Multiple Myeloma

By Dr. Navinee Vongsupathai

Multiple Myeloma

• Definition• Causes and incidence• Clinical feature• Physical examination • Diagnosis• Classification and staging• Threatment• Prognosis

DDefinitionefinition• Multiple myeloma : as myeloma or plasma

cell myeloma

• cancer of the plasma cell • Multiple myelomaMultiple myeloma

– excessive numbers of abnormal plasma cells in the bone marrow

– overproduction of intact monoclonal immunoglobulin (IgG, IgA, IgD, or IgE) or Bence-Jones protein (free monoclonal κ and λ light chains)

DDefinitionefinition

• Normal Plasma Cell Function in the Immune System– Stem cells can develop into B lymphocytes --

>travel to the lymph nodes, mature, and then travel throughout the body.

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

Figure legend: In multiple myeloma, the B cell is damaged and gives rise to too many plasma cells (myeloma cells). These malignant cells do not function properly and their increased numbers produce excess immunoglobulins of a single type that the body does not need along with reduced amounts of normal immunoglobulins.

Figure legend: Bone marrow stromal cells and myeloma cells produce cytokines that help myeloma cells grow and survive. Myeloma cells also produce growth factors that stimulate new blood vessel formation through a process called angiogenesis. New blood vessels provide nutrients and oxygen to the tumor, allowing it to grow. The natural immune response that attacks myeloma cells is suppressed.

DDefinitionefinition• These myeloma cells travel through the

bloodstream and collect in the bone marrow, where they cause permanent damage to healthy tissue.

• As tumors grow, they invade the hard outer part of the bone, the solid tissue.

• In most cases, the myeloma cells spread into the cavities of all the large bones of the body, forming multiple small lesions. This is why the disease is known as "multiple" myeloma.

Incidence• Multiple myeloma is the second most prevalent

blood cancer after non-Hodgkin's lymphoma

• 1% of all cancers and 2% of all cancer deaths. • Age 60-65 years most common• Occurs in men > women

• African Americans and Native Pacific Islanders have the highest reported incidence of this disease and Asians the lowest

CCausesauses• Genetic causesGenetic causes

– Ongoing research is investigating whether HLA-Cw5 or HLA-Cw2 may play a role in the pathogenesis of myeloma.

• Environmental or occupational causesEnvironmental or occupational causes– significant exposures in the agriculture, food,

silicon ,Benzene, Nikel and petrochemical industries

• Radiation:Radiation:– Radiation has been linked to the development of

myeloma.– In 109,000 survivors of the bombing of Nagasaki,

29 died from myeloma from 1950-1976; however, some recent studies do not confirm that these survivors have an increased risk of developing myeloma.

CClinical linical ffeatureseatures• common tetrad of multiple myeloma is CRABCRAB

– C = Calcium (elevated)– R = Renal failure– A = Anemia– B = Bone lesions

CClinical linical ffeatureseatures•Bone pain

– Myeloma bone disease -- >proliferation of tumor cells and release of IL-6 <osteoclast activating factor :OAF>-- >stimulates osteoclasts to break down bone-- > leading to hypercalcemia

– These bone lesions in plain radiographs-- >

"punched-out" / lytic bone lesion

CClinical linical ffeatureseatures•Bone pain

– Myeloma bone pain -- > involves the rib ,sternum, spine , clavicle , skull , humerus & femur

– The lumbar vertebrae are one of the most common sites of pain -- >may lead to spinal cord compression.

– Persistent localized pain may indicate a pathological fracture.

CClinical linical ffeatureseatures

CClinical linical ffeatureseatures

CClinical linical ffeatureseatures

CClinical linical ffeatureseatures• HypercalcemiaHypercalcemia

– Pt. present with confusion, somnolence, bone pain, constipation, nausea, and thirst.

• AnemiaAnemia – The anemia :normocytic and normochromic.

– It results from the replacement of normal bone marrow by infiltrating tumor cells and inhibition of normal red blood cell production (hematopoiesis) by cytokines.

CClinical linical ffeatureseatures• Bleeding

– bleeding resulting from thrombocytopenia. – In some patients, monoclonal protein may

absorb clotting factors and lead to bleeding, but this development is rare.

