Received: 18 June 2018 Revised: 12 July 2018 Accepted: 12 July 2018

DOI: 10.1002/hon.2539

REVIEW

Diagnostic framing of IgM monoclonal gammopathy: Focus on

Waldenström macroglobulinemia
Alessandra Tedeschi1 | Concetta Conticello2 | Rita Rizzi3 | Giulia Benevolo4 |
5
Luca Laurenti | Maria Teresa Petrucci6 | Francesco Zaja7 | Marzia Varettoni8

1
Department of Hematology, Niguarda
Cancer Center, ASST Grande Ospedale Abstract
Metropolitano Niguarda, Milan, Italy The finding of an IgM monoclonal gammopathy often represents a diagnostic chal-
2
Department of Clinical and Molecular
lenge. In fact, there are many pathological disorders associated with this condition,
Biomedicine, Haematology Section, University
of Catania, Catania, Italy each of which has distinctive characteristics and requires specific clinical, instrumen-
3
Department of Emergency and Organ tal, and laboratory assessments to set the appropriate treatment. This review has
Transplantation, Hematology Section,
University of Bari Medical School, Bari, Italy
two aims. Firstly, to provide a framework of the broad spectrum of IgM‐associated
4
Division of Hematology, AOU Città della disorders: (1) monoclonal gammopathy of undetermined significance (MGUS); (2)
Salute e della Scienza, Torino, Italy Waldenström macroglobulinemia (WM); (3) IgM‐related disorders (among which
5
Department of Hematology, Catholic
hyperviscosity syndrome, light chain amyloidosis, cold agglutinin disease,
University Hospital “A. Gemelli”, Rome, Italy
6
Hematology, Department of Cellular cryoglobulinaemia, IgM neuropathy, Polyneuropathy, organomegaly, endocrinopathy,
Biotechnologies and Hematology, “Sapienza” monoclonal gammopathy, skin changes (POEMS) syndrome, Castleman disease); (4)
University, Rome, Italy
7
IgM‐secreting multiple myeloma (IgM‐MM); and (5) other lymphoproliferative
Clinica Ematologica, Centro Trapianti e
Terapie Cellulari “Carlo Melzi”, University of disorders which may be associated with IgM (such as chronic lymphocytic leukemia,
Udine, Udine, Italy
small lymphocytic lymphoma, and B‐cell non Hodgkin lymphoma). Secondly, to give
8
Division of Hematology, Fondazione IRCCS
Policlinico S. Matteo, Pavia, Italy
a detailed insight regarding diagnosis and treatment of WM.
Correspondence
Alessandra Tedeschi, Department of KEY W ORDS
Haematology, Niguarda Cancer Center, ASST IgM monoclonal gammopathy, IgM‐related disorders, IgM‐secreting multiple myeloma,
Grande Ospedale Metropolitano Niguarda,
Waldenström macroglobulinemia
Milan, Italy.
Email: alessandra.tedeschi@ospedaleniguarda.it

1 | I N T RO D U CT I O N tests. Its incidence increases with age and occurs in up to 5.3% of

the population older than 70 years.1 Roughly 15% of individuals
The presence of IgM monoclonal gammopathy is associated with a with MGUS has the IgM subtype. The definition of IgM MGUS
broad spectrum of pathologic disorders. Each of them has characteris- is slightly different according to Mayo Clinic or International
tic manifestations and requires specific diagnostic evaluations workshop on WM (IWWM) criteria (Table 1).2,10 However, virtually
and treatments. The aim of this review is to describe the spectrum all IgM‐MGUS patients have a bone marrow involvement lower
of IgM‐associated disorders with a special focus on diagnosis and than 10% and a serum IgM paraprotein lower than 30 g/L.11,12
treatment of Waldenström macroglobulinemia (WM). Multiple myeloma (MM) is virtually always preceded by MGUS,
but it is unknown whether WM is always preceded by IgM
MGUS.13
2 | M O N O C L O N A L G A M M O P A T H Y OF Several predicting models, based on clinical and laboratory fea-
UNDETERMINED SIGNIFICANCE (MGUS) tures (eg, age, sex, albumin, IgG, IgA, IgM Hb levels), have been devel-
oped to categorize patients' risk of progression.14 In absence of
MGUS is a condition in which an abnormal immunoglobin protein symptoms and signs of active disease, patients are required to be
(paraprotein) is incidentally found during standard laboratory blood followed up in 6 months and then annually for life.

Hematological Oncology. 2018;1–12. wileyonlinelibrary.com/journal/hon © 2018 John Wiley & Sons, Ltd. 1
2 TEDESCHI ET AL.

TABLE 1 Essential characteristics, evaluation approach, and management of IgM MGUS and IgM MM

Disorder Distinctive Presenting Features Focused Investigations Management

3
IgM MGUS IgM M‐protein (irrespective of IgM BM (for intermediate‐high risk ) Follow‐up according to rate of
(15% of all concentration) in asymptomatic patients Echo progression 1.5% to 2% per year. The
MGUS) without bone marrow infiltration by FCL ratio main clinical risk factor for
hematological neoplasm2 progression is the size of the M‐
protein4
less than 10% BM involvement and IgM The presence of the MYD88 (L265P)
M‐protein less than 30 g/L2 mutation is associated with higher risk
of progression to WM5
WM (1%‐3% of Mayo Clinic BM According to the presence of disease‐
hematological ‐IgM monoclonal gammopathy, regardless CT scan/echo related symptoms
malignancies) of the size of the M protein, − ≥10%
bone marrow infiltration (usually
intertrabecular) by lymphoplasmacytic
cells with a typical immunophenotype
(surface IgM+, CD5−, CD10−, CD19+,
CD20+, CD23−)

Consensus Panel
‐IgM monoclonal gammopathy with M
protein of any size
‐histologic evidence of bone marrow
involvement by lymphoplasmacytic
lymphoma
IgM MM (0.5‐1% IgM monoclonal paraprotein in the serum CRAB features International Staging System (ISS)
of all MM) and/or urine, >10% bone marrow clonal (hypercalcaemia: serum calcium stage I: serum β2microglobulin levels of
plasma cells or plasmacytomas, lytic levels of >1 mg per dL higher than <3.5 mg/L and serum albumin levels of
bone lesions, and/or identification of the upper limit of normal levels ≥3.5 g/dL; stage II: not stage I/III;
t(11;14) by fluorescent in situ (>11 mg/dL); stage III: serum β2microglobulin levels of
hybridization (FISH)6 renal insufficiency: presence of ≥5.5 mg/L8
creatinine clearance of <40 mL/
Typical MM features (CRAB features) min or serum creatinine levels of Revised ISS:
>2 mg/dL; Lactate dehydrogenase levels and
WM‐like features adverse cytogenetic abnormalities
anaemia: haemoglobin levels of >2 g/ (t(4;14), t(14;16), t(14;20), and del(17/
dL below the lower limit of normal 17p), in addition to any non‐
levels (<10 g/dL); hyperdiploid karyotype9
bone lytic lesions: presence of one or
more lytic lesions detected by
conventional radiology, CT imaging
(or low‐dose CT) or PET‐CT)6

clonal bone marrow plasma cell

percentage of ≥60% and/or
involved‐to‐uninvolved serum free
light‐chain ratio of ≥100 and/or
≥2 focal lesions on MRI6

Hyperviscosity syndrome
Acquired von Willebrand disease
(vWD)
CD20+ (68% of all cases)7
t(11;14) (40% of all cases)7
cyclin D1 (60% of all cases)7

