i3 Health is pleased to make the Clinician's Resource Guide from this activity available for use as a nonaccredited self-study or teaching resource.

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Clinical Tools and Resources for
Self-Study and Patient Education
WALDENSTROM MACROGLOBULINEMIA
REFERENCE GUIDE
The clinical tools and resources contained herein are provided as educational adjuncts to the
CME/CE-approved online activity Improving Treatment Outcomes of Patients With Waldenstrom
Macroglobulinemia. To access the activity and earn CME/CE credit, visit:
https://www.i3Health.com/
CONTENTS
I. Indicators of Waldenstrom Macroglobulinemia (WM)........................................................................2
II. Diagnostic Work-Up for WM .............................................................................................................3
III. Prognostic Scoring for WM ..............................................................................................................5
IV. Pharmacologic Treatment of WM ....................................................................................................6
V. Consensus for Newly Diagnosed WM...............................................................................................7
VI. WM: Treatment Options ..................................................................................................................8
VII. Treating Symptomatic WM: Fit Versus Unfit ...................................................................................9
VIII. WM: Consensus for Off-Study Salvage Therapy ..........................................................................10
IX. Treating Symptomatic Relapse of WM: Fit Versus Unfit ................................................................11
X. WM Treatment Options According to Stem Cell Toxicity ..............................................................12
XI. WM: Response Categories and Criteria.........................................................................................14

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I. INDICATORS OF WALDENSTROM MACROGLOBULINEMIA (WM)
WM Symptoms
• Hyperviscosity and its effects
• Reduced red blood cell count
• Adenopathy: enlarged lymph nodes
• Neuropathy: nerve problems that cause pain, tingling, and numbness
• Immunoglobulin M (IgM) buildup in places exposed to the cold (cryoglobulins)
o For example, the nose, ears, fingers, or toes turn blue or black and can hurt
• Cold agglutinin disease: IgM breaks down the red blood cells at low temperatures
o This is a form of hemolytic anemia (red blood cells break down quickly)
• Organomegaly: the abnormal enlargement of organs
• Raynaud’s disease: causes some areas of the body, such as fingers and toes, to feel cold and change color in
response to cold temperatures or stress, with numbness or stinging pain upon warming or stress relief
• Rash
• Peripheral edema: swelling in the lower limbs or other areas perfused by the peripheral vascular system
• Skin abnormalities
• Dyspnea: difficult or labored breathing
National Comprehensive Cancer Network (2017). NCCN Guidelines for Patients®: Waldenstrom’s macroglobulinemia. Version 1.2017.
Available at: http://nccn.org/patients

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II. DIAGNOSTIC WORK-UP FOR WM
Diagnostic Work-Up
• History and physical examination
o Include familial history for WM and other B-cell lymphoproliferative disorders
• Review of symptoms: include fundoscopic examination if IgM is high and hyperviscosity is suspected
• Laboratory studies:
o Complete blood count
o Complete metabolic panel
o Serum immunoglobulin (Ig) levels: IgA, IgG, IgM
§ Serum protein electrophoresis and quantitative immunoglobulins; immunofixation can be used
o Serum and urine electrophoresis with immunofixation
o Serum viscosity to check for thickness of blood (too thick is indicative of WM)
o Serum beta-2 microglobulin level: indicates how patient will respond to treatment
o Viral serology: hepatitis B, hepatitis C, human immunodeficiency virus
• Blood marrow aspiration and biopsy
• Lymph node biopsy
• Genetic testing:
o MYD88L265P
gene mutation (occurs in 90% of people with WM)
o CXCR4 mutations
• CT of the chest, abdomen, and pelvis if clinically indicated; perform in all patients being considered for therapy
• Immunophenotyping using flow cytometry and immunohistochemistry to test for the following proteins: sIgM+,
CD19+, CD20, CD5, CD10, and CD23 (all indicative of WM)
• MRI to investigate possibility of Bing-Neel syndrome
CT = computed tomography; MRI = magnetic resonance imaging.
Kastritis E, Leblond V, Dimopoulos MA, et al (2018). Waldenstrom’s macroglobulinaemia: ESMO clinical practice guidelines for
diagnosis, treatment and follow-up. Ann Oncol, 29(suppl_4):iv41-iv50. DOI:10.1093/annonc/mdy146
National Comprehensive Cancer Network (2017). NCCN Guidelines for Patients®: Waldenstrom’s macroglobulinemia. Version 1.2017.
Available at: http://nccn.org/patients

