10968652, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.26796 by Spanish Cochrane National Provision (Ministerio de Sanidad), Wiley Online Library on [02/01/2023].

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Received: 15 November 2022 Accepted: 26 November 2022
DOI: 10.1002/ajh.26796

ANNUAL CLINICAL UPDATES IN

HEMATOLOGICAL MALIGNANCIES

Waldenström macroglobulinemia: 2023 update on diagnosis,

risk stratification, and management

Morie A. Gertz

Division of Hematology, Mayo Clinic,

Rochester, Minnesota, USA Abstract
Disease Overview: Waldenström macroglobulinemia (WM) is a lymphoplasmacytic
Correspondence
lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features
Morie A. Gertz, Division of Hematology,
Mayo Clinic, 200 First St SW, Rochester, include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and
MN 55905, USA.
Email: gertz.morie@mayo.edu
rarely hyperviscosity.
Diagnosis: Presence of IgM monoclonal protein associated with ≥10% clonal lympho-
Funding information
National Cancer Institute, Grant/Award
plasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in
Number: 5P50 CA186781-04 MYD88 is detectable in more than 90% of patients and is found in most IgM MGUS
patients. MYD88 is not required for the diagnosis.
Risk Stratification: Age, hemoglobin level, platelet count, β2 microglobulin, LDH, and
monoclonal IgM concentrations are characteristics that are predictive of outcomes.
Risk-Adapted Therapy: Not all patients who fulfill WM criteria require therapy; these
patients can be observed until symptoms develop. Rituximab-monotherapy is inferior
to regimens that combine it with bendamustine, an alkylating agent, a proteosome
inhibitor, or a BTK inhibitor. The preferred Mayo Clinic induction is either rituximab
and bendamustine (without rituximab maintenance) or zanubrutinib.
Management of Refractory Disease: Bortezomib, cyclophosphamide, fludarabine,
thalidomide, everolimus, Bruton Tyrosine Kinase inhibitors, carfilzomib, lenalidomide,
bendamustine, and venetoclax have all been shown to have activity in relapsed
WM. Given WM's natural history, the reduction of therapy toxicity is an important
part of treatment selection.

1 | PATIENT
A 55-year-old male was found to have an IgM monoclonal gammopa-
thy in January 2005. He was observed until November 2010 when his
IgM level climbed to 9135 mg/dl. He was treated with rituximab, bor-
tezomib, and dexamethasone for 4 months. Treatment was inter-
rupted due to neuropathy, but the IgM level fell to 1150. He was
observed until April 2015. At the time of progression his IgM was
Abbreviations: BTK, Bruton tyrosine kinase; IgM, immunoglobulin M; MGUS, monoclonal
gammopathy of undetermined significance; mTOR, mammalian target of rapamycin; OS,
overall survival; PFS, progression-free survival; R-CHOP, cyclophosphamide, doxorubicin,
vincristine, and prednisone plus rituximab; WM, Waldenström macroglobulinemia.
11 500 mg/dl and he was found to have acquired von Willebrand
disease.1 He was treated with single-agent rituximab which failed
to produce a minor response. He received bendamustine, lenalido-
mide, and rituximab with a response of <1 year. In 2018 he was
placed on an experimental trial of oprozomib with a response of
5 years duration. At relapse in August of 2022, he was placed on a
trial of ixazomib and ibrutinib. Ixazomib was poorly tolerated due
to diarrhea, and he continued ibrutinib alone and has achieved a
very good partial response.
Comment: This patient illustrates many common features of the
disease. A smoldering phase lasted 5 years, multiple therapeutic
interventions resulted in responses more than 4 years. Failure of

Am J Hematol. 2022;1–11. wileyonlinelibrary.com/journal/ajh © 2023 Wiley Periodicals LLC. 1


