Multiple

Myeloma and

Related

Disorders

Zsolt Nagy

Outline

• Biology

• Plasma Cell Dyscrasia

– MGUS

– Plasmacytoma

• Multiple myeloma

– Smoldering

– POEMS

• Waldenstrom’s Macroglobulinemia

• Amyloidosis

Classification of Monoclonal Gammopathies

• Monoclonal Gammopathy of Undetermined Significance

• Malignant Monoclonal Gammopathies Multiple Myeloma Smolderimg Multiple Myeloma Plasma cell leukemia IgD myeloma POEMS

• Plasmacytoma

• Malignant Lymphoproliferative disorders

• Heavy Chain disease

• Amyloidosis

Long-lived plasma cellPre-B cell

G, A,

D, E

Lymphoblast

Plasmablast

Naïve B Cell

Short-lived

plasma cell

Lymph Node

Lymphoplasmacyte

(memory B Cell)

Follicle

center

Bone Marrow

Stimulation

with Antigen

Somatic Hypermutation

of Ig Sequences

Isotype

Switching

::...

::...

IgM

Normal B-cell Development

IgM

Bone

MarrowG,A,E Plasma cell

Virgin B cell

Lymphoblast

Lymphoplasmacyte

Plasmablast

Germinal Center

SOMATIC

Pre-B cell

IgM

HYPERMUTATION

Lymph node

V(D)J

RECOMBINATION

SWITCH

RECOMBINATION

B cell Development As a Framework for Malignancies

B cell Development As a Framework for Malignancies

Bone

Marrow

MULTIPLE

MYELOMAG,A,E Plasma cell

Virgin B cell

Lymphoblast

Lymphoplasmacyte

Plasmablast

Germinal Center

SOMATIC

Pre-B cell

IgM

HYPERMUTATION

WALDENSTROM’S

CLL

BURKITT’S

LYMPHOMAFOLLICULAR

LYMPHOMA

Lymph node

ALL

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

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)

SPEP

Polyclonal

Gammopathy

Monoclonal

Gammopathy

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

Monoclonal Gammopathies – Mayo clinic

MGUS

62% (659)

MM 16% (172)

Extramedullary

1% (8)

SMM 4% (39)

LP 3% (37)

AL 8% (90)

Other 3% (33)

Macro 3% (30)

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

Risk of progression of MGUS to myeloma or related disorder using a risk-stratification model

that incorporates the FLC ratio and the size and type of the serum monoclonal protein.

Rajkumar S V et al. Blood 2005;106:812-817

©2005 by American Society of Hematology

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.

MOLECULAR PATHOGENESIS OF

MYELOMA

Lancet 2004;363:875

Myeloma Cells and BM Microenvironment

Bruno et al, The Lancet Oncology, July 2004, 430-442

MM: Clinical Features

• Disease of the elderly (7th decade)

• Bone pain

– most commonly vertebra and long bones

– lytic lesions

– fractures

Myeloma: Clinical Features

• Bone pain: often with loss of height

• Constitutional: weakness, fatigue, and weight loss

• Anemia

• Renal disease: renal tubular dysfunction

• Infections: neutropenia/hypogammaglobulinemia

• Hypercalcemia: myeloma cells secrete osteoclast-activating

factors

• Hyperviscosity: 2% with myeloma; 50% with

macroglobulinemia

• Neurologic dysfunction: spinal cord or nerve root compression

Major Symptoms at Diagnosis

• Bone pain: 58%

• Fatigue: 32%

• Weight loss: 24%

• Paresthesias: 5%

Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33.

11% of patients are asymptomatic or have only mild symptoms at diagnosis

Multiple Myeloma

Typical “Punched Out” Lesions

Multiple Myeloma

Diagnostic Criteria for Myeloma

1. IMWG. Br J Haematol. 2003;121:749-757. 2. Kyle RA, et al. N Engl J Med. 2002;346:564-569.3. Durie BG, et al. Hematol J. 2003;4:379-398.

Patient Criteria MGUS[1,2] Smoldering

Myeloma[1]

Active Myeloma

M protein < 3 g/dL spike ≥ 3 g/dL spike

and/or

In serum

and/or urine[2]

Monoclonal

plasma cells in

bone marrow, %

< 10 ≥ 10 ≥ 10[2]

End-organ

damage

None None ≥ 1 CRAB*

feature[3]

*C: Calcium elevation (> 11.5 mg/L or ULN)R: Renal dysfunction (serum creatinine > 2 mg/dL)A: Anemia (Hb < 10 g/dL or 2 g < normal)B: Bone disease (lytic lesions or osteoporosis)

Only patients with symptomatic MM should be treated

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

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 <2

B) Creatinine >2

Myeloma: Median Survival

Durie-Salmon stage

Stage I 60 months

Stage II 40 months

Stage III 15 months

International Myeloma Working

Group Revised Staging System

Kyle, Mayo Clin Proc, 2003.

