An Approach !

1. Approach to
Patients with Monoclonal Immunoglobulin
Disorders

2.  Ig abnormalities can be classified as one of three
main categories
 hypogammaglobulinemia,
 polyclonal Ig elevations and
 monoclonal Ig disorders

3.  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

6. General Principles

8.  After these questions have been answered, the
laboratory information is combined with information
from the history and physical examination to narrow
the diagnosis

9. 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

10.  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.

11. 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

12.  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

13.  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

15. 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 nonsecretory
MM
 Immunofixation may also be used to monitor for disease
relapse in patients who have achieved a complete response to
therapy

16.  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.

17. 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.

18.  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.

19. 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 λ
is skewed towards λ

20. 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.

21.  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

22. DIAGNOSIS

23. 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

24. 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.

25.  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

26. 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 appendicular
skeleton (“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

27. NEOPLASTIC IMMUNOGLOBULIN
DISORDERS

28. 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.

29.  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

30.  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

31.  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

32. 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

33.  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

34.  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

35.  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.

36. 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

37.  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

38. 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

40. 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)

41. Multiple Myeloma

42. 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

43. 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 hypercalcemia
should be treated as soon as possible, preferably within hours after
its diagnosis if MM is suspected

44. 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

46. 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 proteinuria
in excess of 1 g/24 hours

47. 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

48. 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

49.  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

50. 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

51. 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

53.  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

54. 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

55. IMMUNOGLOBULIN M MONOCLONAL GAMMOPATHY OF
UNDETERMINED SIGNIFICANCE
 A small proportion of patients with MGUS have an IgM
monoclonal 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

56. 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

57. NONNEOPLASTIC
IMMUNOGLOBULIN DISORDERS

58. Polyclonal Gammopathy
 By definition, polyclonal gammopathy represents an
accumulation of nonneoplastic plasma cells
 It is important to confirm with SPEP that the increased Igs
are 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.

59.  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.

60. 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

61.  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-secretory
MM.
 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