Hematology-High Yield TopicsFor Internal Medicine Boards and Hematology Boards

Target Audience: Internal Medicine Residents, Family Medicine Residents, Hematology Fellows, Medical Students, IM Board

Recertification exam aspirants

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Definition:

Group of lymphoid neoplasms of terminally differentiated B - cells that have in common the expansion of a single clone of immunoglobulin (Ig) - secreting plasma cells and a resultant increase in serum levels of a single homogeneous (monoclonal) Ig or it’s fragments.

Plasma Cell Dyscrasias

Plasma CellPlasma cells :

•Terminally differentiated B-cells

•Not normally found in peripheral blood .

•Account for less than 3.5% of nucleated cells in

the bone marrow

•Oval cells with low N:C ratio. Cytoplasm is

basophilic blue. Nucleus (30-40% of the cell) is

oval or round and typically placed eccentricallyeccentrically

(to one side) of the cell.

•A clear, colorless area adjacent to the nucleus

contains Golgi apparatus

•Russell bodies : Globules (2-3 μm) of

accumulated immunoglobulins in the cytoplasm

of plasma cells. Usually round. Russell bodies may

be found in normal bone marrow.

Plasma CellMott cells Mott cells

Plasma cells crowded with

Russell bodies. An obstruction

blocks the release of Golgi

secretions. These cells can be

found in any case of chronic

plasmacytosis.

Plasma CellFlame CellsFlame Cells

Large, multinucleated plasma

cells seen in Multiple myeloma.

The cytoplasm resembles a red

flame..

Plasma Cell DyscrasiasSynonyms

Plasma Cell Dyscrasias

Investigations in any suspected Monoclonal Gammopathy should include to accurately classify the disorder:

•Complete Blood Count ( look for anemia)

•Comprehensive Metabolic panel • Look for renal insufficiency, hypercalcemia and subtle clues like decreased

anion gap • Total protein and albumin level. Determine Globulin component. Too low

globulin ( < 2gm%) or Elevated Globulin ( > 3.5gm%) is concerning : Determine if Polyclonal vs. Monoclonal. Evaluate further with :

• Quantitative Immunoglobulins : Increase in all components usually, polyclonal. Increase in single component with reciprocal decrease of uninvolved globulin usually, may suggest monoclonal .

• Serum Protein Electrophoresis with immunofixation if monoclonal gammopathy is suspected.

• 24HR-Urine protein electrophoresis with urine immunofixation ( Serum Free Light Chain assay (κ/λ ratio) may be used in place of UPEP}

• Bone marrow biopsy to evaluate % plasma cells if there is monoclonal protein or abnormal UPEP or Light chain assay or if strong clinical picture of myeloma.

• Skeletal survey if monoclonal gammopathy has been established ( Bone scans are usually, negative in MM)

• Beta-2 microglobulin and Albumin for staging and prognosis in MM ( once diagnosis is made).

Investigations

Serum Protein Electrophoresis

Serum Protein Electrophoresis :Serum Protein Electrophoresis :

•Serum is placed on special paper Serum is placed on special paper

treated with agarose gel and exposed treated with agarose gel and exposed

to an electric current. This separates to an electric current. This separates

the serum protein components into the serum protein components into

five classifications by size and five classifications by size and

electrical charge : serum albumin, electrical charge : serum albumin,

alpha-1 globulins, alpha-2 globulins, alpha-1 globulins, alpha-2 globulins,

beta globulins, and gamma globulins.beta globulins, and gamma globulins.

•Immunoglobulins ( IgG, IgM, IgA) Immunoglobulins ( IgG, IgM, IgA)

usually migrate to gamma region but usually migrate to gamma region but

may sometimes extend to beta region.may sometimes extend to beta region.

•SPEP should always be performed in SPEP should always be performed in

combination with serum combination with serum

immunofixation in order to determine immunofixation in order to determine

clonalityclonality

SPEP SPEP showing Monoclonal

Gammopathy

•Shows a tall “narrow” “narrow” band

in gamma region – “M-Spike”

•Also, note reduction in the

normal polyclonal gamma

band

SPEP SPEP showing Polyclonal

Gammopathy

•Shows a broad based peak broad based peak

in gamma region .

