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 M-proteins ,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 one-third of patients now surviving for 5 years, compared with only one-quarter 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.