2 GERTZ
single-agent rituximab is typical. Bortezomib neuropathy was severe
but resolved completely.
2 | D I S E A S E OV E R V I E W
The World Health Organization defines Waldenström macroglobuline-
mia (WM) as a lymphoplasmacytic lymphoma associated with a mono-
clonal immunoglobulin M (IgM) protein.2 The physical manifestations
of the disorder are hepatomegaly (20%), splenomegaly (15%), and
lymphadenopathy (15%). The most common presenting symptom is
fatigue related to a normocytic anemia. The median hemoglobin value
at diagnosis is 10 g/dl. Many patients who fulfill the criteria of WM
do not require immediate therapy because they are asymptomatic
3
(smoldering). Virtually all patients have a preceding phase of IgM
MGUS, but the clonal MGUS B cells already contain the molecular sig-
nature of a malignant clone.4 Patients under the age of 70 have a
median survival in excess of 10 years; those 70–79, approximately
7 years; and those 80 or older, approximately 4 years. In patients with
Waldenstrom over age 65 at diagnosis, the most common cause of
death is not cancer related.5 Clonal hematopoiesis is present in 14%
of patients with macroglobulinemia. These patients are more likely to
progress from IgM MGUS or smoldering macroglobulinemia to symp-
6
tomatic disease. The key clinical features of the disease are repre-
sented in the graphical abstract.
The median age at the time of diagnosis is 71 years. The age-
adjusted incidence rate is .42/100 000 person-years with an age- and
sex-adjusted incidence of 0.57 per 100 000 person-years with a male-
to-female ratio of 3.2:1. There is no evidence of a change in the inci-
dence of WM over the past 50 years.7
WM incidence is higher in whites (4.1 per million per year) than in
blacks (1.8 per million per year). Waldenström patients had a positive
family history of lymphoplasmacytic lymphoma or WM in 4.3%, and a
family history was associated with poorer survival than the non-
familial forms. A study of monoclonal immunoglobulins (MGUS)
showed that the M protein isotype was IgM in 2% and 16% of black
and white patients, respectively. The median M protein concentration
for blacks was 0.44 g/dl, whereas it was 1.2 g/dl in whites. Black
patients less commonly have IgM monoclonal gammopathy compared
with white patients. Median age at diagnosis is 63 years for blacks
and 73 for whites, with blacks having a shorter survival than whites.8
Survival of WM is improving. The SEER database contained 5784
patients with WM. Median OS from 1991 to 2000 and 2001 to 2010
improved from 6 to 8 years, respectively. Deaths in the 2001 to 2010
cohorts were reduced both from WM related and non-WM-related
causes. Age at diagnosis continues to have the greatest impact on sur-
vival. The hazard ratio for death for WM patients' age 80 or greater
was 6.99, compared with a reference group less than age 50.9
The presence of a monoclonal IgM protein adds a unique dimen-
sion to the disorder because it can result in hyperviscosity syndrome,
peripheral neuropathy, hemolytic anemia, and immune complex vascu-
litis. The 10-year survival rate is now 66%. In a population-based
study of Latin American patients with WM and lymphoplasmacytic
10968652, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.26796 by Spanish Cochrane National Provision (Ministerio de Sanidad), Wiley Online Library on [02/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
lymphoma, 5-year relative survival was 81%. Survival improvements
were seen in all age groups, although increasing age was associated
with inferior survival.10
The management of peripheral neuropathy associated with IgM
monoclonal protein remains frustrating for clinicians. The mecha-
nism of the neuropathy is thought to be demyelination due to direct
binding of the antibody to myelin-associated glycoprotein. The
treatment of IgM-associated peripheral neuropathy can be like that
of WM. Overall improvement following rituximab treatment in IgM
associated neuropathy was seen in 54.5%. Six patients who were
unchanged after the 1st treatment with rituximab improved after
another rituximab cycle. Rituximab monotherapy retains a role in
IgM-mediated neuropathy.11 In a double blind, placebo-controlled
trial, 54 patients with anti-MAG IgM chronic demyelinating neurop-
athy were randomized to receive either placebo or rituximab. The
primary outcome of absolute improvement in ISS (INCAT sensory
score) from baseline at 12 months was not achieved in the study as
no significant difference in the change in ISS was seen between
rituximab and placebo groups. Ibrutinib was administered to
3 patients with anti-myelin associated glycoprotein immunoglobulin
M neuropathy all reported an improvement pointing to possible effi-
cacy of ibrutinib in this setting.12 The therapy of IgM-associated
neuropathy remains inadequate.13
2.1 | Diagnosis
In the original description of WM, Jan Gösta Waldenström described
two patients with oronasal bleeding (hyperviscosity), lymphadenopa-
thy, anemia, thrombocytopenia, and an elevated sedimentation rate.
The disorder is a lymphoplasmacytic lymphoma with a monoclonal
pentameric IgM protein. Bone marrow and lymph nodes are infiltrated
with pleomorphic B-lineage cells at different stages of maturation.
The bone marrow pattern is predominantly intertrabecular.14 Many
patients who fulfill all other criteria for the diagnosis have a presymp-
tomatic phase and may not require therapy.3 The cells express pan B-
cell markers (e.g., CD19, CD20) and typically test negative for CD3
and CD103.15 A recurring sequence variant at position 38 182 641 in
chromosome 3p22.2 has been identified. A single-nucleotide change
from T to C in the MYD88 gene resulted in a leucine-to-proline
change at amino acid position 265. This mutation is seen in 93% of
patients. CXCR4 mutations are seen in 29%. 53% of patients with
hyperviscosity have mutations of CXCR4.16 Together, these studies
demonstrate an important somatic variant in the malignant cells of
WM.17 MYD88 status does not predict survival 10.2 (mutant) versus
13.9 years (wild type) in patients not treated with BTK inhibitors.18
Others have reported a survival difference between those with
mutant and those with wild-type MYD88. The estimated 10-year sur-
vival was 73% for MYD88WT versus 90% for mutated MYD88MUT.
Median cause specific survival in cyclophosphamide treated patients
was 166 months.19
MYD88 can be detected by a polymerase chain reaction in the
peripheral blood of patients with WM.20 CXCR4 is mutated in 30% of

GERTZ
TABLE 1 Definitions of IgM-related phenomenon in macroglobulinemia
IgM Monoclonal
Component
MGUS +

