Multiple Myeloma and

Related Disorders

Kumar Rajagopalan

Outline

• Biology• Plasma Cell Dyscrasia

– MGUS– Plasmacytoma

• Multiple myeloma– Smoldering– POEMS

• Waldenstrom’s Macroglobulinemia• Amyloidosis

The Continuum of Plasma Cell Disorders

Normal MGUS Indolent Multiple Myeloma Myeloma

Myeloma, Malpas et al. 2004

• The hallmark of plasma cell disorders is the presence of a paraprotein in the serum and/or urine.

Paraproteinemias

• Normal immunoglobulin pattern – Polyclonal reflects progeny of different

plasma cells

• Paraproteinemia– Monoclonal immunoglobulin band in sera

reflects synthesis from single plasma cell clone

SPEP

Polyclonal Gammopathy

MonoclonalGammopathy

Normal Immunoelectrophoresis

Presentation of Plasma Cell Disorders

• Increased protein on a routine chemistry panel

• Anemia

• Bone pain

• Renal dysfunction

• Hypercalcemia

Pathophysiology: Monoclonal B-Cells/Plasma Cell Dyscrasia

• Marrow replacement– Cytopenias– Constitutional symptoms

• Decreased quantitative immunoglobulins– Infections

• Lytic bone lesions– Fractures– Hypercalcemia

• Extramedullary involvement– Plasmacytomas– Organomegaly

Pathophysiology: Monoclonal Immunoglobulin Proteins

• Heavy chains or Light chains in serum, urine, kidney or other tissues– Renal insufficiency– Neurologic disease– Hyperviscosity– Cold Agglutinin disease– AL Amyloidosis– POEMS: Polyneuropathy, Organomegaly, Endocrine

disturbances, M-protein, Skin changes

MGUS: Monoclonal Gammopathy of Undetermined

Significance

MGUS

• Diagnosis– Serum M-protein

• Usually IgG or IgA, usually <3 g/dL• Stable over time

– Marrow plasma cells <10%– No lytic bone lesions, unexplained anemia,

hypercalcemia, or renal insufficiency

• Incidence– 1-2% of adults– Increases with age

• 6% aged 62-79 y/o, 14% >90 y/o

NEJM 2002;346:564. Kyle ASH 2002 #384.

MGUS Progression

• 1384 patients at Mayo• MGUS: 1% per year progression

– Relative risk 25x (myeloma), 46x (Waldenstrom’s), 8.4x (amyloid), 2.4x (lymphoma)

• IgM MGUS: 1.5% per year• Predictors

– Size of M-spike (> 2.5 g/dL, 41% at 10 yr)

– Serum albumin

NEJM 2002;346:564

MGUS Progression: 1% per Year

MGUS: Management

• Testing– CBC, calcium, creatinine, SPEP with

immunofixation, quantitative immunoglobulins, 24-hour urine protein (with UPEP and immunofixation if positive)

– If M-protein 2-3 g/dl, add bone marrow and skeletal survey

• F/U– SPEP/H&P repeated in 6 months, then annually

Multiple Myeloma and Related Disorders

• Definition:

A group of diseases that involve malignant proliferation of Ig-secreting cells of B-cell lineage that are usually associated with paraproteinemia or paraproteinuria.

Multiple Myeloma

• US Incidence: 15,000 new cases/year– 1% of malignancies

• US Prevalence: 65,000 cases/year• Double incidence rate in African Americans• Median age 65

– 3% <40 years old

• Unknown cause– Radiation, benzene, solvents, pesticides, insecticides

Etiology

• Etiology is not known.

• Risk factors: Race, sex.

• Increased risk with ionizing radiation and exposure to pesticides like Dioxin.

• Recently viruses like HHV-8 and SV-40, have been linked to myeloma development.

Pathogenesis

• Bone marrow microenvironment very important for proliferation and chemotherapy resistance.