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Additional Diagnostic Work-Up
Cryoglobulin
• Test of how IgM responds to certain red blood cell antigens at colder temperatures. This
can cause red blood cell breakdown and anemia
Cold agglutinin
• Test for cold agglutinins, which are antibodies that destroy red blood cells at colder
temperatures. Like cryoglobulins, these can cause the cells to block the blood vessels
Coagulation
• Test of how well your blood is clotting and how long it takes to clot. Blood clots stop your
bleeding. This test can also be done before surgery
Hepatitis B or C • Rituximab may activate Hepatitis B
Neurology • Test for nerve damage
Anti-MAG (myelin-
associated
glycoprotein)
• Test for antibodies that can affect your nerves
Electromyelogram • Measures the electrical way your muscles work
Amyloid
• Test of the bone marrow for this abnormal protein, which can build up and cause damage
to your nerves (peripheral neuropathy) and organs (amyloidosis)
Retinal exam • Exam of the back of the eye to check for any changes or bleeding from hyperviscosity
National Comprehensive Cancer Network (2017). NCCN Guidelines for Patients®: Waldenstrom’s macroglobulinemia. Version 1.2017.
Available at: http://nccn.org/patients

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III. PROGNOSTIC SCORING FOR WM
Risk Factors
• Age ≥50 years
• Gender (male)
• Race and ethnicity: more common in white individuals and those of Ashkenazi descent
• Family history of WM or other lymphomas
• Monoclonal gammopathy of undetermined significance (MGUS): IgM is found in the blood at above-normal levels,
but not at levels high enough to cause symptoms
International Prognostic Scoring System
• Risk Factors:
o Age ≥65 years
o Hemoglobin ≤11.5 g/dL
o Platelet count ≤100,000/mcL
o Beta-2 microglobulin >3 mg/L
o IgM >7 g/dL
• High risk: ≥3 factors
• Intermediate risk: age ≥65 years or 2 factors
• Low risk: 0 or 1 factor (except age)
National Comprehensive Cancer Network (2017). NCCN Guidelines for Patients®: Waldenstrom’s macroglobulinemia. Version 1.2017.
Available at: http://nccn.org/patients

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IV. PHARMACOLOGIC TREATMENT OF WM
Effective Agents for WM
Monoclonal Antibodies
• Rituximab (Rituxan®
)
• Ofatumumab (Arzerra®
)
• Alemtuzumab (Lemtrada®
)
Alkylating Agents
• Chlorambucil (Leukeran®
)
• Cyclophosphamide (Cytoxan®
)
• Melphalan (Evomela®
)
• Bendamustine (Bendeka®
)
• Cladribine (Mavenclad®
)
Purine analogs • Fludarabine (Fludara®
)
Proteasome inhibitors
• Bortezomib (Velcade®
)
• Carfilzomib (Kyprolis®
)
• Ixazomib (Ninlaro®
)
Immunomodulatory drugs
• Thalidomide (Immunoprin®
)
• Pomalidomide (Pomalyst®
)
mTOR inhibitors • Everolimus (Afinitor®
)
Targeted therapies/pathway
inhibitors to B-cell signaling
• Ibrutinib (Imbruvica®
)
• Everolimus (Afinitor®
)
• Acalabrutinib (Calquence®
)
• Venetoclax (Venclexta®
)
mTOR = mammalian target of rapamycin.
American Cancer Society (2019). Biological therapy for immunotherapy for Waldenstrom macroglobulinemia. Available at:
http://cancer.org
Ghobrial IM, Witzig TE, Gertz M, et al (2014). Long-term results of the phase II trial of the oral mTOR inhibitor everolimus (RAD001) in
relapsed or refractory Waldenstrom macroglobulinemia. Am J Hematol, 89(3):237-242. DOI:10.1002/ajh.23620
International Waldenstrom’s Macroglobulinemia Foundation (2019). Chemotherapy – alkylating agents and nucleoside analogs: a
guide to treatment options. Available at http://www.iwmf.com
Kapoor P, Ansell SM, Fonseca R, et al (2017). Diagnosis and management of Waldenstrom macroglobulinemia. JAMA Oncol,
3(9):1257-1265. DOI:10.1001/jamaoncol.2016.5763

