Monoclonal IgM Gammopathy – Differential Diagnosis, Clinical Presentation, and Therapy SUMMARY

Monoclonal IgM Gammopathy –
Differential Diagnosis, Clinical
Presentation, and Therapy
Manfred Hensel, Peter Dreger, Anthony D. Ho
Introduction: One of the commonest incidental findings on routine screening in the elderly is
that of monoclonal gammopathy. In 20% of cases the immunoglobulin isotype IgM is found.
Methods: Selective literature review including the authors’ own research and study data.
Results: IgM gammopathy, commonly known as Waldenström’s macroglobulinemia, is relatively
rare. However, IgM gammopathy can signal a variety of other disorders with complex
pathophysiology and the potential for multiorgan involvement. The detection of monoclonal IgM
gammopathy alone does not automatically imply a diagnosis of malignancy. The most common
differential diagnosis is monoclonal gammopathy of unknown significance (MGUS) type IgM,
which carries a 1.5% per year risk of transformation into a lymphoproliferative disorder. The
„IgM-related disorders“ are characterized by monoclonal IgM in association with findings such
as polyneuropathy, cryoglobulinemia and other autoimmune phenomena, in the absence of
lymphomatous bone marrow infiltration. Discussion: Progress in the understanding of
pathophysiology, better diagnostic procedures and the availability of innovative treatment
strategies promise improved prognosis in Waldenström’s macroglobulinemia and in impairments
associated with other IgM-related disorders.
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Key words: IgM, monoclonal gammopathy, Waldenström, macroglobulinemia, lymphoma
uring routine checks or when investigating the causes of an increased erythrocyte
sedimentation rate, especially in older people a spike-like peak can sometimes be
observed in the gamma fraction of the serum protein electrophoresis. This „M gradient“ is
a sign of a monoclonal gammopathy, whose cause will have to be investigated (diagram).
Multiple myeloma is the best known disorder associated with monoclonal gammopathy,
but not the most common one. Most common is monoclonal gammopathy of undetermined
significance (MGUS). This is found in more than 3% of people older than 70, often as an
incidental finding. Many other diseases or disorders with sometimes complex pathophysiology
and effects on multiple organ systems – such as the nervous system, kidneys, heart, bones,
and blood formation – may also be a cause for this laboratory result (box 1).
In this review article, we show the differential diagnosis of IgM gammopathy and its
multiple implications for clinical practice, on the basis of a selective literature review and
our own research and study data.
Differential diagnosis
When an M gradient is first found on serum protein electrophoresis, serum and urine immune
fixation electrophoresis should be performed additionally to confirm the diagnosis of
monoclonal gammopathy, and the class specific immunoglobulins should be quantitatively
determined. The immunoglobulin isotype can be determined simultaneously, i.e.,
monoclonal IgG, IgA, or IgM, or the corresponding light chain κ or λ (diagram). Immune
fixation electrophoresis is required only for the primary diagnosis and possibly for checking
whether the treatment has been successful. Quantitative measuring of free light chains in
the serum is a new, highly sensitive, method that may be helpful in assessing the prognosis
and controlling the course of the disease. The most important differential diagnosis of IgM
gammopathy is monoclonal gammopathy of undetermined significance (MGUS) of the
Medizinische Klinik und Poliklinik V (Hämatologie, Onkologie und Rheumatologie), Ruprecht-Karls-Universität Heidelberg: PD Dr.
med. Hensel, Prof. Dr. med. Dreger, Prof. Dr. med. Ho
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a) IgM molecule as pentamer
b) M gradient in protein electrophoresis
c) Immune fixation electrophoresis with monoclonal IgM (IgM molecule from: Pezzutto/ Burmester: Taschenatlas Immunologie. Stuttgart: Thieme
1998; with permission from Thieme-Verlag.)
IgM type. To distinguish this finding from the lymphoproliferative disorders described
below, a bone marrow biopsy and ultrasonography of the upper abdomen are required.
Additionally, a detailed medical history and physical examination are indicated, during
which particular attention should be paid to enlarged lymph nodes, an enlarged spleen, and
ostalgia. X-ray investigation of the skeleton including the large tubular bones is usually not
required and should be considered only when bone involvement is suspected, for example
in ostalgia. A diagnosis of MGUS can be made only if no pathological findings are confirmed
during this procedure (box 2).
An important differential diagnosis comprises the so called "IgM-associated disorders."