2.1 | Waldenström macroglobulinemia As bone marrow infiltration is always present, the diagnosis of
WM relies on histologic demonstration of lymphoplasmacytic lym-
WM is a rare indolent B‐cell lymphoproliferative disorder resulting phoma through bone marrow biopsy with immunohistochemistry.
from the accumulation of monoclonal lymphocytes, lymphoplasmacytic Lymphocytes and lymphoplasmacytic cells express IgM, kappa or
cells, and plasma cells secreting a monoclonal IgM protein.15 According lambda, CD19, CD20, and weak CD22. CD5 and CD23 are usually
to the 2008 WHO classification system of lymphoid neoplasms, the negative. Monoclonal plasma cells expressing CD38 or CD138 and
pathological disorder underlying WM is a lymphoplasmacytic showing the same restricted light chain expression as the lymphocytic
lymphoma.10 The overall age‐adjusted incidence of WM is 3.8 per mil- component are also found in the bone marrow of WM patients.
lion persons per year and increases with age. The incidence of WM is Cytogenetic analysis is not required for the routine diagnostic
twice as high in men than in women (5.4 vs 2.7 per million, respec- assessment of WM patients.17 A highly recurrent somatic mutation
tively).16 WM patients may be asymptomatic at presentation and the in the MYD88 gene consisting in a single‐nucleotide change, ie, leu-
diagnosis made after incidental finding of an IgM monoclonal protein cine‐to‐proline at amino acid position 265 (MYD88 L265P) has been
at serum electrophoresis and immunofixation. discovered in recent years.18 Several studies have demonstrated that
TEDESCHI ET AL. 3

this mutation is present in more than 90% of WM and 50% to 80% of in clinical trials; however, its role in guiding treatment decisions is still
IgM‐MGUS patients.5,19-22 The MYD88 mutation is rarely found in unclear.
marginal zone lymphoma (MZL) or chronic lymphocytic leukemia
(CLL) with plasmacytic differentiation, and therefore testing for the
2.3 | Treatment of WM
this mutation is currently recommended in the diagnostic work‐up to
differentiate WM from other lymphoproliferative neoplasms. MYD88 According to current guidelines, the decision to start treatment should
assessment may also be useful to discriminate WM from rare cases not be based on the concentration of the paraprotein, but on the pres-
of IgM MM because the MYD88 mutation is never found in MM, even ence of signs or symptoms of active disease.
of IgM isotype. The most common indications to treatment are represented by
The second most common gene mutated in WM is CXCR4. More peripheral cytopenia due to bone marrow infiltration (mostly anemia),
than 30 different mutations, including nonsense or frameshift muta- constitutional symptoms, bulky lymphadenopathies or splenomegaly,
tions, have been described in 25% to 30% of WM patients using symptoms, and signs due to the paraprotein (mainly hyperviscosity,
23,24
Sanger sequencing, the most frequent being C1013G (S338X). peripheral neuropathy, symptomatic cryoglobulinemia, amyloidosis,
Routine testing for CXCR4 mutations is not currently recommended cold agglutinin disease).
as part of the diagnostic work‐up of WM patients.17 Response criteria27 in WM are based on changes of serum mono-
Due to the low frequency of lymphadenopathies, CT scan of clonal IgM protein and lymphadenopathies or splenomegaly if present
chest, abdomen, and pelvis is not routinely recommended in the initial before treatment (Table 3).
staging of WM and should be reserved to symptomatic patients in To date, immunochemotherapy is considered a standard of care
need of treatment.17 If baseline CT scan shows enlarged lymph nodes, for WM patients. Due to the rarity of WM, a precise treatment algo-
splenomegaly, or pleural effusions, it must be repeated after comple- rithm remains to be defined. Treatment recommendations from the
tion of therapy to assess response. Table 2 summarizes the essential IWWM are published every two years28 and are mostly based on
tests that should be included in the diagnostic work‐up of WM results of phase 2 trials. Most of the compounds considered are off‐
according to the recent international recommendations.17 label and not approved for WM treatment. As a consequence, in most
countries regimens that may be commonly used in clinical practice are
limited and derived from treatments of other lymphoproliferative dis-
2.2 | Prognosis of WM orders. The only drug that, as for now, has been approved specifically
WM is an indolent disease, with a median survival of 7 to 10 years.25 for WM both from FDA and EMA is ibrutinib.
However, in many patients, other factors rather than WM or treat- Therapy should be personalized and several factors (patient's clin-
25,26
ment may be the cause of death. A multicenter collaborative pro- ical characteristics, candidacy for an autologous stem cell transplant,
ject developed the International Prognostic Scoring System for WM symptoms at presentation) have to be considered in the treatment
(ISSWM) on a series of 587 patients with symptomatic WM.6 Accord- choice. Considering that the majority of patients are elderly, an accu-
ing to five adverse covariates (age > 65 years, Hb ≤ 11.5 g/dL, rate evaluation of fitness, comorbidities and tolerance to previous
PLT ≤ 100 × 10 (9)/L, beta2‐microglobulin >3 mg/L, IgM >7.0 g/dL) treatments should be performed to avoid toxicities.
patients are classified as low, intermediate, or high‐risk with 5‐year In patients presenting with hyperviscosity syndrome (HSV) plasma
survival rates of 87%, 68%, and 36%, respectively. The ISSWM has exchange is a validated treatment but should be considered as a tem-
been validated in independent cohorts and is used for stratification porary approach.29

TABLE 2 Essential evaluation of patients with Waldenström Macroglobulinemia (WM)17

History and physical examination • Familial history for WM and other B‐cell lymphoproliferative
disorders
• Funduscopic examination
• Review of systems
Laboratory studies • Complete blood count
• Complete metabolic panel
• Serum immunoglobulin levels (IgA, IgG, IgM)
• Serum and urine electrophoresis with immunofixation
• Serum beta‐2‐microglobulin level
If clinically indicated • Cryoglobulins
• Cold agglutinine titre
• Serum viscosity
• Screening for von Willebrand disease
• 24‐h urine protein quantification
Bone marrow aspiration and biopsy • Immunohistochemistry
• Flow cytometry
• Testing for MYD88 L265P mutation
Computerized tomography scans of the chest, abdomen, • In patients being considered for therapy
pelvis with intravenous contrast
4 TEDESCHI ET AL.

TABLE 3 Categorical response definition in WM27

Response Category Definition

Complete response (CR) • Absence of serum monoclonal IgM protein by immunofixation
• Normal serum IgM level
• Complete resolution of extramedullary disease, ie, lymphadenopathy and splenomegaly if present at baseline
• Morphologically normal bone marrow aspirate and trephine biopsy
Very good partial response (VGPR) • Monoclonal IgM protein is detectable ≥90% reduction in serum IgM level from baseline
• Complete resolution of extramedullary disease, ie, lymphadenopathy/splenomegaly if present at baseline
• No new signs or symptoms of active disease
Partial response (PR) • Monoclonal IgM protein is detectable ≥50% but <90% reduction in serum IgM level from baseline
• Reduction in extramedullary disease, ie, lymphadenopathy/splenomegaly if present at baseline
• No new signs or symptoms of active disease
Minor response (MR) • Monoclonal IgM protein is detectable ≥25% but <50% reduction in serum IgM level from baseline
• No new signs or symptoms of active disease
Stable disease (SD) • Monoclonal IgM protein is detectable <25% reduction and <25% increase in serum IgM level from baseline
• No progression in extramedullary disease, ie,
• lymphadenopathy/splenomegaly
• No new signs or symptoms of active disease
Progressive disease (PD) • ≥25% increase in serum IgM level from lowest nadir (requires confirmation) and/or progression in
clinical features attributable the disease