•Seen in chronic infections,

inflammation, connective

tissue disease,

lymphoproliferative disease.

Immunofixation• More sensitive than SPEP

• Immunofixation is performed when

SPEP shows a sharp “peak” or a

plasma cell disorder is suspected

despite a normal SPEP

• Immunofixation always done to

confirm the presence of M-Protein

and to determine the type (IgM or

IgG etc and the light chain

restriction : k or λ)

• Why do both SPEP and IF ? Why not

just IF in initial diagnosis ?• Unlike SPEP, immunofixation does not give an

estimate of the size of the M protein (ie, its serum concentration), and thus should be done in conjunction with electrophoresis.

Constitute Several Disorders

Examples :

Denotes presence of an M-protein in a patient without a plasma cell or lymphoproliferative disorder i.e; Undetermined Undetermined SignificanceSignificance

Monoclonal Gammopathy of UndeterminedUndetermined Significance ( MGUS)

• Incidence of MGUS increases with age :• 1% of adults in US

• 3% of adults over age 70 years

• 11% of adults over age 80 years

• 14% of adults over age 90 years

• SignificanceSignificance : Can progress to monoclonal Disease

IgG or IgA MGUS IgM MGUSIgM MGUS

Monoclonal Gammopathy of UndeterminedUndetermined Significance ( MGUS)

MGUS - Progression

And it’s Variants

• Both criteria should be met :• Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells

≥10 percent

• No end organ damage related to plasma cell dyscrasia (see CRAB)

• Management : • Does not require any intervention

• Close surveillanace is necessary to ensure stability of the disease ( SPEP, CBC, Creatinine and calcium every 3 to 4 month and Skeletal Survey annually to pick up asymptomatic bone lesions)

Smoldering Myeloma

• Rare variant : About 1% of Myelomas

• May present with Bone lesions ( most common presenting symptom bone pain)

• No serum or urine monoclonal protein ( diagnosis can be missed if one is not aware of this entity, NSMM).

• Renal failure and hypercalcemia are generally lacking

• Anemia may be present

• Bone marrow biopsy must be performed in suspected cases: Immunostaining for a monoclonal protein on bone marrow sections may establish the diagnosis, Clonal plasma cell population in marrow.

• Must rule out IgD and IgE myeloma

Non-Secretory Myeloma

Solitary PlasmacytomaLocalized plasma cell tumorLocalized plasma cell tumor• Absence of a plasma cell infiltrate in random marrow biopsies• No evidence of other bone lesions by radiographic examination• Absence of renal failure, hypercalcemia or anemia

• Plasma cell tumors that arise outside the bone

marrow and no features of Multiple Myeloma

• Most Common Primary Sites - Most Common Primary Sites - Head and

Neck region: Upper air passages and

oropharynx (May involve draining lymph nodes.

• Less Common Sites – Lymph nodes (primary),

salivary glands, spleen, liver, etc.

• 25% have small monoclonal spike

• Rare dissemination, rarer evolution to myeloma

• Management :• If completely resected during biopsy, no

further therapy• If incompletely resected, radiation therapy

locally

Extramedullary Plasmacytoma

All three criteria must be met All three criteria must be met

•Presence of a serum or urinary monoclonal protein

•Presence of 10 percent or more clonal clonal plasma cells in the bone marrow or a plasmacytoma

•Presence of end organ damage felt related to the plasma cell dyscrasia, such as: CRABCRAB : Hyperccalcemia (calcium > 11.5gm%), Renal Insufficiency, Anemia (hgb < 10gm%) or Lytic bbone lesions

Multiple Myeloma

Multiple MyelomaBone Lesions : Bone Lesions :

Conventional radiographs (Skeletal Survey) abnormal in 80% of patients who present with multiple myeloma

