Waldenstrom’s

Macroglobulinemia (WM)
By Dr. Ghiassi, Dr. Shah, & Dr. Saab
 Elderly Woman with Thrombocytosis
• Patient goes to see her annual PCP appointment and her PCP notices that
her CBC showed a new elevation in platelets (454)
• PCP decides to order an ESR, which on multiple occasions comes back
elevated between 70-90
• A Hematology/Oncology consult is made
Hematology/Oncology Appointment 9/28/16

• Patient is asymptomatic
• Has a PMH of R sided breast cancer that was resected in 1985 and had been in
remission since
• Patient never had any radiation, chemotherapy, or hormonal therapy
• Patient used to smoke, but quit years ago
• Specialist examines patient and does not detect splenomegaly
• Does not believe that her lab work is related to a myeloproliferative disorder,
polymyalgia rheumatica, or myeloma
 Specialist Orders Protein Electrophoresis and
Immunofixation
• Everything is wnl except her IgG is low at 5 g/L and her IgM is elevated
at 1.2 g/dL
• Concern for a low-grade lymphoproliferative disorder leads to bone
marrow aspiration and biopsy
• Bone marrow shows slightly hypercellular at 40% with involvement by
lymphoplasmacytic lymphoma
• Genetic and molecular testing ordered
 Genetic & Molecular Test Results
• Test results come back + for MYD 88
• This suggests Waldenstrom’s Macroglobulinemia
• Due to patient being asymptomatic at this time no treatment was started
 What is
Waldenstrom’s Macroglobulinemia ?
 Introduction
• WM is a type of macroglobulinemia that is characterized by production of
excess IgM monoclonal proteins
• WM starts in B cells and shares similar characteristics of other cancers such
as Multiple Myeloma (MM) and NHL
• WM’s cancer cells have similarities of plasma cells and lymphocytes, which
are called lymphoplasmacytoid
• WM demonstrates a lymphoplasmacytic lymphoma (LPL) in the bone
marrow with an IgM monoclonal gammopathy in the blood
 Lymphoplasmacytoids

• Lymphoplasmacytoid lymphocyte has ample pale blue cytoplasm and a slightly eccentric nucleus
• The condensed nuclear chromatin pattern is characteristic of mature lymphocytes
• The overall appearance is midway between a typical mature lymphocyte and a plasma cell
Lymphoplasmacytoids
• Bone marrow aspirate in a WM
patient:
 Mature lymphocytes (thin arrow)
 Plasma cells (thick arrow)
 Lymphoplasmacytic cells
 Introduction
• WM patients may present with symptoms related to:

1- IgM build up: excess bleeding, problems with vision and nervous system

2- Infiltration of the hematopoietic tissue by WM cells : anemia & leukopenia

 Epidemiology
• WM is a rare disorder
• Incidence : three per million people per year
• 1400 new cases diagnosed in the United States each year
• The median age at diagnosis is 70 years
 Risk Factors
• Age: WM is rare in individuals younger than 50 y/o
• Sex: Men are more likely to develop WM than women
• Race: White individuals are more likely than other races to get WM
• Heredity: Individuals with a first degree relative with WM or B-cell disease
are more likely to develop WM themselves
• Hepatitis C
• Sjogren syndrome
 Etiology
• The etiology of WM is unknown
• No obvious causative or predisposing factor
• Some studies have suggested an association with chronic immune stimulation and autoimmune disorders :
o Hepatitis C infection
o Sjogren syndrome
o exposure to farming, pesticides, and wood dust

• Although WM appears to be a sporadic disease but a familial predisposition is present in up to 20 %

