The document discusses plasma cell myeloma, a neoplastic proliferation of plasma cells producing monoclonal immunoglobulin, primarily affecting individuals over 50 years old. It covers the clinical features, laboratory findings, and diagnostic techniques associated with the disease, as well as treatment options including chemotherapy and bone marrow transplantation. The text emphasizes the complexity of diagnosis and the importance of various tests and imaging studies in managing multiple myeloma.

1. PLASMA CELL DISORDER
PART II
Presented by- Dr. Rajani Rajkumari
Coordinator- Dr. Rajendra Malav Sir

2. PLASMA CELL MYELOMA
• Defined as neoplastic proliferation of plasma cells accompanied by
the production of a monoclonal Ig detectable in the serum & urine
• SYNONYMS:
– MULTIPLE MYELOMA
– MYELOMATOSIS
– MEDULLARY PLASMACYTOMA
– KAHLER’S DISEASE
• Equal in men & women(1:1 )
• 90% of case occurring over age 50yrs, median age at diag.is 70yrs
• 3.7 fold higher risk for first degree relative

3. AETIOLOGY
 AETIOLOGY: is unknown.
 Risk factors include exposure to
1. Pesticides and herbicides (in farm workers)
2. Ionising radiation
3. Prolonged use of hair colouring
agents(cosmetologists)
4. Chronic antigenic stimulation

4. PATHOGENESIS

6. MM: CLINICAL FEATURES
The hallmark feature of MM are highlighted by CRAB acronym
 (1) Due to Bone lesions- pain, tenderness, pathological fracture.
Bones involved are ribs, skull, pelvis, spine , scapula and
sternum.
MM cell secretes
IL-6 CXCL-12
Osteoclastic proliferation
Lytic bone changes
Increased osteoclastic mobility
and bone resorption
Lytic lesions in bone

8. CLINICAL FEATURES Contd…
(2) Due to neurological dysfunction-spinal cord/
root compression results in sensory and motor
loss and loss of bowel and bladder control.
(3) Due to renal disease- myeloma cells infiltrates
renal parenchyma along with blockage of renal
tubules by casts as well as hypercalcemia due to
osteolysis result in nephrocalcinosis, thus
contributing to renal failure.
(4) Infections
(5)Pallor

9. CLINICAL FEATURES Contd…
(6)Due to M protein -hyperviscocity affects CNS ,
retina and CVS resulting in headache, dizziness,
confusion,visual disturbance, retinopathy. Paraplegia
may also occur.
(7) Bleeding tendency
(8) Coagulation abnormalities
(9) Amyloidosis
(10)POEMS syndrome- Polyneuropathy,
Organomegaly, Endocrinopathy, M-band and Skin
changes.

13. LABORATORY FINDINGS
1. PBF
RBC –Anemia is normocytic normochromic with rouleaux
formation of RBCs with background of basophilic staining
due to high globulin levels. Hemoglobin of <10 gm/dl
attribute to plasma cell proliferation, is taken as anemia of
end organ damage.
WBC- In later stages, neutropenia develops due to replacement
of hemopoietic islands by myeloma cells. Plasma cells >20%
of the DLC or >2000 /cumm is suggestive of plasma cell
leukemia.
Platelet count-Thrombocytosis may observed in some patient
due to effect of IL6.

15. 2. BONE MARROW
 Bone marrow is hypercellular to normocellular.
Number of plasma cells is not very high. Marrow
is infiltrated by myeloma cells.
Myeloma cells-The hallmark of myeloma is the
increase in monoclonal plasma cells which vary
from 10% to 90%. According to IMWG 2014,
clonal plasma cells >10% is diagnostic, provided
at least one biologic markers of malignancy is
present.

17. Marrow aspirate showing sheets of plasma cells with eccentric nuclei ,
basophollic cytoplasm, many cells show prominent nucleoli suggesting
immaturity of plasma cells

18. BM aspirate smear demonstating immature plasma cells with open nuclear
chromatin and prominent nucleoli. Cytoplasm is basophilic with perinuclear hof.

19. Bone marrow aspirate smear of plasmablastic myeloma which shows
large cells with reticular nuclear chromatin and 1-2 prominent nucleoli. In
majority of the cells, the nucleus is central and cells appear blastoid.

20. Russel bodies- Accumulated immunoglobulins in the
cytoplasm of plasma cells which are small and spherical.
Mott cell – Plasma cell crowded with Russel bodies .

21. Dutcher bodies –intranuclear inclusions of
immunoglobulins that represent cytoplasmic invaginations
into nuclei

22. Flame cells- Here, cytoplasm show flaming/flame-
shaped with peripheral free border showing orange-
red color ( glycogen rich and IgA secreting)

23. 3 .BONE MARROW BIOPSY
Bone marrow biopsy is of particular importance in-
(1) Asymptomatic multiple myeloma ( smoldering multiple
myeloma ), where the plasma cells are few in bone marrow
aspirate and is not diagnostic. BM biopsy reveals tiny foci
of plasma cells in the marrow. Immunoperoxidase or
immunofluorescent techniques can be applied using
antibodies to κ or λ chain to demonstrate monoclonality.
Neoplastic plasma cells will show either κ or λ chain
positivity, while reactive plasma cells are positive for both
κ and λ light chains in a balanced proportion.