Most of the guidelines and the consensus panel from the Eighth collection, there is a general consensus to avoid NA‐based immuno‐
IWWM consider DRC regimen (dexamethasone, rituximab, and oral chemotherapy in front line treatment.
cyclophosphamide) a suitable first line treatment as it exerts a Bortezomib demonstrated high efficacy, but in certain countries
high rate of responses with minimal toxicity, and low rate of sec- its use has been reserved only to salvage treatment. High response
ondary myelodisplasia.30,31 As the median time to response to rates and favourable outcomes have been observed in untreated
DRC is longer as compared with other regimens this combination patients combining bortezomib, dexamethasone, and rituximab.41
is not appropriate in patients with HSV or needing a rapid disease Neurotoxicity was the major concern after the administration of
control. bortezomib twice weekly. Response kinetic after bortezomib is very
Bendamustine is approved for the treatment of indolent lympho- fast with median time to response of 1.4 months in both studies. In
proliferative disorders. Bendamustine and Rituximab (BR) showed view of the rapid disease control, limited hematologic and stem cell
favorable results when compared with R‐CHOP in a phase 3 open‐ toxicity, long‐term safety bortezomib‐based immunotherapy should
label randomized trial of indolent non Hodgkin lymphomas (NHL), be considered a valid treatment option. The most common
including 41 patients with WM.32 immunochemotherapies used are summarized in Table 4.
To evaluate the efficacy of the two most commonly used regi- In less fit patients, in whom standard immunochemotherapy is not
mens in routine clinical practice, Paludo et al compare the outcome appropriate, single agent rituximab, chlorambucil, or fludarabine may
of 27 treatment naïve patients treated with DRC and 50 with BR. be an option.
Overall response rates+ (ORR) was similar in the two groups as well Rituximab alone at the standard schedule (4 weekly infusions at
as the 2 years PFS (88 and 61%, respectively P = 0.07). Importantly, 375 mg/sqm) is associated with an ORR of 30% to 60% with 25% to
BR and DRC activity was unaffected by MYD88 mutation status.33 30% major responses (MR).46,47 The so‐called “extended rituximab
Although the prospective randomized trial comparing R‐CHOP schedule” demonstrated higher MR rates, 44% to 48% with longer
with CHOP demonstrated the advantage of the combination with time to progression exceeding 29 months.48,49
Rituximab, this combination is not considered a treatment of choice Oral chlorambucil has been historically the most commonly used
in frontline WM as vincristine should be avoided because of the agent in WM and has been administered on both a continuous or an
potential neurotoxicity.34 intermittent schedule, with similar outcomes.50 It should be consid-
Nucleoside analogues (NA) have been largely used in WM both ered that responses after monotherapy are slow and these options
either alone or in different combinations. Both fludarabine and should be therefore reserved to patients with an indolent disease
cladribine have been associated with rituximab with or without cyclo- course. In addition, fludarabine and chlorambucil should be avoided
phosphamide.35-39 Response rates with NA combinations are high when stem cell harvest is planned.
(ORRs ranging from 89% to 95%) even in patients with relapsed or The role of rituximab maintenance in WM is still controversial.50
refractory WM, but NA have been associated with a high rate of Suggested treatments and considerations of approved regimens in
myelosuppression, treatment discontinuation, prolonged tardive neu- WM are listed in Table 5.
tropenia, and infections.
WM patients treated with NA who had also previously received
2.4 | Salvage treatment
an alkylator agent showed a higher risk of myelodisplasia/acute mye- WM is incurable, and all patients will eventually relapse after first line
logenous leukemia or disease transformation.40 Based on data of short treatment. All regimens considered as primary treatment options are
and long‐term toxicity and the possible impairment in stem cell effective as salvage treatment (Table 5). Treatment decision should
TEDESCHI ET AL. 5

TABLE 4 Combination treatment with rituximab commonly used in clinical practice for WM

Combination Reference N° Pts Untreated Pts % ORR% MR% Follow‐up

30
Dexamethasone Dimopoulous 2007 72 100 83 74 Median PFS 35 m
Cyclophosphamide Kastritis 201531
Rituximab
Fludarabine Treon 200936 43 63 95 86 Median TTP 51.2 m
rituximab
Fludarabine Tedeschi 201235 43 65 79 74 Median EFS 50.1 m
Cyclophosphamide
Rituximab
Fludarabine Souchet 201639 82 33 81 74 Median PFS at 3y:79%
Cyclophosphamide
Rituximab
2CdA Rituximab Laszlo 201037 29 100 89.6 79 Median PFS n.r. at 43 m
38
2CdA Weber 2003 17 100 94 94 No relapses at 21 mo
Cyclophosphamide
rituximab
Bendamustine Rummel 201332 22 100 95 N.R. median PFS 69.5 m
rituximab
Bendamustine Tedeschi 201542 71 0 80 75 Median PFS n.r. at 19 m
rituximab
Bortezomib Ghobrial 201043 26 100 88 65 1 year EFR 75%
rituximab
Bortezomib Ghobrial 201043 37 0 81 51 median PFS 15.6
rituximab
Bortezomib Treon 200945 23 100 96 83 Estimated median TTP >30 m
rituximab
dexamethasone
Bortezomib Dimopoulous 201339 59 100 85 68 Median PFS 43 m
rituximab Gavriatopoulou 201744
dexamethasone

Abbreviations: EFR, event free rate; n.r. , not reached; N.R., not reported; m, months; MR, major response; ORR, overall response rate; PFS, progression free
survival; TTP, time to progression.

be based not only on patients and disease characteristics but also on Based on the favorable data of the Bone Marrow Transplant
response duration and tolerance to previous treatment. Patients with Registry autologous stem cell transplant (ASCT) may be considered
a short‐lasting response or with refractory disease should be switched in younger patients with chemosensitive disease not heavily
to a different therapeutic regimen. pretreated.52

TABLE 5 Suggested treatments based on approved agents for Waldenström Macroglobulinemia or other indolent NHL
Treatments Indications Considerations

Rituximab single agent ‐ elderly Consider the possible IgM flare

‐ low tumor burden (plasmapheresis indicated if IgM > 4000 mg/dL)
‐ IgM‐related disorders (ie, cryoglobulinemia, hemolytic Avoid in patients needing a rapid disease control
anemia, anti‐myelin‐associated neuropathy)
Fludarabine single agent Elderly not suitable for immunochemotherapy Avoid in patients needing a rapid disease control
Chlorambucil single
agent
DRC ‐ low tumor burdena Long median time to response (4.1 m)
‐IgM‐related disorders (ie, cryoglobulinemia, hemolytic Low myelotoxicity, useful in patients presenting with
anemia, anti‐myelin‐associated neuropathy) peripheral cytopenia
Bendamustine rituximab ‐high tumor burden, hyperviscosity, constitutional symptoms Consider dosage reduction (ie, 70 mg/sqm) in the elderly
and renal impairment
Bortezomib, ‐high IgM level, hyperviscosity Avoid in patients with neuropathy
bortezomib rituximab, ‐renal impairment Weekly schedule exerts lower rate of neuropathy
BDR
Ibrutinib ‐ first line for patients who are not candidates for If ibrutinib held possible rapid increases in serum IgM
immunochemotherapy and reductions in hemoglobin, this should not be
‐ salvage treatment considered as treatment failure
‐ effective in rituximab refractory patients MYD88 and CXCR4 mutations may have an impact on
ibrutinib responses

Abbreviations: BDR, bortezomib rituximab dexamethasone; DRC: cyclophosphamide rituximab dexamethasone.

a
Low tumor burden = no bulky lymphadenopathies.
6 TEDESCHI ET AL.