• Since there are no proven preventative approaches, there is no role for screening asymptomatic relatives
 Pathogenesis
• Both somatic mutations and chromosomal abnormalities have been
identified in the malignant B cells of WM
• A recurrent mutation of the MYD88 gene (MYD88 L265P) is present in
the vast majority of patients with WM but is not entirely specific
• 40 % of WM patients have recurrent mutations in the CXCR4 gene
Pathogenesis
• Somatic mutations in WM consists of
selection by antigenic stimulation at a
relatively late stage of B cell differentiation
such as a post-germinal center IgM memory
B cell that has undergone somatic
hypermutation but has failed to undergo
isotype class switching
• This comprises the major
lymphoplasmacytic compartment in the bone
marrow.
MYD88 Gene
• MYeloid Differentiation primary
response 88
• MYD88 transfers signals from
certain proteins called Toll-like
receptors and interleukin-1 (IL-1)
receptors, which are important for an
early immune response to foreign
invaders such as bacteria
 MYD88 Mutation
• The altered MYD88 protein in WM is overactive
• It stimulates the signaling molecules that activate nuclear factor-kappa-B,
even without signals from outside the cell
• Abnormally active nuclear factor-kappa-B allows survival of abnormal cells
that should undergo apoptosis leading to accumulation of
lymphoplasmacytic cells
• REMEMBER: MYD-88 can be seen with the others <5% of times
 Clinical Presentation
• Most patients with WM present with nonspecific constitutional symptoms
• Up to one-quarter of patients may be asymptomatic at diagnosis with incidental lab finding
• The most common presenting features include:
Weakness
Fatigue
Weight loss
Chronic oozing of blood from the nose or gums
Recurrent infections due to a relative decrease in other immunoglobulins
The population of clonal B cells results in the production of abnormal monoclonal IgM that
may manifest itself clinically via several mechanisms:
Mechanism Resulting Pathology
Act as an autoantibody directed against myelin- Neuropathy
associated glycoprotein or other nerve components
May be directed against antigens on the patient's Coombs-positive autoimmune cold hemolytic anemia
RBCs
May be deposited in the extracellular space of the Renal Insufficiency, Immune-mediated
kidneys, gastrointestinal tract, or skin glomerulonephritis, Severe malabsorption with diarrhea
and steatorrhea
May precipitate out of the serum in cold Cryoglobulinemia
temperatures
The pentameric configuration of IgM molecules Hyperviscosity syndrome
increases serum viscosity
Malignant B cells may directly infiltrate the Cytopenias, lymphadenopathy, hepatomegaly, and/or
hematopoietic tissues splenomegaly
The plasmacytoid lymphocytes may infiltrate the Bing-Neel syndrome
central nervous system or meninges.
 Neuropathy
• 20% of patients may present with symptoms of neuropathy at the time of
diagnosis
• The most frequent neurologic abnormality is a distal, symmetric, and slowly
progressive sensorimotor peripheral neuropathy causing paresthesias and
weakness
• The lower extremities are usually more involved than the upper extremities
• Anti-myelin-associated glycoprotein (MAG) activity is found in 50% of
patients
 Funduscopic Abnormalities 
• Noted in 34 percent of patients
• The most common finding: Dilated, segmented, and tortuous retinal veins,
giving a "sausage link" appearance
• Other retinal lesions: hemorrhages, exudates, and papilledema
• Funduscopic examination is recommended in patients with serum IgM level
>3000 mg/dL and indicated for patients with suspected hyperviscosity related
symptoms
Funduscopic Abnormalities 

• Retinal photograph in WM shows

multiple hemorrhages and dilated,
segmented, and tortuous retinal
veins
 Cryoglobulinemia  
• Approximately 10 % of macroglobulins in WM precipitate in the cold
(cryoglobulins), but are rarely responsible for cold hypersensitivity
• However, if the cryoglobulin precipitates at temperatures greater than 22°C,
serious symptoms can occur and may include Raynaud phenomenon, urticaria,
purpura, acral cyanosis, and/or tissue necrosis
 Cryoglobulinemia  