Multiple MyelomaAnemia: Anemia: Normochromic /normocytic anemia occurs in 75% patients at diagnosisDefined as less than 10gm% in MM

Multiple MyelomaRenal Insufficiency : Renal Insufficiency : Serum creatinine increased in > 50% at diagnosisCreatinine >2g/dL in 20% of patientsRenal failure may be presenting manifestation

Major Causes :• Myeloma cast nephropathy • Hypercalcemia• Amyloidosis• Radiocontrast dye in a patient with myeloma

Multiple MyelomaSpinal Cord Compression : An Oncological EmergencySpinal Cord Compression : An Oncological Emergency

Spinal cord compression occurs in 5 % of patients with multiple myeloma ( plasmacytoma or pathological fracture related)

Managed with urgent:1. Corticosteroids2.Neurosurgical intervention (laminectomy or anterior decompression in pathological #) + radiation therapy to preserve neurological function3. Radiation therapy alone ( plasmacytoma)

Multiple Myeloma - Cytogenetics

Deletion 17p and Abnormalities associated with chromosome 13 carry a particularly unfavorable prognosis & respond poorly to therapy

Multiple Myeloma

Staging :Staging :International Staging System International Staging System :

Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dLStage II — neither stage I nor stage IIIStage III — B2M ≥5.5 mg/L

Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months

Multiple MyelomaTreatment Decisions :

•Indications for treatment : presence of any of CRAB ( bone lesions can be diffuse osteopenia alone)

•Risk Stratification :• FISH for detection of t(4;14), t(14;16), and

del17p13• Conventional cytogenetics (karyotyping) for

detection of del 13 or hypodiploidy• The presence of any of the above markers

defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment

Current Frontline Options

Conventional chemotherapy• Survival ≤ 3 yrs

Transplantation• Prolongs survival 4-5 yrs

Novel agents targeting stromal interactions and associated signaling pathways have shown promise and improved survival.

Chng WJ, et al. Cancer Control. 2005;12:91-104.

MM: INITIAL THERAPYThe initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation

*Thal/dex or dex are additional options especially if immediate response is needed.

Clearly not transplantation candidate based on age, performance

score, and comorbidity

MPT, MPV, Len/dexor clinical trial*

Potential transplantation candidate

Nonalkylator-based induction x 4 cycles

Stem cell harvest

Initial Approach to Treatment of MM

DETERMINING TRANSPLANT ELIGIBILITYAutologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy

All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible

A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational

NOT Eligible for Autologous HCT Age >77 years

Direct bilirubin>2.0 mg/dL (34.2 µmol/liter)

Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis

Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain

New York Heart Association functional status Class III or IV

54

42

Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883.

15 30 45 60

25

50

75

100

OS

(%)

00

High dose

Conventional dose

Mos20 40 60 80

25

50

75

100

Surv

ival

(%)

00

Intensive therapy

Standard therapy

Mos

P = .03 by Wilcoxon testP = .04 by log-rank test

Transplantation vs Conventional Chemotherapy

Autologous Stem Cell Transplantation

Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver,

pulmonary, cardiac function needed Higher PR and CR rates than conventional

chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by

themselves, not contraindications

Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010.

Stem Cell TransplantationKey issues

Efficacy compared with conventional chemotherapy

Timing: early vs delayed

Single vs tandem

Role of allogeneic and miniallogeneic transplantations

Maintenance post-SCT

Novel Frontline Options

Immunomodulatory drugs (IMiDs)• Thalidomide

• Lenalidomide

Proteasome inhibitors• BortezomibBortezomib

• Carfilzomib

Kyle RA, et al. N Engl J Med. 2004;351:1860-1873.Copyright ©2004. Massachusetts Medical Society. All rights reserved.

Proposed Mechanism of Action for Multiple Myeloma Therapies

Thalidomide: Proposed Mechanism of ActionProposed mechanisms• Inhibition of TNF-• Suppression of angiogenesis

• Increase in cell-mediated cytotoxic effects

• Modulation of adhesion molecule expression

Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085.