The use of myeloablative or non‐myeloablative allogeneic SCT is 50% of patients, respectively.57,58 The major concern with everolimus
not recommended in clinical practice and should be considered in is the high rate of grade ≥ 3 adverse events.
selected patients in the clinical trial setting.53 Several drugs approved for the treatment of MM have also been
evaluated in WM. Carfilzomib in combination with rituximab and
dexamethasone lead to a high rate of good quality of responses
2.5 | Ibrutinib
(35% VGPR or better) translating into a prolonged PFS.59
In 2015 FDA and in 2016 EMEA approved Ibrutinib for WM on the The ixazomib, dexamethasone, and rituximab regimen showed to
bases of the favorable results observed in 63 pretreated patients.54 be highly effective (ORR 96%), well tolerated, and neuropathy‐
The EMEA approval is limited to relapsed/refractory patients who sparing.60
have received at least one prior therapy and first line patients unsuit- Thalidomide and lenalidomide have both been considered in
able for immuno‐chemotherapy. The ORR achieved during ibrutinib phase II trials as single agents or in combination with rituximab.61-63
treatment was 91% with a high rate of MR (73%). Importantly, kinetic Thalidomide lead to a 64% of PRs and a prolonged time to progres-
of response was very fast (4 weeks to a minor response), rapid sion. Best results were achieved with higher doses that were however
improvement of cytopenias, and an objective response of lymphade- associated with an excessive toxicity (mainly neuropathy) often lead-
nopathies and splenomegaly. At 6 months, there was a discordance ing to treatment discontinuation.
between IgM level and bone marrow involvement with a stronger cor- An interim analysis on 30 pretreated patients showed that
relation observed during follow‐up. The estimated 2 years PFS and OS Venetoclax exerts a high ORR (80%) with a median time to response
were 69% and 95%, respectively. Previous >3 lines of treatment, high of 9 weeks. Furthermore, MR rate was not statistically different based
IPSSWM and MYD88 and CXCR4 wild type negatively affected PFS. on relapsed or refractory disease, prior BTKi exposure, or CXCR4
These data suggest the need to evaluate MYD88 and CXCR4 to pre- mutation status.64
dict response duration. Although the study population was elderly
and heavily pretreated, severe extrahematological toxicities, including
severe bleeding and atrial fibrillation, were reported in a low rate of
3 | I g M ‐ R E L A T E D D I S O R D E R S ( I g M ‐ RD )
patients (less than 2% each).
The term “IgM‐related disorders” (IgM‐RD) was introduced in 2002 to
Ibrutinib has also shown to be highly effective in rituximab refrac-
identify symptoms attributable to the IgM monoclonal protein occur-
tory patients (ORR 84%).55
ring patients without morphological evidence of lymphoma.15 Regard-
Recently, the phase III randomized trial comparing ibrutinib plus
less of its serum level, IgM paraprotein can cause several
rituximab or placebo plus rituximab showed a longer PFS in patients
complications through different mechanisms resulting, respectively,
treated with the combination (82% vs 28% at 30 months).56 After a
from its physico‐chemical properties, autoantibody activity, tissue
median follow‐up of 26.5 months, the best response rate resulted
deposition, and non‐specific interactions with other proteins.65 Thus,
significantly higher with the combination treatment (92% vs 47%,
it can be responsible for a wide spectrum of associated diseases.65-78
P < 0.001). Although indirect comparisons show that rituximab mono-
Although IgM‐MGUS accounts for only 15% to 20% of all MGUS
therapy is less efficient than combination therapies, the choice of the
cases, it issues a unique diagnostic challenge because it is associated
comparator arm was based on prevalent real life standard. The combi-
with a broad spectrum of pathological entities, ranging from B‐cell
nation of ibrutinib with rituximab compares favorably with the results
LPD to IgM paraprotein complications, that may warrant a therapeutic
obtained with other immunotherapeutic regimens in terms of
intervention. Thus, it is critical not to miss the chance to identify such
responses, PFS and TTNT and, importantly, the benefit in the
concurrent disorders, which may be overlooked because of their low
ibrutinib‐rituximab group was independent of the MYD88 or CXCR4
frequency and insidious presentation.67
genotype.
In Table 6, we outlined the distinctive features of some IgM‐RD.
As for now, there is a general consensus to administer ibrutinib as
The most common presentations are those referred to PN,
first line treatment in patients not suitable for immunochemotherapy.
cryoglobulinaemia, cold agglutinin disease, and HSV. In particular, the
In the salvage setting, Ibrutinib should be considered the treatment of
prevalence of PN association with IgM‐MGUS is 30% to 50%.66
choice in patients showing a short time to progression (≤36 months)
Indeed, treatment should not be introduced until clinical symp-
or poor toleration to previous immune‐chemotherapy.
toms develop, and treatment decisions are dependent mainly on the
severity of specific clinical manifestations.80
2.6 | Off‐label agents and novel agents in Besides being responsible for clinical IgM‐related symptoms, IgM
development monoclonal protein can produce artefacts during laboratory testing
procedures.66
Ofatumumab, fully anti CD20 human antibody, approved only for
CLL, has also been investigated in WM48 leading to an ORR of
59% including 35% of MR with higher responses in rituximab naïve 4 | IgM‐SECRETING MULTIPLE MYELOMA
patients. (Ig M ‐ M M )
Everolimus, an oral inhibitor of the Akt‐mTOR pathway, currently
approved for treatment of solid tumors showed to be effective both in IgM‐secreting MM is rare and accounts for 0.5% to 1% of all MM
untreated or previously treated WM patients leading to MR in 60 and cases.4 Median age at diagnosis is 65 years.6 Smouldering IgM‐MM
TABLE 6 Clinical manifestations, diagnostic work up, and treatment of most common IgM‐related disorders
Patients Characteristics Diagnostic Evaluation Therapy Remarks
TEDESCHI

IgM‐RD Clinical history Symptoms Physical examination Laboratory findings Imaging

ET AL.