Asymptomatic and symptomatic Waldenström's macroglobulinemia (WM) (table 1) have
to be differentiated. For a diagnosis of WM, the following are required:
A confirmed finding of monoclonal IgM at any concentration
Bone marrow infiltration by small lymphocytes with plasmocytoid differentiation or
plasma cell differentiation
Intertrabecular pattern of bone marrow
The characteristic immunophenotype of lymphocytes in the bone marrow.
The differentiation from the "lymphocytoid" variant of chronic lymphatic leukemia
(CLL) may occasionally present difficulties; however, unlike WM, this is positive for CD5
and CD23.
Further, rarer differential diagnosis of monoclonal IgM gammopathy are marginal zone
lymphoma (MZL) – including the mucosa-associated and splenic subtypes (mostly CD11c
Possible causes of monoclonal
gammopathy type IgM
Gammopathy of undetermined
significance (MGUS) (1)
Monoclonal gammopathy of undetermined significance
IgM-associated disorders (e.g. cryoglobulinemia, cold
agglutinin-induced hemolytic anemia, peripheral
Waldenström's macroglobulinemia
Marginal zone lymphoma
Other indolent lymphomas (mantle cell lymphoma, CLL,
follicular lymphoma, IgM myeloma)
Serum concentration of monoclonal immunoglobulin
30 g/l
No osteolysis
No anemia
No hypercalcemia or renal insufficiency that is associated
with monoclonal plasma cell proliferation
10% plasma cells in the bone marrow
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Classification of Waldenström's macroglobulinemia (25)
Monoclonal IgM
Bone marrow infiltration
caused by IgM
caused by bone marrow infiltration
WM, Waldenström's macroglobulinemia; IgM, immunoglobulin M; MGUS, monoclonal gammopathy of undetermined significance
*In some patients possible bone marrow infiltration, i.e., confirmation of clonal B-cells in flow cytometry or polymerase chain reaction, but no findings on bone
marrow histology
positive) – and other B-cell lymphomas, such as mantle cell lymphoma and follicular
lymphoma. Since the histological examination of the bone marrow in WM patients typically
reveals a high proportion of plasma cells, a differentiation will sometimes have to be made
from the rare IgM myeloma. Immunohistologically, IgM myeloma often shows expression
of CD138 or cyclin D1; further, a finding of osteolytes enables a differential diagnosis.
Monoclonal gammopathy of undetermined significance
Monoclonal gammopathy of undetermined significance, which is often an incidental finding,
mostly of the immunoglobulin isotope IgG, more rarely IgA or IgM, is a premalignant pre-stage
of multiple myeloma or other lymphoproliferative disorders. Its incidence increases with age.
According to a recent study in the United States, 3.2% of people older than 50 and 5.3% of
those older than 70 have monoclonal gammopathy of undetermined significance (MGUS) (1).
The isotype IgG occurs in 68.9% of such patients, IgA in 17.2%, and IgM in 10.8%. The
patients are asymptomatic, as per definition, and usually have a monoclonal IgM concentration
below 30 g/l, hemoglobin measurement of more than 12 g/dl, and an absence of bone marrow
infiltration due to lymphoma (2). The rate of progression of MGUS of any isotype into a
multiple myeloma or another lymphoproliferative disorder is 1% per year.
IgM-associated disorders
In patients with an IgM-associated disorder, monoclonal IgM is found as well as the associated
symptoms – e.g., polyneuropathy, cryoglobulinemia, and other autoimmune phenomena –
but no lymphoma infiltration of the bone marrow. Cryoglobulins are immunoglobulins that
precipitate in the cold; they are associated with a range of infectious, autoimmune, and
tumor disorders. The association of essential mixed cryoglobulin type II with HCV
infection in 80–90% of cases is well known. The most common IgM-associated disorders
include immunologically mediated disorders, such as cold agglutinin-induced hemolytic
anemia and the peripheral neuropathies. Responsible are the autoantibody activity of
monoclonal IgM against glycoproteins and glycolipids of the peripheral nerves. The most
common form is distal symmetrical chronic demyelinating peripheral neuropathy (3).
IgM can be deposited directly in tissue, e.g., the renal glomerula, and may thus result in
glomerular damage with proteinuria, dehydration, and uremia. Independent of the level of
the monoclonal protein concentration, amyloidosis due to light chain deposits may be
caused. Additionally, in different rheumatic disorders, in Aids, or after organ transplantation,
secondary monoclonal IgM gammopathies may develop that can result in organ damage in
the way described.