• Hyperviscosity– high volume of monoclonal protein -- > blood

viscosity increases-- >complications such as stroke, myocardial ischemia, or infarction.

CClinical linical ffeatureseatures• Infection Infection

– Organism : polysaccharide encapsulated <strep.pneumoniae, H.influenzae>

– Common pneumonia pathogens :S pneumoniae, S aureus, and K pneumoniae

– Common pathogens causing pyelonephritis : E coli and other gram-negative organisms.

– The increased risk of infection is due to immune deficiency resulting from diffuse hypogammaglobulinemia, which is due to decreased production and increased destruction of normal antibodies.

CClinical linical ffeatureseatures• Renal failureRenal failure

– Renal failure may develop both acutely and chronically.

– It is commonly due to hypercalcemia. – It may also be due to tubular damage from

excretion of light chains, which can manifest as the Fanconi syndrome (type II renal tubular acidosis).

– Other causes include glomerular deposition of amyloid, hyperuricemia, recurrent infections (pyelonephritis), and local infiltration of tumor cells.

CClinical linical ffeatureseatures• Neurological symptomsNeurological symptoms

– Common problems are weakness, confusion and fatigue due to hypercalcemia.

– Headache, visual changes and retinopathy may be the result of hyperviscosity of the blood depending on the properties of the paraprotein.

– Finally, there may be radicular pain, loss of bowel or bladder control (due to involvement of spinal cord leading to cord compression) or carpal tunnel syndrome and other neuropathies (due to infiltration of peripheral nerves by amyloid).

– It may give rise to paraplegia in late presenting cases.

PPhysical hysical EExamination xamination

• Pallor : anemia• Ecchymoses or purpura :

thrombocytopenia

• Bone pain without tenderness is typical : lytic destructive bone lesions or pathologic

fracture.

PPhysical hysical EExamination xamination

• Neurologic findings – Sensory level change (ie, loss of sensation

below a dermatome corresponding to a spinal cord compression)

– Weakness

• Extramedullary plasmacytomas :soft tissue masses of plasma cells, are not uncommon.

PPhysical hysical EExamination xamination

• Amyloidosis – The shoulder pad sign is defined by bilateral

swelling of the shoulder joints secondary to amyloid deposition-- >swelling as hard and rubbery.

– Macroglossia is a common finding in patients

with amyloidosis.

DDiagnosisiagnosis• Lab Studies:

– CBC: anemia, thrombocytopenia, leukopenia

– Peripheral blood smear : rouleaux formation

Rouleaux formation : high plasma protein

ภาพแสดงกลุ่�มเซลุ่ลุ่�ที่��ม�ลุ่�กษณะคลุ่�าย plasma cells ค�อ เซลุ่ลุ่�ม�ลุ่�กษณะเป็�นรู!ป็ไข่� ที่��ม� nucleus อย!�ชิ%ดข่อบด�านใดด�านหน)�งข่องเซลุ่ลุ่� ลุ่�กษณะข่อง nucleus จะเห+น chromatin มาเรู�ยงก�นคลุ่�ายลุ่�อเกวี�ยนหรู�อหน�าป็-ดนาฬิ%กา

DDiagnosisiagnosis– total protein, albumin and globulin, BUN,

creatinine, and uric acid, which is high if the patient has high cell turnover or is dehydrated

– Serum protein electrophoresis, urine protein electrophoresis, and immunofixation

• Serum protein electrophoresis is used to determine the type of each protein present and may indicate a characteristic curve (ie, where the spike is observed).

• Urine protein electrophoresis is used to identify the presence of the Bence Jones proteinBence Jones protein in urine.

• Immunofixation is used to identify the subtype of protein (ie, IgA lambda).

DDiagnosisiagnosis• A 24-hour urine collectionA 24-hour urine collection for the Bence Jones

protein (ie, lambda light chains), protein, and creatinine

– Quantification of proteinuria is useful for diagnosis (>1 g of protein in 24 h is a major criterion) and for monitoring the patient's response to therapy.

– Creatinine clearance can be useful for defining

the severity of the patient's renal impairment.

DDiagnosisiagnosis• Imaging StudiesImaging Studies

– Skeletal series • skull (a very common site ), the long bones

( for impending fractures), and the spine. • Diffuse osteopenia may suggest myelomatous

involvement before discrete lytic lesions are apparent.