Therapy of Newly Diagnosed

Multiple Myeloma: 1985-1998

Novel biologically based therapies targeting

MM cells and the BM microenvironment

A

D

C

B

Angiogenesis

Adhesion

Molecule

Drug Resistance

Proliferation

Apoptosis

Growth Arrest

Inhibition of Adhesion

Inhibition of

Cytokines

bFGF

VEGF

IL-6

IGF-1

VEGF

SDF-1α

Novel Agents

Novel Agents for Myeloma

Targeting both MM cells and interaction of

MM cells with the BM microenvironment

Targeting circuits mediating MM cell

growth and survival

Targeting the BM microenvironment

Targeting cell surface receptors

Novel Agents for Myeloma

Thalidomide and its analogs (Revlimid)

Proteasome inhibitor (Bortezomib)

Arsenic trioxide

2-Methoxyestradiol (2-ME2)

Lysophosphatidic acid acyltransferase-β

inhibitor

Triterpinoid 2-cyano-3, 12-dioxoolean-1, 9-dien-

28- oic acid (CDDO)

N-N-Diethl-8, 8-dipropyl-2-azaspiro [4.5]

decane-2-propanamine (Atiprimod)

Targeting both MM cells and their

interaction with BM microenvironment

Targeting circuits mediating MM cell

growth and survival

VEGF receptor tyrosine kinase inhibitor

(PTK787/ZK222584, GW654652)

Farnesyltransferase inhibitor

Histone deacetylase inhibitor (SAHA, LAQ824)

Heat shock protein-90 inhibitor

(Geldanamycin,17-AAG)

Telomerase inhibitor (Telomestatin)

bcl-2 antisense oligonucleotide (Genasense)

Inosine monophophate dehydrogenase (VX-944)

Rapamycin

Targeting cell surface receptorsTargeting the bone marrow

microenvironment

IĸB kinase (IKK) inhibitor (PS-1145)

p38 MAPK inhibitor (VX-745, SCIO-469)

TFG-β inhibitor (SD-208)

TNF related apoptosis-inducing ligand (TRAIL) /

Apo2 ligand

IGF-1 receptor inhibitor ( ADW)

HMG-CoA reductase inhibitor (statins)

Anti-CD20 antibody (Rituximab)

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: 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

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

Ghobrial et al, Lancet Oncol 2004, Treon et al, Blood 2009

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

Consensus recommendations of the 4th

International WM meeting

• First Line therapy:

– Combination therapy

• (RCD or CPR; Cytoxan+nucleoside analogues+R; R-CHOP, R-CVP)

– Rituximab single agent

– Nucleoside analogues

– Alkylators

• Salvage therapy:

– Re-use therapies

– Bortezomib

– Thalidomide+steroids

– Alemtuzumab

– AHSCT

Dimopoulos, JCO 2009, Treon et al Clin

Lymph and Myeloma 2009

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

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…

Merlini & Bellotti NEJM 2003

localized Amyloidosis

~30 proteins

systemic Amyloidosis

Amyloidosis: Protein Misfolding Diseases

Sipe et al, 2012

proteotoxicity

Misfolded FLC

structural damage

λ1*

1Merlini & Stone, Blood. 2006;

λ6**

*Perfetti et al, Blood. 2012; **Comenzo et al, Br J Haematol. 1999

Small dangerous clone1

(BMPC 7%)

53% LC only 75% l

Amyloid fibrils

Early detection of amyloid heart involvement is vital

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

Merlini et al, Blood 2013 121: 5124-5130

Diagnosis of 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

o Treatment endpoint: at least VGPR

o Hematologic and cardiac response should be assessed

frequently, every 1-2 cycles (or three months after ASCT)

o Rapid switch if no response

o Therapy can be continued for 1-2 cycles beyond best

response for consolidation

Therapy is Highly Individualized and Must be Risk-adapted Based

on Cardiac Biomarkers and Response-tailored

<VGPR Bortez if unexposed and no severe neuropathy

Len, Pom1, Benda2 in resist. to alkyl/bortez/thal

Len requires monitoring renal function

New drugs, such as Ixazomib3

1Dispenzieri et al, Blood 2012;119 :5397-404 -2Merlini et al, Blood. 2012;120(21) Abstr 4057 - 3Merlini et al,

Blood 2012;120(21) Abstr 731

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