Smoldering macroglobulinemia +

IgM-related disorder (eg, cold agglutinin hemolytic +

anemia, type II cryoglobulin, neuropathy, amyloidosis)
Macroglobulinemia + +
Abbreviations: IgM, immunoglobulin M; MGUS, monoclonal gammopathy of undetermined significance; +, positive;
, negative; ±, equivocal.
patients with WM. In animal models, this mutation predicts resistance
to ibrutinib and everolimus. CXCR4 mutation is associated with a
shorter treatment free survival.21
Distinguishing between WM and marginal zone lymphoma can
be challenging. MYD88 mutation L265P is specifically associated
with WM and IgM monoclonal gammopathy of undetermined sig-
nificance. MYD88 L265P also is seen in splenic marginal zone lym-
phoma (4%), IgM amyloidosis (71%), mucosa-associated lymphatic
tissue lymphoma (7%), and WM (67%–90%). MYD88 L265P cannot
be used to differentiate between WM and IgM MGUS. The muta-
tion is not found in IgM multiple myeloma, and mutation expression
is concordant with the extent of bone marrow involvement.
Responses after chemotherapy are associated with declines in
22
mutation expression.
Patients can present with markedly elevated IgM levels and infil-
tration of the bone marrow more than 30% yet still not require ther-
apy because they have no symptoms. Conversely, patients can have
low levels of monoclonal IgM protein and minimal clonal marrow infil-
tration and still require therapy for complications associated with the
IgM protein, including moderate or severe peripheral neuropathy,
amyloid deposition, cold agglutinin hemolytic anemia, and type II
mixed cryoglobulinemia—all a consequence of the antibody-binding
specificity and protein folding of the IgM protein. A classification
scheme for WM is provided in Table 1. Symptoms can be produced
by the tumor mass or the monoclonal protein. The disease is incurable
23
with current therapies.
IgM multiple myeloma is a distinct entity; although constituting
only 1% of all multiple myeloma cases, it must be distinguished from
WM. MYD88 is not mutated in IgM myeloma. Useful clues to the diag-
nosis of multiple myeloma include the presence of lytic bone lesions
(rare in WM) and a translocation at chromosome 14 (does not occur
in WM). Patients with IgM multiple myeloma tend to have plasmacytic
differentiation with high expression of CD138 and cytoplasmic immu-
24
noglobulin, whereas WM expresses CD20.
Monoclonal IgM proteins are found in 1 of 600 persons older
than 50 years. More patients have IgM MGUS than have
WM. However, all patients with IgM MGUS require lifelong monitor-
ing. Among patients with IgM MGUS, the presence of two adverse
risk factors—namely, an abnormal serum free light-chain ratio (ratio of
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3
Symptoms of Tumor Mass/ IgM-
Infiltration (Adenopathy Marrow Mediated
Anemia) Infiltration > 10% Symptoms



+

± +
+ ±
kappa to lambda free light chains) and a high serum monoclonal pro-
tein (M protein) level (≥1.5 g per deciliter)—was associated with a risk
of progression at 20 years of 55%. In a study of 176 IgM MGUS
patients a monoclonal protein peak of >1 gram/deciliter and the pres-
ence of an MYD88 mutation successfully predicted progression to
symptomatic macroglobulinemia with hazard ratios of over 20 for
both variables. The cumulative incidence of progression at 10 years
was 38%.25 MYD88 wild type is also an independent predictor of
transformation to large-cell lymphoma which carries an inferior overall
survival.26
Patients with IgM values greater than 3000 mg/dl may have no
symptoms, a normal hemoglobin value, and no clinically important
increase in serum viscosity. In these instances, observation continues
to be an appropriate option. Symptomatic hyperviscosity was only
seen in 13% of Mayo Clinic patients with WM. Even among patients
presenting with an IgM greater than 6000 mg/dl the median time to
initial therapy was 6.9 years.27 In patients with smoldering macroglob-
ulinemia independent predictors of disease progression to symptomatic
disease included immunoglobulin M level greater than 4500 mg/dl, bone
marrow infiltration with 70% or greater lymphoplasmacytic lymphoma,
beta 2 microglobulin >4 mg/L or greater and albumin <3.5 g/dl.28
Wild type MYD 88 is also an independent predictor of progression
to symptomatic disease.29 The Box 1 lists the recommended diag-
nostic tests for a new patient with suspected WM. Imaging plays a
minor role since the majority of patients have modest lymphade-
nopathy, however, there is a suggestion that the results from FDG
PET are prognostic in patients with macroglobulinemia.30
Response in WM is defined by reduction in the M protein. A
minor response is an M-spike reduction of at least 25%. A partial
response is defined as a 50% or greater reduction in M protein. A
very good partial response is a 90% reduction in M protein, and a
complete response is immunofixation negativity in the serum.
There may be discrepancies between IgM levels and bone marrow
response. The involved serum free light chain is a useful marker of
tumor burden and acts as a leading indicator of response and pro-
gression before the intact IgM. The immunoglobulin free light chain
assay, which is quite valuable in myeloma, has not been well estab-
lished in WM. It is not required for serial monitoring of patients
with WM.31
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4 GERTZ

