Prognostic Factor for myeloma patients after ASCT

Multiparameter Flow Cytometric Remission Is the Most Relevant Prognostic Factor for Multiple Myeloma Patients Who Undergo Autologous Stem Cell Transplantation
Blood. 2008 Nov 15;112(10):4017-4023, B Paiva, M-B Vidriales, J Cerveró, G Mateo, JJ Pérez, MA Montalbán, A Sureda, L Montejano , NC Gutiérrez, A García de Coca, N de las Heras, MV Mateos, MC López-Berges, R García-Boyero, J Galende, J Hernández, L Palomera, D Carrera, R Martínez, J de la Rubia, A Martín, J Bladé, JJ Lahuerta, A Orfao, JF San Miguel, on behalf of the GEM/PETHEMA cooperative study groups

Minimal residual disease (MRD) assessment is standard in many hematologic malignancies but is considered investigational in multiple myeloma (MM). We report a prospective analysis of the prognostic importance of MRD detection by multiparameter flow cytometry (MFC) in 295 newly diagnosed MM patients uniformly treated in the GEM2000 protocol VBMCP/VBAD induction plus autologous stem cell transplantation (ASCT).

MRD status by MFC was determined at day 100 after ASCT. Progression-free survival (PFS; median 71 vs 37 months, P < .001) and overall survival (OS; median not reached vs 89 months, P = .002) were longer in patients who were MRD negative versus MRD positive at day 100 after ASCT. Similar prognostic differentiation was seen in 147 patients who achieved immunofixation-negative complete response after ASCT. Moreover, MRD− immunofixation-negative (IFx−) patients and MRD− IFx+ patients had significantly longer PFS than MRD− IFx+ patients. Multivariate analysis identified MRD status by MF Cat day 100 after ASCT as the most important independent prognostic factor for PFS (HR = 3.64, P = .002) and OS (HR = 2.02, P = .02). Our findings demonstrate the clinical importance of MRD evaluation by MFC, and illustrate the need for further refinement of MM response criteria.

3 Comments

  1. John E. Smith

    Beth, I could use a little help with defining the terms of this report. Do you know if MFC is another way to measure a value for the M-spike? And, what does it mean to be MRD negative or positive? Anybody know?

  2. Beth

    Hi John,

    MFC is is an analysis of the bone marrow. I’m pasting in my very first flow cytometry findings as an example. I was thinking that MRD is drawn from one or more of these values. I’ll find out for sure. I won’t see my doctor at Duke again until December 9th, but that’s not too far off.

    FLOW CYTOMETRY FINDINGS:

    SAMPLE COMPOSITION
    67% Myeloid 10% Lymphoid 2% CD19
    4% Monocytic 7% CD3 1% kappa
    4% Erythroid 4% CD4 1% lambda
    1% CD8

    Antibodies (antigens) tested: CD71, CD33, CD45, CD5, CD22, CD3, Kappa, Lambda, CD19, CD4, CD, CD38, CD56 and CD138.

    INTERPRETATION: Present is a phenotypically abnormal population exhibiting forward and right-angle scatter features of large cells and low CD45 expression, which constitutes 3% of analyzed events. It expresses bright surface CD38 and CD138. It is weakly positive for CD56. It is negative for surface expression of CD19, CD20 and CD22. This low proportion of plasma cells is not accurate when compared to bone marrow morphology, and is likely due to poor in-vitro survival of plasma cells. Please see microscopic description.

  3. John E. Smith

    Thanks Beth,

    Here is a copy of a portion of my BMB report from 12-07:

    Concurrent flow cytometry studies also performed at US Labs revealed a
    monoclonal plasma cell population with cytoplasmic lambda light chain
    restriction representing 4% of the marrow cellularity by flow
    cytometry.

    COMMENT:
    The diagnosis of multiple myeloma is a clinical and pathologic diagnosis. The
    marrow shows a variable plasmacytosis (13-20%) which fulfills minor criteria for
    the diagnosis of multiple myeloma.

    FINAL DIAGNOSIS:
    H07-3503 (12/27/2007): Bone marrow aspirate and clot section: Normocellular
    trilineage hematopoiesis with: Increased and atypical plasma cell population
    representing 13-20% (by morphology) and 4% (by flow cytometry) consistent with
    plasma cell dyscrasia (See COMMENT).

    Then I had a BMB performed in 06-08 just before the SCT:

    Flow cytometry offers sensitive detection of abnormal, monoclonal plasma cells,
    but does not offer reliable plasma cell enumeration. To best enumerate the
    plasma cells and characterize their morphology and distribution,
    immunohistochemistry is performed.

    IMMUNOHISTOCHEMISTRY REPORT:
    Formalin, deparaffinized sections are incubated with the following panel of
    monoclonal and/or polyclonal antibodies. Localization is via a polymer
    immunoperoxidase method, with or without the use of heat induced epitope
    retrieval techniques. Results on the population(s) of interest are as indicated
    in the table(s) below.

    Block (Original Label): B1
    Population: Marrow Biopsy, RPIC
    Label Marker For: Discrete Result/Units Comment
    CD138 SCCA CD138 antibody by immunoperoxidase 15% positive 10+ in
    clusters, interstitial

    Block (Original Label): C1
    Population: Marrow Aspirate, LPIC
    LabelMarker For:Discrete Result/UnitsComment
    CD138 SCCA CD138 antibody by immunoperoxidase 20% positive 10+ in
    clusters, interstitial

    Block (Original Label): D1
    Population: Marrow Biopsy, LPIC
    LabelMarker For:Discrete Result/UnitsComment
    CD138 SCCA CD138 antibody by immunoperoxidase 80% positive Small
    sample

    IHC INTERPRETATION:
    There are varying frequencies of plasma cells the marrow averaging about 20% of
    the nucleated cells. The plasma cells appearing large and atypical and are often
    in clusters of 10 or more.

    COMMENT:
    The most representative marrow cellularity is an average of 20%. Flow cytometry
    finds the plasma cell in the marrow are abnormal monoclonal lambda plasma cells
    (UW Hematopathology HP08-9182). Enumeration by flow is usually an underestimate,
    and the best estimate is deemed to be the IHC result.

    FINAL DIAGNOSIS:
    A, B, C & D: Bilateral bone marrow biopsies and aspirates: Hypocellular bone
    marrow (cell:fat ratio 20:80) 40% of normal cellularity, with 20% plasma cells,
    consistent with plasma cell myeloma. (See COMMENT)

    I see my oncologist tomorrow. He has spoken in the past about the unreliability of BMBs due to the tendency for false negatives of abnormal plasma cells. I’ve a few questions for him. Sorry about the huge comment but, what the hell, it’s just bits and bytes. :)

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