Multiple Myeloma 101: Understanding Your Labs

Tim Wassenaar MD MS Hematologist, Director of Clinical Trials

UW Cancer Center at ProHealth Care

Disclosures

• None

Outline

• Define hematopoiesis

– WBCs, RBCs, platelets

• What is multiple myeloma?

• How do we diagnose myeloma?

Outline

• Laboratory studies – Monoclonal protein – Immunoglobulins, beta 2 microglobulin – Bone marrow biopsy

• Laboratory results in the setting of multiple myeloma – CRAB – Free light chains

• Conclusions

Hematopoiesis

• Websters defines as:

– “the formation of blood or of blood cells in the living body.”

• Where are blood cells made?

Bone Marrow

Williams, 2009

White Blood Cells (Leukocytes)

• Neutrophils – eat bacteria – produce inflammatory molecules

• Lymphocytes

– make antibodies – kill foreign or infected cells – regulate immune system

• Monocytes

– eat bacteria and other unwanted things – regulate immune system

Plasma Cell

Red Blood Cells (Erythrocytes)

• Biconcave discs

• Little bags of hemoglobin

• Function: carry 02 to tissues, CO2 to lungs

top side

Platelets

• Smallest formed elements in blood

• Not really cells (no nuclei) but fragments of large cells called megakaryocytes found mainly in bone marrow

• Function: help blood clot, prevent bleeding

How do we diagnose multiple myeloma?

• Laboratory evaluation – Complete blood count – Protein studies (serum, urine) – Serum immunoglobulins (IgG, IgM, IgA) – Kidney function, chemistries, calcium, albumin

• Radiographic evaluation

– Xrays (skeletal survey) – CT, MRI, PET scan also used in certain circumstances

• Pathologic evaluation

– Bone marrow biopsy

Laboratory Studies

• Monoclonal protein – 97% of patients will have a protein in the blood or

urine • 80% of time protein is seen by SPEP

• Up to 93% of time if immunofixation performed

• 97% if serum free light chains and urine protein studies are performed

– No detectable monoclonal protein (3%) • Non-secrectory myeloma

Monoclonal Protein

Uptodate, 2017

Laboratory Studies

• Monoclonal protein – IgG – 52 percent

– IgA – 21 percent

– Kappa or lambda light chain only (Bence Jones) – 16 percent

– IgD – 2 percent

– Biclonal – 2 percent

– IgM – 0.5 percent

– Negative – 6.5 percent

Uptodate, 2017

Laboratory Studies

• Free light chain – Measures kappa and lambda

immunoglobulin chains not bound to heavy chains • Normal is Kappa:Lambda ratio of

2:1

– Abnormal free light chain ratio

seen in 90% of patients with multiple myeloma

– Now considered a diagnostic criteria for multiple myeloma

Laboratory Studies

• Serum Immunoglobulins – Measurement of normal and abnormal protein

• IgG, IgM, IgA

– If no localized band seen on SPEP, 20% have hypogammaglobulinemia

– Reduction of normal uninvolved immunoglobulin levels common • 91% have one, 73% have both reduced

Laboratory Studies

• Beta 2 microglobulin

– Serum test

– Prognostic factor for multiple myeloma staging

– Elevated in 75% of patients at diagnosis

– Higher level represents:

• Greater tumor burden

• Can be associated with renal failure

Laboratory Studies

• Bone Marrow biopsy

– Key component to diagnosis of myeloma

– 3 main components:

• Morphology – # and appearance of plasma cells

• Immunophenotype – Monoclonal, kappa/lambda ratio

• Cytogenetics – Chromosome abnormalities of myeloma cells

Bone Marrow

Williams, 2009

Bone Marrow: Cytogenetics

• Chromosome abnormalities play a major role in development of multiple myeloma

• Detected by: – Karyotype (20-30% detection rate)

• Ploidy (Gain/trisomy, loss/hypodiploidy) • Deletion/monosomy

– Flourescent in situ hybridization (FISH)

• Play a major role in prognosis

Bone Marrow: Cytogenetics

Bone Marrow Cytogenetics

• No abnormality better than any – Detection of a clone reflects dividing cells

• High Risk – Hypodiploidy

• Intermediate Risk – Deletion 13

• Low Risk/Favorable – Hyperdiploidy

Bone Marrow: FISH

Blood 2002;99:3735

Bone Marrow Cytogenetics/FISH

Msmart guidelines, accessed 11/2017

Laboratory Studies: Clinical Presentation

• Calcium increased

• Renal dysfunction

• Anemia

• Bone lesions

CRAB: Hypercalcemia

• Increase in the level of calcium – Seen in approximately 30% at diagnosis

– Serum calcium > 11 mg/dL (15%)

• Causes – Bone destruction, loss of kidney function,

monoclonal protein

• Symptoms – Drowsiness, confusion, loss of appetite, nausea,

constipation, excessive urination

CRAB: Kidney damage/failure

• Kidneys don’t filter the blood as well – Usually acute and reversible if caught early – Creatinine above normal (0.9-1.2 mg/dL) in 50%, > 2.0 mg/dL in

20% of cases at presentation – Can be the presenting symptom of the disease

• Causes

– Monoclonal protein (ie cast nephropathy) – Hypercalcemia – Medications

• Symptoms – Drowsiness, loss of appetite, nausea, constipation, excessive

urination/ loss of urination’

CRAB: Anemia

• Decrease in red blood cells, lower hemoglobin and hematocrit – Hemoglobin ≤12 g/dL

– Present in 73% of patients at diagnosis (97% overall)

• Causes – Bone marrow replacement

– Kidney damage

– Dilution in the case of a large M-protein

• Symptoms – Fatigue, shortness of breath

CRAB: Bone Pain/Destruction

• Present 60% of the time at diagnosis

• Causes

– Plasma cell invasion of bone (plasmacytoma)

– Plasma cell induced bone destruction

• Symptoms • Back or chest pain most common, but

also in arms and legs – Pain worse with movement, goes

away with rest • Can cause loss of height • Spinal cord compression (weakness in

arm/leg, incontinence) (5% of patients)

Laboratory Studies: Immune system dysfunction

• Increased risk of infections

• Causes – Impaired lymphocyte function

– Impaired plasma cell function

– Hypogammaglobulinemia (too little normal protein)

– Other

Laboratory Studies: Hyperviscosity Syndrome

• Blood becomes “thick and sticky” and prone to clot – Proteins (typically IgM) secreted by plasma cells

• Symptoms

– Bleeding from nose/mouth, blurred vision, headache, slurred speech, confusion, and heart failure

• Treatment

– Remove proteins from blood

Google®, 2009

Myeloma Diagnosis Criteria

Uptodate, 2017

Conclusions

• Multiple myeloma is characterized by excess immunoglobulin protein production by plasma cells with: – Detection of abnormal protein in serum and urine

– Increased abnormal plasma cells in bone marrow

• > 10% plus CRAB or FLC ratio > 100, or greater than 60%

– Associated symptoms:

• Calcium elevated • Renal dysfunction • Anemia • Bone destruction/lesions

Conclusions

• Can cause other symptoms:

– Immune system dysfunction

– Hyperviscosity

• Prognosis determined by genetic/molecular testing

• Clinical symptoms/findings and genetic studies drive treatment decisions

Questions