Waldenström's macroglobulinemia
In 1944, Jan Gostar Waldenström, a Swedish specialist in internal medicine, described a
clinical picture in 2 patients that was characterized by fatigue, nosebleeds, swollen lymph
nodes, severe anemia, low serum fibrinogen levels, and high blood viscosity. In these
patients, an abnormal high molecular serum protein level was confirmed, which was later
found to be monoclonal IgM (4).
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Figure 1: Bone marrow smear cytology (Pappenheim staining x 630) of a patient with newly
diagnosed Waldenström's macroglobulinemia (male, age 78, IgM serum concentration 8 g/l).
Bone marrow infiltration with small, mature, lymphatic cells (arrows), individual plasma cells
(*) and a tissue mast cell (#). (Image thanks to Professor T. Haferlach, MLL Münchner
Figure 2: Computed tomography of the abdomen of a patient with newly diagnosed
Waldenström's macroglobulinemia. Clearly visible: splenomegaly without further lymph node
The terms Waldenström's disease or Waldenström's macroglobulinemia have subsequently
been used for many lymphatic neoplasias that are characterized by monoclonal IgM. In the
current WHO classification, WM is grouped with lymphoplasmocytic lymphoma and
termed "lymphoplasmocytic lymphoma/Waldenström's macroglobulinemia." The mere
confirmation of monoclonal IgM production does not automatically equate to WM, because
this abnormality can occur in several other B-cell lymphomas and in MGUS. The term WM
as an independent clinical-pathological entity should be used only in patients with histologically
proved lymphoplasmocytic lymphoma – defined as per the WHO classification – in whom
monoclonal IgM protein has been found concomitantly (consensus recommendation, 2nd
IWWM, 2002, Athens [13]).
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Therapeutic options with evidence level for disorders with IgM gammopathy
Evidence level
No therapy, watchful waiting
(1, 2)
IgM-associated disorders
(e.g., polyneuropathy)
(19, e2–e5)
No treatment, watchful waiting
(7, 8)
With indication for therapy*
Purine analogues (F, CI)
(e6, e7)
Purine analogue combination
(e.g., PC-R)
(20, e8)
Other combinations
(e.g., R-CHOP)
(21, e9)
Autologous/allogenic stem cell transplant
(23, e10, e11)
Waldenström's disease
MGUS, monoclonal gammopathy of undetermined significance; F, fludarabine; Cl, cladribine, PC-R, pentostatin-cyclophosphamide-rituximab;
R-CHOP, rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone.
*See box 3
WM is a rare disorder. In the US, the estimated prevalence is 1 500 newly diagnosed
cases per year (5). In several large cohorts of patients, a median age of 63 has been described,
as well as a slight predominance of the disorder in men (5). Familial clustering has been
described in individual cases; which implies a certain genetic predisposition. The presenting
symptoms of WM are due to direct tumor formation on the one hand, and to the specific
characteristics of monoclonal IgM on the other hand. Usually, IgM results in a strongly
increased erythrocyte sedimentation rate.
In addition to bone marrow infiltration (figure 1) with subsequent hematopoietic
insufficiency, splenomegaly is the primary presenting symptom. In its progressive stages it
may lead to abdominal pain in many patients, but also – in the sense of hypersplenism – to
cytopenia (figure 2). However, excessive lymphadenopathy, as found in other entities, is
rare. Practically every organ system may be affected by direct infiltration or paraneoplastic
Circulating IgM molecules in the form of aggregates and due to hydropexia may result
in increased osmotic pressure and a decreased flow rate, in turn resulting in disrupted
microcirculation (hyperviscosity syndrome). In some 20% of patients, agglutination of the
IgM molecules at low temperatures can be observed (type I cryoglobulinemia). Up to 20%
of patients with WM develop IgM-associated peripheral neuropathy. Of practical relevance
is the observation that when IgM measurements and blood viscosity are very high, and the
plasma volume subsequently expanded, Hb measurements may be falsely low. In this
situation, erythrocyte concentrates should be transfused only hesitantly as they increase the
blood viscosity further.
Prognosis in IgM MGUS and WM
A current study of 213 patients with IgM gammopathy in the US (Olmsted Country,
Minnesota) found the mean age at diagnosis of gammopathy to be 74. The likelihood of a
transformation into a lymphoproliferative malignant disorder was 10% after 5 years, 18%
after 10 years, and 24% after 15 years. The resulting transformation rate was 1.5% per year,
which is higher than that of MGUS in other isotypes. Seventeen patients developed
non-Hodgkin's lymphoma, 6 patients WM, 3 patients primary amyloidosis, and 3 patients
chronic lymphocytic leukemia (6). In patients with a high IgM serum level at first diagnosis
(>25 g/l) and a low serum albumin level, the risk of malignant transformation was higher.
