Plasma Cell Dyscrasias

Multiple Myeloma (MM) Definition and epidemiology

• Malignant proliferation of plasma cells producing a monoclonal Ig "M component"

• 14.600 new cases and 10,900 deaths y in U.S.; median age at diagnosis 66 y

• African-American:Caucasian ratio - 2:1

Clinical manifestations

• Anemia (normocytic) due to myelophthisis, I bone marrow production, autoimmune Ab

• Bone pain and hypercalcemia due to f osteoclast activity lytic lesions, pathologic fx

• Recurrent infections due to hypogammaglobulinemia (excluding M component)

pneumonia and pyelonephritis are the most common infections

• Renal disease: multiple mechanisms toxic effect of filtered light chains — renal failure (cast nephropathy) or type II RTA amyloidosis or light chain deposition disease -» nephrotic syndrome hypercalcemia, urate nephropathy, type I cryoglobulinemia

• Neurologic: cord compression; POEMS (polyneuropathy. Qrganomegaly.

gndocrinopathy. M protein, skin changes) syndrome

• Hyperviscosity: usually when IgM >4 g dl. IgG >5 g dl. or IgA >7 g dl

• Coagulopathy: inhibition of or Ab against clotting factor; Ab-coated platelets

• Amyloidosis (see "Amyloidosis")

Diagnostic and staging evaluation

• Criteria marrow plasmacytosis 10% (or presence of a plasmacytoma) and one of following: lytic bone lesions or M component in either serum (usually >3 g dl) or urine

smoldering MM (asx w M >3 g dl and or plasmacytosis >10%) solitary bone plasmacytoma (single lytic lesion w o marrow plasmacytosis) extramedullary plasmacytoma (usually upper respiratory tract) plasma cell leukemia (plasma cell count >2,000 jxl)

nonsecretory MM (marrow plasmacytosis & lytic lesions, but no M component)

• Ddx of M component: MM, MGUS (see below). CLL lymphoma, cirrhosis, sarcoidosis. RA

• Peripheral smear -» rouleaux; ✓ Ca. alb. Cr; 1 anion gap." globulin,! ESR

• Protein electrophoresis and immunofixation serum protein electrophoresis (SPEP): quantitates M component; © in 80% of Pts urine protein electrophoresis (UPEP): detects the 20% of Pts who secrete only light chains (= Bence Jones proteins), which are filtered rapidly from the blood immunofixation: shows component is monoclonal and identifies Ig type IgG (50%).

IgA (20%). IgD (2%). IgM (0.5%). light chain only (20%). nonsecretors (<5%) serum-free light chain assay: important test for dx and to follow treatment response

• Bone marrow biopsy

• Skeletal survey (plain radiographs) to identify lytic bone lesions and areas at risk for pathologic fracture; bone scan is not useful for detecting lytic lesions

• Staging: International (JCO 2005:23:3412) vs. Durie-Salmon System (Cancer 1975:36 842)

Stage

ISS (t (J2m most powerful independent poor prognostic factor)

32-microglobulin Albumin

1

<3.5 mg 1 and

3.5 g dl

II

3.6-5.4 mg 1 or

3.5 g dl

III

»5.5 mg 1

Any

Durie-Salmon Staging System

Stage

Criteria

Median survival

Hb >10 g dl;Ca <12 mg dl; 0-1 lytic bone lesions IgG 5 g dl or IgA <3 g dl or urine light chain - 4 g 24 h

61 mo

II

fulfilling criteria for neither 1 nor III

55 mo

Hb <8.5 g dl; Ca -12 mg dl; >5 lytic bone lesions IgG 7gdlorlgA 5 g dl or urine light chain -12 g 24 h

30 mo for IIIA 15 mo for IIIB

Subclassification by serum Cr: A 2 mg dl; B ¡=2 mg dl

Treatment (Nejm 2004.351:1860)

• Treatment not indicated for smoldering MM or asymptomatic stage I disease

• Systemic chemotherapy: T median survival, but not curative regimens include melphalan, prednisone or dexamethasone, thalidomide or lenalidomide (nejm 1999.341:1565). bortezomib (proteasome inhibitor; nejm 2003:348:2609; 200S;352:2487). or combinations melphalan »- prednisone • thalidomide if auto-HSCT not an option (Lancet 2006:367:825)

• High-dose chemo • auto-HSCT: not curative, but T survival c w conventional chemo

(nejm 1996.33S:91 & 2003:348:1875);.. offer to good candidates <70 y; + thalidomide ' response rate but no A in overall survival (NEjM 2006.3S4:1021) double auto-HSCT 1 survival, espec. if poor response to 1st auto (nejm 2003:349:2495)

• Local radiation for solitary or extramedullary plasmacytoma

• Adjunctive treatment bone: bisphosphonates (NEJM 1996:334:488). XRT for sx bony lesions renal: ovoid NSAIDs & IV contrast; consider plasmapheresis for acute renal failure hyperviscosity syndrome: plasmapheresis infections: consider IVIg for recurrent infections

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