8/18- Plasma Cell Dyscrasias Flashcards
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
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
What is seen on this PBS?
Stacks of RBC (Rouleaux)
What is shown here? Feature of what?
Lytic bone lesions in multiple myeloma:
What is shown here?
Protein peak (in gamma)
- Reported as monoclonal
- Compare it to high peak of albumin
- Indicative of hyperproduction (typ of IgG or IgM)
What is shown here?
This is a polyclonal gammopathy (rather than monoclonal peak)
What is shown here?
Multiple myeloma
- Uninvolved immunoglobulins are depressed! (cleans up gels real nicely)
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?
What is shown here?
Plasma cells in multiple myeloma (BM)
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
What are manifestations of multiple myeloma?
CRAB criteria
- Elevated Ca
- Renal failure (light chains choking kidney)
- Anemia
- Bone lesions
What is this?
Binucleate plasma cells (>90%) in multiple myeloma
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
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)
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
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
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
Gradation from MGUS to PCL (picture)
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
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
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
What is this?
Myeloma kidney
- Red stuff = protein (kappa or lambda light chain mostly)
What is this?
Amyloid
- “Apple green” birefringence on Congo red stain
Common effect of hypercalcemia?
Dehydration
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
Diagnostic cirteria for MM
Need (1 and 2) OR (either 1/2 as well as 3, 4, 5, or 6)
- BM plasma cells > 10%
- Plasmocytoma
- M-protein in serum > 3.0 gm IgG
- Light chains in urine > 1.0 gm/dL
- Lytic bone lesions, hypercalcemia
- Plasma cells seen in peripheral blood
CRAB:
- Elevated Calcium
- Renal failure
- Anemia
- Bone lesions
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)
Normal values (don’t need to memorize)
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
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
Describe autologous BMT process
- Stems cells obtained after mobilization from patient
- High dose melphalan TX
- Rescue with Stem Cells
- Tandem Transplants “Total Therapy”
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
What does MGUS stand for?
Monoclonal Gammopathy of Uncertain Significance
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
Table comparing MGUS to MM
M-Spikes by population/demographic?
Range of M spikes for disease?
Prognosis of MM?
Overall a rate of transformation to something new of 1% per year
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
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
Describe in more detail AL amyloidosis (primary amyloidosis)
- Immunoglobulin light chain fragments
- Often lambda light chain (6x: lambda > kappa)
- Bone marrow plasma cells often
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
What AA (secondary) amyloidosis?
(He skipped this slide)
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.
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
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
Another name for Lymphoplasmacytic Lymphoma?
Waldenstrom’s Macroglobulinemia
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
What is seen here?
Fundi in Waldenstrom’s
What is this showing?
BM aspirate in Waldenstrom’s
What is this showing?
Immuno-electrophoresis in Waldenstrom’s
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
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
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
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
(:
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