The probability of a patient dying of a lymphoproliferative disorder at old age was much
lower than for other causes of death – e.g., cardiovascular or cerebrovascular disorders.
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Indications for therapy in Waldenström's disease
Constitutional symptoms, such as sustained fever, strong night sweats,
fatigue as a result of anemia, weight loss
Progressive symptomatic lymphadenopathy or splenomegaly
Anemia with hemoglobin levels <10 g/dl subsequent to bone marrow
Thrombopenia <100/nl subsequent to bone marrow infiltration
Hyperviscosity syndrome
Symptomatic sensomotor peripheral neuropathy
Systemic amyloidosis
Renal insufficiency
Symptomatic cryoglobulinemia
Recommendations of the consensus panel of the 2nd International Workshop on Waldenström's
macroglobulinemia, Athens 2002 (13)
The life expectancy of patients with WM is comparable to that of patients with other
indolent lymphomas. With or without therapy, the mean survival is 5 to 10 years. All larger
studies found in agreement that age over 60 and a low hemoglobin level below 10 g/dl are
unfavorable prognostic variables (7–10). The level of IgM paraprotein does not allow conclusions
about the prognosis in the individual case. Patients with IgM-MGUS, asymptomatic or
"smoldering" WM often remain stable for years, even without treatment. At least 20% of
patients with WM survive beyond 10 years; 10–20% die due to other causes (8, 11, 12).
Patients with IgM-MGUS as a rule do not require treatment. But because of the enduring
risk of transformation into a lymphoproliferative malignancy, unlimited annual follow-up
of the laboratory variables and the physical condition are advisable. Patients with IgMassociated disorders, e.g., peripheral neuropathy, may benefit from treatment with
rituximab. Individual observations confirm this (table 2).
As in all indolent B-cell lymphomas, asymptomatic patients with WM do not require
treatment. The consensus recommendations of the 2nd IWWM for therapy indications are
listed in box 3 (13).
Plasmapheresis can be used to lower effectively the serum level of circulating IgM. This
complex procedure is rarely necessary, however. It is indicated in patients with a very high
IgM measurement and life threatening symptoms caused by hyperviscosity, e.g., severe
bleeds, visual impairment, vertigo, ataxia, impaired consciousness. The effects of
plasmapheresis are short lasting.
Alcylating agents as well as purine analogues and the monoclonal anti-CD20 antibody
rituximab have been found to be effective in the primary treatment of WM (table 2). Thus
far, no comparative studies have been done that would justify the preferential use of one of
these substances.
Alcylating agents
Until recently, alcylating agents were regarded as standard treatment. As a rule, chlorambucil
was given orally. Partial remission can be achieved in 50–70% of cases with chlorambucil (14).
Complete remission is rare. The extent to which more aggressive combination regimens
containing alcylating agents, such as the CHOP regimen (cyclophosphamide, doxorubicin,
vincristine, prednisolone), may be superior to chlorambucil monotherapy has so far not
been investigated in comparative studies. Especially in older patients, chlorambucil is
therefore still a well tolerated and cost effective therapeutic option.
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Purine analogues
For 15 years now, purine analogues, such as fludarabine, cladribine, and pentostatin, have
been used in diverse lymphoproliferative disorders including WM. Treatment response
rates of 40–90% were achieved (e6, e7).
Monoclonal antibodies
The availability of monoclonal antibodies, especially of the anti-CD20 antibody rituximab,
has notably improved the treatment of B-cell lymphomas in recent years. Monotherapy
with rituximab resulted in a response in 20–50% of patients with WM (15–17). Because of
the lack of myelosuppression, rituximab is an attractive therapeutic option especially in
patients with severe cytopenia.
In patients with a very high IgM level at onset (>50 g/l) or high serum viscosity, caution
is advised because occasionally, a temporary increase in the IgM value has been observed
after rituximab had been administered, which in individual cases increased the viscosity
and thus resulted in further complications (18). Initial observations have shown that rituximab
is also efficacious in IgM-associated peripheral neuropathies (19, e2–e5).
Chemotherapy combined with monoclonal antibodies
The most recent treatment strategies have attempted to combine rituximab with cytotoxic drugs.