• Blood smear with large clumps of • Blood smear with small

cryoglobulins (×16 objective)at room precipitates of cryoglobulins after
temperature (20˚C) incubation for 15 minutes at 37˚C
 Hyperviscosity syndrome  
• Present in up to 30 % of patients
• The pentameric configuration of IgM molecules increases serum viscosity
• Symptoms: blurring or loss of vision, headache, vertigo, nystagmus, dizziness, tinnitus, sudden
deafness, diplopia, or ataxia
• Marked hyperviscosity can rarely lead to confusion, dementia, disturbances of consciousness,
stroke, or coma
• When accompanied by anemia, hyperviscosity and the associated plasma volume expansion may
precipitate or aggravate heart failure
• Symptomatic hyperviscosity is a medical emergency > Consider emergency plasmapherisis
Hyperviscosity Syndrome
 Can WM be Prevented?
• Most risk factors such as: Age, sex, race, etc. cannot be changed. As
mentioned before hepatitis C is one of the only preventable risk factors
that is known at this time.
 Diagnosis
To make a diagnosis of WM, the following criteria must be met :
• An IgM monoclonal gammopathy (of any size) must be present in the serum
• ≥10 % of the bone marrow biopsy sample must demonstrate infiltration by small lymphocytes that
exhibit plasmacytoid or plasma cell differentiation (lymphoplasmacytic features or
lymphoplasmacytic lymphoma) with an intertrabecular pattern
• This infiltrate should express a typical immunophenotype (eg, surface IgM+, CD5-/+, CD10-,
CD11c-, CD19+, CD20+, CD22+, CD23-, CD25+, CD27+, FMC7+, CD103-, CD138-). The
plasmacytic component will be CD138+, CD38+ and CD45- or dim.
The MYD88 L265P gene mutation has been identified in over 90 percent of patients with WM, and
can be of help on differentiating WM from other conditions
 Lab Findings in WM
CBC
  Anemia can be seen in 40 % of patients with newly diagnosed WM
 Anemia in WM is multifactorial:
• Inadequate red cell synthesis due to bone marrow replacement
• Iron deficiency due to decreased gastrointestinal absorption
• Chronic inflammation with increased hepcidin
• Decreased erythrocyte survival, which may rarely be due to an autoimmune hemolytic anemia
 Lymphocytosis and monocytosis are also common findings in WM
 Leukopenia due to marrow infiltration
 Thrombocytopenia may be due to bone marrow infiltration, autoimmune destruction, and/or hypersplenism.
 Lab Findings in WM
Platelet function and blood coagulation
•  A clinically important bleeding diathesis is common in WM and is secondary to
hyperviscosity, and IgM paraprotein interference with clotting factor and platelet
function
• The most common lab finding is Prolongation of the thrombin time
• Alterations in platelet function result in prolongation of the bleeding time, impaired
clot retraction, defective in vivo platelet aggregation
 Lab Findings in WM
Serum Protein ElectroPhoresis 
• Serum protein electrophoresis (SPEP) reveals a sharp, narrow spike or dense band
of monoclonal IgM, usually migrating in the gamma area
• Immunoperoxidase staining detects either kappa or lambda light chain
• 75% of the IgM proteins are of the kappa light chain type
• Reciprocal reductions in the concentrations of IgG and IgA are often present, but
are not as profound as in multiple myeloma
 Lab Findings in WM
Serum Protein ElectroPhoresis 
• SPEP pattern in a patient with WM
• monoclonal (M) protein in the gamma region
(asterisk).
• Immunofixation (IFE) shows that the M protein
is IgM kappa
 Lab Findings in WM
Serum viscosity  
•  Serum viscosity should be performed in any patient with a monoclonal
gammopathy and signs and symptoms suggesting the hyperviscosity syndrome
• Serum viscosity should also be determined whenever the monoclonal IgM protein
spike is >4 g/dL
• The normal value for serum viscosity is 1.5 centipoise (CP), but hyperviscosity
symptoms are rarely present unless the viscosity is >4 CP
 Flow Cytometry
• Flow cytometry immunophenotyping is used primarily to help diagnose and classify blood cell cancers
(leukemias and lymphomas) and to help guide their treatment. It may be used in follow up to a complete blood
count (CBC) and WBC differential that show an increased number of lymphocytes or the presence of
immature blood cells or other abnormal cell counts.
• It is an objective and quantitative diagnostic tool that allows quick multiparametric analysis of a very large
number of cells (20.000–50.000 cells per sample) which could be obtained from small tissue sample (0.1
cm3 or even smaller).
• flow cytometry (FCM) allows a more precise definition of individual cell types since the cells of interest are
identified by a combination of physical characteristics and the use of multiple antibodies directly conjugated
with different fluorochromes. It also has the ability to assess monoclonality through detection of
immunoglobulin light chain expression and the results can be available within few hours after receiving the
specimen.
 Other Tests to Help Detect WM
• Urine Protein Electrophoresis (UPEP): Excessive immunoglobins often leak
out into the urine and can be detected by UPEP
• Beta-2 Microglobin (B2M): This protein is associated with prognosis of
WM. The higher the B2M number the worse the prognosis
• Cold Agglutinins: These antibodies are associated with WM and often kill
RBCs in cooler parts of the human body (extremities)
• Fat Pad Fine Needle Aspiration: Test to differentiate Amyloidosis from WM
 How to Stage WM?
Unlike many other cancers WM does not have a typical staging process. When
physicians are looking at prognosis of patients with WM, they look at five main
factors:
• Age: Is the patient older than 65?
• HGB: Is the HGB below 11.5 g/dL?
• Platelets: Are the platelets below 100,000/mcL?
• B2M: Is it more than 3 mg/L?
• IgM: Is it more than 7 g/dL?
 International Prognostic Scoring System for
Waldenstrom Macroglobulinemia (ISSWM)
Using the five factors as mentioned in the previous slide patients can be
categorized into three separate groups. The groups are designated by how many
risk factors a patient has. Each risk factor equals a point (except for age):
 Low-risk group: includes patients 65 or younger who have no more than 1 point
 Intermediate-risk group: includes those who are older than 65 with 2 or fewer
points, and those younger than 65 who have 2 points
 High-risk group: includes those of any age who have at least 3 points
 ISSWM Continued
Survival rates of each group:
• Low Risk: 5-year survival rate is 87% and median survival is 12 years
• Intermediate Risk: 5-year survival rate is 68% and median survival is 8
years
• High Risk: 5-year survival rate is 36% and median survival is 3.5 years
 Who requires Treatment for WM?
• Not everyone with WM needs treatment right away
• Many patients are diagnosed with WM before they even have symptoms
 What is the Treatment for WM?
• The drugs used to treat WM can be given in a variety of combinations and
schedules
• Some doctors like to combine drugs (often some type of chemotherapy plus
rituximab), while others prefer to start with a single drug
• The patient’s age, overall health, and symptoms can also affect which treatments
are recommended
• Hyperviscosity Syndrome is a risk with WM and requires urgent plasmapheresis
• Stem cell transplant is an option for some patients
• WM in general is not considered curable, but the treatment can slow its progression
 What is the Treatment for WM? Cont’d
List of chemotherapy drugs that have been successful in treating WM
Bendamustine, with or without rituximab
Bortezomib, with or without dexamethasone
and/or rituximab
Carfilzomib, rituximab, and dexamethasone
Cladribine, with or without rituximab
Cyclophosphamide, prednisone, and rituximab
(CPR)
Fludarabine, with or without rituximab
Fludarabine, cyclophosphamide, and rituximab (FCR)
Ibrutinib, with or without rituximab
Ixazomib, rituximab, and dexamethasone
Rituximab
Rituximab, cyclophosphamide, and dexamethasone
(RCD)
Zanubrutinib
What is the Treatment for WM? Cont’d
 What is the Treatment for WM? Cont’d
• In general, rituximab is not usually given when the IgM level is very high because it
can make the IgM level temporarily go up even higher
• Plasmapheresis may be used first to lower the IgM level before starting rituximab.
• Another option is to give rituximab along with ibrutinib because the combination can
rapidly reduce the level of IgM
• If a stem cell transplant might be used later, many experts recommend not giving
certain chemo drugs (chlorambucil, bendamustine, cladribine, or fludarabine) because
they might affect the stem cells in the bone marrow making a stem cell transplant less
feasible in the future
In less fit, older adults use
Bruton Tyrosine Kinase
inhibitor
 What is the Treatment for WM? Cont’d

