Epidemiology

• 12,000 deaths in United States per year• Median age of diagnosis is 65 years• Two-fold more common in African-Americans

than Caucasians• Higher incidence in men than women• Median survival is three years

Diagnosis

• CBC, CMP, Uric Acid• SPEP, UPEP, Immunofixation• Quantitative Ig’s• Skeletal survey• Bone marrow aspirate and Trephine biopsy• Cytogenetics

Diagnostic Criteria

Durie and Salmon

1. Major criteria-- >30% plasma cells in BM or biopsy proven plasmacytoma, M spike of >3.5 IgG, 2.0 IgA or >1 g/24h in urine 2. Minor criteria-- BM with 10-30% plasma cells, M-component of serum or urine less than

above, lytic lesions, Normal IgM <500 mg/L, IgA<1g/L and IgG<6g/L

Need at least one major and one minor or three minor including +BM and M spike.

Classical Diagnostic Features of Myeloma

• Plasmacytosis in marrow• Monoclonal protein in serum or urine• Lytic disease of bone

Marrow Plasmacytosis in Myeloma

• Plasma cells > 10%• Usually much higher• Often present in ‘sheets’• Alternatively, biopsy-proven plasmacytoma• Other causes of plasmacytosis:

inflammation, cirrhosis, AIDS

Diagnosis of Myeloma: Monoclonal Proteins

• 75-80% have serum monoclonal Ig(M-component, paraprotein, or ‘spike’ on electrophoresis)

• 10-20% make light chains only → rapid renal excretion → serum paraprotein absent→ do urine electropheresis

• Non-secretory myeloma rare (<1%)• Other causes of monoclonal proteins

CLL, lymphomaAutoimmune disease, infectionBenign monoclonal gammopathy

Bone Disease in Myeloma

• Unbalanced osteoclast activity• Radiographic manifestations

- Osteoporosis almost invariable- Usually multiple lytic lesions- Axial skeleton involved (active

marrow)- Osteoblastic reaction minimal

• Hypercalciuria and hypercalcemia

Benign Monoclonal Gammopathy

• Monoclonal Ig as isolated finding• More common than myeloma• No bone disease, anemia, renal dysfunction• Most remain stable• About 10% eventually develop classical

myeloma

Clinical Features of Myeloma at Presentation

• Early – asymptomatic, incidental diagnosis

Paraprotein on electropheresisMild marrow plasmacytosisSolitary plasmacytoma (10% of cases)

• Late – symptomaticBone pain (usually lower back)Pneumococcal infectionSystemic symptoms (e.g. weakness, weight loss)

Related to anemia, renal failure, hypercalcemia

Hyperviscosity Syndrome

• Due to aggregating paraprotein• Pathogenesis

- Circulatory insufficiency, abnormal hemostasis

• Manifestations- Bleeding- Dyspnea (congestion on CXR)- Encephalopathy and visual disturbances

Immunological Features of Myeloma

• Monoclonal Ig and/or monoclonal light chain• ↓ levels of normal Ig’s (functional

hypogammaglobulinemia)• Cellular immune responses usually preserved • Bacterial infections common

Early: S pneumoniaeLate: S aureus, Gram negative rods

Amyloidosis in Myeloma

• Due to light chain deposition in tissues• Incidence: λ amyloid > K amyloid • Organs commonly involved:

SkinTongue and GIHeartPeripheral nervesKidneysSoft tissues

• No effective therapy, except ? Stem cell transplant

Therapy for Myeloma

• Biphosphonates (pamidronate, zoledronate)

• Radiotherapy• Conventional dose chemotherapy

Alkylators and corticosteroidsThalidomide

• Myeloablative therapy and stem cell transplantation

Autografting → survival improved, but relapse inevitableAllografting → cure is possible, but

transplant-related mortality is high

MyelomaMyeloma MGUSMGUS

Bone marrow plasma cellsBone marrow plasma cells >10% on aspirate>10% on aspirate <10% on aspirate<10% on aspirate

Serum paraproteinSerum paraproteinVariable concentration in serum:Variable concentration in serum:

no specific diagnostic levelsno specific diagnostic levels

IgG usually IgG usually <20 g/l<20 g/l

IgA usually IgA usually <10 g/l<10 g/l

Bence-Jones proteinuriaBence-Jones proteinuria >50% cases>50% cases RareRare

Immune paresisImmune paresis >95% cases>95% cases RareRare

Lytic bone lesionLytic bone lesion Often presentOften present AbsentAbsent

SymptomsSymptoms FrequentFrequent AbsentAbsent

AnaemiaAnaemia FrequentFrequent AbsentAbsent

HypercalcaemiaHypercalcaemia May be presentMay be present AbsentAbsent

Abnormal renal functionAbnormal renal function May be presentMay be present Absent Absent

Differential diagnosis of myeloma and monoclonal Differential diagnosis of myeloma and monoclonal gammopathy of undetermined significance (MGUS)gammopathy of undetermined significance (MGUS)

• Stage I—Hb>10. Ca<12. NI bones or solitary plasmacytoma of bone only. Low M-component production (IgG<5, <4g/24 hours) urine light chain.

• Stage II—Not I or III• Stage III-Hb<8.5, Ca>12. Advanced lytic

lesions. High M-component production.

Staging Subclassification

• A = Cr<2 • B= Cr>2 • Prognosis also predicted adversely by high

Beta 2 microglobulin, chr 13 deletions

Indications for Therapy

• Management of symptomatic myeloma or radiographic evidence of bone disease

• Chemo is not indicated for MGUS, or indolent myeloma

• Two randomized controlled trails have shown no benefit to early intervention