Our own data on the combination of the purine analogue pentostatin with cyclophosphamide
and rituximab have shown a favorable profile of side effects, with a lower rate of severe
cytopenias, as have often been observed in combination treatment with other purine analogues
(20). The multicenter PERLL study, conducted in collaboration with the Deutsche Studiengruppe
für niedrig maligne Lymphome (GLSG, the German study group for lymphomas of low
malignancy), is planning 6 cycles of rituximab, pentostatin, and cyclophosphamide at 3 week
intervals for patients with previously treated and not previously treated WM, followed by
2 years of maintenance therapy with rituximab at 3 month intervals (
The most persuasive proof so far of the therapeutic use of combining chemotherapy with
alcylating agents and rituximab was provided by a prospective, randomized study of primary
treatment for WM. The only study up to now, it compared standard CHOP therapy with the
combination of rituximab and CHOP in patients with lymphoplasmocytoid or lymphoplasmocytic lymphoma according to the currently valid REAL classification. R-CHOP was found
to be significantly superior, with an overall response rate of 94% versus 69% and a mean time to
treatment failure of 85 months versus 45 months (21). When treating especially elderly patients
according to combined chemotherapy protocols, however, it has to be borne in mind that
cytopenias and infections are to be expected and infection prophylaxis may be necessary (22).
High dose treatment with stem cell transplantation
In spite of an initial good response to cytotoxic agents and antibodies, however, all patients
will develop a recurrence sooner or later; their disorder will become refractory to treatment
after several therapeutic options have been exhausted, and they mostly die from their
disease. For this reason, as in other lymphomas of low malignancy, myeloablative therapy
with autologous stem cell transplantation (SCT) has been introduced, with a curative
intention. In the globally largest series on autologous SCT, which included 14 patients, the
median progression free interval was 69 months, with a follow-up observation period of 50
(12 to 121) months (23). The extent to which early autologous SCT really does achieve a
prognostic improvement in WM is currently being investigated in a randomized comparison
Only few case reports and small studies have been published regarding allogenic stem
cell transplantation (23, e10, e11). Primarily the reduced intensity of the conditioning
seems an interesting therapeutic option for young patients with WM, in whom conventional
therapies have not resulted in longer term control of the disease.
Treatment strategy
The mainstays of WM therapy are:
Alcylating cytotoxic agents (chlorambucil)
Purine analogues (fludarabine, cladribine, pentostatin)
The monoclonal antibody rituximab.
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So far, no sufficient data are available from prospective randomized trials that would
justify a general recommendation for one of these therapeutic options. The selection should
be made according to individual, patient specific criteria. The substances with the highest
likelihood of resulting in remission are the purine analogues. Particularly high remission
rates and sometimes even a longer remission period are to be expected mainly by using
chemo-immunotherapies including rituximab. Especially in elderly patients, chlorambucil
is a good treatment option.
When the disease takes an unfavorable course – in the shape of early recurrence or therapy
resistant disease – allogenic stem cell transplantation in the context of prospective studies
may be considered if the patient's age and general condition permit this. In a scenario of
refractoriness to all 3 treatment groups listed above, therapy with the newer substances may
be considered in the context of studies, e.g., thalidomide/dexamethasone, alemtuzumab,
bortezomib. A current overview over recent therapeutic options can be found in the
summary of the 3rd international workshop on Waldenström's macroglobulinemia (24).
Although WM is a rare disorder, significant progress has been made recently with regard to
treatment. Through the targeted and considered use of the substances mentioned, stable
control of the disease and a good quality of life can be achieved, often for years. The
progress of recent years in the understanding of molecular pathogenesis and pathophysiology
help even now in the development of new, targeted drugs and in using these successfully.
By supporting the study groups in researching the molecular basis, developing new
substances, and conducting large, multicenter studies, it is hoped that in the long term, the
life expectancy of patients with WM can be improved.
Conflict of Interest Statement
Dr Hensel has received study support from Roche, Amgen, and MSO. Professor Dreger has received study support from Roche,
Amgen, Chugaiu, and Schering. Professor Ho has received study support from Roche, Amgen.
Manuscript received on 11 April 2006, final version accepted on 13 February 2007.
Translated from the original German by Dr Birte Twisselmann.
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Corresponding author
PD Dr. med. Manfred Hensel
Medizinische Klinik und Poliklinik V
(Hämatologie, Onkologie und Rheumatologie)
Ruprecht-Karls-Universität Heidelberg
Im Neuenheimer Feld 410
69120 Heidelberg, Germany
[email protected]
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