8/18- Plasma Cell Dyscrasias Flashcards Preview

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Flashcards in 8/18- Plasma Cell Dyscrasias Deck (55):
1

Case)

- 60 yo man with anemia and pathologic fracture of L humerus

- Hb is 7.5 gm/dL, platelets are normal, white count is normal

- Total protein is 11.5 gm/dL; albumin is 2.8 gm/dL

- Calcium and renal function are normal

- PBS as shown

Which one of the following is most likely to be the cause of his anemia and broken bone?

A. Anemia of chronic disease

B. Anemia of renal disease

C. Blood loss

D. Multiple Myeloma

E. Iron deficiency 

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Which one of the following is most likely to be the cause of his anemia and broken bone?

A. Anemia of chronic disease 

B. Anemia of renal disease

C. Blood loss 

D. Multiple Myeloma 

E. Iron deficiency 

2

What is seen on this PBS? 

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Stacks of RBC (Rouleaux)

3

What is shown here? Feature of what?

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Lytic bone lesions in multiple myeloma:

 

4

What is shown here? 

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Protein peak (in gamma)

- Reported as monoclonal

- Compare it to high peak of albumin

- Indicative of hyperproduction (typ of IgG or IgM)

5

What is shown here?

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This is a polyclonal gammopathy (rather than monoclonal peak)

6

What is shown here?

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Multiple myeloma

- Uninvolved immunoglobulins are depressed! (cleans up gels real nicely)

7

What is seen in the urine of pts with multiple myeloma?

Urine protein Electrophoresis (UPEP) shows excreted intact of IgG or IgA protein

- Plasma cells often release a light chain that has not hooked up with heavy chains

- Light chain excreted (either lambda or kappa) in urine

- "" bodies?

8

What is shown here? 

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Plasma cells in multiple myeloma (BM)

9

What is multiple myeloma? Basic characteristics?

A proliferation of malignant plasma cells

- Secretion of a monoclonal Immunoglobulin Protein

- Typically Multiple Foci of Plasma Cells in the Bone Marrow

10

What are manifestations of multiple myeloma?

CRAB criteria

- Elevated Ca

- Renal failure (light chains choking kidney)

- Anemia

- Bone lesions

11

What is this? 

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Binucleate plasma cells (>90%) in multiple myeloma

12

Epidemiology of multiple myeloma?

- 10% of hematologic malignancies

- 4/100,000 annual incidence

- 15,000 new patients per year

- Blacks > whites (2:1)

- Median Age at onset: 66

(Only 2 % are younger than 40)

- Rajkumar SV and Kyle RA

13

Cell markers of multiple myeloma?

Nl plasma cell:

- CD38, 138, 19, 45 (NO 56)

Multiple myeloma plasma cell:

- CD38, 138, 56 (NO 19 or 45)

14

Oncogenic events in multiple myeloma (don't need to know)

IgH (14q2) or IgL translocations

- Frequency increases as pts evolve form MGUS to MM

Partners include:

- CyclinD 11q13

- CyclinD1, D2

- MAF, MMSET

Oncogenes

- IgH rearrangements; loss of 13- haplo insufficiency of RB1

- Ras

- 17p loss and p53 abnormalities

- C myc

- Activation of NFkB

15

Chromosomal content in multiple myeloma?

Hyperlipoid

- 50 % of MGUS and MM

- 49-56 chromosomes

- Extra copies of 3 or more specific chromosomes: 3,5,7,9,11,15,19, 21

Non hyperdiploid

- under 48 and >75

16

Process of events in multiple myeloma?

- Angiogenesis

- Decreased cellular immunity

- Cytokines—paracrine production of IL6 anemia

- Adhesion molecules—extramedullary disease

- Up-regulation of factors that resorb bone

 

17

Gradation from MGUS to PCL (picture)

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18

Mainfestations of multiple myeloma (MM)?

- Bone destruction, Pathological Fractures

- Osteoporosis, Hypercalcemia

- Monoclonal hyperglobulinemia

----Rouleaux, viscosity, sed rate

----Coagulopathy

- Anemia

- Immune dysfunction; ​Recurrent pneumonias

- Myeloma kidney (kidney failure)

- Amyloidosis (due to deposition of light chain as indissolvable substance in endothelium of BVs)

- Neuropathy

Especially bad depending on location

- e.g. if in spine, MM may present as SC lesion

19

Lytic Bone Disease in MM marked by (low/normal/high) levels of Ca? Process?