T A B L E 2 International prognostic scoring system for

BOX 1 Diagnostic approach to suspected Waldenström macroglobulinemia

Waldenström macroglobulinemia Factor associated with prognosis Value

Age, year >65
Hemoglobin, g/dl ≤11.5
• Serum protein electrophoresis.
Platelet count, No./mcL ≤100 000
• Serum immunofixation to validate the immunoglobulin M
β2-Microglobulin, mg/L >3
(IgM) heavy chain and the type of light chain.
Monoclonal IgM, g/dl >7
• Quantitative test for immunoglobulin G, immunoglobulin A,
Risk stratum and survival
and IgM.
• 24-Hour urine collection for protein electrophoresis; Risk category Scorea Median
survival, month
monoclonal light chains are detected in the urine of
Low 0 or 1 (except age) 142.5
40%–80% of patients tested.
Intermediate 2 or age > 65 years 98.6
• Immunoglobulin free light chain assay (long-term value
High >2 43.5
not established).
Abbreviation: IgM, immunoglobulin M.
• Serum β2 microglobulin and LDH evaluation for progno- a
One point is assigned for each positive factor and the risk score is the
sis; part of the international staging system for Walden- sum of points.
ström macroglobulinemia.
• Bone marrow biopsy; intertrabecular monoclonal lym-
phoplasmacytic infiltrate ranges from predominantly lym-
cannot be in a low-risk category. Although IgM protein levels are
phocytic cells to overt plasma cells.
important prognostically, they do not enter the staging system until
• Perform MYD88L265P mutational analysis on bone mar-
the IgM level exceeds 7000 mg/dl. In the largest study of single-agent
row sample in all cases of WM by allele-specific
rituximab therapy for WM, the IgM level did not affect response
polymerase-chain-reaction (AS-PCR) assay.
rate.32 Lactate dehydrogenase is absent from the International Prog-
• CXCR4 mutational analysis, if available.
nostic Scoring System for Waldenström Macroglobulinemia. In a revi-
• Computed tomography of abdomen and pelvis to detect
sion of the prognostic scoring system age (≤65 vs 66–75 vs
organomegaly and lymphadenopathy or a combined 18F-
≥76 years), β2-microglobulin ≥4 mg/L, serum albumin <3.5 g/dl, and
FDG positron emission tomography (PET)/CT scan
LDH ≥250 IU/L (ULN < 225) was able to stratify patients in five dif-
(a skeletal survey and radiographic imaging of the bones
ferent prognostic groups and identify a very-low risk as well as a very-
are unnecessary in the absence of symptoms; lytic bone
high risk group with a 3-year WM-related death rate of 0, 10, 14, 38,
lesions are unusual).
and 48% (p < 0.001) and 10-year survival rate of 84, 59, 37, 19, and
• Serum viscosity required when signs and symptoms of
9% (p < 0.001). LDH is a predictor of early mortality in this disease.
hyperviscosity syndrome are present or when IgM
Age is the most powerful predictor of outcome. The 10 year survival
>4000 mg/dl.
of patients age 45 years or younger is 86%.33
• Ophthalmologic evaluation for hyperviscosity.
The International Prognostic Scoring System for Waldenström
• Based on clinical presentation, analysis involves Coombs
Macroglobulinemia is to be used only for patients who require treat-
test (cold autoantibody), cryoglobulin, Von Willebrand
ment. The system should not be used to determine whether a patient
Ag, Factor VIII C or tissue stains for amyloid deposits.
requires intervention; this determination continues to be a clinical
• Of myeloma patients, 1% have IgM, and their disorder
decision. Serial measurements of β2 microglobulin are not useful in
behaves like other multiple myeloma.
monitoring therapy. Both hemoglobin and beta 2 microglobulin levels
• Hepatitis B and C screening is necessary if rituximab
at diagnosis are independent predictors of progression to active
therapy is planned.
macroglobulinemia.34
Because most patients with WM have an indolent disease course
and often are elderly, nearly half of all patients succumb to diseases
2.2 | Risk stratification unrelated to WM.35 The impact of age on OS was investigated in
238 patients with WM. The poorest survival of patients older than
As WM is a distinct lymphoproliferative process with unique cell sur- 65 years at diagnosis was attributable to the higher number of non-
face and genetic characteristics, the International Prognostic Index WM-related deaths.7 Cause-specific survival has been introduced as
and the Follicular Lymphoma International Prognostic Index are not an important outcome measure.36 This statistical technique censors
used to determine prognosis. Table 2 gives the currently accepted patients who die of causes unrelated to the malignancy and accounts
international staging system for WM. for the competing risks of death that these patients face. In a compet-
The five criteria shown in Table 2 are not weighted equally. Age ing risk survival analysis, 23% of deaths were unrelated to WM, and
has the greatest impact on prognosis. Patients older than 65 years 40% of patients >75 years do not die of WM. Patients with WM have
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GERTZ 5

