Approach to

Patients with Monoclonal Immunoglobulin

Disorders

Ig abnormalities can be classified as one of three

main categories

hypogammaglobulinemia,

polyclonal Ig elevations and

monoclonal Ig disorders

For any of these abnormalities, a careful medical

history and thorough laboratory evaluation are

needed to confirm a suspected diagnosis,

particularly because of the major implications of

the diagnosis and potential prognosis for a

person with a monoclonal Ig disorder

General Principles

After these questions have been answered, the

laboratory information is combined with information

from the history and physical examination to narrow

the diagnosis

IMMUNOGLOBULIN

ABNORMALITIES: METHODS OF

DETECTION

Clinical Scenarios

Monoclonal Ig disorders are diagnosed in the

asymptomatic stage, with many of the patients

having MGUS or SMM

These patients require no immediate therapy and

must be distinguished from those with active MM.

Monoclonal protein may be detected when the

clinical suspicion of MM is high

One has to be alert to the possibility that in a small

fraction of patients with MM (<2%), no monoclonal

protein can be detected in the serum or urine

If the patient has monoclonal light chains (no heavy

chains) in the blood only (not in the urine) and no

symptoms, the condition has been called idiopathic

Bence Jones proteinemia.

Protein Electrophoresis

The best method for detecting a monoclonal protein

is high-resolution agarose gel electrophoresis.

This test detects abnormalities in the migration of the

proteins on electrophoresis

The test can be performed with samples from the

serum (SPEP) or urine (UPEP).

The resulting densitometric tracing shows a spike

that is commonly referred to as the monoclonal

spike, or M spike

After a localized band or spike has been recognized

on electrophoresis, immunofixation or

immunosubtraction with capillary electrophoresis

should be performed to determine the type of

monoclonal protein

A monoclonal spike is seen as a discrete band that usually migrates to the ɣ or ß region of the electrophoretic strip, and rarely the α2 region.

A polyclonal increase in Igs produces a broad-band or broad-based peak and is limited to the ɣ region.

Two monoclonal proteins (biclonal gammopathy) occur in 8 to 9% of sera containing monoclonal protein abnormalities.

Rarely, a triclonal gammopathy (three monoclonal proteins) is found

Immunofixation,

Immunoelectrophoresis, and

Immunodiffusion

Structural type of a monoclonal protein is determined best by immunofixation

Thus immunofixation should be performed whenever a monoclonal protein of unknown identity is detected with SPEP

Immunofixation may also be performed when a B-cell or plasma cell neoplasm is suspected but no monoclonal spike is apparent, as is frequently the case with AL or nonsecretoryMM

Immunofixation may also be used to monitor for disease relapse in patients who have achieved a complete response to therapy

In the past, immunoelectrophoresis was used to

characterize monoclonal proteins. This test is

more difficult to perform, and it is not as sensitive

as immunofixation.

Other methods for characterizing monoclonal

proteins include capillary zone electrophoresis

and immunosubtraction.

Monoclonal proteins of the IgD and IgE isotypes

usually are measured by immunodiffusion.

Quantitative Immunoglobulins

(Nephelometry)

At the time of diagnosis and to monitor disease, Igs

may be quantified directly with rate nephelometry.

This test is frequently ordered as “quantitative Igs.”

In addition to determining the serum concentration of

the same isotype as the monoclonal protein, the test

can detect a decrease in uninvolved, normal Igs.

Nephelometry is rapid and reliable.

However, it is not useful when the concentration

of the monoclonal protein is low, because

nephelometry cannot differentiate between

monoclonal and polyclonal Igs.

Free Light Chain Assays

Tests for serum free light chains are an important

part of the workup of patients with suspected

plasma cell neoplasms or AL.

These tests measure both free K and λ light

chains and provide a ratio between them.

Excessive skewing indicates the possibility of a

monoclonal protein. It is noteworthy that for

serum free light chains, the ratio between K and λis skewed towards λ

Urine Studies The excretion of light chains in the urine has been

referred to as Bence Jones proteinuria.

If patients have measurable monoclonal Igs (usually =10 g/L) in the serum or if MM or AL are suspected, urine should be collected for determining protein excretion

A timed 24-hour collection is best.

For patients in whom this is done for the first time, immunofixation is also recommended to characterize fully the monoclonal protein present.

Immunofixation is also recommended if no monoclonal protein is detected with UPEP.

Generally, the amount of monoclonal light chain in

the urine reflects the tumor mass of the patient.