Nephropathies History of proteinuria None characteristic None characteristic Nephrotic syndrome and/ Kidney Multi‐disciplinary approach Kidney biopsy is requested.
and/or impaired symptom. In acute sign except possible or impaired renal ultrasound. between hematologist, Heterogeneous spectrum
renal function. renal injury nausea peripheral edema. function. nephrologist, and of renal damage
and vomiting. Acute kidney injury (rare). pathologist could establish (intracapillary monoclonal
causal relation and deposits disease with
therapeutic actions to take. granular, electron dense
IgM‐thrombi occluding
capillary lesions; atypical
membranoproliferative
glomerulonephritis and
acute tubular
necrosis).70,72
Neuropathies History of sensorimotor Distal, symmetric, Neurological Serum myelin associated NCS; EMG. No international clinical Loss of myelinated fibers;
neuropathy. chronic examination glycoprotein (MAG) MRI of column to consensus. A course of IgM antibodies bound to
demyelinating including low titers. If negative, exclude anatomical plasmapheresis is myelin and separation of
progressive extremities consider testing for anti‐ causes of particularly suggested for myelin lamellae are found
neuropathy. examination and ganglioside M1 (GM1) neuropathy. patients with aggressive by pathologist when nerve
Numbness in lower reflexes. and anti‐sulfatide IgM course PN, followed by biopsy is done.
extremities; antibodies. systemic chemotherapy A minority of idiopathic
progressive burning with rituximab. neuropathies (10%) are
pain in toes that When PN is slowly associated with a
progresses to involve progressive, consider monoclonal protein, mostly
both feet; ataxia; single‐agent rituximab. IgM (30%). Currently,
tremor. When symptoms are international consensus
moderate to severe, on how to assess and
consider chemotherapy and treat patients is still
rituximab such as lacking.74-77
fludarabine, DRC, and Diagnosis is based on
bendamustine.65-73 exclusion of other causes of
polineuropathy and on
positivity to anti‐myelin‐
associated glycoprotein
(MAG) antibodies or other
antibodies against neural
antigens (sulfatide,
gangliosides, etc).76
Amyloidosis Unexplained fatigue Fatigue and Periorbitary purpura, In addition to SPEP and Echocardiography. We are unable to remove Apple green birefringence
with heterogeneous polineuropathy. macroglossia, UPEP: IF, IgM, IgG, IgA Abdomen tissue deposition of and immuno‐
aspecific systemic Diarrhea, mal‐ lymphoadenopathy, serum free light chains Ultrasound. EMG. amyloid, but it is possible, histochemical
symptoms. absorption, bleeding, organomegaly, (sFLC), creatinine, BUN, CT scans of chest, with chemotherapy characterization of
weight loss, edema. peripheral edema, urinary protein loss, abdomen, pelvis. till high dose followed by amyloid. MYD88
organ dysfunction. glomerular filtration rate, Cardiac MRI in autologous transplantation, genotyping.67,78
Neurological ALP, natriuretic peptides, selected cases. to eliminate the
examination. NT‐proBNP and BNP, amyloidogenic clone.
LDH,
beta 2‐microglobulin,
albumin, and calcium.
NCS; EMG. Use diagnostic criteria.
7

(Continues)
 8

TABLE 6 (Continued)

Patients Characteristics Diagnostic Evaluation Therapy Remarks

IgM‐RD Clinical history Symptoms Physical examination Laboratory findings Imaging
POEMS History of neurological Sensory motor Organomegaly. Skin Vascular endothelial growth CT scan Radiation; corticosteroid; Rarely associated with HHV‐
syndrome dysfunction (numbness, polyradiculo‐ changes such as factor (VEGF) elevation, (lymphadenopathy, melphalan‐dexamethasone; 8‐negative plasma cells
pain, weakness) or skin neuropathy. hyperpigmentation, findings of organomegaly, cyclo‐phosphamide‐ variants of CD
thickening or skin pigment Endocrine‐related thickened skin, endocrinopathy ascites, pleural dexamethasone; ASCT;
changes, body hair quantity symptoms. hypertrichosis. (excluding diabetes effusions, and thalidomide‐
and texture, skin color of Skin alterations mellitus or edema). CT body dexamethasone;
distalextremities changes, hypothyroidism), and/or PET/CT lenalidomide‐
and development of cherry thrombocytosis. bone windows dexamethasone;
angiomata. History of bortezomib;
menstrual and sexual bevacizumab.68
dysfunction.

Castleman Frequently From traditional B Lymphoadenopathy Anemia, thrombocytopenia, Abdomen ultrasound, Treatment is localized for Human herpesvirus 8 (HHV‐
disease (CD) HIV‐positivity symptoms (fever, Organomegaly. hypoalbuminemia, CT scans of chest, unicentric form (surgical 8) and interleukin 6 have a
chills, night sweats) polyclonal hypergamma‐ abdomen, pelvis, resection and/or radiation relevant role in the
to severe globulinemia, IgM and PET/CT. therapy) whereas systemic pathogenesis.
inflammatory lambda light chain therapy such as There are a unicentric (UCD)
vascular leak positivity elevation of chemotheraphy or and a multicentric (MCD)
syndrome (ascites, acute phase reactants rituximab alone or in form, the latter being quite
pleural, pericardial such as CRP. combination with rare (23% of cases) and with
effusions and/or chemotherapy (CD20 is worst prognosis. Among the
peripheral edema) typically found on MCD form, a proportion of
plasmoblasts) or anti IL‐6 plasmacell variant cases are
biologics are indicated in HHV8‐positive and present
multicentric forms. IgM‐positive plasmoblasts.
There are limited trials on These cases have a
antiviral agents alone.79 significant risk of
progression to more
aggressive lymphoma.
Diagnosis is based on analysis
of involved lymph node
biopsy that is characteristic
and shows, in the
plasmoblast form, positivity
to CD20 while CD138 is
often negative and there is
usually lambda chain
restriction.

Abbreviations: ALP, alkaline phosphatase; BUN, blood urea nitrogen; CD, Castleman disease; CT, computed tomography; DRC, dexamethasone, rituximab, cyclophosphamide; EMG, electromyography; GM1, ganglioside
M1; HHV‐8, human herpesvirus 8; IF, immunofixation; IL‐6, interleukin 6; LDH, lactic dehydrogenase; MAG, myelin associated glycoprotein; MCD, multicentric; MRI, magnetic resonance imaging; NCS, nerve conduction
studies; PET/CT, 18F‐positron emission tomography/computed tomography; PN, polyneuropathy; sFLC, serum free light chains; SPEP, serum protein electrophoresis; UCD, unicentric; UPEP, urine protein electropho-
resis; VEGF, vascular endothelial growth factor.
TEDESCHI
ET AL.
TEDESCHI ET AL. 9

TABLE 7 Other lymphoproliferative disorders which may be associated with IgM

Ig M
Frequency Level Monoclonal IgM
Disorder among IgM (g/L) Biological Effects Presenting Features Focused Investigations Management

B‐NHL subtypes Only when • Generally indolent in LG NHL • Staging of NHL • WW policy in
More frequent (up 5‐9 associated • Possible related with microbial • Particular attention to indolent
• MZL to 20%); to with IgM‐ agents (mainly MZL, HCV, HPV, IgM‐related disorders to asymptomatic
differentiate related CP) evaluate specific NHL
with WM. 4‐5 disorders • Constitutional symptoms investigations • Eradication of
Rare 4‐5 • Lymphoadenopathies • Biological study in specific infectious
• FL Rare 4‐5 • Splenomegaly (mainly MZL) histotype agent driving
• MCL Rare • Possible extranodal involvement disease
• DLBCL • Different behaviour according to • Treatment of
histotype (indolent vs aggressive IgM‐related
course) and biological disorder
characteristic • Standard
treatment as
indicated
• Patients follow‐
up
CLL 2.5% to 20% 4 Only when • Generally indolent • Staging of CLL/SLL in • WW policy in
SLL Rare associated • Constitutional symptoms patients necessitating indolent
with IgM‐ • Lymphoadenopathies treatment asymptomatic
related • Splenomegaly • Particular attention to cases
disorders • Infectious complications IgM‐related disorders to • Treatment of
• Different behaviour according to evaluate specific IgM‐related
biological characteristics investigations disorder
• Transformation • Biological study (IGHV, • Standard
FISH analysis, TP53) treatment as
before treatment indicated
• Patients follow
up

Abbreviations: B‐NHL, B non Hodgkin's lymphoma; CLL, chronic lymphocytic leukaemia; CP, Cap Pierce hematology analyzer; DLBCL, diffuse large B‐cell
lymphoma; FISH, fluorescent in situ hybridization; FL, follicular lymphoma; HCV, hepatitis C virus; HPV, human papilloma virus; IGHV, immunoglobulin
heavy‐chain variable region gene; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; NHL, non‐Hodgkin's lymphoma; SLL, small lymphocytic lym-
phoma; TP53, tumor protein p53; WM, Walndenström macroglobulinemia; WW, wait and watch.

