the same
• the BCP-ALL panel comprises antibodies against CD 10, CD 19, CD20, CD34, CD45, one or more antibodies selected from the group of antibodies against CD38, CD81, Cylgu, NuTdT, and two or more sets of antibodies selected from (a) set of antibodies against CD66c and CD123; (b) set of antibodies against CD304 and CD73; and (c) set of antibodies against SmIgK and SmIgA, wherein the antibodies within each set are conjugated to the same fluorochrome.
• a reagent composition comprises distinct fluorochrome-conjugated antibodies directed against one of the following combinations of markers:
• it comprises distinct fluorochrome-conjugated antibodies directed against the markers CD20, CD45, CD81, NuTdT, CD34, CD19, CD10 and CD38, and one or more sets of antibodies selected from (a) set of antibodies against CD66c and CD 123; (b) set of antibodies against CD304 and CD73; and (c) set of antibodies against SmIgK and SmIgA, wherein the antibodies within each set are conjugated to the same fluorochrome. See for instance the 10-color tube in Panel IB comprising antibodies against the markers CD20, CD45, CD81, NuTdT, CD66c, CD 123, CD304, CD73, CD34, CD19, CD10 and CD38.
• the composition comprises a combination of fluorochrome- conjugated antibodies directed against the markers CD20, CD45, CD81, NuTdT, CD66c, CD 123, CD304, CD73, SmIgK, SmIgA, Cylgp, CD34, CD 19, CD 10 and CD38, wherein the antibodies against each of the sets CD66c/CD123, CD304/CD73 and
• SmIgK/ SmIgA are conjugated to the same fluorochrome. See for instance the 12-color tube in panel 1C.
• Suitable fluorochromes for conjugating antibodies for use in the present invention against the recited markers are known in the art. As will be understood, the fluorochromes used within a reagent composition should be distinguishable from each other by flow cytometry. The fluorochromes are preferably selected for brightness, limited spectral overlap and limited need for compensation, stability, etc (see: Kalina et al. Leukemia 2012: 26: 1986-2010).
• composition according to the invention (1) pacific blue (PacB), brilliant violet 421
• BV421 or Horizon V450 (2) pacific orange (PacO), Horizon V500 (HV500), BV510, Khrome orange (KO) or OC515, (3) fluorescein isothiocyanate (FITC) or Alexa488, (4) phycoerythrin (PE), (5) peridinin chlorophyl protein/cyanine 5.5 (PerCP-Cy5.5), PerCP or PE-TexasRed, (6) phycoerythrin/cyanine7 (PE-Cy7), (7) allophycocyanine (APC) or Alexa647, and (8) allophycocyanine/hilite 7 (APC-H7), APC-Cy7, Alexa680, APC- A750, APC-C750 or Alexa700.
• fluorochromes are chosen: Pacific Blue, brilliant violet 421 or Horizon V450, PacO or Horizon V500,
• the invention provides for a reagent composition shown in Table 1, panel 1A, panel IB or panel 1C.
• Panel 1A Marker Composition of 8-color BCP-ALL MRD panels of the invention tube PacB PacO FITC PE PerCPCy5.5 PECy7 APC APCC750
• CD20 CD45 NuTdT 6 ⁇ 3 ⁇ 4 ⁇ CD19 CD34 CD10
• Panel 1C Marker Composition of 12-color BCP-ALL MRD panel of the invention
• the invention provides a reagent composition for flow
• B-CLL B-cell chronic lymphocytic leukemia
• the panel comprising at least antibodies against the seven "core markers” CD5, CD27, CD79b, CD3 , CD200, CD81 and CD19. It was found that CD22 and/or
• Receptor tyrosine kinase-like orphan receptor 1 (ROR1) can be used as valuable
• Preferred marker combinations for detecting B-CLL are as follows:
• pacific blue PacB
• brilliant violet 421 BV421
• PE phycoerythrin
• PE-Cy7 peridinin chlorophyl protein/cyanine 5.5
• PE-Cy7 PE-Cy7
• APC allophycocyanine
• APC-H7 allophycocyanine/hihte 7
• the invention provides for a reagent composition shown in Table 2.
• Panel 2A Composition of 8-color CLL MRD panel
• MM/PCD multiple myeloma/plasma cell disease
• a still further aspect of the invention relates to a reagent composition for detecting
• the panel comprises antibodies against the four "core markers"
• CD 138, CD38, CD56 and CD 19 supplemented with at least four additional markers
• CD27 selected from the group consisting of CD27, CD117, CD81, CD229, CD45, CylgK and
• CD45 is a preferred fifth marker, preferably in combination with CD27, CD 117 and CD81 or CD229, CylgK and CylgA.
