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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

MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

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Page 1: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

The paraproteinaemias

• MGUS (Monoclonal Gammopathy of Unknown Significance)

• Multiple Myeloma:

- variant: plasmocytoma (without BM involvement)

- smoldering, extramedullary

• Waldenström macroglobulinaemia

• Amyloidosis

• Heavy chain disease

Page 2: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda
Page 3: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

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

Page 4: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

Pathogenesis of MM

Page 5: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

Multiple myeloma

Page 6: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

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

Page 7: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda
Page 8: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

Protein electrophoresis in

myeloma

Page 9: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda
Page 10: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

Elfo Normal/ MGUS / MM

MGUS

Page 11: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

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

Page 12: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

Rouloux formation in MM

Check the blood smear also for circulating plasma cells!

Page 13: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

Scalp lytic lesions in MM

Page 14: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

MM in humerus

Page 15: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda
Page 16: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

MRI of MM involvement of vertebral

columne

Page 17: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

Jaw lesions might happen in myeloma causing

pain / pathological fracture upon tooth extraction

Destruction of the maxilla bone

Page 18: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda
Page 19: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

Durie Salmon classification of MM

Page 20: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda
Page 21: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

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.

Page 22: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

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

Page 23: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda
Page 24: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

Supportive care

• Epo

• GM-CSF

• In hypercalcaemia: bisphosphonates,

hydration, steroid

• Allopurinol

• Irradiation

• plasmapheresis

Page 25: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda
Page 26: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda
Page 27: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda
Page 28: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

Primary amyloidosis causing macroglossia, infiltrating

salivary glands leading to their enlargement and

xerostomia

Page 29: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

Amyloid deposition in the skin

Page 30: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

Black-eye syndrome

Page 31: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

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

Page 32: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

Oral manifestations of Waldenstrom's macroglobulinaemia

• Gingival and mucosal bleeding

(spontaneous or postextraction)

• Mucosal ulcers

• Infiltration caused enlargement of the

salivary glands

Page 33: MGUS (Monoclonal Gammopathy of Unknown …semmelweis.hu/belgyogyaszat2/files/2016/10/20161010_FOK_EN_myeloma...(Monoclonal Gammopathy of Unknown Significance) ... • Kappa Lamabda

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