• BM stromal cells produce IL-6, responsible for pathogenesis and progression.

• IL-6 inhibits apoptosis of plasma cells.• IL-6 contributes to bone loss by stimulating

osteoclasts and inhibiting bone formation.• Interaction with extracellular matrix proteins

protect cells from chemo and radiation.

MM: Clinical Features

• Disease of the elderly (7th decade)

• Bone pain – most commonly vertebra and long bones– lytic lesions– fractures

Multiple Myeloma Typical “Punched Out” Lesions

Multiple Myeloma

Multiple Myeloma Diagnosis(1 major+1 minor or 3 minor)

• Major Criteria– Plasmacytoma on

tissue biopsy

– 30% Marrow plasmacytosis

– M-protein• 3.5 g/dL IgG

• 2 g/dL IgA

• 1g/24 hr urine Bence Jones

• Minor Criteria– 10-29% Marrow

plasmacytosis

– M-protein• Less than major

– Lytic bone lesions

– Low immunoglobuins• IgM <50 mg/dL

• IgA <100 mg/dL

• IgG <600 mg/dL

Kyle, Mayo Clin Proc, 2003.

Newly Diagnosed Multiple Myeloma: 1985-1998

• N=1027• Median age: 66 years• Median survival: 33 months

– Did not improve 1985 through 1998

• Multivariate analysis– Age, plasma cell labeling index,

thrombocytopenia, serum albumin, creatinine (log value)

Kyle, Mayo Clin Proc, 2003.

Newly Diagnosed Multiple Myeloma: 1985-1998

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Ca Cr >2 Anemia Skel Surv UPEP SPEP

Myeloma Diagnostic Work-Up

• SPEP and UPEP (24 collection) with immunofixation– 3% nonsecretory: check serum free light chains

• Skeletal survey (not a bone scan)• Quantitative serum immunoglobulins (IgA, IgG,

IgM)• Bone Marrow Aspirate and Biopsy

• Other tests (calcium, creatinine, beta-2 microglobulin, CRP, albumin, plasma cell labeling index, etc, etc) are only for staging/prognosis

M-Protein Tests

• Urine Dipstick not sensitive to Bence Jones proteins, need sulfosalicylic acid (SSA)

• Screening (SPEP/UPEP)– Gamma-globulins

• Polyclonal gammopathy: liver disease, connective tissue disease, chronic infection, others

• Hypogammaglobulinemia: Immunodeficiency, nephrotic syndrome (amyloidosis), myeloma/CLL

• Monoclonality– Immunofixation with monospecific antibodies– Immunoelectrophoresis– Immunoassay for serum free light chains (Mayo Clinic)

Myeloma Prognostic Work-Up

• Hemoglobin• Calcium• Serum creatinine• Beta-2 microglobulin• Albumin• Bone Marrow cytogenetics

– FISH chromosome 13 and 11?

• C-reactive protein??• Plasma cell labeling index??• Serum IL-6??

Myeloma Renal Disease

• “Myeloma kidney”– Normal glomerular function

– Concentrated light chains precipitate in tubules

– Monoclonal light chains seen in UPEP with immunofixation

• Glomerular lesions– Deposits of amyloid or light chain deposition disease

– Nonselective leakage of all serum proteins

– UPEP preponderance of albumin

Renal Manifestations

Amyloidosis

Light chain Deposition

Pierre Ronco JNEPHROL 2000; 13 (suppl. 3):

Myeloma Kidney Cast Formation

Pathology

Myeloma: Durie-Salmon Staging

Stage I• Hemoglobin >10 g/dL

• Normal calcium

• No lytic bone lesions

• Low M-protein

– IgG <5 g/dL

– IgA <3 g/dL

– Bence Jones <4 g/24h

Stage II (not Stage I/III)

Stage III• Hemoglobin <8.5• Calcium >12 (adjusted)• >3 lytic bone lesions• High M-protein

– IgG >7 g/dL– IgA >5 g/dL– Bence Jones >12 g/24h

A) Creatinine <2B) Creatinine >2

Myeloma: Median Survival

Durie-Salmon stage

Stage I 60 months

Stage II 40 months

Stage III 15 months

International Myeloma Working Group Staging System

Stage 2Microglobulin Albumin

I < 3.5 > 3.5

II <3.5

3.5 – 5.5

<3.5

any

III

> 5.5

any

Kyle, Mayo Clin Proc, 2003.