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V. CONSENSUS FOR NEWLY DIAGNOSED WM
Kapoor P, Ansell SM, Fonseca R, et al (2017). Diagnosis and management of Waldenstrom macroglobulinemia. JAMA Oncol,
3(9):1257-1265. DOI:10.1001/jamaoncol.2016.5763

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VI. WM: TREATMENT OPTIONS
First-Line Treatment According to Disease Presentation
Clinical Syndrome Treatment Options
Hyperviscosity
• Proteasome inhibitor-based therapy (bortezomib/dexamethasone/rituximab,
bortezomib/rituximab)
• Ibrutinib
• Bendamustine/rituximab
Cytopenia
Bulky disease
Need for immediate tumor
reduction due to WM-related
complications
Neuropathy
• Dexamethasone/rituximab/cyclophosphamide
• Bendamustine/rituximab
• Rituximab monotherapy
AL amyloidosis
• Proteasome inhibitor-based therapy (bortezomib/dexamethasone/rituximab,
bortezomib/rituximab)
• Bendamustine/rituximab
AL = immunoglobulin light chain.
Kastritis E, Leblond V, Dimopoulos MA, et al (2018). Waldenstrom’s macroglobulinaemia: ESMO clinical practice guidelines for
diagnosis, treatment and follow-up. Ann Oncol, 29(suppl_4):iv41-iv50. DOI:10.1093/annonc/mdy146
Additional Treatment Options
Plasmapheresis
• To remove IgM from the blood
• May need red blood cell transfusion after plasmapheresis
Stem cell transplant
• Autologous stem cell transplant: stem cells come from you when chemotherapy
is working
• Allogeneic stem cell transplant: stem cells come from donor
o Risk of graft-versus-host-disease (GVHD)
National Comprehensive Cancer Network (2017). NCCN Guidelines for Patients®: Waldenstrom’s macroglobulinemia. Version 1.2017.
Available at: http://nccn.org/patients

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VII. TREATING SYMPTOMATIC WM: FIT VERSUS UNFIT
DRC = dexamethasone/rituximab/cyclophosphamide; BR = bendamustine/rituximab; BDR =bendamustine/dexamethasone/rituximab;
VR = vincristine/rituximab; QD = once a day.
Kastritis E, Leblond V, Dimopoulos MA, et al (2018). Waldenstrom’s macroglobulinaemia: ESMO clinical practice guidelines for
diagnosis, treatment and follow-up. Ann Oncol, 29(suppl_4):iv41-iv50. DOI:10.1093/annonc/mdy146

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VIII. WM: CONSENSUS FOR OFF-STUDY SALVAGE THERAPY
Kapoor P, Ansell SM, Fonseca R, et al (2017). Diagnosis and management of Waldenstrom macroglobulinemia. JAMA Oncol,
3(9):1257-1265. DOI:10.1001/jamaoncol.2016.5763

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IX. TREATING SYMPTOMATIC RELAPSE OF WM: FIT VERSUS UNFIT
R = rituximab.
Kastritis E, Leblond V, Dimopoulos MA, et al (2018). Waldenstrom’s macroglobulinaemia: ESMO clinical practice guidelines for
diagnosis, treatment and follow-up. Ann Oncol, 29(suppl_4):iv41-iv50. DOI:10.1093/annonc/mdy146

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X. WM TREATMENT OPTIONS ACCORDING TO STEM CELL TOXICITY
Primary Treatment
• Drugs without stem cell toxicity:
o Bortezomib with or without rituximab
o Bortezomib/dexamethasone
o Bortezomib/dexamethasone/rituximab
o Carfilzomib/rituximab/dexamethasone
o Cyclophosphamide/doxorubicin/vincristine/prednisone/rituximab
o Ibrutinib
o Rituximab
o Rituximab/cyclophosphamide/prednisone
o Rituximab/cyclophosphamide/dexamethasone
o Thalidomide with or without rituximab
• Drugs with possible stem cell toxicity and/or risk of transformation, or unknown risk:
o Bendamustine with or without rituximab
o Cladribine with or without rituximab
o Chlorambucil
o Fludarabine with or without rituximab
o Fludarabine/cyclophosphamide/rituximab
o Clinical trial
National Comprehensive Cancer Network (2017). NCCN Guidelines for Patients®: Waldenstrom’s macroglobulinemia. Version 1.2017.
Available at: http://nccn.org/patients