is an intermediate clinical stage between MGUS and MM in which the Sometimes, IgM‐RD as immune cytopenia may be the main clinical
risk of progression to overt disease in the first 5 years after diagnosis manifestations in otherwise indolent CLL requiring specific therapeu-
is approximately 10% per year.80 Several risk classification systems for tic approaches.86,87
8,9
MM have been proposed. Treatment has changed dramatically in
the past decade with the introduction of new drugs both in the front-
line and relapse settings with a significant improvement in the median
5.2 | B‐cell non Hodgkin lymphoma
OS, which now approaches 6 to 10 years depending on the age at
diagnosis (Table 1). Patients with IgM‐MM, which remains an incurable Besides WM and CLL/SLL, the presence of IgM paraproteinemia may
disease, are treated similarly, and their outcome is comparable to that be observed also in other B‐cell NHL with different prevalence and
of patients with more common myeloma subtypes. levels of IgM according to the different histotypes.
Arcaini et al88 while evaluating the distinctive features of WM and
SMZL found that a monoclonal component was present in 30% of
5 | O T H E R LY M P H O P R O L I F E R A T I V E SMZL patients among whom 17% had an IgM.
D I S O R D E R S WH I C H M A Y BE A S S O C I A T E D The possible prognostic impact of IgM monoclonal component in
WIT H Ig M DLBCL has been recently highlighted by Cao et al in 151 patients.89

In Table 7 are shown lymphoproliferative disorders which may be

associated with IgM.
6 | CO NC LUSIO NS

5.1 | Chronic lymphocytic leukemia and small The incidental finding of a IgM monoclonal gammopathy is associated
lymphocytic lymphoma with a broad spectrum of hematologic disorders with characteristic

CLL and small lymphocytic lymphoma (SLL) share similar morphologic manifestations that require specific work‐up for diagnostic and

and biologic features with the main difference being the main blood- treatment.

stream and bone marrow involvement for CLL and lymph node
involvement for SLL.82 An IgM peak may occur in CLL/SLL with a COMP ET ING INTE R ES TS
83-85
prevalence of 2.5% to 20% according to different studies. None declared.
10 TEDESCHI ET AL.

ORCID 19. Xu L, Hunter ZR, Yang G, et al. MYD88 L265P in Waldenström macro-
globulinemia, immunoglobulin M monoclonal gammopathy, and other
Alessandra Tedeschi http://orcid.org/0000-0001-8724-2771 B‐cell lymphoproliferative disorders using conventional and quantita-
Luca Laurenti http://orcid.org/0000-0002-4527-4131 tive allele‐specific polymerase chain reaction. Blood.
2013;121(11):2051‐2058.
RE FE R ENC E S 20. Varettoni M, Arcaini L, Zibellini S, et al. Prevalence and clinical signifi-
1. Kyle RA, Therneau TM, Rajkumar SV, et al. A long‐term study of prog- cance of the MYD88 (L265P) somatic mutation in Waldenstrom's
nosis in monoclonal gammopathy of undetermined significance. N Engl macroglobulinemia and related lymphoid neoplasms. Blood.
J Med. 2002;346(8):564‐569. 2013;121(13):2522‐2528.

2. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification 21. Jiménez C, Sebastián E, Chillón MC, et al. MYD88 L265P is a marker
and response assessment of multiple myeloma. Leukemia. highly characteristic of, but not restricted to, Waldenström's macro-
2009;23(1):3‐9. globulinemia. Leukemia. 2013;27(8):1722‐1728.
22. Poulain S, Roumier C, Decambron A, et al. MYD88 L265P mutation in
3. Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain ratio
Waldenstrom macroglobulinemia. Blood. 2013;121(22):4504‐4511.
is an independent risk factor for progression in monoclonal
gammopathy of undetermined significance. Blood. 2005;106(3): 23. Treon SP, Cao Y, Xu L, Yang G, Liu X, Hunter ZR. Somatic mutations in
812‐817. MYD88 and CXCR4 are determinants of clinical presentation and
overall survival in Waldenstrom macroglobulinemia. Blood.
4. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with
2014;123(18):2791‐2796.
newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78(1):21‐33.
24. Hunter ZR, Xu L, Yang G, et al. The genomic landscape of
5. Varettoni M, Zibellini S, Arcaini L, et al. MYD88 (L265P) mutation is an
Waldenstrom macroglobulinemia is characterized by highly recurring
independent risk factor for progression in patients with IgM monoclo-
MYD88 and WHIM‐like CXCR4 mutations, and small somatic deletions
nal gammopathy of undetermined significance. Blood. 2013;122(13):
associated with B‐cell lymphomagenesis. Blood. 2014;123(11):
2284‐2285.
1637‐1646.
6. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Mye-
25. Gertz MA. Waldenström macroglobulinemia: 2013 update on diagno-
loma Working Group updated criteria for the diagnosis of multiple
sis, risk stratification, and management. Am J Hematol. 2013;88(8):
myeloma. Lancet Oncol. 2014;15(12):e538‐e548.
703‐711.
7. King RL, Howard MT, Hodnefield JM, Morice WG. IgM multiple mye-
26. Ghobrial IM, Fonseca R, Gertz MA, et al. Prognostic model for disease‐
loma: pathologic evaluation of a rare entity. Am J Clin Pathol.
specific and overall mortality in newly diagnosed symptomatic patients
2013;140(4):519‐524.
with Waldenstrom macroglobulinaemia. Br J Haematol. 2006;133(2):
8. Greipp PR, San Miguel J, Durie BG, et al. International staging system 158‐164.
for multiple myeloma. J Clin Oncol. 2005;23(15):3412‐3420.
27. Owen RG, Kyle RA, Stone MJ, et al. Response assessment in
9. Palumbo A, Avet‐Loiseau H, Oliva S, et al. Revised international staging Waldenstrom macroglobulinemia: update from the VIth International
system for multiple myeloma: a report from International Myeloma Workshop. Br J Haematol. 2013;160(2):171‐176.
Working Group. J Clin Oncol. 2015;10;33(26):2863‐2869.
28. Leblond V, Kastritis E, Advani R, et al. Treatment recommendations
10. Owen RG, Treon SP, Al‐Katib A, et al. Clinicopathological definition of from the Eighth International Workshop on Waldenström's Macro-
Waldenström's macroglobulinemia: consensus panel recommendations globulinemia. Blood. 2016;128(10):1321‐1328.
from the Second International Workshop on Waldenström's Macro-
29. Stone MJ, Bogen SA. Evidence‐based focused review of management
globulinemia. Semin Oncol. 2003;30(2):110‐115.
of hyperviscosity syndrome. Blood. 2012;119(10):2205‐2208.
11. Paiva B, Montes MC, García‐Sanz R, et al. Multiparameter flow cytom-
30. Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, et al. Primary
etry for the identification of the Waldenström's clone in IgM‐MGUS
treatment of Waldenström macroglobulinemia with dexamethasone,
and Waldenström's Macroglobulinemia: new criteria for differential
rituximab, and cylophosphamide. J Clin Oncol. 2007;25(22):3344‐3349.
diagnosis and risk stratification. Leukemia. 2014;28(1):166‐173.
31. Kastritis E, Gavriatopoulou M, Kyrtsonis MC, et al. Dexamethasone,
12. Kyle RA, Therneau TM, Rajkumar SV, et al. Long‐term follow‐up of IgM
rituximab, and cyclophosphamide as primary treatment of
monoclonal gammopathy of undetermined significance. Blood.
Waldenström macroglobulinemia: final analysis of a phase 2 study.
2003;102(10):3759‐3764.
Blood. 2015;126(11):1392‐1394.
13. Landgren O, Kyle RA, Pfeiffer RM, et al. Monoclonal gammopathy of
32. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus
undetermined significance (MGUS) consistently precedes multiple
rituximab versus CHOP plus rituximab as first‐line treatment for
myeloma: a prospective study. Blood. 2009;113(22):5412‐5417.
patients with indolent and mantle‐cell lymphomas: an open‐label,
14. Baldini L, Guffanti A, Cesana BM, et al. Role of different hematologic multicentre, randomised, phase 3 non‐inferiority trial. Lancet.
variables in defining the risk of malignant transformation in monoclonal 2013;381(9873):1203‐1210.
gammopathy. Blood. 1996;87(3):912‐928.
33. Paludo J, Abeykoon JP, Shreders A, et al. Bendamustine and rituximab
15. Owen RG, Treon SP, Al‐Katib A, et al. Clinicopathological definition of Q9 (BR) versus dexamethasone, rituximab, and cyclophosphamide
Waldenstrom's macroglobulinemia: consensus panel recommendations (DRC) in patients with Waldenström macroglobulinemia. Ann Hematol.
from the Second International Workshop on Waldenstrom's macro- 2018;97(8):1417–1425.
globulinemia. Semin Oncol. 2003;30(2):110‐115. 34. Buske C, Hoster E, Dreyling M, et al. The addition of rituximab to
16. Wang H, Chen Y, Li F, et al. Temporal and geographic variations of front‐line therapy with CHOP (R‐CHOP) results in a higher response
Waldenstrom macroglobulinemia incidence: a large population‐based rate and longer time to treatment failure in patients with
study. Cancer. 2012;118(15):3793‐3800. lymphoplasmacytic lymphoma: results of a randomized trial of the
17. Castillo JJ, Garcia‐Sanz R, Hatjiharissi E, et al. Recommendations for German Low‐Grade Lymphoma Study Group (GLSG). Leukemia.
the diagnosis and initial evaluation of patients with Waldenström 2009;23(1): 153–161.
Macroglobulinaemia: a Task Force from the 8th International Work- 35. Tedeschi A, Benevolo G, Varettoni M, et al. Fludarabine plus cyclo-
shop on Waldenström Macroglobulinaemia. Br J Haematol. phosphamide and rituximab in Waldenstrom macroglobulinemia: an
2016;175(1):77‐86. effective but myelosuppressive regimen to be offered to patients with
18. Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in advanced disease. Cancer. 2012;118(2):434–443.
Waldenström's macroglobulinemia. N Engl J Med. 2012;367(9): 36. Treon SP, Ioakimidis L, Soumerai JD, et al. Primary therapy of
826‐833. Waldenström macroglobulinemia with bortezomib, dexamethasone,
TEDESCHI ET AL. 11

