Lecture 10: Plasma Cell Disorders Flashcards
1
Q
Essential monoclonal gammopathy (aka MGUS) is most commonly seen in what age group and is more prevalent in which ethnicity?
A
- Occur in older pt’s >50 y/o
- 2-3x more common in pt’s of African descent
2
Q
Essential monoclonal gammopathy (aka MGUS) is defined by what 2 key features?
A
- Presence of a monoclonal Ig or monoclonal Ig light chain in serum
- Absence of evidence for an overt malignancy of B lymphocytes or plasma cells (i.e., lymphoma, myeloma, or amyloidosis)
3
Q
How is essential monoclonal gammopathy (aka MGUS) best managed?
A
- Long term follow-up at appropriate intervals to detect conversions from a stable asymptomatic condition to a progressive lymphoma or myeloma
- In absence of symptomatic gammopathy, periodic follow-up is all that’s required
4
Q
Multiple myeloma should be considered in pt’s with what signs/sx’s?
A
- Anemia, fatigue, weight loss, bone pain
- Pathological fractures, lytic bone lesions
- Hypercalcemia
- Kidney failure
- Recurrent infections (particularly pneumococcal)
5
Q
Which plasma cell tumor may arise in some pt’s with multiple myeloma and what complications can this lead to?
A
Plasmacytomas; if in vertebrae, ↑ risk of spinal cord compression
6
Q
The large number of M proteins in the blood of pt with multiple myeloma lead to what abnormal finding on blood smear?
A
Rouleaux formation = red cells sticking together
7
Q
Evaluation of multiple myeloma begins with what 2 tests?
A
Serum protein electrophoresis and urine protein electrophoresis on a 24-hour urine sample
8
Q
After serum electrophoresis what other labs/tests should be ordered for suspected multiple myeloma?
A
- CBC
- Radiographic bone survery
- Serum creatinine, BUN, and calcium levels
- Bone marrow aspirate and biopsy
9
Q
Why are bone scans not obtained for dx of multiple myeloma?
A
Because myeloma lesions are usually lytic and lack assoc. increase in osteoblast activity that leads to (+) bone scans
10
Q
Why is β2-microglobulin and LDH important for the diagnosis of multiple myeloma?
A
Measures tumor burden
11
Q
Which chromosomal abnormality is associated with shorter disease-free and overall survival in multiple myeloma pt’s?
A
Deletion of the long arm of chromosome 13
12
Q
What does a bone marrow plasma cell labeling index measure and why is it useful in multiple myeloma?
A
Specifically measures plasma cell proliferation; prognostic for survival
13
Q
What should always be in the differential of a patient with an A:G ratio <1?
A
Plasma cell disorder (MGUS, myeloma, etc,)
14
Q
What is treatment for MGUS and pt’s with myeloma who lack any end-organ damage and who are asymptomatic?
A
No treatment; just observation
15
Q
Which serum β2-microglobulin level is considered stage III and poor prognosis for myeloma?
A
>5.5 mg/L
16
Q
What is considered the best therapy for multiple myeloma and who should it be used for?
A
Autologous stem cell transplantation; pt’s <75 y/o with good performance status
17
Q
Beyond advanced age and poor performance, what are 3 contraindications to autologous stem cell transplant in multiple myeloma pt?
A
- Unstable and progressive kidney disease
- Decompensated cirrhosis
- New York Heart Association class III or IV heart failure
18
Q
What must be done first in multiple myeloma pt’s who are eligible for transplantation therapy?
A
Induction chemotherapy regimen for 2-4 months to reduce tumor burden and to demonstrate responsiveness to chemo
19
Q
Which chemotherapeutic agents are used for induction therapy in multiple myeloma pt’s prior to transplantation?
A
- High-dose dexamethasone + thalidomide
- Newer agents = lenalidomide and bortezomib
20
Q
Why must thalidomide and lenalidomide be used cautiously in treating women of child-bearing age?
A
Potent teratogens
21
Q
Multiple myeloma pt’s receiving either thalidomide or lenalidomide with dexamethasone as combination therapy have a very high risk for what; how is this managed?
A
- Risk for venous thrombombolism
- Require thromboprophylaxis w/ low-molecular-weight heparin or warfarin
22
Q
What is the follow-up like for pt with multiple myeloma?