LenalidomideImmunomodulatory derivative of thalidomide

More potent than thalidomide in preclinical models• Dose-dependent decrease in TNF-α and interleukin-6 • Directly induces apoptosis, G1 growth arrest• Enhances activity of dexamethasone

More favorable toxicity profile than thalidomide

Difficult to use in renal insufficiency ( dose adjust)

Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950.

Lenalidomide Dosing for MM and Impaired Renal Function

Renal Impairment (CrCl)Renal Impairment (CrCl) Lenalidomide DosageLenalidomide Dosage

Moderate (30 to < 60 mL/min)Moderate (30 to < 60 mL/min) 10 mg QD10 mg QD

Severe (< 30 mL/min, not requiring Severe (< 30 mL/min, not requiring dialysis)dialysis) 15 mg Q 48 hrs15 mg Q 48 hrs

ESRD (< 30 mL/min, requiring dialysis)ESRD (< 30 mL/min, requiring dialysis) 5 mg QD5 mg QDOn dialysis days, On dialysis days,

administer following administer following dialysisdialysis

Lenalidomide [package insert].

Bortezomib:A Reversible Proteasome Inhibitor

Chymo-tryptic

Site

Post-Glutamyl

Site

TrypticSite

b1 b2

3

4

b5

6

7

Cross section of ring

Bortezomib

Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338.

H N B

N H

O

O

OHN

N

OH

Interferes with intracellular Interferes with intracellular pathway that degrades proteins pathway that degrades proteins regulating cell cycle, regulating cell cycle, apoptosis,angiogenesisapoptosis,angiogenesis

Peripheral Neuropathy Following Bortezomib Therapy in Advanced MMPeripheral neuropathy was reported in 90/256 (35%) patients with MM treated with bortezomib in phase II trials

80% of patients entered these trials with preexisting peripheral neuropathy

3% patients without vs 16% with baseline peripheral neuropathy developed grade 3 peripheral neuropathy

Richardson PG, et al. ASH 2003. Abstract 512.

Initial Approach to Treatment of MM

Clearly not a transplantation candidate

MPT, MPV, Len/dexor clinical trial*

Potential transplantation candidate

Nonalkylator-based induction

Stem cell harvest

Frontline Therapy in Elderly MM Patients

For elderly patients or those who are not suitable candidates for transplantation, MP has been a standard treatment• ORR: 60%

• Long-term CR: < 5%

Trials with MP-based combinations reported improved response rates and time to progression• MPT

• VMP

NCCN Practice Guidelines. Myeloma. V.3.2010.

ConclusionsIn elderly patients, the addition of novel agents to standard MP has provided improved response rates• MP alone (ORR: 50%; CR: 5%)• MPR (50% to 95% reduction in myeloma protein in 55.6%)

• VMP (ORR: 86%)

Care should be taken with IMiD-based therapy to include aspirin prophylaxis for DVT/PECare should be taken with bortezomib-based regimens to include herpes zoster herpes zoster prophylaxisprophylaxis

MM & Skeletal Complications

~ 80% of patients with multiple myeloma will have evidence of skeletal involvement on skeletal survey• Vertebrae: 65%• Ribs: 45%• Skull: 40%• Shoulders: 40%• Pelvis: 30%• Long bones: 25%

Dimopoulos M, et al. Leukemia. 2009:1-12.

The Central Role of the Osteoclast in Osteolytic Bone Destruction

Growthfactors

Osteoclast differentiation

Osteolysis

Direct effects on osteoclast differentiation

Tumor cells

Bone loss

Activeosteoclast

Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664.

Mechanism of Bisphosphonate Inhibition of Osteoclast Activity

Bisphosphonates inhibit osteoclast activity, and promote osteoclast apoptosis[1]

Bisphosphonates are released locally during bone resorption[1]

Bisphosphonates are

concentrated under

osteoclasts[1]

Bisphosphonates may modulate signaling from osteoblasts to osteoclasts

New bone

X

Bone

Increased OPG production[2]

Decreased RANKL expression[3]

1. Reszka AA, et al. Curr Rheumatol Rep. 2003;5:65-74. 2. Viereck V, et al. Biochem Biophys Res Commun. 2002;291:680-686. 3. Pan B, et al. J Bone Miner Res. 2004;19:147-154.