• There is always a risk that WM, which normally is an

indolent cancer can change into an aggressive NHL
• In this case urgent chemotherapy and/or stem cell
transplant is needed due to the lower survivability of
aggressive NHL compared to a standard WM diagnosis
 Increased Cancer Risks after Diagnosis of
WM
• Patients who have been diagnosed with WM are not only at risk of
developing worsening WM symptoms at any point of the treatment
process, but are also at increased risks of other cancers, such as:
 Acute myeloid leukemia (AML)
 Diffuse B-Cell Lymphoma
 Thyroid Cancers
 Melanoma
 Differential Diagnosis of WM
Multiple Myeloma:
• Significant increase in IgG and/or IgA
• Predominately in the elderly
• Monoclonal gammopathy >30g/L and Plasma cells >10% on bone marrow
• CRAB syndrome:
 HyperCalcemia: Due to bone destruction from lytic bone lesions
 Renal Failure: Immunoglobulin precipitation in renal tubules leads to tubular casts of Bence Jones
protein
 Anemia: Normocytic normochromic. Also, leukopenia, thrombocytopenia
 Bone pain: Due to osteolytic lesions and vertebral fractures
 Differential Diagnosis of WM
Smoldering Multiple Myeloma (SMM):
• Most cases are asymptomatic
• More common in the elderly
• Monoclonal gammopathy >30g/L
• Plasma cells >10% on bone marrow
• No CRAB syndromes
• No treatment needed
 Differential Diagnosis of WM
Monoclonal Gammopathy of Undetermined Significance (MGUS):
• Most cases are asymptomatic
• More common in the elderly
• Monoclonal gammopathy <30g/L
• Plasma cells <10% on bone marrow
• No CRAB syndromes
• No treatment needed, but must be monitored as 1-1.5% will progress to other cancers
that do cause symptoms (multiple myeloma)
Differential Diagnosis of WM
Differential Diagnosis of WM
 OMM
Osteopathic principles:

• The body is a unit.

• Structure affects function.
• The body can heal and regulate itself.
• Inbecause
cancer, multitude of OMM treatments are contraindicated according to research since they promote spread of tumor
of lymphatic drainage, however since leukemia has already spread everywhere, can do lymphatic techniques to
help patient feel better

• As osteopathic physicians treat the whole person (body, mind, spirit), help address physical, mental and emotional
stressors

• Can do ME/FPR/counterstrain techniques for pain

 Patient Conclusion
• Patient was mostly asymptomatic her first 2 years after being diagnosed with
WM
• Afterwards she developed significant fatigue and would even faint at one point
• She was started on ibrutinib (Bruton Tyrosine Kinase inhibitor ), and her IgM
has dropped to below 0.9 g/dL
• The patient’s symptoms improved after starting ibrutinib
• The patient continues to do well
 References
• UpToDate
• American cancer society
• American society of hematology