Multiple Myeloma

Dr. Gajanan Pandit

Mb.P.T.Hospital, Mumbai

Definition

Multiple Myeloma (also k/a Myeloma, Plasma cell myeloma or Kahler disease )

is a progressive hematologic (blood) disease. It is a cancer of the plasma cell, an important part of the immune system that produces immunoglobulins (antibodies) to help fight infection and disease.

Pathology

Multiple myeloma is characterized by excessive numbers of abnormal plasma cells in the bone marrow and overproduction of intact monoclonal immunoglobulin (IgG, IgA, IgD, or IgE) or Bence-Jones protein (free monoclonal κ and λ light chains). Hypercalcemia, anemia, renal damage, increased susceptibility to bacterial infection, and impaired production of normal immunoglobulin are common clinical manifestations of multiple myeloma. It is often also characterized by diffuse osteoporosis, usually in the pelvis, spine, ribs, and skull.

When foreign substances (antigens) enter the body, B cells develop into plasma cells that produce immunoglobulins (antibodies) to help fight infection and disease.

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Immunoglobulins

Heavy chains

-IgG ( 60%-70% )

-IgA ( ~20% )

-IgM

-IgE

-IgD Light chains

-kappa ( -lambda ( l )

Bence Jones proteins

15% to 20% of patients with myeloma produce incomplete immunoglobulins, containing only the light chain portion of the immunoglobulin

Primarily in the urine, rather than in the blood (immunoelectrophoresis)

Different from monoclonal (M) protein or paraprotein

Absent in nonsecretory myeloma (1%)

cytokines IL-6,RANK,TNF

AngiogenesisVEGF

immune response

Multiple myeloma is the 2nd most prevalent blood cancer after non-Hodgkin's lymphoma.

Average age at diagnosis is 62 yrs for men and 61 yrs for women

Decline in the immune system, genetic factors, certain occupations, certain viruses, exposure to certain chemicals e.g.Agent Orange and exposure to radiation.

Kidney problems

* Excess protein in the blood filtered through kidneys kidney damagerenal failure.

* Hypercalcemia overworks the kidneys and can cause variety of symptoms ie. loss of appetite, fatigue, muscle weakness, restlessness, difficulty in thinking or confusion, constipation, increased thirst, increased urine production, and nausea and vomiting.

Hydration, steroids plus furosemide, bisphosphonates, avoid NSAIDs/ i.v.contrast.

Pain

Early sym. pain in the lower back or in the ribs. Due to tiny fractures by accumulation of plasma cells and weakened bone structures.

Proper positioning and support; increasing physical activity in consultation with physical/occupational therapists; bisphosphonates; radiation therapy; for spinal fractures: surgical procedures such as kyphoplasty or vertebroplasty

Hematological

Fatigue and Recurrent infection Erythropoietin therapy

Transfusions Appropriate antibiotic therapy

immunoglobulin therapy

Nervous system dysfunction

Root compression & hyperviscosity syndrome-- radiculopathy, breathlessness, confusion, and chest pain.

Treat as a medical emergency

Cryoglobulinemia,

Amyloidosis.

Diagnosis

Major criteria: A biopsy-proven plasmacytoma. A bone marrow sample showing 30% plasma cells. Elevated monoclonal Ig levels in the blood or urine

Minor criteria: A bone marrow 10%-30% plasma cells. Minor monoclonal Ig levels in blood or urine Imaging --- holes in bones due to tumor growth Antibody levels (not produced by the cancer cells) in the

blood are abnormally low.

Lab Investigations

CBC - Hb,TLC, DLC, PLT Biochem. -albumin, BUN, LDH, Ca, S.Creatinine S. beta-2 microglobulin (β2-M), CRP Quantitative immunoglobulins (QIGs) 24 hr urine protein & UPEP serum-based assay called FREELITE

(MGUS to MM )

Electrophoresis (EP) / Immunoelectrophoresis ( IEP )

a serum or urine sample

gel is stained and read

tall spike M proteins of identical

molecular size urine - B.J.Protein

Bone (skeletal) survey

Pathological fracture

Bone & Marrow

CT / MRI bone marrow

aspiration / biopsy (percentage of plasma cells )

Chromosomal analysis (karyotyping) and fluorescence in situ hybridization (FISH)

Classification of Myeloma

Monoclonal Gammopathy of Undetermined Significance (MGUS)

Asymptomatic Multiple Myeloma

[Smoldering (SMM) / Indolent (IMM) ] Symptomatic Multiple Myeloma (MM)

Monoclonal Gammopathy of Undetermined Significance (MGUS)

Serum M protein <3 g/dL

Bone marrow plasma cells <10%

Absence of anemia, renal failure, hypercalcemia, lytic bone lesions

1% of the general population and in about 3% of normal individuals over 70 years of age

16% -malignant plasma cell disorder

Disease Management - observation

Asymptomatic Multiple Myeloma

Smoldering Multiple Myeloma (SMM)

Serum M protein >3 g/dL and/or bone marrow plasma cells ≥10%

Absence of anemia, renal failure, hypercalcemia, lytic bone lesions

Indolent Multiple Myeloma (IMM)

Stable serum/urine M protein

Bone marrow plasmacytosis

Mild anemia or few small lytic bone lesions

Absence of symptoms

Asymptomatic Multiple Myeloma

Observation with treatment beginning at disease progression

Bisphosphonates Supportive care

Symptomatic Multiple Myeloma (MM)

