MGUS (Monoclonal Gammopathy of Unknown...

The paraproteinaemias

• MGUS (Monoclonal Gammopathy of Unknown Significance)

• Multiple Myeloma:

- variant: plasmocytoma (without BM involvement)

- smoldering, extramedullary

• Waldenström macroglobulinaemia

• Amyloidosis

• Heavy chain disease

Myeloma pathogenesis

• B-cell malignancy

• c-myc,RAS oncogen activation,cytokin-

deregulation (IL-6/IL-6R),suppressor-gene

mutation(p53), viral infection(HHV8)

• IL-6+IL-6R complex attaching membrane

gp130 result in induction of tyrosin

phosphorilation---and so the signal

transduction is initiated

Pathogenesis of MM

Multiple myeloma

Disease characteristics

• Monoclonal protein production /serum and

urine samples/, elevated ESR

• Lytic bony lesions( or diffuse osteoporosis)

bone pain and fractures, hypercalcaemia

●Bone marrow involvement-cytopenia

●Renal involvement mostly of lambda light

chain production

Protein electrophoresis in

myeloma

Elfo Normal/ MGUS / MM

MGUS

Characteristic laboratory alterations • Total protein 105.7 g/L H 64.0-83.0

• Albumin 27.7 g/L L 34.0-48.0

• IgG 71.59 g/L H 7.00-16.00

• IgA 0.48 g/L L 0.70-4.00

• IgM 0.27 g/L L 0.40-2.30

• Protein electrophoresis:

• M=62,89 g/L.

• A/G 0.39 - L 1.50-2.00 F

• Serum Immunfixation IgG lambda & free lambda chain

• Béta-2 mikroglobulin 8.9 mg/L H 0.9-2.0

• Kappa light chain in serum 2.91 mg/L L 6.70-22.40

• Lambda light chain in serum 1190.00 mg/L H 8.30-27.00

• Kappa Lamabda ratio in serum 0.00 - L 0.26-1.65

• Urin total protein 1379.50 mg/L H 0.00-110.00 F

• Urin total protein 1655.40 mg/24h F

• Bence-Jones protein pozitív F

• Immunfixation: monoclonal IgG lambda and free lambda chain

• We: 96 mm/h H 3-15

• RBC 3.44 Tera/L L 4.10-5.10

• Hemoglobin 97 g/L L 123-153

• Hematokrit 0.31 L/L L 0.35-0.45

MCV 91.4 fL 80.0-96.0

• Calcium 2.62 mmol/L H 2.20-2.55

• Kreatinin 61 umol/L 44-80

Rouloux formation in MM

Check the blood smear also for circulating plasma cells!

Scalp lytic lesions in MM

MM in humerus

MRI of MM involvement of vertebral

columne

Jaw lesions might happen in myeloma causing

pain / pathological fracture upon tooth extraction

Destruction of the maxilla bone

Durie Salmon classification of MM

Other prognostic Indicators in

Myeloma

• Chromosome analysis (cytogenetic testing)Assesses the number and structure of chromosomes. It is evaluable only in proliferating cells. Hypoploidity is of poor prognostic significance.

• fluorescence in situ hybridization (FISH) is a test that detects abnormalities of specific chromosomes like 13/13q- wich loss is a poor prognostic marker in MM. FISH is evaluable on interphase cells

• Lactate dehydrogenase (LDH)Measures tumor-cell burden

• Plasmablastic morphologyThe general appearance of plasma cells; increased numbers of immature plasma cells (plasmablasts) indicates poor prognosis.

Therapeutic considerations

• Overall survival: 3 yrs

1960.Gold standard : Alkeran, Prednisolon

• Others:VAD,M2,VMCP+/-Alpha interferon

From 2006.

• VEGF-INH /THALIDOMID,LENALINOMID (combination with Melphalan and prednison (response 80% 3-yr survival:74%) (side effect: neuropathy, DVT!)

• BORTESOMIB /VELCADE in combination with cyclophosphamide, melphalane, dexamtehasone ( side effect : neuropathy)

• ARSENIC TRIOXIDE

• CY/weekly, dex/monthly, low dose Thal (CR: 17%, PR: 62%)

• (OS at 2 yrs : 66%)

• ASCT( for good performance status age<65): prolongation of life: +2-3 yrs, after that inevitable recurrence of the disease.

Near future: anti CD38 Ab immunotherapy

Supportive care

• Epo

• GM-CSF

• In hypercalcaemia: bisphosphonates,

hydration, steroid

• Allopurinol

• Irradiation

• plasmapheresis

Primary amyloidosis causing macroglossia, infiltrating

salivary glands leading to their enlargement and

xerostomia

Amyloid deposition in the skin

Black-eye syndrome

Waldenström macroglobulinaemia

• IgM monoclonality: hyperviscosity

• Fever,Hepato-splenomegaly, lymphadenopathy

• Fundus paraproteinaemicus: segmentated

dilatation of the retinal veins

• Staging: bone marrow analysis, US, CT

• Therapy: plasmapheresis,

myeloma-protocols

anti-CD20 immunotherapy

Oral manifestations of Waldenstrom's macroglobulinaemia

• Gingival and mucosal bleeding

(spontaneous or postextraction)

• Mucosal ulcers

• Infiltration caused enlargement of the

salivary glands

Haevy chain disease: called according to the

secreted haevy chain

• Gamma: lgl,H,S>, fever, anemia, involvement of the

Waldeyer ring - palatum-oedema

• Alpha: Mediterranean lymphoma: small intestine lamina

propria lymphoplasmocytoid infiltration- secondary

chr.diarrhoea, weight loss,mediastinal lgl↑, antibiotic

therapy might be effective in the begining

• μ(mű): frequent association to CLL, κ (kappa) light chain

in the urine, vacuolizated lymphocytes in the smear