However, the presence of Bence Jones

proteinuria alone does not necessarily indicate a

diagnosis of MM, as it also occurs in up to 30% of

patients with MGUS.

Patients with a pattern of nonselective proteinuria

(i.e., albumin predominance) are more likely to

have AL with kidney involvement

DIAGNOSIS

Bone Marrow Examination

For most patients with evidence of a monoclonal

protein, an examination of the bone marrow is

recommended.

This examination should include both an aspirate

and a biopsy sample and an MM-specific test

Bone Marrow Plasma Cell

Labeling Index (PCLI)

The PCLI is a surrogate of cells undergoing mitosis and is the most useful prognostic marker in multiple myeloma.

This is a slide-based test (one slide is labeled with anti-k and one with anti-λ fluorescent antibodies) that scores the number of plasma cells (usually out of 500) that incorporate bromodeoxyuridine.

Bromodeoxyuridine is taken up by cells undergoing DNA synthesis and can be detected with fluorescent-specific antibodies.

The test can also be performed on blood samples mainly to detect circulating plasma cells. Because the test is also done with clone-specific fluorescent antibodies, it provides an estimate of the plasmacytosis and the ratio between k and λ (to detect clonality).

The test can provide information about clonality, plasmacytosis, and labeling index (mitotic activity).

The major limitation to the test is that it can be done only on samples incubated with bromodeoxyuridine at the time of bone marrow aspiration

Radiologic Tests

Patients with an IgM monoclonal protein should have abdominal and chest computed tomography to exclude organomegaly (hepatomegaly and splenomegaly) and bulky lymphadenopathy .

Patients with evidence of MM should have a radiologic examination of the axial and appendicularskeleton (“bone survey”).

In some special circumstances, more sophisticated tests such as magnetic resonance imaging (MRI) have been recommended .

Other tests such as positron emission tomography are being explored

NEOPLASTIC IMMUNOGLOBULIN

DISORDERS

Non–Immunoglobulin M Monoclonal Gammopathy of Undetermined

Significance

MGUS represents the earliest stage of a monoclonal

plasma/lymphoid cell proliferation.

It is critical to distinguish between IgM MGUS and

non-IgM MGUS.

By definition, non-IgM MGUS is a discrete

proliferation of monoclonal plasma cells.

Multiple diagnostic criteria have been applied but

the essence is the same—a discrete proliferation

of plasma cells without evidence of the clone

resulting in disease for the host

One criterion for diagnosis is fewer than 10%

plasma cells in the bone marrow

Because of the heterogeneous nature of disease

involving the bone marrow and different ways for

determining the percentage of plasma cells, the

size of the monoclonal proteins is usually

considered a diagnostic criterion

MGUS to have evolved into a more advanced

plasma cell neoplasm if the serum monoclonal

spike is greater than 30 g/L

An important focus of the physical examination in non-IgM MGUS is the search for bone disease.

Percussion tenderness (spine and sternum) should raise the diagnostic possibility of MM. This is particularly important in patients with IgA MGUS, which may be more difficult to differentiate from MM.

Also, clinicians must be aware of the classic signs and symptoms of AL. AL may be present even with the smallest concentration of monoclonal proteins (occasionally not even detectable), and this possibility should always be kept in mind

CLINICAL MANAGEMENT AND

MONITORING

Because of the nonmalignant nature of MGUS,

patients do not experience end-organ damage

If a patient has evidence suggestive of possible

bone disease (pain in the shaft of extremities that

worsens with movement or weight bearing), a

bone radiographic survey should be done

It has long been the practice not to examine the

bone marrow of patients with suspected MGUS

Monoclonal gammopathy of the IgD or IgE type

presents unique problems because the size of the

monoclonal spike is usually small and cannot be

used to estimate tumor burden. In these cases, a

bone marrow examination is mandatory.

Patients with IgE monoclonal proteins often

present with the most aggressive phenotype of

plasma cell neoplasms, namely, plasma cell

leukemia

Although MGUS includes the term “undetermined

significance,” non-IgM MGUS clearly is the most

important risk factor for the subsequent

development of MM

MGUS is not only a marker of persons at high risk

for the development of MM, but, more important,

is the latent, premalignant condition

When MGUS evolves to MM, the same Ig isotype is expressed in MGUS and MM.

Patients should be followed indefinitely because the risk of progression to MM is never eliminated and has been estimated to be almost 1% per year.

Globally, the risk is greater for patients with higher concentrations of monoclonal proteins.