A
Followed on a monthly basis to determine response to therapy and to assess kidney function, blood cell counts, and calcium levels
23
Q
All pt’s with multiple myeloma receiving prolonged glucocorticoid should receive what prophylactic tx?
A
TMP-SMX to prevent Pneumocystis pneumonia
24
Q
Pt’s with multiple myeloma who are being treated with bortezomib should be treated prophylactically with what?
A
Acyclovir to prevent reactivation of VZV
25
What should be given to multiple myeloma patients to decrease bone fractures and bone pain; this tx can only be administered for how long
**Bisphosphonates** (pamidronate or zoledronate); therapy limited to **2 years**
26
Patients with multiple myeloma and back pain need prompt radiographic evaluation with what type of imaging modality; why?
**MRI**, to rule out spinal cord compression
27
What is an effective palliation therapy for localized bone pain in pt with multiple myeloma?
**Radiation therapy**
28
How should the acute kidney injury of patient with multiple myeloma be managed; what about when severe?
- Maintain **hydration** and **avoidance** of **nephrotoxic drugs + contrast dyes**
- Mild **hyper**calcemia may resolve with **hydration alone;** this may also improve **early AKI**
- **Severe kidney injury** may require **dialysis**
29
Which findings are suggestive of Waldenström Macroglobulinemia in contrast to multiple myeloma?
- Assoc. w/ **lymphadenopathy**, **hepatosplenomegaly** and **hyperviscosity**
- **NO** bone lesions or hypercalcemia!
30
How is IgM myeloma distinguished from Waldenström Macroglobulinemia?
Pt's with **lytic bone lesions** and **predominant** infiltration w/ **CD138+ plasma cells** in the **BM**
31
Which distinct somatic mutation is present in \>90% of pt's with Waldenström Macroglobulinemia?
**MYD88 L265P** somatic mutation
32
What is the role of the MYD88 mutations in the pathogenesis of Waldenström Macroglobulinemia?
Triggers **Bruton tyrosine kinase**, **hematopoietic cell kinase growth**, and **survival signaling**
33
What is the basis for some patients with Waldenström Macroglobulinemia developing a peripheral neuropathy before the appearance of a neoplasm?
Some pt's have **IgM** with **specificity** for **myelin-associated glycoprotein (MAG)**; which is assoc. w/ **demyelinating** disease of **peripheral nervous system**
34
Patients with Waldenström Macroglobulinemia commonly present how, which features are distinct?
- **Weakness, fatigure**, and **recurrent infections** (like MM)
- But **epistaxis****, visual disturbances**and**neurological sx's**such as**peripheral neuropathy**+**dizziness**+**HA**+**transient paresis**=**more common**
35
How does the presence of CXCR4 mutations vs. MYD88 mutations in Waldenström Macroglobulinemia affect the course of disease?
- **CXCR4** is assoc. with **higher bone marrow disease burden** and **higher incidence** of **hyperviscosity**
- Pt's with **wild-type MYD88** show **lower bone marrow disease burden**
36
What are common PE findings assoc. with Waldenström Macroglobulinemia?
- **Adenopathy** and **hepatosplenomegaly**
- **Opthalmoscopic** exam may reveal **vascular segmentation** and **dilation** of the **retinal veins**
37
Which peripheral smear and lab findings associated with Waldenström Macroglobulinemia are much more common than in MM?
- **Normocytic, normochromic anemia**
- **Rouleaux formation** and a **(+) coombs test** = much more common
- **Malignant lymphocytes** usually present in **peripheral blood**
- About 10% of macroglobulins are **cryoglobulins** = **pure M cells components**
38
Patients suspected of having a cryoglobulin based on hx and PE should have their blood drawn how specifically?
Into a **warm syringe** and delivered to lab in container of **warm water** to **avoid errors** in **quantitating** the **cryoglobulin**
39
How can control of serious hyperviscosity sx's such as altered state of consciousness or paresis in pt with Waldenström Macroglobulinemia be achieved?
**Plasmapheresis**
40
What are 4 pretreatment parameters in pt with Waldenström Macroglobulinemia which define a high-risk population?
- **Older age**
- **Male sex**
- **General sx's**
- **Cytopenias**
41
What is general tx for pt with Waldenström Macroglobulinemia that is indolent?
Generally **no therapy**
42
When treatment is warranted for Waldenström Macroglobulinemia, which drug can be used to target the constitutively activated Bruton tyrosine kinase?