• a reagent composition for flow cytometric detection of MM or PCD in a human subject comprising a panel of at least eight distinct fluorochrome-5 conjugated antibodies, the panel comprising at least antibodies against the core
• CD45 is the fifth marker, more preferably in
• Preferred reagent compositions comprise distinct
• fluorochrome-conjugated antibodies directed against one of the following combinations of markers: (iv) CD45, CD138, CD38, CD56, CD27, CD19, CD117 and CD81
• CD28 and (b) set of antibodies against CylgK and CylgA. See for instance the 10-color tube in Panel 3B and the 12-color tube in Panel 3C.
• the following panel of fluorochromes is of particular use in a MM/PCD reagent composition according to the invention: (1) pacific blue (PacB), brilliant violet 421 (BV421) or Horizon V450, (2) pacific orange (PacO), Horizon V500 (HV500), BV510, Khrome orange (KO) or OC515, (3) fluorescein isothiocyanate (FITC) or Alexa488, (4) phycoerythrin (PE), (5) peridinin chlorophyl protein/cyanine 5.5 (PerCP-Cy5.5), PerCP or PE-TexasRed, (6) phycoerythrin/cyanine7 (PE-Cy7), (7) allophycocyanine (APC) or Alexa647, and (8) allophycocyanme/hilite 7 (APC-H7), APC-Cy7, Alexa680, APC- A750, APC-C750 or Alexa700.
• PacB pacific blue
• fluorochromes are chosen: Pacific Blue, brilliant violet 421 or Horizon V450, PacO or Horizon V500, FITC, PE, PerCP-Cy5.5, PE-Cy7, APC, and APC-H7 or APC-A750 or APC-C750.
• Panel 3B Composition of 10-color PCD MRD panel
• a further aspect of the invention relates to a diagnostic kit for detecting MRD, in particular BCP-ALL MRD, CLL MRD or MM/PCD MRD comprising one or more of the reagent compositions described herein above, optionally together with instructions for use, buffer, and/or control samples (see: Kalina et al. Leukemia 2012: 26: 1986- 2010).
• a BCP-ALL kit comprising one or more reagent compositions of Table 1.
• a CLL kit comprising one or more reagent compositions of Table 2.
• a PCD kit comprising one or more reagent
• the invention also relates to a method for flow cytometric detection of MRD, comprising the steps of providing a biological sample from a human subject and contacting at least a portion (aliquot) of the sample with a reagent composition provided herein.
• a biological sample from a human subject
• a reagent composition provided herein.
• Any type of sample known or suspected to contain leukocytes may be used directly, or after lysing non-nucleated red cells, or after density centrifugation, or after cell sorting procedures.
• the sample is peripheral blood, bone marrow, tissue sample such as lymph nodes, adenoid, spleen, or liver, or other type of body fluid such as cerebrospinal fluid, vitreous fluid, synovial fluid, pleural effusions or ascitis. Peripheral blood or bone marrow is preferred.
• the analysis in step (iv) involves multivariate analysis, preferably principal component analysis (PCA), wherein each marker has added value in the distinction process via the principal component analysis.
• PCA principal component analysis
• MDS multidimensional scaling
• PCA is a mathematical procedure that uses an orthogonal transformation to convert a set of observations of possibly correlated variables into a set of values of uncorrelated variables called principal components.
• the number of principal components is less than or equal to the number of original variables.
• This transformation is defined in such a way that the first principal component has as high a variance as possible (that is, accounts for as much of the variability in the data as possible), and each succeeding component in turn has the highest variance possible under the constraint that it be orthogonal to (uncorrelated with) the preceding components.
• Principal components are guaranteed to be independent only if the data set is jointly normally distributed.
• PCA is sensitive to the relative scaling of the original variables.
• KLT discrete Karhunen-Loeve transform
• POD proper orthogonal decomposition
• MDS any other type of well-established multivariate analysis, can be used (see: Pedreira et al. Trends Biotechnol 2013).