Lytic bone disease and HYPERcalcemia MIP-1alpha

- Macrophage inflammatory protein 1-alpha RANKL

- Receptor activator of nuclear factor kB ligand

- Interacts with RANK on osteoclasts

Osteoprotegerin (deficiency)

- Decoy receptor for RANKL

20

How does MM affect the kidney?

- Tubules choked with light chain—myeloma kidney—either lambda or kappa light chain

- Glomerular sub endothelium with amyloid deposits—nephrotic syndrome—most often lambda light chain.

Glomerulus with deposits of light chain—light chain deposition disease—most often a kappa light chain

Renal manifestations of MM:

- Myeloma kidney

- Nephrotic syndrome

- Hypercalcemia

- Hyperviscosity

- Stones

- Hyperuricemia

- Dye Nephropathy

- Pyelonephritis

21

What is this? 

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Myeloma kidney

- Red stuff = protein (kappa or lambda light chain mostly)

22

What is this? 

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Amyloid

- "Apple green" birefringence on Congo red stain

23

Common effect of hypercalcemia?

Dehydration

24

Anemia in MM?

- IL6 increased -> stimulates production of hepcidin

- Hepcidin decreases release of iron from macrophages

- Anemia

- Can respond to EPO

- B12 deficiency may occur with MM

25

Diagnostic cirteria for MM

Need (1 and 2) OR (either 1/2 as well as 3, 4, 5, or 6)

1. BM plasma cells > 10%

2. Plasmocytoma

3. M-protein in serum > 3.0 gm IgG

4. Light chains in urine > 1.0 gm/dL

5. Lytic bone lesions, hypercalcemia

6. Plasma cells seen in peripheral blood

CRAB:

- Elevated Calcium

- Renal failure

- Anemia

- Bone lesions

26

Monoclonal proteins in MM?

- IgG: 56%

- IgA: 24%

- IgD: 1%

- Light chains only 19%

- 2-M proteins

- IgE

- Non secretory myeloma under 3.0% (looks like myeloma/abnormal plasma cells, but can't even make weird cells that you can measure)

27

Normal values (don't need to memorize)

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28

Current Tx options for pts with multiple myeloma?

Patient not a candidate for auto-BMT

- MP +/- thalidomide (birth defects; still being made for leprosy?)

Patient is a candidate for auto-BMT

- Dex

- Dex + Lenalidomide

- Dex + Bortezomib (can be used in renal failure)

- Dex + Lenalidomide + Bortezomib

Newer agents:

- Thalidomide: sedation, constipation, birth defects, neuropathy, DVT (in combination with Dex)

- Velcade (bortezomib): cytopenia, neuropathy, zoster

- Revlimid (lenalidomide): cytopenia, fewer DVT than thalidomide, less constipation, neuropathy, $$$$, stem cell issues

29

Treatments for each of these factors of MM:

- Hypercalcemia, lytic bone dz

- Recurrent infections

- Hyperviscosity

Hypercalcemia, lytic bone dz

- Pamidronate/Zoledronate

----Watch renal function

----Osteonecrosis of jaw—relationship to dental work

-----Atypical fractures of femur

- Vertebroplasty, kyphoplasty

Recurrent infections

- IgG

- Vaccinations: pneumococcal

- Dex-PCP, Zoster prophylaxis

Hyperviscosity

- Plasmapharesis

30

Describe autologous BMT process

- Stems cells obtained after mobilization from patient

- High dose melphalan TX

- Rescue with Stem Cells

- Tandem Transplants “Total Therapy”

31

Outlook for pts with MM?

- Old Treatments—survival 3-5 years at most

- New Treatments—survival much improved—possibly 6-10 years or better; pts also have a lot less bone disease and pain

32

What does MGUS stand for?

Monoclonal Gammopathy of Uncertain Significance

33

Characteristics/definition of MGUS?

- Monoclonal immunoglobulin level less than 3 gm/dL.

- Under 10% plasma cells in the bone marrow.

- No bone lesions or symptoms.

- Normal levels of immunoglobulins

34

Table comparing MGUS to MM

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35

M-Spikes by population/demographic?

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36

Range of M spikes for disease?

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37

Prognosis of MM?

Overall a rate of transformation to something new of 1% per year 

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38

What happens in amyloidosis?

- Amyloid fibrils are formed by low molecular weight protein subunits.

- Deposited in multiple organs, with severe organ dysfunction, often irreversible.

- Cardiomyopathy

- Hepatomegaly

- Nephrotic syndrome

- Neuropathy

- Carpal tunnel syndrome

- Periorbital purpura

39

Different types of Amyloidossi?