greater overall risk of a second malignancy that is 1.69 times higher
than expected (p = 0.002). Compared with the general population,
patients with WM appear to have a higher risk of large cell lymphoma,
myelodysplasia, and brain cancer. Therapy related myeloid neoplasms
occur in 2.7% of patients.
3 | MANAGEMENT
3.1 | Hyperviscosity syndrome
Hyperviscosity syndrome is seen in a decreasing proportion of
patients with WM because WM is being diagnosed earlier. Symptom-
atic hyperviscosity is rare in patients with an IgM concentration less
than 4000 mg/dl, and viscosity measurements are not required in
patients whose IgM levels are below that threshold. The symptoms of
hyperviscosity are primarily due to shear forces that rupture unsup-
ported venous channels. Therefore, the presentation generally
includes epistaxis, gingival bleeding, and visual changes due to retinal
hemorrhage.37 Central nervous system findings, including dizziness,
light-headedness, and generalized fatigue, are nonspecific and must
be confirmed with measures of serum viscosity. Reference serum vis-
cosity is 1.8; water has a viscosity of 1. Hyperviscosity syndrome is
not likely unless the serum viscosity exceeds 4. When hyperviscosity
is present, plasma exchange should be considered a temporizing mea-
sure until systemic therapy successfully lowers the tumor mass and
thereby reduces the IgM protein concentration in the serum. A single
plasma exchange is often sufficient to relieve symptoms and allow ini-
tiation of systemic therapy.27
3.2 | Systemic chemotherapy to reduce
tumor mass
3.2.1 | Rituximab cyclophosphamide
type II cryoglobulinemia, MGUS-associated neuropathy and cold
agglutinin disease.
Use of rituximab is associated with the risk of “flare” for many
patients. In this phenomenon, the initiation of rituximab treatment
results in a transient rise in the level of IgM, which can produce an
increase of serum viscosity. This flare is seen less frequently when
rituximab is combined with cytotoxic chemotherapy. In some trials,
rituximab is delayed until the second cycle to allow cytotoxic therapy
to reduce IgM levels and reduce the risk of hyperviscosity associated
with the introduction of rituximab.39
The use of maintenance rituximab therapy has been controversial.
In a trial of patients treated with bendamustine and rituximab fol-
lowed by randomization to observation or rituximab, an improvement
in progression-free survival was not seen.40
Rituximab is not the only monoclonal antibody that has been
used in WM. Ofatumumab, an anti-CD20 monoclonal human anti-
body, has shown activity in WM. In a trial of 37 Waldenstrom
patients receiving ofatumumab 15 (41%) achieved a partial
response, seven (19%) a minor response. All 37 patients had at least
one adverse event.41
3.3 | Rituximab cyclophosphamide
dexamethasone RCd
Rituximab treatment combined with cyclophosphamide (orally) and
dexamethasone has been reported, with a response rate of 83%
and minimal toxicity. Two-year PFS was 67%; 2-year disease-
specific survival was 90%. In an updated final analysis in
72 patients treated with rituximab cyclophosphamide and dexa-
methasone, the response rate on an intent-to-treat basis was 83%.
Median PFS was 35 months. Median OS was 95 months. This
three-agent combination is currently an alternative regimen for
first-line therapy if the disease burden is low, based on Mayo Clinic
mSMART guidelines.

Rituximab is a widely available treatment for the management of

Selected outcomes with RCd.
WM. Its lack of long-term toxicity and nonmyelosuppressive treat-
ment profile has led to its incorporation in most therapeutic regi- Response
ND/ Rate Response Response PFS,
mens for this disorder. However, rituximab alone is generally a poor
Regimen RR > MR, % Rate > PR rate > VGPR mo Reference
choice for patients in need of therapy. Including both minor (25%–
RCd 72/0 83 74 7 (CR) 35 42
50% reduction of M protein) and objective (>50% reduction of IgM RCd 35/36 92 69 3 31.2 43
protein) responses, the response rate to rituximab (<55%) is inferior RCd 50/50 96/87 87/68 17/4 34/32 44
to every other reported combination regimen. A meta-analysis con-
firmed that a greater response was produced with combination ther-
apy of 2+ drugs than with rituximab monotherapy (73% vs. 44%). In 3.4 | Proteosome inhibition
a double-blind randomized placebo-controlled phase 3 trial rituxi-
mab was the control arm. The median progression-free survival with Bortezomib has been shown to have high levels of activity in the
rituximab was 20.3 months partial response or better was observed management of relapsed WM in schedules of twice weekly, 2 of
in only 31%. Median time to next treatment was 18 months. Hemo- 3 weeks, with response rates ranging from 81% to 96%.45 CXCR4
38
globin improvement was seen in only 43%. Rituximab monother- mutation does not lower the response rate to bortezomib. In
apy is generally only suited for IgM-associated symptoms such as newly diagnosed patients, weekly treatment with bortezomib and
 10968652, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.26796 by Spanish Cochrane National Provision (Ministerio de Sanidad), Wiley Online Library on [02/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
6 GERTZ

