Lecture 10: Plasma Cell Disorders Flashcards
Essential monoclonal gammopathy (aka MGUS) is most commonly seen in what age group and is more prevalent in which ethnicity?
- Occur in older pt’s >50 y/o
- 2-3x more common in pt’s of African descent
Essential monoclonal gammopathy (aka MGUS) is defined by what 2 key features?
- 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)
How is essential monoclonal gammopathy (aka MGUS) best managed?
- 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
Multiple myeloma should be considered in pt’s with what signs/sx’s?
- Anemia, fatigue, weight loss, bone pain
- Pathological fractures, lytic bone lesions
- Hypercalcemia
- Kidney failure
- Recurrent infections (particularly pneumococcal)
Which plasma cell tumor may arise in some pt’s with multiple myeloma and what complications can this lead to?
Plasmacytomas; if in vertebrae, ↑ risk of spinal cord compression
The large number of M proteins in the blood of pt with multiple myeloma lead to what abnormal finding on blood smear?
Rouleaux formation = red cells sticking together
Evaluation of multiple myeloma begins with what 2 tests?
Serum protein electrophoresis and urine protein electrophoresis on a 24-hour urine sample
After serum electrophoresis what other labs/tests should be ordered for suspected multiple myeloma?
- CBC
- Radiographic bone survery
- Serum creatinine, BUN, and calcium levels
- Bone marrow aspirate and biopsy
Why are bone scans not obtained for dx of multiple myeloma?
Because myeloma lesions are usually lytic and lack assoc. increase in osteoblast activity that leads to (+) bone scans
Why is β2-microglobulin and LDH important for the diagnosis of multiple myeloma?
Measures tumor burden
Which chromosomal abnormality is associated with shorter disease-free and overall survival in multiple myeloma pt’s?
Deletion of the long arm of chromosome 13
What does a bone marrow plasma cell labeling index measure and why is it useful in multiple myeloma?
Specifically measures plasma cell proliferation; prognostic for survival
What should always be in the differential of a patient with an A:G ratio <1?
Plasma cell disorder (MGUS, myeloma, etc,)
What is treatment for MGUS and pt’s with myeloma who lack any end-organ damage and who are asymptomatic?
No treatment; just observation
Which serum β2-microglobulin level is considered stage III and poor prognosis for myeloma?
>5.5 mg/L
What is considered the best therapy for multiple myeloma and who should it be used for?
Autologous stem cell transplantation; pt’s <75 y/o with good performance status
Beyond advanced age and poor performance, what are 3 contraindications to autologous stem cell transplant in multiple myeloma pt?
- Unstable and progressive kidney disease
- Decompensated cirrhosis
- New York Heart Association class III or IV heart failure
What must be done first in multiple myeloma pt’s who are eligible for transplantation therapy?
Induction chemotherapy regimen for 2-4 months to reduce tumor burden and to demonstrate responsiveness to chemo
Which chemotherapeutic agents are used for induction therapy in multiple myeloma pt’s prior to transplantation?
- High-dose dexamethasone + thalidomide
- Newer agents = lenalidomide and bortezomib
Why must thalidomide and lenalidomide be used cautiously in treating women of child-bearing age?
Potent teratogens
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?
- Risk for venous thrombombolism
- Require thromboprophylaxis w/ low-molecular-weight heparin or warfarin
What is the follow-up like for pt with multiple myeloma?
Followed on a monthly basis to determine response to therapy and to assess kidney function, blood cell counts, and calcium levels
All pt’s with multiple myeloma receiving prolonged glucocorticoid should receive what prophylactic tx?
TMP-SMX to prevent Pneumocystis pneumonia
Pt’s with multiple myeloma who are being treated with bortezomib should be treated prophylactically with what?
Acyclovir to prevent reactivation of VZV
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
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
What is an effective palliation therapy for localized bone pain in pt with multiple myeloma?
Radiation therapy
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 hypercalcemia may resolve with hydration alone; this may also improve early AKI
- Severe kidney injury may require dialysis
Which findings are suggestive of Waldenström Macroglobulinemia in contrast to multiple myeloma?
- Assoc. w/ lymphadenopathy, hepatosplenomegaly and hyperviscosity
- NO bone lesions or hypercalcemia!
How is IgM myeloma distinguished from Waldenström Macroglobulinemia?
Pt’s with lytic bone lesions and predominant infiltration w/ CD138+ plasma cells in the BM
Which distinct somatic mutation is present in >90% of pt’s with Waldenström Macroglobulinemia?
MYD88 L265P somatic mutation
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
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
Patients with Waldenström Macroglobulinemia commonly present how, which features are distinct?
- Weakness, fatigure, and recurrent infections (like MM)
- But epistaxis, visual disturbancesandneurological sx’ssuch asperipheral neuropathy+dizziness+HA+transient paresis=more common
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
What are common PE findings assoc. with Waldenström Macroglobulinemia?
- Adenopathy and hepatosplenomegaly
- Opthalmoscopic exam may reveal vascular segmentation and dilation of the retinal veins
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
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
How can control of serious hyperviscosity sx’s such as altered state of consciousness or paresis in pt with Waldenström Macroglobulinemia be achieved?
Plasmapheresis
What are 4 pretreatment parameters in pt with Waldenström Macroglobulinemia which define a high-risk population?
- Older age
- Male sex
- General sx’s
- Cytopenias
What is general tx for pt with Waldenström Macroglobulinemia that is indolent?
Generally no therapy
When treatment is warranted for Waldenström Macroglobulinemia, which drug can be used to target the constitutively activated Bruton tyrosine kinase?
Ibrutinib
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
What are the 4 criteria which must be met for diagnosis of POEMS syndrome?
- Polyneuropathy
- Monoclonal plasma cell proliferative disorder
- Any one of the following: (a) sclerotic bone lesions; (b) Castleman’s disease (c) ↑ levels of VEGF
- 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
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
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
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)
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!
Gamma heavy chain disease (Franklin disease) is frequently assoc. w/ autoimmune disease, especially what?
Rheumatoid arthritis
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
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
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
What is the most common of the heavy chain diseases?
Alpha heavy chain disease (Seligmann Disease)
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
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
What is an effective combo therapy for alpha heavy chain disease (Seligmann Disease)?
Chemotherapy + antibiotics
Immunoproliferative Small-Intestinal Disease (IPSID) is recognized as an infectious pathogen-associated human lymphomas that is associated with what bacteria?
Campylobacter jejuni
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
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
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)
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
Diagnosis of mu heavy chain disease requires what?
Ultracentrifugation or gel filtration to confirm non-reactivity of the paraprotein with the light chain reagent
How are patients with mu heavy chain disease treated?
No different from other pt’s with CLL
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
What is the most easily accessible tissue for biopsy and is positive in >80% of patients with systemic amyloidosis?Ad
Abdominal fat
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
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
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
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
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
How does splenic involvement in AL amyloidosis present?
Functional hypersplenism WITHOUT significant splenomegaly
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
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
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
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
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
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
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
