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Plasma cell proliferative disorders are a group of plasma cell derived clonal hematologic neoplasms which exhibit a wide range of biologic activity ranging from monoclonal gammopathy of uncertain significance (MGUS), a usually indolent disorder with a low rate of disease progression, to multiple myeloma (MM), a disease that is often aggressive with poor long-term survival. Detecting plasma cell clonality through demonstrating immunoglobulin (Ig) light chain restriction (ie, the presence of either predominately kappa or predominately lambda light chains), supplemented by the plasma cell immunophenotype and DNA index, is an important element in establishing the diagnosis.
It is important to correctly classify patients with plasma cell proliferative disorders as the various disease entities are treated differently. A number of factors are used for this classification including the proportion clonal bone marrow plasma cells, the DNA index of the clonal plasma cells, and their proliferative activity. The plasma cell DNA index and proliferation assessment by flow cytometry are rapid and reliable. This information can be used to distinguish patients with overt, active MM from less aggressive diseases such as MGUS and smoldering MM.
Furthermore, in combination with other laboratory data, the results of these studies can be used as a measure of disease aggressiveness in newly diagnosed MM and also to determine therapeutic efficacy and detect disease relapse in treated MM patients.
See Laboratory Screening Tests for Suspected Multiple Myeloma in Special Instructions. Also see Diagnosis and Monitoring of Multiple Myeloma in Publications.
Establishing a diagnosis of a plasma cell proliferative disorder
Providing prognostic information for newly diagnosed multiple myeloma and other plasma cell proliferative disorders
Assessing response to therapy and detecting disease relapse and progression in treated plasma cell proliferative disorder patients
Determining plasma cell DNA content and proliferation
Plasma Cell Clonality:
Plasma cell populations with a kappa to lambda ratio of either >3.9 or <0.5 will be considered either kappa or lambda immunoglobulin light chain restricted (monotypic), respectively. As, in rare instances, immunoglobulin light chain restricted plasma cell populations may be polyclonal at the genetic level, the term monotypic rather than monoclonal plasma cells will be used.
In addition to immunoglobulin light chain expression, other data collected will be used to supplement the detection of abnormal plasma cell populations. In plasma cells, CD19 expression is associated with the presence of benign, polytypic cell populations. Therefore CD19 expression will be used as a secondary element in detecting clonal plasma cells. While loss of plasma cell CD45 expression is associated with neoplasia, CD45 is expressed by both normal and neoplastic plasma cells. Therefore, absence of plasma cell CD45 expression will be used as an aid in detecting abnormal plasma cells. In some plasma cell proliferative disorders there are both CD45-positive and CD45-negative subsets within the clonal cell population, therefore inclusion of antibodies to this antigen allows for more sensitive detection of both subtypes. In addition, as DNA content will be simultaneously assessed, the detection of plasma cell aneuploidy will also serve as a tool for identifying abnormal plasma cell populations. These additional phenotypic tools for identifying abnormal plasma cells will increase the sensitivity of the method beyond examining light chain expression; particularly in biclonal plasma cell proliferative disorders in which there are both kappa and lambda immunoglobulin light chain expressing subsets.
Plasma Cell Proliferation:
The proportion of plasma cells in S-phase will be determined by measuring the proportion of cells with DNA content between the G0/G1 and G2/M peaks. In some instances, plasma cell proliferation will not be able to be determined by this method; including when there are fewer than 300 abnormal plasma cell events and when there are multiple aneuploid plasma cell populations. In newly diagnosed multiple myeloma, a plasma cell labeling index (PCLI) of > or =3.0 is associated with a more aggressive disease course.(1,2) As there was a 100% concordance between a PCLI of >3.0 and an estimated S-phase of >1.5%, and this value is published standard for identifying plasma cell neoplasms with a high proliferative rate, it will be noted in the report if the estimated S-phase exceeds this value.(3,4)
Processed cells are stained with DAPI to determine the DNA index of the abnormal plasma cells. This will be determined by dividing the measured DNA content of the G0/G1 abnormal plasma cells by the DNA content of the normal G0/G1 plasma cells present. For this determination, normal plasma cells are the optimal control cell population due to similarities in nuclear and overall cell size. Plasma cells with a G0/G1 DNA content index of <0.95 will be considered hypodiploid (worst prognosis); those with a G0/G1 DNA content index of >1.05 will be considered hyperdiploid (favorable prognosis). Plasma cells with a DNA index of 1.9 to 2.1 will be considered tetraploid (nonfavorable prognosis) if a confirmatory G2/M population with a DNA index of 4 is identified. As noted above, since normal plasma cells are neither hyper- nor hypodiploid, DNA index will be used as a supplemental tool in detecting clonal plasma cells.
Percent Polyclonal Plasma Cells in Total Plasma Cells:
It has been shown that higher percent polyclonal plasma cells in total plasma cells can mean longer progression-free survival, higher response rates, and lower frequency of high-risk cytogenetics abnormalities. Studies have also shown a higher incidence of polytypic plasma cells in monoclonal gammopathy of uncertain significance and smoldering myeloma in comparison to multiple myeloma.
In order to provide an adequate specimen, it is important that the marrow specimen be from a "redirect" marrow aspirate. The marrow needle should be redirected so the marrow can be aspirated from a previously unsampled site.
Plasma Cell Clonality:
Normal bone marrow
No monotypic clonal plasma cells detected
Normal polytypic plasma cells
DNA index (G0/G1 cells): Diploid 0.95-1.05
1. Kumar SK, Mikhael JR, Buadi FK, et al: Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines. Mayo Clin Proc 2009 Dec;84(12):1095-1110
2. Rajkumar SV, Greipp PR: Prognostic factors in multiple myeloma. Hematol Oncol Clin North Am 1999 Dec;13(6):1295-1314
3. Garcia-Sanz R, Gonzalez-Fraile MI, Mateo G, et al: Proliferative activity of plasma cells is the most relevant prognostic factor in elderly multiple myeloma patients. Int J Cancer 2004 Dec 10;112(5):884-889
4. Morice WG, Hanson CA, Kumar S, et al: Novel multi-parameter flow cytometry sensitively detects phenotypically distinct plasma cell subsets in plasma cell proliferative disorders. Leukemia 2007 Sep;21(9):2043-2046
5. Morice WG, Chen D, Kurtin PJ, et al: Novel immunophenotypic features of marrow lymphoplasmacytic lymphoma and correlation with Waldenstrom's macroglobulinemia. Mod Pathol 2009 Jun;22(6):807-816
6. Paiva B, Vidriales MB, Mateo G, et al: The persistence of immunophenotypically normal residual bone marrow plasma cells at diagnosis identifies a good prognostic subgroup of symptomatic multiple myeloma patients. Blood 2009 Nov;114(20):4369-4372