No single marker can reliably differentiate normal plasma cells from their neoplastic counterparts.

Normal plasma cells in the bone marrow are CD19+ CD20-. Myeloma cells are CD19- CD20-.
Myeloma cells express CD20 in 10% of cases.

Plasma cells are CD38+ and CD138+.
CD38 is widely expressed in hematopoietic cells, but its intensity in plasma cells is higher than that in other cells.
(syndecan-1) is a heparin sulphate proteoglycan, expressed on the surface of both normal and malignant plasma cells (universal marker of plasma cells). It is shed from the cell surface (soluble syndecan-1). CD138 is a reliable marker for identifying plasma cells in bone marrow biopsies, and it is more specific than CD38.

CD45 is expressed in all B cells and T cells. MM cells are CD45-.

CD56 is a neural cell adhesion molecule present in NK cells and NK-like T cells, but it is aberrantly expressed in myeloma cells (about 75%). It can distinguish plasma cells of MM from those of reactive plasmacytosis, MGUS, and lymphoplasmacytic lymphoma.


Immunostaining for CD138 in the bone marrow of a patient with multiple myeloma detects the malignant plasma cells (my personal archive):





Immunohistochemistry (IHC) analyses the expression of different protein biomarkers in tissue sections.

Primary extramedullary plasmacytoma and multiple myeloma: phenotypic differences revealed by immunohistochemical analysis.
J Pathol. 2005 Jan;205(1):92-101.
Kremer M, Ott G, Nathrath M, Specht K, Stecker K, Alexiou C, Quintanilla-Martinez L, Fend F.
This study compares the IHC phenotype of 28 cases of primary extramedullary plasmacytoma with 17 cases of myeloma and 9 cases of extramedullary myeloma. Among the patients with primary extramedullary plasmacytoma, none of them progressed to multiple myeloma, 1 progressed to NHL, and 9 experienced local relapse. In comparison to extramedullary myeloma, primary extramedullary plasmacytoma was associated with a more mature morphology, lower proliferation indices, infrequent expression of CD56, and absence of cyclin D1.

Plasmablastic lymphomas and plasmablastic plasma cell myelomas have nearly identical immunophenotypic profiles.
Mod Pathol. 2005 Jun;18(6):806-15.
Vega F, Chang CC, Medeiros LJ, Udden MM, Cho-Vega JH, Lau CC, Finch CJ, Vilchez RA, McGregor D, Jorgensen JL.
According to the WHO classification of lymphomas, plasmablastic lymphoma is a variant of diffuse large B-cell lymphoma (DLBCL). These authors performed IHC on 9 cases of plasmablastic lymphoma and 7 cases of plasmablastic myeloma, and they found that all cases of plasmablastic NHL and plasmablastic myeloma were negative for CD20, and positive for CD38, CD138, and MUM1/IRF4. i.e., they had a profile seen in myeloma plasma cells but not in DLBCL cells. Therefore, these results did not support the notion that plasmablastic lymphoma is a variant of DLBCL. After testing for several antigens, the authors found that the only significant difference between plasmablastic NHL and plasmablastic myeloma was the presence of EBV RNA, which was negative in all cases of plasmablastic myeloma, and positive in all cases of plasmablastic NHL.

Immunophenotypic differentiation between neoplastic plasma cells in mature B-cell lymphoma vs plasma cell myeloma.
Am J Clin Pathol. 2007 Feb;127(2):176-81.
Seegmiller AC, Xu Y, McKenna RW, Karandikar NJ.
It is often difficult to differentiate between plasmacytoma/myeloma and non-Hodgkin lymphomas with marked plasmacytic differentiation. This study compares the immunophenotypic differentiation of 41 cases of B-cell NHL with the findings in plasma cell myeloma, and it showed that plasma cells in NHL are more likely to be negative for CD56 and positive for surface immunoglobulin, CD19, and CD45 than myeloma cells. Myeloma and NHL with plasmacytic differentiation can be reliably distinguished based on CD19 and CD56 expression. Since extramedullary plasmacytoma shows a lymphoma-like phenotype, the authors believe that at least some cases of primary extramedullary plasmacytomas may in fact be NHL with marked plasmacytic differentiation.





See specific section





  Major criteria
  I.   Plasmacytoma on tissue biopsy
  II.  BM plasmacytosis with >30% plasma cells
  III. Monoclonal globulin spike on SPEP
        IgG >3.5 g/dL (50%)
        IgA >2.0 g/dL (20%)
        k or l light-chain excretion >1 g/24 h on UPEP (65%)

  Minor criteria
  a.   BM plasmacytosis with 10-30% plasma cells
  b.   Monoclonal globulin spike on SPEP, but with lower levels
  c.   Lytic bone lesions
  d.   Decreased normal Ig
        IgG <600 mg/dL
        IgA <100 mg/dL
        IgM  <50 mg/dL

Diagnosis is confirmed if:

  -   I + b,   I + c,   I + d
  -  II + b,  II + c,  II + d
  - III + a, III + c, III + d
  - a + b + c


CRAB symptoms define the presence of symptomatic myeloma.
According to the IMWG 2014 revised definition of myeloma, patients with previously considered smoldering myeloma should start therapy if one of the following criteria is present:
  - Involved FLC/uninvolved FLC > 100 (with involved FLC >100 mg/L)
  - Bone lesions detected by CT, MRI, or PET
  - Plasma cells in the bone marrow are >60%



Guidelines on the diagnosis and management of multiple myeloma 2005.
Br J Haematol. 2006 Feb;132(4):410-51.
Smith A, Wisloff F, Samson D; UK Myeloma Forum; Nordic Myeloma Study Group; British Committee for Standards in Haematology.

International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.
Lancet Oncol. 2014 Nov;15(12):e538-48 (Review).
Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, Kumar S, Hillengass J, Kastritis E, Richardson P, Landgren O, Paiva B, Dispenzieri A, Weiss B, LeLeu X, Zweegman S, Lonial S, Rosinol L, Zamagni E, Jagannath S, Sezer O, Kristinsson SY, Caers J, Usmani SZ, Lahuerta JJ, Johnsen HE, Beksac M, Cavo M, Goldschmidt H, Terpos E, Kyle RA, Anderson KC, Durie BG, Miguel JF.



Giampaolo Talamo, M.D.