Multiple myeloma may be diagnosed during the work-up of anemia, bone pain, bone fractures, or after an incidental finding of elevated amounts of proteins in the blood or excessive loss of proteins in the urine. Diagnostic delays of several months are common, due to the rarity of the disease. A bone marrow biopsy is usually required for diagnosis.




Monoclonal immunoglobulinS in serum and/or urine

See "Laboratory findings"




BM aspiration and biopsy

BM aspirate and biopsy usually show >10% plasma cells, but no minimal percentage is required for the diagnosis. In fact, neoplastic plasma cells may be absent in about 5% of cases, due to the patchy nature of the neoplasm.
When the percentage of plasma cells in the aspirate is discordant to that seen in the biopsy, the number to be indicated in the medical record is the highest number obtained by either procedure.

The morphology of myeloma cells is variable, because they may appear as normal plasma cells, but they may also exhibit blast-like features that makes them hardly recognizable as plasma cells. The four main categories include: mature, intermediate, immature, and plasmablastic.

Normal plasma cells tend to be located in the perivascular regions of the bone marrow, whereas neoplastic plasma cells can aggregate in large clusters and sheets. Atypical plasma cells are usually large-sized (30-40 mcM instead of 8-15 mcM), binucleated, with hyperchromatic chromatin, and with prominent nucleoli.

The BM aspiration and biopsy is useful also for:
 - Flow cytometry of DNA and cytoplasmic Ig
 - Plasma cell labeling index
   It measures the proliferation rate of the plasma cells.
 - Cytogenetic analysis



Bone marrow biopsy of patients with multiple myeloma, showing diffuse infiltration by neoplastic plasma cells (my personal archive):





Bone marrow aspirate from a patient with multiple myeloma, showing numerous plasma cells, which can be recognized by the eccentric nucleus and perinuclear halo (courtesy of Dr. Michael G. Bayerl - Hematopathology, Penn State Hershey Medical Center):




Perivascular location of normal plasma cells in the bone marrow (courtesy of Dr. Michael G. Bayerl - Hematopathology, Penn State Hershey Medical Center):




Malignant plasma cells may contain Dutcher and Russell bodies. These are intracellular spherical inclusions which consist of accumulated immunoglobulins. Dutcher bodies are intranuclear, whereas Russell bodies are seen within the cytoplasm. Dutcher bodies result from the invagination of the cytoplasm into the nucleus. Cells containing multiple Russell bodies are called Mott cells.


Bartl system

Histologic classification and staging of multiple myeloma. A retrospective and prospective study of 674 cases.
Am J Clin Pathol. 1987 Mar;87(3):342-55.
Bartl R, Frisch B, Fateh-Moghadam A, Kettner G, Jaeger K, Sommerfeld W.
This study evaluates the bone marrow histologic features of 674 patients with multiple myeloma, and it correlates findings with clinical features to determine prognostic factors.
Myeloma was classified into 6 histologic types and 3 prognostic grades:
1) Low grade:
       - Marschalko type
       - Small cell type
2) Intermediate grade:
      - Cleaved type
      - Polymorphous type
      - Asynchronous type
3) High grade:
Blastic type



t(11;14) and t(4;14) translocations correlated with mature lymphoplasmacytoid and immature morphology, respectively, in multiple myeloma.
Leukemia. 2003 Oct;17(10):2032-5.
Garand R, Avet-Loiseau H, Accard F, Moreau P, Harousseau JL, Bataille R.
This study evaluates the bone marrow aspirates and FISH of 178 patients with newly diagnosed myeloma.
  - The plasma cells of patients with t(11;14) exhibited a lymphoplasmacytoid morphology in 25 of 48 cases (52%)
  - The plasma cells of patients with t(4;14) exhibited an immature morphology with diffuse chromatin pattern in 17 of 28 cases (61%)
t(4;14) translocation and immature morphology correlated with higher incidence of high tumor mass and chromosome 13 abnormality.

Diverse niches within multiple myeloma bone marrow aspirates affect plasma cell enumeration.
Br J Haematol. 2006 Jun;133(5):530-2.
Nadav L, Katz BZ, Baron S, Yossipov L, Polliack A, Deutsch V, Geiger B, Naparstek E.
This study demonstrated that flow cytometry underestimates the number of plasma cells in BM aspirates by an average of 60%, when compared with morphological analysis. This discrepancy may be explained by the fact that bone marrow smears contain plasma cells associated with lipid-enriched spicules, whereas flow cytometry counts plasma cells in the fluid of the bone marrow aspirate, which is depleted of the lipid-adhesive plasma cells.

