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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