Presence of serum/urine M protein

Bone marrow plasmacytosis (>30%)

Anemia, renal failure, hypercalcemia, or lytic bone lesions

chemotherapy, stem cell

transplantation, Thalidomide, Bortezomib, pamidronate, and Zoledronic acid,

Staging of Myeloma

Durie-Salmon systemclinical stage of disease

(stage I, II, or III) is based levels of M protein, number of lytic bone

lesions, hemoglobin values and serum calcium levels.Stages are further divided

(A/B) according to renal function

International Staging System (ISS)

new, simpler, more cost-effective

beta 2-micro globulin (β2-M) and

albumin

*Stage II = β2-M <3.5 or β2-M 3.5 – 5.5 mg/dL, and albumin <3.5 g/dL

sub classification A) S. Creat.<2.0 mg/dl & B) S. Creat.>2.0 mg/dl

Stage Durie-Salmon Criteria ISS Criteria

I • Hb >10 g/dL• S. Ca

++ ≤12 mg/dL

• x-ray, normal bone stru.

or solitary bone plasmacytoma• Low M-component production rate —

( IgG <5 g/dL; IgA <3 g/dL) • Bence Jones protein <4 g/24 h

β2-M < 3.5 mg/dL and

albumin ≥3.5 g/dL

II* Neither stage I nor stage III Neither stage I nor stage III

III •Hb <8.5 g/dL•S. Ca

++>12 mg/dL

•Advanced lytic bone lesions•High M-component production rate —

(IgG>7 g/dL; IgA>5 g/dL)•Bence Jones protein >12 g/24 h

β2-M ≥ 5.5 mg/dL

Prognostic indicatorsTest Values indicating favorable prognosis

B 2-M <3 μg/mL

Albumin ≥3.5 g/dL

PCLI < 1%

CRP <6 μg/mL

LDH Age ≤60 y: 100-190 U/L Age >60 y: 110-210 U/L

Plasmablastic morphology

Absence of plasmablastic morphology

Chromosomal analysis (FISH)

Normal chromosome 13

Genetic Expression Profiling in Myeloma

Varied response to therapy 50% deletion of chromosome 13 40% one of five specific translocations

e.g. translocation k/a t(4;14)

Myeloma bone disease

Rapid growth of myeloma cells inhibits normal bone-forming cells osteoblasts

production of substances that activate the cells that resorb bone called osteoclasts is increased

Normal Bone Cell ActivityProcess of bone

remodelingOsteoclasts are attracted to the

area of fatigued bone.

Osteoclasts remove the fatigued bone by breaking it down, creating a cavity in the bone.

Osteoblasts are attracted to the cavity in the bone.

Osteoblasts fill in the cavity with a matrix or framework.

Eventually, new bone forms.

Bone Cell Activity in Myeloma

Bone Marrow Microenvironment Tumor cells adhere to the bone marrow stromal cells (BMSCs),the

structural cells of BM.

Adherence increases the stromal cell production of the growth factor interleukin 6 (IL-6), >continued growth and survival of the myeloma cells.

Adherence also allows the myeloma tumor cells to produce other osteoclast-activating factors including interleukin 1-beta (IL-1β) and tumor necrosis factor-alpha (TNF-α).

Osteoclast-stimulating factors prompt the bone marrow stromal cells and the osteoblasts to produce growth factor-RANKL.

TNF induces osteoclast cells and increases osteoclast activity that results in the bone disease of myeloma.

Osteoclastic activity also results in the release of certain cytokines such as IL-6, which contribute to tumor cell growth and survival.

Treatment Decisions in Myeloma

results of the physical exam

results of laboratory tests

the specific stage or classification of their disease

their age and general health

their symptoms

whether complications of the disease are present

whether they have previously received treatment for their disease

their lifestyle and their view and philosophy on quality of life

Goals of Treatment Eradicating all evidence of disease, which may require

accepting higher levels of toxicity Controlling disease activity to prevent damage to other organs

of the body, using a regimen with an acceptable toxicity level Preserving normal performance and quality of life for as long

as possible with minimal intervention Providing lasting relief of pain and other disease symptoms When applicable, managing myeloma that is in remission over

the long-term

Treatment Approaches

Inactive DiseaseActive Disease

> Non-transplant Candidates

> Transplant Candidates Relapsed or Refractory Disease

Rajkumar et al. Mayo Clin Proc. 2002;77:814

Options for relapsed/refractory disease

Repeat initial therapy if relapse after 6mths of discontinuing therapy

Corticosteroids Thalidomide based regimens Bortezomib Salvage chemotherapy ( eg. VAD, Cyclophosphamide-

VAD, EDAP or oral cyclophosphamide Consider second transplant if stem cells available/

harvest possible investigation regimen in clinical trial

Potential Outcomes of Treatment

TreatmentOutcome

Definition

Molecularcomplete response

--No evidence of disease using the most sensitivetechniques available

Complete response(CR)

--No detectable M protein in the serum and urine andNormal percentage of plasma cells in the bone marrow orAbsence of myeloma cells by staining techniques

Near completeresponse

--As listed for CR, but with a positiveimmunofixation test

Very good partialresponse

--Greater than 90% decrease in M protein

Partial response(PR)

--Greater than 50% decrease in M protein

Minimal response --Less than 50% decrease in M protein

Stable disease (SD) --Stable disease parameters (including number and extentof lesions) with some decrease in M protein

Progressive disease --Greater than 25% increase in M protein, new bonylesions, or a new plasmacytoma