No good biologic markers are available that can discern or predict which patients will develop into MM

For these patients the recommendation is to have a repeat SPEP in 6 months and, if that is normal, at least yearly thereafter.

Smoldering Multiple Myeloma

(Asymptomatic Multiple Myeloma)

SMM is an intermediate stage between MGUS

and MM

Conceptually, SMM is almost identical to

MGUS—a plasma cell neoplasm without disease

in the host—but represents a more advanced

clone than that found in MGUS, usually with little

evidence of proliferation

Diagnostic criteria have been proposed, including

a clonal plasmacytosis greater than 10% or a

serum monoclonal protein of 30 g/L or greater.

For the diagnosis of SMM to be made, no

anemia, hypercalcemia, bone disease, or renal

insufficiency related only to the plasma cell

neoplasm must be present.

A related diagnosis is indolent MM, which is

nearly identical to SMM but with a small number

of discrete bone lesions

EVOLUTION TO MULTIPLE

MYELOMA

It is important to note that plasma cell neoplasms

do not need to go through all the stages in an

orderly fashion, and patients may quickly

advance to the malignant phase of the disease

from MGUS without a recognizable SMM stage.

Similarly, patients may present to the

hematologist with MM, without MGUS having

been recognized previously

MONITORING

Monitoring should occur every 3 months initially,

and if the condition is stable, at least every 6

months thereafter.

Follow-up tests should include a complete blood

count, serum levels of calcium and creatinine,

SPEP with measurement of the monoclonal

spike, and quantitative measurement of the

involved Ig (e.g., IgG levels in patients with IgG

SMM)

Multiple Myeloma

Magnitude

MM is the most common malignancy of plasma

cells

The diagnosis of MM is straightforward when the

patient has advanced bone lesions and anemia.

However, a high level of suspicion is needed to

make the diagnosis promptly in a patient who

presents with hypercalcemia or renal insufficiency

HYPERCALCEMIA

Hypercalcemia must be diagnosed and treated promptly in MM.

A classic complex may include polydipsia, polyuria, nausea, constipation, somnolence, confusion, and anorexia. Patients may have this constellation of signs and symptoms and believe they have a viral infection of the upper respiratory tract.

Although the workup of other causes of hypercalcemia may be needed, the possibility of MM should take precedence, and empirical treatment may be considered while the diagnosis is being confirmed.

Confirmatory tests can be performed rapidly, and hypercalcemiashould be treated as soon as possible, preferably within hours after its diagnosis if MM is suspected

BONE DISEASE

Bone destruction is an integral part of MM and is seen in at least 70% of patients.

When more sensitive tests are used, nearly all patients have evidence of bone destruction, and its complications

Bone disease associated with MM may involve the extremities, but most frequently it involves the spine.

A characteristic feature is that movement and weight bearing exacerbate the pain

RENAL FAILURE Patients may present because of symptoms of uremia

and only later report other symptoms of MM such as extensive bone pain.

It is critical to assess renal function quickly by measuring the serum level of creatinine.

Renal function (e.g., creatinine clearance) may be investigated in detail after therapy has been initiated.

Patients with MM and renal failure (assuming they are not oliguric) commonly have Bence Jones proteinuriain excess of 1 g/24 hours

BACK PAIN Approximately 5 to 10% of patients with MM have

back pain as a presenting feature.

This pain may be severe and require hospitalization.

Characteristically, it is movement related and

aggravated by cough, sneeze, and strain. Patients

may walk stiffly and have great difficulty getting onto

and off the examination or x-ray table.

MRI is the only reliable way to examine for a possible

epidural tumor with potential spinal cord compression

SOLITARY PLASMACYTOMA

Plasma cell neoplasms may present as a

localized growth of plasma cells referred to as

plasmacytomas

Plasmacytomas can occur in association with

bony structures ( medullary) or in other areas,

most commonly the nasopharynx (

extramedullary)

The term solitary plasmacytoma is applied to

tumor growth in patients with no other evidence of

MM.

Patients with plasmacytoma frequently present

with back pain, and, subsequently, a vertebral

mass is discovered

A site-directed biopsy is usually recommended except in patients with overt MM

Plasmacytomas that arise from bone marrow have a high propensity (approximately 75%) for progressing to MM, but those originating from extramedullary sites are less likely to do so

With the disappearance of a detectable monoclonal protein after radiation treatment for plasmacytoma, the likelihood of definitive control is higher

MULTIPLE MYELOMA MIMICRY

Without overt MM, it is erroneous to assume that

a person with a monoclonal protein in the serum

and a bone lesion identified on radiologic study

has a plasmacytoma.