Recommended Doses and Infusion Times

DrugDrug Dose/Infusion Dose/Infusion TimeTime

IntervalInterval

Estimated CrCl > 60 mL/minEstimated CrCl > 60 mL/min

PamidronatePamidronateZoledronic acidZoledronic acid

90 mg over 2-3 hrs90 mg over 2-3 hrs4 mg over 15 mins4 mg over 15 mins

3-4 wks3-4 wks3-4 wks3-4 wks

Estimated CrCl 30 to < 60 mL/minEstimated CrCl 30 to < 60 mL/min

PamidronatePamidronate

Zoledronic acidZoledronic acid

90 mg over 2-3 90 mg over 2-3 hrs*hrs*

Reduced dosageReduced dosage††

3-4 wks3-4 wks3-4 wks3-4 wks

Estimated CrCl < 30 mL/minEstimated CrCl < 30 mL/min

PamidronatePamidronate

Zoledronic acidZoledronic acid

90 mg over 4-6 90 mg over 4-6 hrs*hrs*

Not recommendedNot recommended

3-4 wks3-4 wks

*Consider dose reduction .†3.5mg (CrCl 50-60 mL/min); 3.3 mg (CrCl 40-49 mL/min); 3.0 mg (CrCl 30-39 mL/min).

Kyle R, et al. J Clin Oncol. 2007;25:2464-2472.

Bisphosphonates and Osteonecrosis

Uncommon complication causing avascular necrosis of maxilla or mandible

Suspect with tooth or jaw pain or exposed bone

May be related to duration of therapy

True incidence unknown

Always enquire recent dental therapy or tooth related problems before starting bisphosphonates

Papapetrou PD. Hormones (Athens). 2009;8:96-110.

POEMS (Osteosclerotic myeloma)

POEMS (Osteosclerotic myeloma)

Plasma Cell Leukemia • >2 X 109/L plasma cells in blood (

seen on peripheral smear)

• Younger age

• Higher incidence of organomegaly

and lymphadenopathy

• More extensive bone marrow

infiltration

• Renal failure more common

• Less bone pain, fewer lytic lesions

• Poor response to therapy

Peripheral smear showing Plasma cellsPeripheral smear showing Plasma cells

• Monoclonal gammopathy - IgM typeIgM type

• Plasmacytoid lymphoma

• Median age at diagnosis - 60 yrs

• Presentation :• Hyperviscosity syndromeHyperviscosity syndrome (15%) : visual impairment, neurologic

manifestations• Bleeding ( Acquired VWD)• Cryoglobulinaemia• Organomegaly, lymphadenopathy + (20%-40%)• Autoimmune hemolysis - common• Bone marrow involvement 90%• Lytic bone lesions 2%• Hypercalcemia 4%

• Management : • Asymptomatic patients not treated until symptoms develop• If Hyperviscocity features urgent Plasmapheresis • Symptomatic WM : Rituximab based therapy

Waldenstrom’s Macroglobulinemia

Amyloidosis

Evaluate for amyloidosis in patients Evaluate for amyloidosis in patients with a monoclonal with a monoclonal protein in serum or urineprotein in serum or urine plus plus:

• Nephrotic syndrome or renal insufficiency• Congestive heart failure• Peripheral neuropathy• Carpal tunnel syndrome• Hepatomegaly• Idiopathic malabsorption

• Diagnostic Criteria: Diagnostic Criteria: • Tissue biopsy showing typical morphology• Apple green birefringence under polarized light after Congo Red

staining• Typical fibrillar ultrastructure

• Diagnostic methods and Sensitivity Diagnostic methods and Sensitivity • Bone marrow examination 56%• Abdominal fat aspiration 80%• Combined BM & fat aspirate 89%

Amyloidosis

Questions?