Therapy of Newly Diagnosed Multiple Myeloma: 1985-1998

Myeloma: Therapy Principles

• Observation for stage I• Incurable despite conventional chemotherapy and

high-dose therapy• Bisphosphonates• Chemotherapy

– Conventional– High-dose with stem cell rescue– New agents

• Graft-versus-myeloma

Myeloma: Therapy

• Alkylating agents– Melphalan: low-dose oral to high-dose myeloablative

• Steroids– Alone (pulse Dexamethasone) or combination (M&P, VAD,

Thal/Dex)

• Cyclophosphamide• Thalidomide and the IMiD’s• Bortezomib (Velcade): proteosome inhibitor• Graft-versus-myeloma effect

– Mini-allogeneic transplantation

• Interferon: maintenance

Therapy of Multiple Myeloma

• Chemotherapy– pulse dexamethasone

– pulse dexamethasone+ thalidomide

– pulse dexamethasone +lenalidomide (revlimid)

– pulse dexamethasone + bortezimib (velcade)

– melphalan+prednisone + imid (not transplant candidate)

• Autologous stem cell transplant• Radiation

Kyle, R. A. et al. N Engl J Med 2004;351:1860-1873

Major Classes of Drugs Used in the Treatment of Myeloma

NEJM 2003; 348: 1875.

Autologous Transplantation

Myeloma: Supportive Therapy

• Bisphosphonates– Phase III: monthly pamidronate (JCO 1998;16:593)

• Skeletal-related events 38% versus 51%, p=0.015• Median survival 21 versus 14 months

• Compression fractures: vertebroplasty• DVT risk: steroids, steroids + thalidomide• Hypercalcemia• Renal insufficiency: ?Plasmapheresis• Infections• Anemia: Eyrthropoietins

Myeloma Bone Marrow Microenvironment

• Interactions– Myeloma cell adhesion molecules react with

stroma– Release of osteoclast activating factors (IL-1B,

IL-6, TNFB)– Vascular endothelial growth factor (VEGF)

secreted by myeloma cells

• Myeloma Bone Disease

New Agents

JCO 2002;20:1625.

Smoldering Myeloma

• Serum M-protein >3 g/dL

• Marrow plasma cells >10%

• No lytic bone lesions, unexplained anemia, hypercalcemia, or renal insufficiency

• Evolve to overt multiple myeloma– 3.3% per year– Greatest for IgA

Plasmacytoma

Extramedullary Plasmacytoma

• ~3% of plasma cell neoplasms• Isolated plasma cell tumors of soft tissues

– Upper respiratory tract common

• Uninvolved marrow, negative skeletal survey

• M-protein present ~25% cases– Disappears following treatment

• Curable with local radiation therapy

Solitary Plasmacytoma of Bone

• ~3% of plasma cell neoplasms• One isolated bony lesion of plasma cells• Uninvolved marrow <5% plasma cells• M-protein present ~25% cases

– Disappears following treatment

• Curable with local radiation therapy– Median OS 10 years– Multiple myeloma develops in 50-60%

Osteosclerotic Myeloma (POEMS)