Thus, needle aspiration or biopsy of the mass is

recommended.

A patient with metastatic cancer may present with

lytic bone lesions

Light Chain–Associated

Amyloidosis

AL is a serious complication of any B-cell

neoplasm capable of producing a monoclonal

protein

AL is associated most commonly with non-IgM

MGUS and, in many cases, the amount of

monoclonal protein may be minimal.

Although AL is slightly more common with λ-type

light chains, it is also seen with k-type light chains

Other features include post proctoscopic

periorbital purpura (4P sign), carpal tunnel

syndrome, macroglossia, jaw claudication,

orthostatic hypotension, diarrhea, and muscle

pseudohypertrophy.

Tissue diagnosis of AL should be sought,

including Congo red staining of suspicious

amyloid deposits

In some patients, AL is diagnosed on the basis of

symptoms, and then tests for monoclonal protein

are performed

Macroglobulinemia and Other

Immunoglobulin M–Producing

Neoplasms

IgM monoclonal gammopathy is rarely a

presenting sign of MM and should immediately

point to the possibility of a lymphoproliferative

disorder, particularly Waldenström

macroglobulinemia

IMMUNOGLOBULIN M MONOCLONAL GAMMOPATHY OF

UNDETERMINED SIGNIFICANCE

A small proportion of patients with MGUS have an IgMmonoclonal protein.

In this case, lymphadenopathy, hepatomegaly, and splenomegaly are evidence of malignant disease, usually Waldenström macroglobulinemia, CLL, or a malignant lymphoma.

All patients should have computed tomography of the abdomen and a bone marrow examination performed unless they are completely asymptomatic and the monoclonal protein level is less than 10 g/L.

The probability of IgM MGUS evolving to one of these disorders is greater than 1% per year

WALDENSTRöM

MACROGLOBULINEMIA

Hepatomegaly, lymphadenopathy, splenomegaly, epistaxis, retinal

hemorrhages, tortuosity of the retinal veins and “sausaging” are clues to

the diagnosis of Waldenström macroglobulinemia.

These signs are characteristic of Waldenström macroglobulinemia and

are distinctly uncommon in MM.

In most patients with Waldenström macroglobulinemia, the bone marrow

is replaced extensively by monoclonal lymphocytes or cells with

lymphoplasmacytic differentiation.

In typical cases of Waldenström macroglobulinemia, the IgM

monoclonal spike is greater than 30 g/L, although there is no reliable

cut-off value for excluding or making the diagnosis.

Hyperviscosity is the hallmark of the disease, but it is clinically

significant in only 15% of patients

NONNEOPLASTIC

IMMUNOGLOBULIN DISORDERS

Polyclonal Gammopathy By definition, polyclonal gammopathy represents an

accumulation of nonneoplastic plasma cells

It is important to confirm with SPEP that the increased Igsare polyclonal; if the SPEP results are equivocal, immunofixation should be used.

Polyclonal increases in the Igs can involve all or just one class of Igs .

For most cases, no major diagnostic workup is needed because the cause is apparent.

For other patients, a complete history and physical examination may provide clues to the origin of the polyclonal gammopathy.

An increase in the erythrocyte sedimentation rate may be

due to the increase in Igs; it is not a good surrogate

marker of inflammation.

Other markers of inflammation, such as C-reactive

protein, may be used.

A special condition to keep in mind as a cause of

polyclonal gammopathy is temporal arteritis, for which

effective treatment is available.

Even if liver enzyme abnormalities are mild, liver disease

should be suspected.

Hypogammaglobulinemia

In patients with recurrent encapsulated bacterial

infections, humoral immune deficiency should be

suspected. In these situations, it is advisable to

perform SPEP and quantitative Igs. Knowing the

age at onset of the problem facilitates diagnosis.

In adults with recurrent sinus or pulmonary

infections and low levels of IgG, IgA, and IgM, the

most likely diagnosis is common variable

immunodeficiency. Replacement therapy with

intravenous Igs is corrective

It is especially important to rule out MM in patients older than 50 years because Ig depression of the uninvolved Igs is frequently seen. This scenario is particularly common in patients with non-secretoryMM.

UPEP and immunofixation are also recommended because patients who have MM that produces only light chains may not have an apparent monoclonal protein in the serum.

Children with hypogammaglobulinemia most likely have a hereditary condition such as Bruton type hypogammaglobulinemia, which is usually an X-linked recessive disorder