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National Comprehensive Cancer Network (2017). NCCN Guidelines for Patients®: Waldenstrom’s macroglobulinemia. Version 1.2017.
Available at: http://nccn.org/patients
Relapsed/Refractory Treatment
• Treatments without stem cell toxicity:
o Alemtuzumab
o Bortezomib with or without rituximab
o Bortezomib/dexamethasone
o Bortezomib/dexamethasone/rituximab
o Cyclophosphamide/doxorubicin/vincristine/prednisone/rituximab
o Everolimus
o Ibrutinib
o Ofatumumab (given alone or with other drugs to people who can’t tolerate rituximab)
o Rituximab
o Rituximab/cyclophosphamide/prednisone
o Rituximab/cyclophosphamide/dexamethasone
o Thalidomide with or without rituximab
• Treatments with possible stem cell toxicity and/or risk of transformation, or unknown risk:
o Bendamustine with or without rituximab
o Cladribine with or without rituximab
o Chlorambucil
o Fludarabine with or without rituximab
o Fludarabine/cyclophosphamide/rituximab
o Stem cell transplant
o High-dose therapy with stem cell rescue
o Allogeneic stem cell transplant (in a clinical trial)
o Clinical trial

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XI. WM: RESPONSE CATEGORIES AND CRITERIA
Response
Category
Definition Next Steps In Case of Relapse
Complete
response
• Absence of serum monoclonal IgM protein
by immunofixation
• Normal serum IgM level
• Complete resolution of lymphadenopathy
and splenomegaly if present at baseline
• Wait and watch for
disease to progress
• Consider rituximab
• Relapse after <2 years:
begin a different
treatment
• Relapse ≥2 years: try
prior treatment or begin
a new one
Very good partial
response
• Detectable monoclonal IgM protein
• ≥90% reduction in serum IgM level from
baseline
• Complete resolution of extramedullary
disease (lymphadenopathy/splenomegaly)
if present at baseline
• No new signs or symptoms of active
disease
• If no symptoms: wait
and watch for
disease to progress
• If symptoms
continue: commence
a different treatment
• Relapse <2 years: begin
different treatment
• Relapse ≥2 years: try
prior treatment or begin
a new one
• If minor response:
begin a different
treatment
Partial response • Detectable monoclonal IgM protein 50%
• <90% reduction in serum IgM level from
baseline
• Reduction in extramedullary disease
(lymphadenopathy/splenomegaly) if
present at baseline
• No new signs or symptoms or active
disease
• Same as guidelines
for very good partial
response
• Same as guidelines for
very good partial
response
Minor response • Detectable monoclonal IgM protein ≥25%
• <50% reduction in serum IgM level from
baseline
• No new signs or symptoms
• Same as guidelines
for very good partial
response
• Same as guidelines for
very good partial
response
Stable disease • Detectable monoclonal IgM protein <25%
reduction
• <25% increase in serum IgM level from
baseline
• No progression in extramedullary disease
(lymphadenopathy/splenomegaly)
• No new signs or symptoms of active
disease
• Begin a different treatment
Progressive
disease
• ≥25% increase in serum IgM level from
lowest nadir, and/or
• Progression in clinical features attributable
to the disease
• Same as guidelines for stable disease
Kastritis E, Leblond V, Dimopoulos MA, et al (2018). Waldenstrom’s macroglobulinemia: ESMO clinical practice guidelines for
diagnosis, treatment and follow-up. Ann Oncol, 29(suppl_4):iv41-iv50. DOI:10.1093/annonc/mdy146
National Comprehensive Cancer Network (2017). NCCN Guidelines for Patients®: Waldenstrom’s macroglobulinemia. Version 1.2017.
Available at: http://nccn.org/patients