105 Essential Monoclonal Gammopathy

Question 1

Two important characteristics of essential monoclonal gammopathy

Monoclonal gammopathy of unknown significance (MGUS) is ensconced as a designation, replacing benign monoclonal gammopathy because approximately one-quarter of patients eventually progress to myeloma, macroglobulinemia, amyloidosis, or a B-cell lymphoma over 2 decades of observation.

Thus, it is monoclonal gammopathy of indeterminate progression or MGIP, not MGUS

Answer 1

1. Plasma immunoglobulin (Ig) or Ig light chain that has the molecular features of the product of a single clone of B lymphocytes or plasma cells: homogeneous electrophoretic migration and a single Ig light-chain type
2. Absence of evidence of an overt neoplastic disorder of B lymphocytes or plasma cells, such as lymphoma, macroglobulinemia, myeloma, or amyloidosis.

Question 2

TRUE OR FALSE

Monoclonal gammopathy can occur at any age, but it is unusual before puberty, and its frequency increases with age.

Answer 2

TRUE

Monoclonal gammopathy can occur at any age, but it is unusual before puberty, and its frequency increases with age.

The frequency of a serum paraprotein using zonal electrophoresis is approximately 1% in persons older than age 25 years, approximately 3% in those older than age 70 years, and approximately 10% in those older than age 80 years

Males are more frequently affected than females.

Question 3

_________________ monoclonal gammopathy arises from somatically mutated postswitch preplasma cells and may have translocations involving the Ig heavy-chain region on chromosome 14.

Answer 3

IgG or IgA monoclonal gammopathy

Question 4

_________________ monoclonal gammopathy arises from a mutated postgerminal center lymphocyte that does not have evidence of isotype switching.

Answer 4

IgM monoclonal gammopathy

Question 5

IgG and IgA monoclonal gammopathies tend to evolve into ________________________, and IgM monoclonal gammopathies tend to evolve into __________________________

Answer 5

IgG and IgA monoclonal gammopathies : myeloma or plasmacytoma (plasma cell phenotypes)

IgM monoclonal gammopathies:lymphomas and Waldenstrom macroglobulinemia (lymphocytic phenotypes)

Question 6

A protein associated with inherited increased risk of IgA and IgG monoclonal gammopathy and myeloma

Answer 6

Paratarg-7 (also known as STOML2, HSPC108, and SLP-2)

Question 7

A somatic mutation found in approximately 50% of individuals with IgM monoclonal gammopathy and in more than 90% of patients with Waldenström macroglobulinemia.

Answer 7

MYD88 L265

Question 8

“Low-risk” monoclonal gammopathy:

Answer 8

(a) those with less than 1.5 g/dL IgG and a normal serum free Ig light-chain ratio or

(b) less than 1.5 g/dL of IgM or light-chain monoclonal gammopathy with a normal serum free light-chain ratio accompanied by an absence of unexplained symptoms (eg, back pain) or other laboratory features of concern

A marrow examination and skeletal imaging may be omitted because they have been shown to be very unlikely to be informative in these settings

Question 9

Blood cell and marrow findings in essential monoclonal gammopathy

Answer 9

Anemia is not present

The proportion of plasma cells in marrow is less than 10%

Microvessel density on average is threefold greater than in normal persons but far less than in patients with myeloma,

Frequent binucleate plasma cells and large plasma cell nucleoli, is a finding more specific for myeloma

Question 10

Patients with essential monoclonal gammopathy categorized risk of progression into four categories:

High:
Intermediate:
Standard:
Low:

Answer 10

High-risk patients: t(4;14) and del 17p

Intermediate-risk: trisomies without translocation

Standard-risk: t(11;14), translocations other than t(4;14) with or without trisomies or chromosome 13 abnormalities

Low-risk: normal results or an insufficient marrow plasma cell sample

Question 11

Percentage of types of monoclonal gammopathy:

IgG:
IgM:
IgA:

Answer 11

Percentage of types of monoclonal gammopathy:

IgG: 70%
IgM: 20%
IgA: 10%

A low percentage of persons may have biclonal or triclonal gammopathy

Question 12

Most patients with essential monoclonal gammopathy have a monoclonal protein concentration of less than _____ g/L, but exceptions occur.

Answer 12

Less than 30 g/L

Question 13

Diagnosis of essential monoclonal gammopathy

Answer 13

• The monoclonal protein level
• The marrow plasma cell concentration (<10%)
• The absence of other features of progressive plasma cell neoplasm (eg, hypercalcemia, osteolysis, otherwise unexplained anemia, otherwise unexplained renal disease)
• The absence of progression on periodic long-term follow-up.

Question 14

The normal range of the κ-to-λ ratio of free light chains in serum is

Answer 14

0.26–1.65

> 1.65: excess κ light chains
< 0.26: excess λ light chains

Question 15

Used to confirm a monoclonal protein found on gel electrophoresis

Answer 15

Immunofixation electrophoresis

May also detect a monoclonal protein not evident on serum protein gel electrophoresis, usually because the protein is in too low a concentration or is embedded in the normal polyclonal α- or β-globulin peak.

Monoclonal proteins identified by immunofixation electrophoresis may be transient (~15–20%) and have a greater likelihood to progress to a disease if they are of an IgA or IgM isotype.

Question 16

In a patient with a presumptive diagnosis of essential monoclonal gammopathy, reexamination should be made at_______months to confirm the diagnosis of a stable clone

Answer 16

3–6 months

Question 17

A term to denote a monoclonal gammopathy that can produce disease, often quite serious, without lymphoproliferation and progression of the neoplastic cell population.