24. BONE MARROW BIOPSY
CONTD…
(2) Myeloma cases with hypocellular marrow with
inadequate marrow aspirate.
(3)Myeloma associated fibrosis in which aspirate is
usually a dry tap.
(4)Congo red staining on the marrow biopsy section
helps in picking up cases of amyloidosis.
(5)More useful due to larger amount of tissue is
sampled and myeloma cell infiltration is made out.
(6)BM necrosis in MM yields a dry tap and the biopsy
is diagnostic, if plasma cells are present.

25. Reticulin deposition / Fibrosis in MM
Reticulin deposition is seen in 20-25% cases as coarse
fibrils amongst plasma cells and is associated with worse
prognosis

26. Infiltration pattern of MM
1) Interstitial
Myeloma cells are dispersed amongst fat and hemopoietic cells of
the bone marrow and the tumor load is low. CD138 expression
on myeloma cells confirms interstitial pattern.

27. 2) Focal /nodular
Myeloma cells form nodules ,but the marrow architecture is
intact

28. 3) Packed marrow
Myeloma cells replace the normal hemopoietic cells and are
present in sheets. The hemopoietic reserve is decreased
significantly and patients present with cytopenias

29. 4) Paratrabecular pattern and angiogenesis
Myeloma cells are present along the left
border of bony trabeculae (a rare pattern),
while the right half of the picture shows
normal hemopoietic cells.
Increase neovascularization
(demonstrable with CD34) of marrow
is associated with worse prognosis

30. Bone alterations
There is thinning of bony trabeculae with increased osteoclastic
resorption of bone, resulting in characteristic lytic lesions on
X-ray.
4. IMMUNOPHENOTYPE
 Flow cytometry is useful for diagnosis and monitoring of MM
abnormal plasma cells which are-
Positive for CD38, CD138, CD56 (expressed in 70 to 80% cases
and associated with poor prognosis) , Cytoplasmic kappa or
lambda.
Negative for CD19, CD20, CD45, CD27, CD22 and surface
light chain.

31. 5. PLASMA CELL LEUKEMIA
It is defined as >20% plasma cells in peripheral blood or absolute
plasma count of >2×109
/L. It is an aggressive disease with a
fulminant course and short survival. There are 2 variants-
Primary PCL- A de novo disease with no previous evidence of
MM. Lack of aberrant CD56 expression.
Secondary PCL- Leukemic trasformation of MM.
Clinical features of primary and secondary PCL-
 Extramedullary lesion
 Hepatosplenomegaly
 Anemia
 Thrombocytopenia
 Impaired renal function

32. 6. Free light chain assay
 Measuring kappa and lambda ratio, normal is 0.26 to1.65
 <0.26 show monoclonal lambda free light chain
 >1.65 show monoclonal kappa free light chain
 Use for diagnosis, prognostication and monitoring treatment
response of MM patients.
7. Cryloglobulins
8.Bence jones protein in urine
9. Imaging studies –CT scan, MRI, Bone scan, PET scan .
10. Cytogenetics in MM- poor prognosis associated with
monosomy 13, loss of 13q14, Del 13q ,Del 11q, t 4p16, t16q23
and t(11;14)

33. 12. Other tests
 Serum calcium- hypercalcemia >11mg/dl
 Serum albumin- for staging/prognosis
 Serum β2 microglobulin – for cardiac status.
 Serum troponin T
 ECG, Echocardiogram
 Kidney function test –for staging and prognosis
-S. Creatinine
-S. Uric acid
-Creatinine clearance
 24 hr urine sample for protein electrophoresis and M-protein

34. DIFFERENTIAL DIAGNOSIS
 Reactive plasmacytosis
 Monoclonal gammopathy of
undetermined significance(MGUS)
 Waldenstrom macroglobulinemia
 Metastatic deposits in BM

35. 1)Reactive bone marrow plasmacytosis
 Marked plasmacytosis in bone marrow, mostly occurs
in autoimmune disorders, chronic inflammatory
conditions, viral infections, Hodgkins lymphoma and
HIV infections.
 Mature plasma cells are seen in single or in small
group around blood vessels .
 Polyclonal hypergammaglobunemia
 Normal kappa to lambda ratio.
 Immunophenotype-CD38(bright)+,CD138((bright)
+,CD19+,CD45+, both kappa and lambda light chain
+

36. 2) Monoclonal gammopathy of
undetermined significance(MGUS)
 The presence of monoclonal protein in serum
without clinical or laboratory manifestation to
underlying plasma cell disorder or
lymphoproliferative disease.
 Two type of MGUS are distinguished:
1. IGM- MGUS(15%)
2. NON IGM- MGUS(85%)

37. 3) Waldenstrom’s macroglobunemia
 M>F
 BM show neoplastic proliferation of
lymphoplasmacytic cells which are CD20+ with
secretion of IgM.
 Fatigue ,weakness, weight loss are common
symptoms.
 Macroglobulin increase blood viscocity that lead to
hyperviscocity syndrome.
 Physical examination- organomegaly present

38. Treatment of Multiple Myeloma
 Conventional chemotherapy
 BM transplantation
◦ Survival is more
 Supportive treatment
◦ Recombinant erythropoietin
◦ Immunoglobulins
◦ Plasma exchange
◦ Radiation therapy