• MRD minimal residual disease
• BCP-ALL reagent composition preferably a composition selected from any one of panels 1A, IB or 1C,;
• MRD minimal residual disease
• CLL reagent composition preferably a composition selected from any one of panels 2A, 2B or 2C;
• MRD minimal residual disease
• MM/PCD reagent composition preferably a composition selected from any one of panels 3A, 3B or 3C;
• Figure 1 Typical example of how to use the CD19 and CD45 identification markers in combination with SSC (Panel A to C) for the distinction between BCP cells and other nucleated cells in a bone marrow sample from a BCP-ALL patient during therapy.
• SSC Session Control System
• light grey events correspond to non-B cells in the sample, while dark grey events are mature B-cells and black events BCP cells.
• APS1 multivariate analysis representation
• both mature B cells and BCP cells are clearly separated from all other events based on all informative parameters (e.g. CD 19, CD45, SSC).
• FIG. 2 Illustrating example of how to use immunophenotypic characterization markers CD 10, CD20, CD34, CD66c/CD123, and CD38 in combination with SSC for the distinction between BCP-ALL cells and normal residual B-cells in a bone marrow sample from a BCP-ALL patient during therapy (Panels A to D). Only bone marrow B-cells are displayed, after gated/selected as described in Figure 1. In each plot, black dots correspond to BCP-ALL cells in the sample, while grey dots are normal B-cells. Compared to normal B-cells, BCP-ALL cells show overexpression of CD81 (Panel D), CD 10 (Panels A and D), and CD66c/CD123 (Panel C). In the APSl (principal component 1 versus principal component 2) representation based on all
• Figure 3 Illustrating example of how to use the CD19 and CD3 identification markers in combination with SSC (Panels A to C) for the distinction between mature B-cells and other nucleated cells in a peripheral blood sample from a CLL patient.
• grey events correspond to non-B-cells in the sample, while black events are total peripheral blood B-cells.
• APSl multivariate analysis representation
• principal component 1 vs. principal component 2
• B-cells are clearly separated from all other events based on all informative parameters (e.g. CD19, CD3, SSC).
• FIG. 4 Illustrating example of how to use immunophenotypic characterization markers CD27, CD5, CD22, CD200 and CD79b (panels A to C) for the distinction between CLL cells and normal mature B-cells in a peripheral blood sample from a CLL patient. Only peripheral blood B-cells are displayed, after gated/selected as described in Figure 3. In each plot, black dots correspond to CLL cells in the sample, while grey dots are normal peripheral blood B-cells. Compared to normal B-cells, CLL cells show underexpression of CD22 (Panel B) and CD79b (Panel C) together with overexpression of CD200 (Panel B) and CD5 (Panels A and C). In the APSl (principal component 1 vs. principal component 2) representation based on all
• black dots correspond to myeloma/clonal plasma cells in the sample, while grey dots are normal residual bone marrow plasma cells.
• myeloma/clonal plasma cells show underexpression of CD81, CD 19, CD45, CD27 and CD38 together with higher SSC and overexpression of CD 56 and CD 117.
• APS1 principal component 1 vs. principal component 2 representation
• grey dots are clearly discriminated from myeloma/malignant plasma cells (black dots) , while this degree of discrimination could not be achieved based on individual markers.
• the power of the Euro Flow approach disclosed herein is based on the combination of sets of markers and the usage of multivariate analyses for both the identification of normal cells (e.g. normal precursor B-cells, normal B-lymphocytes and normal plasma cells) and the distinction between normal/reactive cells vs. clonal/malignant cells.
• normal cells e.g. normal precursor B-cells, normal B-lymphocytes and normal plasma cells
• Such a strategy was used to evaluate the selected combinations of most discriminating markers in multiple sequential rounds of experimental testing. Because of this the final proposed antibody combinations became extremely strong when used in combination with the principal component analysis, specifically with the automated population separation (APS) tool of the Infinicyt software, so that the added (independent) value of each marker is used in a single step of analysis.
• APS automated population separation
• Pre-gatmg using the CD 19 marker is essential for identifying a pure B-cell population.
• BCP normal B-cell precursors
• CD45-negativity or weak positivity can be used to discriminate BCP from CD45-positive mature B- cells.
• CD19-directed therapies CD 19 might be replaced by CD22.
• SSC sideward light scatter
• FSC forward light scatter
• markers like CD 10, CD20, CD38 and CD34, which are used for discriminating BCP-ALL cells from normal BCP cells (see below), may also contribute to the gating of the total BCP cell population (e.g. CD34+, CD 10+, CD20-to dim, CD38+).