**Ibrutinib**
43
Other than Ibrutinib, what are the other first-line agents used in symptomatic Waldenström Macroglobulinemia?
- **Rituximab** (anti-CD20) **alone** or in **combo with**:
- **Alkylators** (bendamustine or cyclophosphamide)
**or**
- **Proteasome inhibitors** (bortezomib)
- **Fludarabine** and **Cladribine** are also **highly effective** single agents
44
What are the 4 criteria which must be met for diagnosis of POEMS syndrome?
1. **Polyneuropathy**
2. **Monoclonal** plasma cell proliferative disorder
3. Any one of the following: (a) **sclerotic bone lesions**; (b) **Castleman's** **disease** (c) ↑ levels of **VEGF**
4. Any one of the following: (a) **organomegaly**; (b) **extravascular volume overload** (edema, pleural effusion, ascites); (c) **endocrinopathy**; (d) **skin changes**; (e) **papilledema**; (f) **thrombocytosis/polycythemia**
45
High circulating levels of what proinflammatory cytokines and low levels of what have been documented in POEMS syndrome?
- **High** levels of **IL-1, IL-6, VEGF,** and **TNF**
- **Low** levels of **TGF-**β
46
Pt's with POEMS syndrome presenting with isolated sclerotic lesions may have resolution of neuropathic symptoms after what tx?o
Local therapy for **plasmacytoma** w/ **radiotherapy**
47
What are some of the common endocrine manifestations of POEMS syndrome?
- **Amenorrhea** in **women** and **impotence + gynecomastia** in **men**
- **Hyperprolactinemia** --\> **papilledema** and ↑ **CSF pressure**
- **Type 2 DM**
- **Hypothyroidism** and **adrenal insufficiency** (Cushing syndrome)
48
Gamma heavy chain disease (Franklin disease) affects which individuals and what are the common manifestations; what is its distinctive sx?
- Affects people of **all ages**
- Characterized by **LAD, fever, anemia****, malaise****, hepatosplenomegaly** and **weakness**
- **Distinctive sx** = **palatal edema**, which may progress to **respiratory compromise!**
49
Gamma heavy chain disease (Franklin disease) is frequently assoc. w/ autoimmune disease, especially what?
**Rheumatoid arthritis**
50
Diagnosis of gamma heavy chain disease (Franklin disease) is made how?
Demonstration of an anomalous **serum M component** (often **\<20 g/L**) that **reacts** with **anti-IgG** but **NOT** anti-light chain reagents
51
What is the typical course of the disease for pt's with gamma heavy chain disease (Franklin disease)?
Usually **rapid downhill course**; however, some pt's have survived **5 years** with **chemotherapy**
52
When symptomatic what does the therapy for gamma heavy chain disease (Franklin disease) include?
- **Chemo** combos used in **low-grade lymphoma**
- **Rituximab** has shown some efficacy
53
What is the most common of the heavy chain diseases?
**Alpha heavy chain disease** (**Seligmann Disease**)
54
Alpha heavy chain disease (Seligmann Disease) is due to what?
**Infiltration** of the **lamina propria** of the **small intestine** with **lymphoplasmacytoid cells** that secrete **truncated alpha chains**
55
How do pt's with alpha heavy chain disease (Seligmann Disease) commonly present?
**Chronic diarrhea**, weight loss, and **malabsorption** + **extensive mesenteric** and **para-aortic adenopathy**
56
What is an effective combo therapy for alpha heavy chain disease (Seligmann Disease)?
**Chemotherapy** + **antibiotics**
57
Immunoproliferative Small-Intestinal Disease (IPSID) is recognized as an infectious pathogen-associated human lymphomas that is associated with what bacteria?
*Campylobacter jejuni*
58
Immunoproliferative Small-Intestinal Disease (IPSID) involves what part of the intestine and is associated with excessive what?
- Mainly the **proximal small intestine** --\> malabsorption, diarrhea, and abdominal pain
- **Excessive plasma cell differentiation** and production of **truncated** **alpha heavy chain proteins** lacking the light chains as well as the first constant domain
59
How is early stage Immunoproliferative Small-Intestinal Disease (IPSID) treated and what happens if left untreated?
- **Eary stage** responds to **antibiotics (30-70% complete remission)**
- Most **untreated** pt's progress to **lymphoplasmacytic** and **immunoblastic lymphoma**
60
The secretion of isolated mu heavy chains into the serum appears to occur in a very rare subset of which pt's?