Answer 17

Dangerous small B-cell clone

Functional impairment from a monoclonal protein

Examples: red cell aplasia, TEMPI (telangiectasia, erythrocytosis, monoclonal gammopathy, perinephric fluid, intrapulmonary shunting) syndrome, immune hemolytic anemia, acquired von Willebrand disease,acquired thrombasthenia, immune neutropenia,insulin autoimmune syndrome, and other functional manifestations

Question 18

Medications favored for renal injury in monoclonal gammopathy

Answer 18

Cyclophosphamide, thalidomide, bortezomib, and bendamustine

A glucocorticoid (eg, dexamethasone) and rituximab can also be useful

Plasmapheresis in an effort to decrease plasma monoclonal Igs quickly has been used as an adjunct to chemotherapy

Question 19

TRUE OR FALSE

IgM monoclonal gammopathy has a significantly higher frequency of neuropathy than does IgG or IgA monoclonal gammopathy.

Answer 19

TRUE

IgM monoclonal gammopathy has a significantly higher frequency of neuropathy than does IgG or IgA monoclonal gammopathy.

Question 20

Mechanisms of nerve damage in IgM monoclonal gammopathy

Answer 20

Monoclonal antibodies can react with peripheral nerve myelin, specifically with myelin-associated glycoprotein, glycolipids, or sulfatides.

Question 21

The monoclonal antibodies reactive with nerve antigens usually are of the _____type

Answer 21

IgM type

Question 22

Patients with _________ monoclonal gammopathy usually have chronic inflammatory demyelinating polyneuropathy; a minority have sensory axonal or mixed neuropathy

Answer 22

IgG or IgA monoclonal gammopathy

Question 23

____ gammopathy is associated with dysautonomia

Answer 23

IgA gammopathy

Question 24

Seven treatment approaches have been used to ameliorate the neuropathies:

Answer 24

(a) immunoglobulin (IVIG) administration;
(b) glucocorticoids alone;
(c) immunoadsorption of perfused blood with staphylococcal protein A;
(d) plasma exchange or plasmapheresis;
(e) immunosuppressive cytotoxic chemotherapy, such as cyclophosphamide, chlorambucil, or fludarabine with or without added glucocorticoids;
(f) rituximab (anti–cluster of differentiation [CD] 20 antibody) to deplete B cells; and
(g) high-dose cytotoxic therapy with autologous hematopoietic cell rescue

A recommendation has been made to start therapy with IVIG, especially in essential monoclonal IgM-associated neuropathy, because of the relative safety of this approach.

Question 25

In monoclonal gammopathy of the IgG type, the concentration of monoclonal Ig usually is less than __________

Answer 25

less than 3 g/dL

Patients with monoclonal gammopathy usually have normal polyclonal Ig levels, and if a decrease of their polyclonal Ig levels is present, it is usually not as severe as in myeloma.

Question 26

In the IgA or IgM type, the concentration usually is less than _______

Answer 26

less than 2.5 g/dL

Patients with monoclonal gammopathy usually have normal polyclonal Ig levels, and if a decrease of their polyclonal Ig levels is present, it is usually not as severe as in myeloma.

Question 27

The concentration of plasma cells in the marrow is less than ____%, and the incorporation of tritiated thymidine into marrow plasma cells is negligible (<1%) in essential monoclonal gammopathy.

Answer 27

Less than 10%

Question 28

TRUE OR FALSE

Marrow plasma cells in monoclonal gammopathy express neural cell adhesion molecule (CD56), myeloma cells strongly express this surface protein as well

Answer 28

FALSE

Marrow plasma cells in monoclonal gammopathy do not express neural cell adhesion molecule (CD56), myeloma cells strongly express this surface protein

Blood T-lymphocyte subset levels are normal

Blood B-cell concentration is normal

Question 29

β2M concentration is (low, normal, elevated) in essential monoclonal gammopathy.

Answer 29

not elevated

Question 30

Ophthalmic injury from a monoclonal proteins results from what element deposits on the eye

Answer 30

Copper

Question 31

Prognosis of essential monoclonal gammopathy:

Do not progress to a lymphocytic neoplasm over 25–30 years:

Die of an unrelated cause:

Develop a plasmacytoma, myeloma, amyloidosis, macroglobulinemia, lymphoma, or chronic lymphocytic leukemia over several decades of observation:

Answer 31

Prognosis of essential monoclonal gammopathy:

Do not progress to a lymphocytic neoplasm over 25–30 years: 25%

Die of an unrelated cause: 50%

Develop a plasmacytoma, myeloma, amyloidosis, macroglobulinemia, lymphoma, or chronic lymphocytic leukemia over several decades of observation:25%

Question 32

The actuarial risk of progressing to a clonal B-cell malignancy for all classes of monoclonal protein is approximately _____% per year depending on the population studied.

Answer 32

0.75% per year

Question 33

Drug that may decrease the risk of progression of monoclonal gammopathy to myeloma.

Answer 33

Metformin

Clinical trials have not been reported, and the drug is not approved for that purpose.

Question 34

Patients with low risk of progression to a malignant disorder (eg, myeloma) need not be followed at least _________

Some authorities have suggested that after the diagnosis of essential monoclonal gammopathy is confirmed by a second analysis 3–6 months after the presumptive diagnosis

Answer 34

Once a year

Question 35

The most efficient method of follow-up is to assess three of several factors that may inform the time to progression:

Answer 35

(a) a serum monoclonal protein concentration greater than 1.5 g/dL
(b) an IgM or IgA isotype, and
(c) an abnormal free light-chain ratio

There are two considerations that argue for less frequent follow-up of those deemed less likely to progress based on the height of their monoclonal Ig, the normality of serum light-chain ratio, and an IgG isotype