• Do not use bone scans to evaluate myeloma

– MRI scan• MRI to obtain a clear view of the spinal

column and to assess the integrity of the spinal cord.

DDiagnosisiagnosis• Procedures Procedures

– bone marrow aspirate & biopsy • samples to calculate the percent of plasma

cells in the aspirate (reference range, <3%) and to look for sheets or clusters of plasma cells in the biopsy specimen.

Bone marrow aspirate : plasma cells of multiple myeloma.Note the blue cytoplasm, eccentric nucleus, and perinuclear pale zone (or halo).

Bone marrow biopsy : sheets of malignant plasma cells in MM

DDiagnostic iagnostic ccriteriariteria•Durie-Salmon criteriaDurie-Salmon criteria

Dx : 1 major & 1 minor or 3 minor criteria

– Major criteriaMajor criteria• Plasmacytoma on tissure biopsy• BM plasmacytosis with > 30% plasma cell• Monoclonal globulin spike on serum

electrophoresis 3.5 g/dl for Ig G ,> 2g/dl for IgA

• Or urine Bence Jones > 1g/24 hr

DDiagnostic iagnostic ccriteriariteria•Durie-Salmon criteriaDurie-Salmon criteria

– Minor criteriaMinor criteria• Marrow plasmacytosis 10-29 %• Monoclonal globulin spike present ,but less

than above• Lytic bone lesion• Normal Ig M< 0.05g/dl , IgA <0.1g/dl ,

IgG<0.6 g/dl

SStagingtaging• Durie-Salmon staging systemDurie-Salmon staging system

1. High tumor mass <stage III > one of following abnormalitie mus be present

a. Hb <8.5 g/dl, Hct < 25 %b. Sr Ca > 12 gm/dlc. Very high Sr or Urine myeloma protein production

rate 1. Ig G peak >7 gm/dl 2. IgA peak > 5 gm/dl 3. Bence Joneprotein > 12 gm/ 24 hr

d. > 3 lytic bone lesion on bone survey

SStagingtaging• Durie-Salmon staging systemDurie-Salmon staging system2. Low tumor mass2. Low tumor mass <stage I>

all of following must be presenta. Hb > 15 gm/dl, Hct> 32%b. Sr Ca normalc. Low Sr myeloma protein production rate 1. Ig G

peak< 5 gm/dl 2. IgA peak < 3 gm/dl 3. Bence Jone protien < 4 g/ 24 hr

d. No bone lesion or osteoporosis

SStagingtaging•Durie-Salmon staging Durie-Salmon staging

systemsystem3. Imtermediate tumor mass <stage II>a. no renal failure <Cr < 2 mg/dl>b. Renal failure <Cr > 2 mg/dl>

SStagingtaging• The International Staging System The International Staging System

(ISS)(ISS)

– Stage I : β2-microglobulin (β2M) < 3.5 mg/L, albumin >= 3.5 g/dL

– Stage II : β2M < 3.5 and albumin < 3.5; or β2M between 3.5 and 5.5

– Stage III : β2M > 5.5

TThreatmenthreatment• Active careActive care

– Chemotherapy– Autologous / Allogenic stem cell transplamtation– Drug : Arsenic trioxide, Thalidomide &

Immunomodulator– Interferon

• Supportive careSupportive care– Radiation therapy– Bisphosphonate– Kayphoplasty

TThreatmenthreatment• Radiation therapy <palliative>

– Rx : plasmacytoma post surgery

• Chemotherapy– Melphalan & Prednisolone– VADVAD < vincristine, adriamycin,

dexamethasone>– VMCPVMCP < vincristine , melphalan,

cyclophosphamide, prednisolone>

TThreatmenthreatment• Arsenic trioxide : inhibit leukemic growth

factor & + apoptosis

• Thalidomide : Antiangiogenesis-- >apoptosis of MM cell

• Bisphosphonate <Pamidronate,Zoledronic acid> -- > inhibit osteoclast

PPrognosisrognosis• The International Staging System can help

to predict survival– Stage 1 : 62 months – Stage 2 : 45 months – Stage 3 : 29 months