rituximab resulted in a better-than-minimal response in 23 of and 19 received R-CHOP. In both groups, the response rate was 95%, but
26 patients and a 1-year event-free survival rate of 79%. Most median PFS was significantly prolonged with bendamustine. The median
importantly, no grade 3 or 4 neuropathy was seen with the weekly PFS for R-CHOP was 36 months in contrast to not being reached with
bortezomib schedule. The European Myeloma Network reported bendamustine and rituximab (p < 0.001). At the time of analysis, 4 relapses
outcomes of bortezomib, rituximab, and dexamethasone in previ- were identified (18%) in the bendamustine and rituximab group and
ously untreated symptomatic patients. Rituximab was delayed to 11 relapses (58%) in the R-CHOP group. Bendamustine and rituximab
cycles 2 and 5 to reduce the risk of flare. No patient required treatment was better tolerated, with no alopecia, less hematotoxicity,
plasma exchange for flare. The response rate was 85%, the median lower frequency of infection, lower incidence of neuropathy, and
PFS was 42 months, and the 3-year OS was 81%. Peripheral neu- reduced stomatitis.51 Twenty-four previously treated patients
ropathy was seen in 46%. Bortezomib-rituximab-dexamethasone received Bendamustine (90 mg/m2) plus rituximab on two consecu-
is a reasonable choice for front-line therapy, but attention to early tive days. Each cycle was 4 weeks, with a median of five treatment
neurotoxicity is required. Bortezomib also has reported activity in cycles. The overall response rate was 83% (20/24). The median PFS
cold agglutinin disease with an overall response rate of 32%. was 13.2 months. Prolonged myelosuppression was more common
In view of the high neuropathy rates, the less neurotoxic pro- in patients who previously had received fludarabine or cladribine.52
teosome inhibitor, carfilzomib, was combined with rituximab and In a cohort of 71 patients, with a median age of 72, all with
dexamethasone in patients not previously treated with the combi- relapsed/refractory WM (median two prior lines of therapy), R-
nation of rituximab and bortezomib. The overall response rate was bendamustine produced a PR of 74.6% and PR + MR of 80.2%.
87%, with 36% having at least a very good partial response. At One- and 3-year PFS was approximately 80% and 60%, respec-
2 years, 65% were progression-free. The peripheral neuropathy tively. The risk of progression appears to be lower in patients trea-
rate and cardiomyopathy rates were both 3%. The oral proteo- ted with bendamustine-rituximab or bortezomib-dexamethasone-
some inhibitor, ixazomib, was combined with dexamethasone and rituximab when compared to cyclophosphamide-dexamethasone-
rituximab, 26 patients were enrolled with an overall response rate rituximab.53 At Mayo Clinic 60 patients receiving rituximab benda-
of 96%, and a major response rate of 77%. The median time to mustine were compared to100 patients receiving rituximab cyclo-
response was 8 weeks. Fifty-nine previously treated patients phosphamide dexamethasone. Two-year PFS was 88 vs. 61%
received ixazomib subcutaneous rituximab and dexamethasone. favoring bendamustine, outcomes independent of MYD88 status. A
After 8 cycles overall response rate was 71% with 14% very good total of 69 patients enrolled in a study of bendamustine plus rituxi-
partial response. Median response duration was 36 months. At mab. The overall response rate at 18 months was 97%. The
2 years progression-free and overall survival were 56 and 88% progression-free survival at 2 years was 87%. MYD 88 and CXCR4
respectively.46 Proteosome Inhibitiors are an important treatment mutations had no impact on response rate or PFS. One patient
option for the management of macroglobulinemia. developed myelodysplastic syndrome 6 months after bendamustine
initiation (1.4%).52
In an East German lymphoma Study group trial 293 patients
received bendamustine rituximab. The overall response rate was
Selected Outcomes with Proteosome Inhibitors. 91.4% The 5 year survival is estimated to be 78%, two therapy
Response Response Response related myeloid neoplasms were seen (0.7%). Median progression-
ND/ Rate > Rate rate > free survival was 65.3 months, There was no difference between
Regimen RR MR, % > PR, % VGPR, % PFS, mo Reference
those receiving maintenance rituximab and those that did not. As a
Vd 10/0 80 20 39 47
result of this large trial Mayo clinic does not recommend rituximab
RituximabVd 0/34 59 32 3 15.3 48
maintenance therapy.54
VCd 4/11 93 53 7 18.6/7.3 49
(TTP) Rituximab-bendamustine is one of the Mayo Clinic preferred induc-
Carfilzomib rituximab 28/3 86 67 35 75%@1 41 tion regimen for newly diagnosed WM due to its ease of use and low
dex year
rates of non-hematologic adverse events. It also has the advantage of
Ixazomib rituximab 26/0 96 77 15 75%@22 50
time limited therapy usually less than 6 months and there is no risk of
dexamethasone months
IgM flare. However, in the presence of central nervous system infiltration
so-called Bing Neel syndrome ibrutinib is preferred as it is known to
cross the blood–brain barrier. Ibrutinib shows rapid and durable symp-
tomatic and radiologic responses in patients with central nervous system
3.5 | Bendamustine infiltration with lymphoplasmacytic lymphoma.55 A patient with Bing
Neel syndrome was treated with tirabrutinib and within 2 months of
In a prospective randomized study of bendamustine plus rituximab com- treatment lower extremity muscle strength had normalized and T2
pared with R-CHOP in low-grade lymphoma, a subset analysis identified weighted magnetic resonance imaging showed improvement in contrast
41 patients with WM, of whom 22 received bendamustine and rituximab, enhancement in the spinal cord.56
 10968652, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.26796 by Spanish Cochrane National Provision (Ministerio de Sanidad), Wiley Online Library on [02/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
GERTZ 7

