Para-proteinaemias
dr.Mousa Qasim Hussein
Assistant Professor
7th march 2016
Para-proteinaemias
A gammopathy refers to over production of one or
more classes of immunoglobulin. It may be:
Polyclonal: in association with acute or chronic
inflammation as infection sarcoidosis, autoimmune
disorders or some malignancies
Monoclonal: increase in a single Ig
class may occur in association
with or reduce level of other
immunoglobulines.
Gammopathies are detected by plasma
Immmmunoelectrophoresis ,such
monoclonal proteins also called Mproteins ,paraprotien or monoclonal
Gammopathies ,occur as a feature of
myeloma ,lymphoma, and amyloidosis.
Monoclonal gammopathy of uncertain
significance
(MGUS)
Also called benign monoclonal gammopathy
or monoclonal gammopathy unclassified
Paraprotien present in the blood but with no
other features of myeloma, Waldenstrom
macroglobulinaemia, lymphoma or related
disease.
MGUS is a Common condition
associated with increasing age
;paraprotien can be found in 1%
over 50 years, increasing to 5%
over 80 years.
Patients are asymptomatic.
Investigations:
Routine blood count and biochemistry
are normal.
Paraprotien: present in small amounts
with no immune paresis.
Bone marrow study: increase plasma
cells but these usually constitute less
than 10% of nucleated cells.
No lytic bone lesions.
Prognosis:
After follow up of 20 years ,only one
quarter will progress to myeloma or
related disorders.
 There is no way of predicting
progression in an individual patient
and if investigations remain stable,
 Annual monitoring is all that is
required.
Multiple myeloma :
This is a malignant proliferation of plasma cells.
Normal plasma cells are derived from B cells and
produce immunoglobulins which contain heavy and
light chains. Normal immunoglobulins are polyclonal,
which means that a variety of heavy chains are
produced and each may be of kappa or lambda light
chain type .
In myeloma, plasma cells
produce immunoglobulin of
a single heavy and light chain, a
monoclonal protein commonly
referred to as a paraprotein. In
some cases only light chain is
produced and this appears in the
urine as Bence Jones proteinuria.
Classification of multiple myeloma :
According to the frequency of different
paraprotien type:
IgG
55%
IgA
21%
Light chain only
22%
Other(D,E,Non secretory) 2%
Pathology
The majority of plasma cells present in the
bone marrow .
These cells produce cytokines ,which
stimulate ostioclasts and result in bone
absorption .the resulting lytic lesions cause
bone pain ,fractures and hypercalcaemia .
Marrow involvement can result in anaemia
and pancytopenia .
Clinical features:
Incidence is 4/100000 new cases per year .
Male:femle ratio 2/1
Age 60-70 years
The clinical manifestations arise from :
1-Presence of malignant plasma cells in the
bone marrow.
2-Effects of monoclonal proteins in the blood
or urine .
3-Immunologic deficiencies caused when
the Ig production by remaining plasma cells
is inadequate.
4-Hyperviscosity:fewer than10%of patients
,paraprotiens,usually IgA,forms polymers causing
hyperviscosity producing decreased visual acuity,
bleeding and neurological manifestations such as
dizzness,headache ,confusion, vertigo and ataxia.
5-Excess light chain may result in Amyloidosis
manifested by carpal tunnel syndrome and proteinurea .
6-Renal failure: caused by:
a-formation in the renal tubeulesof casts consisting of
Ig and free light chain
Bence-Jonce protein).
b-M-protien can cause glomerular damage
c-Intravascular volume depletion due to polyurea and
vomiting.
7-anaemia :normochromic normocytic
,occasionally macrocytic.
8-Increased susceptibility to infections
specially strept.pneumonia,hemophilus
infuenzae due to decreased normal Ig
production.
9-tumours of plasma cells can also form
outside the marrow (extramedullary
plasmacytoma) presenting as a mass in
the skin, lymph nodes, liver, spleen and
other locations
Diagnosis: requires two of the following
criteria:
1-Increased malignant plasma cells in the bone marrow.
2-Serum and or urinary paraprotein.
3-skletal lytic lesions.
Investigations
1-Blood film morphology:
Anaemia, normochromic normocytic.occasionlly
macrocytic
Leukoerythroplastosis ,nucleated erythrocytes and
immature granulocytes Sometimes present.
Paraproteinaemia can cause an elevated ESR , but this is a
non-specific test; only approximately 5% of patients with
a persistently elevated ESR above 100 mm/hr have
underlying myeloma.
2-Bone marrow aspirate and trephine biopsy:
Plasma cells in the marrow.
.
The cells bear characteristic morphologic features of plasma cells,
round or oval cells with an eccentric nucleus composed of coarsely
clumped chromatin, a densely basophilic cytoplasm, and a
perinuclear clear zone containing the Golgi apparatus. Binucleate
and multinucleate malignant plasma cells.