and rituximab: WMCTG clinical trial 05‐180. J Clin Oncol. 2009;27(23): 54. Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated
3830–3835. Waldenström's macroglobulinemia. N Engl J Med. 2015;372(15):
1430–1440.
37. Laszlo D, Andreola G, Rigacci L, et al. Rituximab and subcutaneous 2‐
chloro‐2′‐deoxyadenosine combination treatment for patients with 55. Dimopoulous MA, Trotman J, Tedeschi A, et al. Ibrutinib for patients
Waldenstrom macroglobulinemia: clinical and biologic results of a with rituximab‐refractory Waldenström's macroglobulinemia (iNNO-
phase II multicenter study. J Clin Oncol. 2010; 28(13):2233–2238. VATE): an open‐label substudy of an international, multicentre, phase
3 trial. Lancet Oncol. 2017;18(2):241–250.
38. Weber DM, Dimopoulos MA, Delasalle K, Rankin K, Gavino M,
Alexanian R. 2‐Chlorodeoxyadenosine alone and in combination for 56. Dimopoulos MA, Tedeschi A, Trotman J, et al. Phase 3 trial of ibrutinib
previously untreated Waldenstrom's macroglobulinemia. Semin Oncol. plus rituximab in Waldenström's macroglobulinemia. N Engl J Med.
2003;30(2):243–247. 2018 Jun;1. [Epub ahead of print].

39. Souchet L, Levy V, Ouzegdouh M, et al. Efficacy and long‐term 57. Ghobrial IM, Witzig TE, Gertz M, et al. Long‐term results of the phase II
toxicity of the rituximab‐fludarabine‐cyclophosphamide combination trial of the oral mTOR inhibitor everolimus (RAD001) in relapsed
therapy in Waldenstrom's macroglobulinemia. Am J Hematol. or refractory Waldenstrom Macroglobulinemia. Am J Hematol.
2016;91(8):782–786. 2014;89(3):237–242.

40. Leleu X, Soumerai J, Roccaro A, et al. Increased incidence of transfor- 58. Treon SP, Tripsas CK, Meid K, et al. Prospective, multicenter study of
mation and myelodysplasia/acute leukemia in patients with the mTor inhibitor everolimus (RAD001) as primary therapy in
Waldenström macroglobulinemia treated with nucleoside analogs. J Waldenstrom's macroglobulinemia. Blood. 2013;122. Abstract 1822.
Clin Oncol. 2009;27(2):250–255. New Orleans, Louisiana.

41. Dimopoulos MA, Garcia‐Sanz R, Gavriatopoulou M, et al. Primary 59. Treon SP, Tripsas CK, Meid K, et al. Carfilzomib, rituximab, and dexa-
therapy of Waldenstrom macroglobulinemia (WM) with weekly methasone (CaRD) treatment offers a neuropathy‐sparing approach
bortezomib, low‐dose dexamethasone, and rituximab (BDR): longterm for treating Waldenström's macroglobulinemia. Blood. 2014;124(4):
results of a phase 2 study of the European Myeloma Network 503–510.
(EMN). Blood. 2013;122(19):3276–3282. 60. Castillo JJ, Meid K, Gustine J, et al. Prospective clinical trial of
42. Tedeschi A, Picardi P, Ferrero S, et al. Bendamustine and rituximab ixazomib, dexamethasone and rituximab as primary therapy in
combination is safe and effective as salvage regimen in Waldenström Waldenström macroglobulinemia. Clin Cancer Res. 2018 Apr; 16. [Epub
macroglobulinemia. Leuk Lymphoma. 2015;56(9):2637‐2642. ahead of print].

43. Ghobrial IM, Xie W, Padmanabhan S, et al. Phase II trial of weekly 61. Dimopoulos MA, Zomas A, Viniou NA, et al. Treatment of
bortezomib in combination with rituximab in untreated patients with Waldenstrom's macroglobulinemia with thalidomide. J Clin Oncol.
Waldenström Macroglobulinemia. Am J Hematol. 2010;85(9):670‐674. 2001;19(16):3596–3601.