with ibrutinib–rituximab than with placebo–rituximab (73%

Bendamustine based therapies.
vs. 41%, p < 0.001). Events of grade 3 or higher that occurred
ND/ ≥25%# ≥50%# ≥90%# more frequently with ibrutinib–rituximab than with placebo–
Regimen RR IgM;% IgM;% IgM;% PFS, mo Reference
rituximab included atrial fibrillation (12% vs. 1%) and hypertension
B±R 0/30 87 84 17 13.2 57
(13% vs. 4%). 38 When treating macroglobulinemia with ibrutinib,
BR 0/71 80.2 74.6 22.5 60%@2 years 58
administered dose is important. Patients with a dose intensity
BR 69/0 97 96 56 87%@2 years 59
lower than 97% had a shorter progression-free survival.67 Holding
BR 288/0 92.4 89.9 78 60
ibrutinib for longer than 1 week is associated with a 4-fold
increased risk of progression. When initiated, ibrutinib therapy
should be considered indefinite and compliance should be empha-
3.6 | BTK inhibitors sized to optimize outcomes. Following discontinuation of ibrutinib
rapid increase in serum immunoglobulin M level was observed in
Sixty-three previously treated patients received 420 mg of the BTK 60% of patients. Ten acutely developed symptomatic hyperviscos-
inhibitor ibrutinib. The major response rate was 73.0%, including ity.68 Adverse events associated with stopping ibrutinib include
minor responses of 90.5%. Two-year PFS and OS survival rates were fever, body aches, night sweats, arthralgias, chills and headache.
69.1% and 95.2%, respectively. Neutropenia and thrombocytopenia Acalabrutinib was developed to be more potent and selective
were the most common adverse events. The median time to response than ibrutinib. Acalabrutinib is rapidly absorbed, has a short half-
was 4 weeks. Median IgM fell from 3610 to 1340. Median Hb rose life, and lacks irreversible targeting to alternative kinases including
from 10.5 to 12.6. Diarrhea, bleeding, and atrial fibrillation (10.7%) the epidermal growth factor receptor, interleukin-2-inducible T-cell
were seen as non-hematologic toxicities.61 Ibrutinib should be given kinase, and T cell X chromosome kinase. Acalabrutinib is approved
indefinitely as rapid IgM increases have been reported on its cessa- for the treatment of chronic lymphatic leukemia and mantle cell
tion.62 Unmutated MYD 88 patients have a lower response rate to lymphoma. In a trial of 106 patients with WM a response was
ibrutinib. achieved in 93%. Grade 3/4 atrial fibrillation occurred in only
In an open-label sub-study of Ibrutinib that was multi-center 1 patient.69
and phase 3, 31 patients, all of whom were rituximab refractory Zanubrutinib is a second-generation Bruton tyrosine kinase inhib-
with a median age of 67, were enrolled. Overall response rate was itor. At a dose of 160 milligrams twice daily 77 patients achieved an
71%, progression-free survival at 18 months was 86%, and overall overall response rate of 95.9% with a ≥ VGPR rate at 24 months of
survival was 97%.63 A trial of 30 patients who were newly diag- 43.8%. Three year progression-free survival was 80.5%. However, the
nosed and received ibrutinib was reported. The major response incidence and severity of toxicities was lower with zanubrutinib. Atrial
rate was 80% with no difference between patients with wild-type fibrillation was seen in only 2% of zanubrutinib patients compared
or mutated MYD 88. Atrial arrhythmias were seen in 10%. In treat- with 15% of those receiving ibrutinib. In both arms, 84 and 85% of
ment naïve patients overall (minor or more than minor) and major patients were progression-free at 18 months with ibrutinib and zanu-
(partial or greater than partial) responses for all patients were brutinib, respectively.69–71
100% and 83%, respectively.64 It does not appear that a deep Tirabrutinib is a 2nd generation irreversible BTK inhibitor. Of
response is critical with ibrutinib. Comparing patients with a 27 enrolled patients the major response rate was 93%. Including
greater than very good partial response at 6 months versus others 1 complete and 5 very good partial responses. The progression-free
no significant differences in progression-free survival were and overall survival rates at 24 months were 92.6 and 100%. One
observed.65 patient experienced grade 2 atrial fibrillation. Treatment related
Outside of a clinical trial setting (“real world”) 80 patients skin adverse events were observed in 14 patients (52%).72
were reported receiving ibrutinib therapy, achieving an overall
response rate of 91% with an 18 month progression free survival
of 82%; 21% of patients discontinued therapy due to treatment
Selected outocimes with BTKi.
related toxicity. Atrial fibrillation was seen in 11%. IgM rebound
66
was seen in 36% of patients following ibrutinib discontinuation. ND/ ≥25%# ≥50%# ≥90%#
In newly diagnosed and relapsed Waldenstrom a phase 3 trial Regimen RR IgM;% IgM;% IgM;% PFS, mo Reference
ibrutinib 0/63 90.5 79.4 30.2 54%@5 years 61
randomized patients to ibrutinib with rituximab vs. rituximab
ibrutinib 30/0 100 87 30 76%@48mo 64
placebo. At 30 months, the progression-free survival rate was
Ibrutinib-R 34/41 93 73 26 82%@30mo 38
82% with ibrutinib–rituximab versus 28% with placebo–rituximab
acalabrutinib 14/92 93/94 79/81 0/9 90/82@2 years 69
(hazard ratio for progression or death, 0.20; p < 0.001). The
zanubrutinib 19/83 94 77 28 85%@18mo 71
benefit in the ibrutinib–rituximab group over that in the placebo–
Tirabrutinib 27 93 22 81% on therapy 72
rituximab group was independent of the MYD88 or CXCR4 geno-
@ 24.8
type. More patients had sustained increases in hemoglobin level
 10968652, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.26796 by Spanish Cochrane National Provision (Ministerio de Sanidad), Wiley Online Library on [02/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
8 GERTZ