Plasma cells
Myeloma cells
3-Blood and urine Immmmunoelectrophoresis :
Presence of urine or plasma paraprotien.
4-Quatificationof paraprotien:
Amount of paraprotien.
5-Plasma Immunoglobulin :
Degree of immune paresis
6-Urea,creatinine,electrolytes,ureate:
Renal function.
7-Blood calcium,Albumine:
Presence of hypercalcaemia.
8-Bleeding time,coagulation screen:
Degree of haemostasis.
9-MRI spine:
Spinal cord compression.
10-X-RAY(skeletal survey) +Alkaline phosphatase:
Presence of lytic lesion , bone fractures
In the absence of fractures, the plasma alkaline phosphatase
and isotope bone scan will be normal despite the lytic
lesions.
Points to note in the diagnosis
1-Plasma alkaline phosphatase and bone scan are
normal in absence of fractures or bone repair.
2-Serum B2-microglobuline estimations may
provide a useful assessment of prognosis.
3-Normal Ig levels,i.e,absence of immune paresis,
should cast doubt on the diagnosis.
4-Only 5%of patients with an ESR persistently
above 100 mm/hr have myeloma.
Management:
If patients are asymptomatic ,treatment may not
be required .otherwise treatment consist of :
1-Immediat support :
a-High fluid intake to treat renal impairment
and hypercalcaemia.
b-Analgesia for bone pain.
c-biphosphonates for hypercalcaemia and to
delay other skeletal related events.
d-Allopurinol to prevent urate nephropathy.
e-Plasmapharesis ,as necessary for
hyperviscosity.
2-Chemotherapy:
Myeloma therapy has improved with the
addition of novel agents, initially thalidomide
and more recently the proteasome inhibitor
bortezomib, to first-line treatments.
In older patients, thalidomide combined with the
alkylating agent melphalan and prednisolone has
increased the median overall survival to 51 months.
Thalidomide has both anti-angiogenic effects against
tumour blood vessels and immunomodulatory effects.
It can cause somnolence, constipation
and a peripheral neuropathy.
It is vital that females of child-bearing
age use adequate contraception, as
thalidomide is teratogenic.
Treatment is administered until
paraprotein levels have stopped
falling. This is termed 'plateau phase'
and can last for weeks or years
In younger, fitter patients, standard
treatment includes first-line chemotherapy to
maximum response and then an autologous
HSCT, which improves qualityof life and
prolongs survival but does not cure
myeloma.
The role of allogeneic transplantation and of
reduced-intensity allografting after
autologous transplantation in younger
patients is under
evaluation
3-Radiotherapy:
Effective for localized bone pain not
responding to simple analgesia and for
pathological fractures.
Emergency treatment of spinal cord
compression complicating extradural
plasmacytomas.
4-Biphosphonates:
Long term biphosphonate therapy,as
pamidronate,Clodronate ,Zoldronate ,reduces bone pain and
skeletal events
These drugs protect bone and may cause apoptosis of
malignant plasma cells. Osteonecrosis of the jaw may be
associated with long-term use; therefore regular dental
review is advisable.
Prognosis
The international staging system (ISS) identifies
poor prognostic features, including
a high β2-microglobulin
and low albumin at diagnosis (ISS stage 3, median
survival 29 months).
Those with a normal albumin and a
low β2-microglobulin (ISS stage 1) have a median
survival of 62 months.
use of autologus HCST and
advances in drug therapy have
increased survival, with over onethird of patients now surviving for 5
years, compared with only onequarter 10 years ago.
The outlook may improve further
with new drugs and combinations
of treatments.
WALDENSTROM
MACROGLOBULINAEMIA:
This is a low- grade lymphoplasmacytoid
lymphoma associated with an
IgMparaprotien causing clinical features of
hyperviscosity syndrome .
It is rare tumor occurring in elderly ,slight
male excess.
Clinical features:
Classical presentation: features of
hyper viscosity such as
nosebleeds,bruising,Confusion
and visual disturbance.
Patients may present with
anaemia,systemic symptoms,
Splenomegay
orLymphadenopathy.
Investigations:
1-Plasma electrophoresis:IgM
paraprotien.
2-Plasma viscosity: Increased.
3-Bone marrow aspirate: infiltration
of lymphoid cells and prominent
mast cells.
Waldenstrom macroglobulinemia
Increased lymphocytes, occasional plasma cells and a mast cell
Management:
Sever hyperviscosity and
anaemia may necessitate
plasmaphresis to remove IgM
and make blood transfusion
possible.
Chlorambucil orally is effective
,fludarabine may be more active
.Median survival is 5 years.