Pt's with **chronic lymphocytic leukemia** **(CLL)**
61
The only features that may distinguish patients with mu heavy chain disease are the presence of what?
**Vacuoles** in the **malignant lymphocytes** and the **excretion** of **kappa light chains** in the **urine**
62
Diagnosis of mu heavy chain disease requires what?
**Ultracentrifugation** or **gel filtration** to confirm **non**-reactivity of the paraprotein with the light chain reagent
63
How are patients with mu heavy chain disease treated?
**No different** from other pt's with **CLL**
64
How does AL differ from AA amyloid?
- **AL** is amyloid composed of **Ig light chains**; also known as **primary amyloidosis** and can be assoc. with **myeloma** or **lymphoma**
- **AA** is **acute phase reactant** protein **serum amyloid A (SAA)** and occurs in setting of **chronic inflammation** or **infection**; is known as **secondary amyloidosis**
65
What is the most easily accessible tissue for biopsy and is positive in \>80% of patients with systemic amyloidosis?**Ad**
**Abdominal fat**
66
Amyloid deposits will impart which unique staining characteristic when viewed under light microscopy?
**"Apple green" birefringence** by **polarized light microscopy** when stained with **Congo red dye**
67
What are the most frequently involved organ in systemic amyloidosis (AL) and how does this present?
- **Kidneys**
- Manifsts as **proteinuria** (often **nephrotic range**) and assoc. **hypoalbuminemia**, 2' **hypercholesterolemia**, **hypertriglyceridemia** + **edema** or **anasarca**
- Some pt's have **interstital** deposits prod. **azotemia** without proteinuria
68
The heart is the 2nd most common organ involved in systemic amyloidosis (AL) and how can this be seen clinically on EKG and other imaging modalities?
- **Early** on, ECG show **low voltage** in **limb leads** with a **pseudo-infarct pattern**
- Echocardiographic features, include **concentrically** thickened **ventricles** and **diastolic dysf.** w/ **abnormal global longitudinal strain pattern**; a **"sparkly" appearance**
69
Pt's with cardiac involvement in systemic amyloidosis (AL) are at risk for what complications due to poor atrial contractility?
Development of **atrial thrombi** and **stroke**
70
What are 2 pathognomonic findings of AL amyloidosis
- **Macroglossia** (only **10%** of pt's)
- **Cutaneous ecchymoses**, particularly around the **eye**, producing the "**raccoon-eye**" sign
71
How does splenic involvement in AL amyloidosis present?
**Functional hypersplenism** WITHOUT significant **splenomegaly**
72
What is key in making the diagnosis of AL amyloidosis?
**Identification** of an **underlying clonal plasma cell** or **B lymphoprolierative process** and a **clonal LC** are **key**
73
How can serum or urine monoclonal LC or whole immunoglobulin detectable in 90% of AL amyloidosis pt's be detected?
- **Immunofixation electrophoresis** of **serum** or **urine** or by **measurement** of **serum "free" LC's**
- Examining the **ratio** as well as the absolute amount of **serum-free LCs** is **ESSENTIAL**
74
Kappa or lambda clonality in pt with suspected AL amyloidosis should be demonstrated how?
By **flow cytometry**, immunohistochemistry, or **in situ hybridization** for **LC** **mRNA**
75
What are some of the aggressive treatment options for pt's with AL amyloidosis?
- **Dexamethasone**
- **High-dose IV melphalan** followed by **autologous stem cell transplant** (HDM/SCT) is **aggressive** tx that is only suitable for **minority**
- **Cardiac transplant** followed by HDM/SCT in those with **impaired cardiac function**
76
For patients with AL amyloidosis and nephrotic syndrome what is the best supportive methods of tx for edema and to produce diuresis?
- **Diuretics** and **supportive stocking** can ameliorate edema
- **Effective diuresis** can be facilitated w/ **albumin infusions** to raise **intravascular oncotic pressure**
77
CHF and atrial/ventricular arrhythmias due to amyloid cardiomyopathy is best treated how?
- **Diuretics** for CHF
- **Amiodarone** can be used for arrhythmias
- **_AVOID_** digitalis, CCB's and beta blockers
78
Atrial contraction dysfunction is common in amyloid cardiomyopathy and increases risk for thromboembolic complications, how can this be managed?
Consider **anti-coagulant** even in absence of **Afib**
