Multiple Myeloma

• Definition:

B-cell malignancy characterised by abnormal proliferation of plasma

cells able to produce a monoclonal immunoglobulin (M protein)

• Incidence:

3 - 9 cases per 100000 population / year

more frequent in elderly

modest male predominance

Multiple myeloma

Multiple Myeloma

Multiple Myeloma

Clinical symptoms:

• bone pains, pathologic fractures• weakness and fatigue • serious infection • renal failure• bleeding diathesis

Multiple Myeloma

Laboratory tests:• ESR > 100• anaemia, thrombocytopenia• rouleaux in peripheral blood smears• marrow plasmocytosis > 10 %• hyperproteinemia• hypercalcemia• proteinuria

Multiple myeloma INITIAL DIAGNOSTIC WORKUP

2011

Diagnostic Criteria for Multiple Myeloma (old)

Major criteria

I. Plasmacytoma on tissue biopsy

II. Bone marrow plasma cell > 30%

III. Monoclonal M spike on electrophoresis IgG > 3,5g/dl,

IgA > 2g/dl, light chain > 1g/dl in 24h urine sample

Minor criteria

a. Bone marrow plasma cells 10-30%

b. M spike but less than above

c. Lytic bone lesions

d. Normal IgM < 50mg, IgA < 100mg, IgG < 600mg/dl

Diagnostic Criteria for Multiple Myeloma

Diagnosis:

• I + b, I + c, I + d • II + b, II + c, II + d• III + a, III + c, I II + d• a + b + c, a +b + d

Multiple Myeloma

Diagnostic Criteria for Multiple Myeloma (present)

–Plasmocytosis >= 10% and/or plazmocytoma infiltration

–M protein

– Myeloma related damage (CRAB)

Diagnostic Criteria for Multiple Myeloma (present)

• C (Calcium) (> 2,75 mmol/l)

• R (Renal Insufficiency) creatinine concentration >173 mmol/l (1,96 mg/dl)

• A (Anemia) Hg <10 g/dl

• B (Bone lesions)

Monoclonal gammopathy of undetermined significance ( MGUS)

• M protein present, stable

• levels of M protein: IgG < 3,0g IgA < 2g LC<1g/day

• normal immunoglobulins - normal levels

• marrow plasmacytosis < 10%

• complete blood count - normal

• no lytic bone lesions

• no signs of disease

Smouldering multiple myeloma

• M protein present, stable

• levels of M protein: IgG 3,0g IgA 2g LC 1g/day

• normal immunoglobulins - normal levels

• marrow plasmacytosis 10%

• complete blood count - normal

• no lytic bone lesions

• no signs of disease

Staging of Multiple Myeloma

Clinical staging (Salmon-Durie) • is based on level of haemoglobin, serum

calcium, immunoglobulins and presence or not of lytic bone lesions

• correlates with myeloma burden and prognosis I. Low tumor mass II. Intermediate tumor mass

III. High tumor mass• subclassification

A - creatinine < 2mg/dlB - creatinine > 2mg/dl

ISS (International Staging System for multiple myeloma)

Stage MOS (months)

I β2 microglobulin < 3,5 mg/l and albumins > 3,5 g/dl

62

II No criteria for I and III 44

III β2 mikroglobulin >5,5 mg/l 29

MM treatment

• Thalidomide

– TNF-α inhibitor

– b-FGF and VEGF2 inhibitor (antiangiogenic factor)

– Apoptosis promotion ( NF-κB )

– Induktion of Th1 activity with production of IFN-γ i IL-2)

MM treatment

• MP („gold standard” )• Melfalan 9 mg/m2 po 1-4 day every 6 weeks • Prednison 60 mg/m2 po 1-4 day every 6

weeks• Up to 9 cycles

– OR (CR+PR+MR) 47%– OS 32 months – Infections (3 i 4 NCI grade) 18%

MM treatment

• Bortesomib

– Reversible proteasoms’ inhibitor

– NFκB inhibitor (promotes apoptosis)

– registered for 2nd and 3rd line

Multiple myeloma diagnosis

Pt qualified for auto PBSCT (younger than 65) Older than 65

or not qualified for PBSCT

MelphalanPrednisone

Thalidomide

Thalidomide Dexamethasone

Mobilization chemotherapy and collection of stemm cells

Melphalan 200 mg and PBSCT

Thalidomide as sustaining treatment ?

Thalidomide as sustaining treatment ?

Treatment of Multiple Myeloma

Event-free and overall survival times of 515 patients receiving autotransplants and a median follow-up of at least 5 years.

Treatment of Multiple Myeloma

• New methods– Non-myeloablative therapy and allogeneic

transplantation– Tandem transplants– Bortesomib (proteasome inhibitor)– Lenalidomide– Arsenic trioxide – Statins

Treatment of Multiple Myeloma

• Supportive treatment– biphosphonates, calcitonin– recombinant erythropoietin– immunoglobulins– plasma exchange – radiation therapy

2011

Disorder Associated with Monoclonal Protein• Neoplastic cell proliferation

– multiple myeloma– solitary plasmacytoma– Waldenstrom macroglobulinemia– heavy chain disease– primary amyloidosis

• Undetermined significance– monoclonal gammopathy of undetermined

significance (MGUS)• Transient M protein

– viral infection– post-valve replacement

• Malignacy– bowel cancer, breast cancer

• Immune dysregulation– AIDS, old age

• Chronic inflamation