44. Gavriatopoulou M, Terpos E, Kastritis E, Dimopoulos MA. Current 62. Treon SP, Soumerai JD, Branagan AR, et al. Thalidomide and rituximab
treatment options and investigational drugs for Waldenstrom's Macro- in Waldenstrom macroglobulinemia. Blood. 2008;112(12):4452–4457.
globulinemia. Expert Opin Investig Drugs. 2017;26(2):197‐205. 63. Treon SP, Soumerai JD, Branagan AR, et al. Lenalidomide and
rituximab in Waldenström's macroglobulinemia. Clin Cancer Res.
45. Treon SP, Soumerai JD, Branagan AR, et al. Lenalidomide and
2009;15(1):355–360.
rituximab in Waldenström's macroglobulinemia. Clin Cancer Res.
2009;15(1):355–360. 64. Castillo J, Gustine J, Meid K, et al. Prospective phase ii study of
Venetoclax (VEN) in patients (PTS) with previously treated
46. Gertz MA, Rue M, Blood E, Kaminer LS, Vesole DH, Greipp PR. Multi-
Waldenstrom Macroglobulinemia (WM). EHA 2018. Abstract S854.
center phase 2 trial of rituximab for Waldenström macroglobulinemia
Available from https://learningcenter.ehaweb.org/eha/2018/stock-
(WM): an Eastern Cooperative Oncology Group Study (E3A98). Leuk
holm/214547/jorge.castillo.prospective.phase.ii.study.of.venetoclax.
Lymphoma. 2004;45(10):2047–2055.
28ven29.in.patients.html
47. Treon SP, Agus TB, Link B, et al. CD20‐directed antibody‐mediated
65. Ghobrial IM. Are you sure this is Waldenstrom macroglobulinemia?
immunotherapy induces responses and facilitates hematologic recov-
Hematology Am Soc Hematol Educ Program. 2012;2012:586–594.
ery in patients with Waldenstrom's macroglobulinemia. J Immunother.
2001;24(3):272–279. 66. D'Sa S, Kersten MJ, Castillo JJ, et al. Investigation and management
of IgM and Waldenström‐associated peripheral neuropathies:
48. Dimopoulos MA, Zervas C, Zomas A, et al. Treatment of
recommendations from the IWWM‐8 consensus panel. Br J Haematol.
Waldenström's macroglobulinemia with rituximab. J Clin Oncol.
2017;176(5):728–742.
2002;20(9):2327–2333.
67. Merlini G, Stone MJ. Dangereous small B‐cell clones. Blood.
49. Treon SP, Emmanouilides C, Kimby E, et al. Extended rituximab
2006;108(8):2520–2530.
therapy in Waldenström's macroglobulinemia. Ann Oncol. 2005;16(1):
132–138. 68. Berentsen S. Cold agglutinin disease. Hematology Am Soc Hematol Educ
Program. 2016;2016(1):226–231.
50. Kyle RA, Greipp PR, Gertz MA, et al. Waldenström's
macroglobulinaemia: a prospective study comparing daily with inter- 69. Dispenzieri A. POEMS syndrome: 2017 Update on diagnosis, risk strat-
mittent oral chlorambucil. Br J Haematol. 2000;108(4):737–742. ification, and management. Am J Hematol. 2017;92(8):814–829.

51. Owen RG, Pratt G, Auer RL, et al. Guidelines on the diagnosis and 70. Vos JM, Gustine J, Rennke HG, et al. Renal disease related to
management of Waldenström macroglobulinaemia. Br J Haematol. Waldenström macroglobulinaemia: incidence, pathology and clinical
2014;165(3):316–333. outcomes. Br J Haematol. 2016;175(4):623–630.

52. Kyriakou C, Canals C, Sibon D, et al. High‐dose therapy and autologous 71. Simon A, Asli B, Braun‐Falco M, et al. Schnitzler's syndrome: diagnosis,
stem‐cell transplantation in Waldenstrom macroglobulinemia: the Lym- treatment, and follow‐up. Allergy. 2013;68(5):562–568.
phoma Working Party of the European Group for Blood and Marrow 72. Audard V, Georges B, Vanhille P, et al. Renal lesions associated with
Transplantation. J Clin Oncol. 2010;28(13):2227–2232. IgM‐secreting monoclonal proliferations: revisiting the disease spec-
trum. Clin J Am Soc Nephrol. 2008;5:1339–1349.
53. Kyriakou C, Canals C, Cornelissen JJ, et al. Allogeneic stem‐cell
transplantation in patients with Waldenström macroglobulinemia: 73. Dimopoulos MA, Kastritis E, Owen RG, et al. Treatment recommenda-
report from the Lymphoma Working Party of the European tions for patients with Waldenström macroglobulinemia (WM)
Group for Blood and MarrowTransplantation. J Clin Oncol. and related disorders: IWWM‐7 consensus. Blood. 2014;124(9):
2010;28(33):4926–4934. 1404–1411.
12 TEDESCHI ET AL.

74. Rosenbaum E, Marks D, Raza S. Diagnosis and management of 84. Rizzo D, Chauzeix J, Trimoreau F, et al. IgM peak independently pre-
neuropathies associated with plasma cell dyscrasias. Hematol Oncol. dicts treatment‐free survival in chronic lymphocytic leukemia and
2018;36(1):3–14. correlates with accumulation of adverse oncogenetic events. Leukemia.
75. Klein CJ, Moon JS, Mauermann ML, et al. The neuropathies of 2015;29(2):337–345.
Waldenström macroglobulinemia (WM) and IgM‐MGUS. Can J Neurol 85. Xu W, Wang YH, Fan L, et al. Prognostic significance of serum immu-
Sci. 2011;38(2):289–295. noglobulin paraprotein in patients with chronic lymphocytic leukemia.
76. Nobile‐Orazio E. Antigenic determinants in IgM paraprotein‐related Leuk Res. 2011;35(8):1060–1065.
neuropathies. Clin Lymphoma Myeloma. 2009;9(1):107–109. 86. Berentsen S, Ulvestad E, Langholm R, et al. Primary chronic cold
77. Pruppers MHJ, Merkies ISJ, Notermans NC. Recent advances in out- agglutinin disease: a population based clinical study of 86 patients.
come measures in IgM‐anti MAG+ neuropathies. Curr Opin Neurol. Haematologica. 2006;91(4):460–466.
2015;28(5):486–493. 87. Mauro FR, Foa R, Cerretti R, et al. Autoimmune hemolytic anemia in
78. Milani P, Merlini G. Monoclonal IgM‐related AL amyloidosis. Best Pract chronic lymphocytic leukemia: clinical, therapeutic, and prognostic
Res Clin Haematol. 2016;29(2):241–248. features. Blood. 2000;95(9):2786–2792.

79. Chan KL, Lade S, Prince HM, Harrison SJ. Update and new approaches 88. Arcaini L, Varettoni M, Boveri E, et al. Distinctive clinical and
in the treatment of Castleman disease. J Blood Med. 2016;7:145–158. histological features of Waldenström's macroglobulinemia and splenic
marginal zone lymphoma. Clin Lymphoma Myeloma Leuk. 2011;11(1):
80. Kyle RA, Treon SP, Alexanian R, et al. Prognostic markers and criteria
103–105.
to initiate therapy in Waldenstrom's macroglobulinemia: consensus
panel recommendations from the Second International Workshop on 89. Cao XX, Meng Q, Mao YY, et al. The clinical spectrum of IgM monoclo-
Waldenstrom's Macroglobulinemia. Semin Oncol. 2003;30(2):116–120. nal gammopathy: a single center retrospective study of 377 patients.
Leuk Res. 2016;46:85–88.
81. Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and
prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J
Med. 2007;356(25):2582–2590.
82. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the How to cite this article: Tedeschi A, Conticello C, Rizzi R,
World Health Organization classification of lymphoid neoplasms.
et al. Diagnostic framing of IgM monoclonal gammopathy:
Blood. 2016;127(20):2375–2390.
Focus on Waldenström macroglobulinemia. Hematological
83. Lin P, Hao S, Handy BC, Bueso‐Ramos CE, Medeiros LJ. Lymphoid
neoplasms associated with IgM paraprotein: a study of 382 patients. Oncology. 2018;1–12. https://doi.org/10.1002/hon.2539
Am J Clin Pathol. 2005;123(2):200–205.