• Polyneuropathy– Sensorimotor peripheral neuropathy in 75%

• Organomegaly– Lymphadenopathy, hepatomegaly, splenomegaly

• Endocrinopathy– Adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic

• M-Protein• Skin changes

– Hyperpigmentation, hypertrichosis, plethora, hemangiomata, white nails

Osteosclerotic Myeloma

Lymphoplasmacytic Lymphoma (Waldenstrom’s Macroglobulinemia)• Malignant proliferation of plasmacytoid

lymphocytes secreting IgM M-protein• 1400 cases/year• Organomegaly/Peripheral neuropathies• Cryoglobulinemia

– Type I: Raynaud’s phenomenon, cold urticaria, etc.– Type II: Purpura, arthralgias, renal failure, mononeuritis

• IgM tissue infiltration/AL amyloidosis• Coagulation abnormalities

Hyperviscosity

• Usually IgM >5 g/dL, viscosity >4.0• Eyes

– “Sausage link” conjunctival and retinal veins– Retinal hemorrhages, Papilledema

• CNS– Ataxia, nystagmus, vertigo, confusion, altered consciousness

• Increased intravascular volume– Dilutional anemia– Risk congestive heart failure with transfusion

• Therapy: plasmapheresis/chemotherapy

Waldenstrom’s Macroglobulinemia: Therapy

• Plasmapheresis for hyperviscosity

• 2-Chlorodeoxyadenosine (2-CdA, cladribine)

• Fludarabine

• Rituximab

• Other myeloma-like therapies

Monoclonal IgM: DDx

• MGUS• Multiple myeloma• Waldenstrom’s• CLL• Chronic cold agglutinin disease

– No evidence of neoplasia– Hemolytic anemia aggravated by cold exposure– 90% have kappa light chains

Amyloidosis

• Extracellular tissue deposition of low molecular weight fibrils– Beta-pleated sheets, bind Congo red

• Precursor proteins involved– Monoclonal immunoglobulin light chains: Primary (AL)

Amyloidosis– Serum amyloid A protein: Reactive or Secondary (AA)

Amyloidosis– Beta-2 microglobulin: Dialysis (DA) Amyloidosis– Transthyretin, apolipoprotein A-I, Alzheimer amyloid

precursor protein, prion protein, Prolactin, Atrial natriuretic protein, Procalcitonin, Insulin, Keratin…

Amyloidosis: Presentation

• Nephrotic syndrome• Refractory CHF, Arrhythmia, Heart block• Orthostatic hypotension, Peripheral neuropathy• Bleeding diathesis (Raccoon eyes)

– Factor X deficiency, liver disease

• GI bleeding, Gastroparesis/Dysmotility, Malabsorption

• Macroglossia, Shoulder pad sign, Carpal tunnel syndrome, Organomegaly

• Skin thickening/waxy, easy bruising

Amyloidosis

Amyloidosis: Work-up

• Biopsy– Involved organs or bone marrow– Fat pad, salivary glands, rectal mucosa: 50-70%

success for diagnosis

• Echocardiography suggestive– Speckled myocardium– Interventricular septal thickening

• Distinguish from hereditary forms (10%)• Evaluate for myeloma (rare)

AL Amyloidosis: Course

• Rare progression to multiple myeloma (0.4%)• Poor long-term prognosis

– Cardiac, renal, hepatic failure, and infection– Prognostic factors: circulating plasma cells, high beta-2

microglobulin, marrow plasmacytosis >10%, dominant cardiac involvement

– High B2M, marrow plasmacytosis: median survival• 0: 54 months• 1: 19 months• 2: 13.5 months

Dhodapkar, Blood 2004;104:3520. Skinner, Annals 2004;140:85

AL Amyloidosis: Therapy

• Chemotherapy– Dexamethasone with

Dex/IFN maintenance

• High-dose melphalan with Auto transplantation– Risky with cardiac, renal,

GI involvement

Summary

• Spectrum of mature B-cell neoplasms/plasma cell dyscrasias

• Clinical manifestations:– Tumor growth, marrow and tissue infiltration

– M-protein accumulation or infiltration

– Immune dysfunction

– Kidney and bone disease

• Therapy not curative, but increasingly effective