AL (primary)

- Due to deposition of protein fibrils derived from immunoglobulin light chain fragments

- May have multiple myeloma

AA (secondary)

- Due to deposition of other types of protein that polymerize to form fibrils

40

Describe in more detail AL amyloidosis (primary amyloidosis)

- Immunoglobulin light chain fragments

- Often lambda light chain (6x: lambda > kappa)

- Bone marrow plasma cells often

41

Clinical symptoms of amyloidosis?

- Nephrotic syndrome

- Heart failure, cardiac conduction abnormalities

- Hepatomegaly

- Waxy skin and easy bruising

- Enlarged muscles (tongue, deltoids); carpal tunnel

- Peripheral and/or autonomic neuropathy

- Impaired coagulation

- Fatigue

42

What AA (secondary) amyloidosis?

(He skipped this slide)

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43

Genetics/pathophysiology of AA (seondary) amyloidosis?

Multiple inherited amyloidosis syndromes

- At least 12 proteins identified.

Age-related (senile) systemic amyloidosis

- Fibril composed of transthyretin (formerly called prealbumin).

Organ-specific amyloid

- In brain, (Alzheimer’s), fibril composed of beta protein, derived from amyloid precursor protein.

44

Diagnosis of amyloidosis?

Amyloid has apple green birefringence with Congo red stain; characteristic EM structure

Diagnosis by biopsy of affected tissue

- Abdominal fat pad

- Bone marrow

- Rectum

- Kidney

Immunohistochemical stains to determine type of amyloid

45

Treatment of amyloidosis?

Depends on source of amyloid protein

For AL amyloidosis

- Melphalan and prednisone

- Bortezomib

- High-dose melphalan chemotherapy and autologous stem cell transplantation

46

Another name for Lymphoplasmacytic Lymphoma?

Waldenstrom's Macroglobulinemia

47

What is lymphoplasmacytic lymphoma? Cells involved? Grade? ig?

- Uncommon, low-grade malignancy.

- Malignant plasmacytoid lymphocytes produce IgM.

- The malignant B cell is in an earlier stage of B cell differentiation than the malignant plasma cell involved in multiple myeloma

48

What is seen here? 

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Fundi in Waldenstrom's

49

What is this showing? 

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BM aspirate in Waldenstrom's

50

What is this showing? 

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Immuno-electrophoresis in Waldenstrom's

51

What are clinical characteristics of Waldenstrom's Macroglobulinemia?

Lymphadenopathy and splenomegaly, hyperviscosity, cryoglobulinemia, neuropathy.

Often presents as with nonspecific symptoms:

- Weakness

- Fatigue

- Weight loss

- Epistaxis and gingival bleeding

- Anemia, fever, night sweats

52

What is hyperviscosity syndrome?

- Blurring or loss of vision

- Headache, vertigo, nystagmus, dizziness

- Sudden deafness, diplopia, or ataxia

- Mental confusion

- Disturbances of consciousness, stroke, or coma

The bigger the molecule involved (IgM > IgA > IgG/IgD/IgE > Ig), the easier it is to see hyperviscosity

53

Treatment of Waldenstrom's Macroglobulinemia?

- Smoldering WM: no therapy

- Symptomatic patients:

----Hyperviscosity syndrome: plasmapheresis

----Other symptoms: Chemotherapy or biologics

- Responds well to cladribine (2-CdA), fludarabine, Anti CD 20, or bortezomib.

- Alkylating agents (chlorambucil), CHOP-Rituxan

54

Conclusions:

- M-proteins are common in the elderly

- Not all are MM, most are MGUS (look out for amyloidosis)

- Treatment options include

----Novel chemotherapy (Lenalidomide, bortezomib)

----Autologous stem cell transplant

(:

55

When to order a SPEP?

- When MM, Waldenström’s, or amyloid is suspected

- Anemia (after testing for the usual suspects)

- Osteolytic lesions or fractures

- Osteopenia, Osteoporosis (particularly in a man)

- Unexplained back pain

- Weakness or fatigue

- Hypercalcemia

- Renal Insufficiency

- Presence of Bence Jones proteinuria

- Recurrent bacterial infections

----Unexplained sensorimotor neuropathy

- Carpal tunnel syndrome

Nephrotic syndrome

In terms of possibly amyloidosis:

- Renal insufficiency

- Cardiomyopathy

- CHF

- Orthostatic hypotension

- Malabsorption

- Purpura