Conventional diagnostics in multiple myeloma.
Eur J Cancer. 2006 Jul;42(11):1510-9.
San Miguel JF, Gutiérrez NC, Mateo G, Orfao A.

Myeloma cell morphology and morphometry in correlation with clinical stages and survival.
Diagn Cytopathol. 2013 Nov;41(11):947-54.
Seili-Bekafigo I, Valković T, Babarović E, Duletić-Načinović A, Jonjić N.

Auer rod-like inclusions in plasma cells in multiple myeloma.
J Clin Pathol. 2014 Jun;67(6):547-8.
Ho WK, Zantomio D.
Auer rods are rod-shaped cytoplasmic inclusions, usually observed in patients with acute myelogenous leukemia. Interestingly, most cases of Auer rods reported in multiple myeloma were associated with production of kappa light chains. They do not contain immunoglobulins/light chains. They stain negatively for myeloperoxidase (unlike AML) and positive for alpha-naphtyl acetate esterase and beta-glucuronidase, which suggests a lysosomal origin.

Plasma cell myeloma with unusual morphology - a series of 6 cases.
Eur J Haematol. 2014 Aug;93(2):165-70.
Gupta R, Hussain N, Rahman K, Nityanand S.
The authors describe 6 cases of myeloma with atypical morphology of the malignant plasma cells, which could be challenging for a pathologist:
  - Plasma cells with deep nuclear convolution
  - Plasma cells with irregular and deeply indented nuclear contour
  - Plasma cells with vacuolated cytoplasm and Burkitt-like morphology
  - Crystal-storing histiocytes

A systematic study comparing aspirate versus trephine for quantifying plasma cell infiltration in newly-diagnosed myeloma.
Br J Haematol. 2016 Sep;174(5):818-20.
Gabriel J, McGovern A, Robinson S, Wright D, Chevassut T.
The diagnosis of multiple myeloma is based on the presence of 10% or more of malignant plasma cells in the bone marrow. In this retrospective study, the authors reviewed data in 87 patients with myeloma, and compared the number of plasma cells found in the bone marrow aspirate to those found in the biopsy. Aspirate samples underestimated the number of plasma cells compared to the trephine biopsy. The causes of the lower number of plasma cells in the aspirate is possibly due to niche adherence or fibrosis that compromises the aspiration of cells. When enumerating the plasma cells in the marrow for diagnostic purposes, it is recommended that the higher infiltration number is used.




It is often difficult to distinguish between a plasmablastic myeloma and a lymphoma with plasmablastic differentiation. This is important, because the treatment of the two neoplasms involves different strategies and drugs.
Factors favoring the diagnosis of myeloma:
   1 - Presence of paraproteins
   2 - Lytic bone lesions
   3 - CD117+ (KIT)
   4 - In-situ hybridization for cyclin D1 positive
Factors favoring the diagnosis of lymphoma with plasmacytic differentiation:
   1 - Adenopathy
   2 - Oropharyngeal soft tissue mass
   3 - In-situ hybridization for EBV-encoded RNA positive (but this is negative in about 40% of plasmablastic lymphoma)
   4 - HIV test positive
   5 - HHV-8 (primary effusion lymphoma or large B-cell lymphoma arising in HHV-8-associated multicentric Castleman disease)
   6 - ALK (positive in ALK large B-cell lymphoma)
   7 - Plasma cells are CD138+, but also CD19+ and CD45+


CD117 (KIT) is a useful marker in the diagnosis of plasmablastic plasma cell myeloma.
Histopathology. 2017 Jul;71(1):81-88.
Marks E, Shi Y, Wang Y.
In this study, 6 of 8 patients with myeloma were positive for CD117 (KIT), vs 0 of 8 with plasmablastic lymphoma.

Plasmablastic lymphoma versus plasmablastic myeloma: an ongoing diagnostic dilemma.
J Clin Pathol. 2017 Sep;70(9):775-780.
Ahn JS, Okal R, Vos JA, Smolkin M, Kanate AS, Rosado FG.



Giampaolo Talamo, M.D.