F I G U R E 1 Mayo Clinic
Consensus for Newly Diagnosed
Waldenström Macroglobulinemia
(WM). Hb indicates hemoglobin; IgM,
immunoglobulin M; MGUS,
monoclonal gammopathy of
undetermined significance; RCD,
rituximab, cyclophosphamide, and
dexamethasone. (https://www.
msmart.org/wm-treatment-
guidelines)

F I G U R E 2 Mayo Clinic
Consensus for Salvage Therapy in
Waldenström Macroglobulinemia.
(https://www.msmart.org/wm-
treatment-guidelines)

A multi Center global case series of 347 symptomatic patients
compared the use of rituximab bendamustine to ibrutinib. Deeper
responses were obtained with rituximab bendamustine. Overall sur-
vival and progression-free survival were not different between the
2 groups. Both are rational options for the treatment of macroglobuli-
nemia. Often the decision rests on the patient's desire for oral versus
73
parenteral therapy or indefinite versus time-limited therapy.
Since macroglobulinemia cells highly express Bcl-2 venetoclax
is a logical therapy for this disorder. Waldenstrom macroglobuline-
mia cells devoid of BTKC481S or CXCR4WHIM-like mutations
acquire resistance to ibrutinib through upregulation of Bcl-2 and
AKT resulting in vulnerability toward venetoclax treatment. In a
phase 2 clinical trial, venetoclax (at a maximum target dose of
800 mg daily) demonstrated an ORR and MRR of 87% and 80%,
respectively.74 CD19 directed car T therapy is currently being
explored in macroglobulinemia. Three patients were treated all
responded but all 3 developed recurrent disease from 3 to
26 months after infusion.75
Figure 1 shows the Mayo Clinic algorithm for the recommended
management of patients with newly diagnosed WM. Figure 2
illustrates treatment recommendations for patients with relapsing
WM, based on consensus criteria developed by the WM treatment
and research group at Mayo Clinic. Unlike other low-grade lympho-
mas, early disease progression within 24 months does not impact
mortality. Survival after progression is not influenced by time to pro-
gression regardless of treatment.76 The National Comprehensive Can-
cer Network has recently published its consensus recommendations
on diagnosis and therapy of WM. (NCCN Guidelines for Waldenström
Macroglobulinemia/Lymphoplasmacytic Lymphoma V.1.2022) Recent
consensus reviews on WM are available.77
4 | CONC LU SION
When WM is diagnosed before the development of symptoms,
patients may be safely observed and monitored. However, patients
with symptoms require chemotherapy. Nonstudy Mayo Clinic–
preferred options are rituximab and bendamustine or zanubrutinib.
The clinician should focus on methods to minimize the toxicity associ-
ated with therapy and avoid late complications.

GERTZ
CONF LICT OF IN TE RE ST
Dr Gertz has received honoraria from Celgene Corporation (Summit,
NJ), Millennium: The Takeda Oncology Company (Cambridge, MA),
The Binding Site Group Ltd (Birmingham, United Kingdom), Onyx (San
Francisco, CA), Novartis (Basel, Switzerland), Ionis (Carlsbad, CA),
Amgen (Thousand Oaks, CA); Prothena (San Francisco, CA) Sandoz
(Princeton, NJ), AbbVie (North Chicago, IL), Alnylam (Cambridge, MA),
Prothena (South San Francisco, CA), Janssen (Beerse, Belgium), Spec-
trum (Henderson, NV), Apellis (Louisville, KY), Medscape(New York,
NY), Physicians Education Resource(Cranbury NJ), Research to Prac-
tice (Miami, FL), Teva (Petah Tikva, Israel), Astra Zeneca.
ORCID
Morie A. Gertz https://orcid.org/0000-0002-3853-5196
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How to cite this article: Gertz MA. Waldenström
macroglobulinemia: 2023 update on diagnosis, risk
stratification, and management. Am J Hematol. 2022;1‐11.
doi:10.1002/ajh.26796