• CD 38 underexpressed in BCP-ALL/malignant vs. normal B-cell precursor cells
• CD 10 over- or underexpressed in BCP-ALL/malignant B-cell precursor cells
• CD45 underexpressed (usually negative) in BCP-ALL/malignant vs. normal B- cell precursor cells
• CD20 under- or overexpressed in BCP-ALL/ malignant vs. normal B-cell
• CD81 over- or underexpressed in BCP-ALL/ malignant vs. normal B-cell
• CD66c overexpressed in BCP-ALL/ malignant vs. normal B-cell precursor cells (particularly BCR-ABL positive ALL; generally negative in TEL-AMLl- posiitve or MLL-AF4-positive ALL)
• CD 123 overexpressed in BCP-ALL/ malignant vs. normal B-cell precursor cells
• CD304 overexpressed in BCP-ALL/ malignant vs. normal B-cell precursor cells
• CD 73 overexpressed in BCP-ALL/ malignant vs. normal B-cell precursor cells
• CD 34 under- or overexpressed in BCP-ALL/ malignant vs. normal B-cell precursor cells
• SSC increased or decreased intensity in BCP-ALL/ malignant vs. normal B- cell precursor cells.
• FSC increased or decreased intensity in BCP-ALL/ malignant vs. normal B- cell precursor cells.
• EXAMPLE 2 Antibody panels and diagnostic method for MRP detection in CLL patients.
• Pre-gating using this marker combination is essential for identifying a pure B-cell population, and removing T-cell/B-cell doublets.
• These markers may be used in combination also with sideward light scatter (SSC) or forward light scatter (FSC) or both FSC and SSC to identify B-cells in peripheral blood or bone marrow or other types of samples (e.g. tissue biopsy, spinal fluid).
• SSC sideward light scatter
• FSC forward light scatter
• both CD5 and CD27 may be used.
• CD27 positive on CLL cells and a small fraction of normal B-cells
• CD5 positive on CLL cells and a small fraction of normal B-cells
• CD 79b underexpressed on CLL cells as compared to normal transitional and mature B-lymphocytes
• CD22 underexpressed on CLL cells as compared to normal transitional and mature B-lymphocytes
• CD20 underexpressed on CLL cells as compared to normal transitional and mature B-lymphocytes
• CD200 overexpressed on CLL cells as compared to normal transitional and mature B-lymphocytes
• ROR1 overexpressed on CLL cells as compared to normal transitional and mature B-lymphocytes
• CD43 overexpressed on CLL cells as compared to normal transitional and mature B-lymphocytes
• CD81 underexpressed on CLL cells as compared to B-cell precursors and both transitional and mature B-lymphocytes
• CD38 underexpressed on CLL cells as compared to B-cell precursors
• EXAM PLE 3 Antibody panels and diagnostic method for MRP detection in MM/PCP patients Markers for identification of total plasma cells in the bone marrow:
• any combination of the three markers in any fluorochrome position works; also it is possible to use any combinations of two of the three markers or in a subset of cases (not all) even one of the three markers alone. Preferable combinations are order as follows: 1 ) CD138/CD38/CD229; 2) CD138/CD38, 3) CD138/CD229; 4) CD38/CD229; 5) CD138; 6) CD38); 7) CD229. Note that any of these markers individually and in combination may be used in combination also with sideward light scatter (SSC) or forward light scatter (FSC) or both FSC and SSC to identify plasma cells in the bone marrow or other types of samples (e.g. peripheral blood, tissue biopsy, spinal fluid). Markers for distinguishing normal vs clonal/malignant plasma cells:
• CD38 underexpressed in malignant plasma cells compared to normal plasma cells
• CD27 underexpressed in malignant plasma cells compared to normal plasma cells
• CD45 underexpressed in malignant plasma cells compared to normal plasma cells
• CD 19 underexpressed (usually negative) in malignant plasma cells compared to normal plasma cells
• CD81 underexpressed in malignant plasma cells compared to normal plasma cells
• CD56 overexpressed in malignant plasma cells compared to normal plasma cells
• CD28 overexpressed in malignant plasma cells compared to normal plasma cells
• CD 117 overexpressed in malignant plasma cells compared to normal plasma cells
• Cylgk and Cylglambda expression restricted to either one or the other Ig light chains in malignant plasma cells while showing a balanced distribution
• SSC increased or decreased intensity in malignant plasma cells compared to normal plasma cells.
• FSC increased or decreased intensity in malignant plasma cells compared to normal plasma cells.

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