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CLINICAL TRIALS AND OBSERVATIONS

AL amyloidosis associated with IgM paraproteinemia: clinical profile and

treatment outcome
Ashutosh D. Wechalekar,1 Helen J. Lachmann,1 Hugh J. B. Goodman,1 Arthur Bradwell,2 Philip N. Hawkins,1 and
Julian D. Gillmore1

1National Amyloidosis Centre, Centre for Amyloidosis & Acute Phase Proteins, Department of Medicine (Hampstead Campus), Royal Free and University

College Medical School, London; and 2Immunity and Infection, Medical School, University of Birmingham, Birmingham, United Kingdom

AL amyloidosis associated with immu-
noglobulin M (IgM) paraproteinemia is
rare. We report 103 consecutive such
patients evaluated at the National Amy-
loidosis Centre (London, United King-
dom) between 1988 and 2006. Renal,
cardiac, and lymph node amyloid was
present in 53%, 35%, and 21% of pa-
tients, respectively, at presentation and
2 or more organs were involved in 54%.
Seventy-three percent had an abnormal
bone marrow infiltrate (lymphoid in
87%). The median IgM paraprotein was
8 g/L and serum free light chain (FLC)
ratio was abnormal in 77 (88%) of 87.
The abnormal FLC component was more
than 100 mg/L in only 31% cases. Thirty-
two percent achieved a partial hemato-
logic response to treatment with no
complete responders, and there ap-
peared to be a greater response to com-
bination regimens than single-agent oral
alkylators (59% vs 20%, respectively;
P ⴝ .003). Four achieved amyloidotic or-
gan responses; organ function remained
stable in 68%. None with lymph node
involvement showed nodal improve-
ment. Median overall survival was
49 months. AL amyloidosis with IgM
paraproteinemia represents a distinc-
tive subset of patients with AL amyloid-
osis who have a wider variety of under-
lying clonal disorders (often lymphoid)
than AL in general, have low-level FLC
abnormality, and should be treated with
appropriately tailored chemotherapeu-
tic regimens for the underlying clonal
disorder. (Blood. 2008;112:4009-4016)

Introduction
AL amyloidosis is caused by misfolding, aggregation and
deposition of certain monoclonal immunoglobulin (Ig) light
chains as extracellular insoluble fibrillar deposits that stain with
Congo red and produce pathognomonic red-green birefringence
when viewed in cross-polarized light. The age-adjusted inci-
dence of AL amyloidosis is 5.1 to 12.8 per million patient years,1
and it is usually associated with very subtle clonal plasma cell
dyscrasias2 that are usually best monitored by the very sensitive
serum free light chain (FLC) assay.3 When a whole paraprotein
can be identified, it is much more commonly either IgG or IgA
than IgM.4 Indeed, in contrast to the 20% frequency of IgM
paraproteinemia among patients with monoclonal gammopathy
of uncertain significance (MGUS),5 remarkably few patients
with AL amyloidosis consequent on IgM paraproteinemia have
been reported.6 Only 50 such patients were identified among the
very large experience of AL amyloidosis at the Mayo clinic over
a 22-year period.7,8 Other reports are of single individuals or
small case series.9,10 The response to chemotherapy in this rare
group of patients is even less well reported.
We report here the manifestations of amyloidosis and
characteristics of the underlying clonal disease at diagnosis, and
clinical outcome following various types of chemotherapy in
103 consecutive patients with AL amyloidosis complicating IgM
paraproteinemia, who were evaluated in our center between
1988 and 2006.
Methods
Patients, diagnosis, and protocol
All patients with AL amyloidosis in whom a single paraprotein of IgM class
had been demonstrated in the serum or urine by electrophoresis or
immunofixation, who were first seen at the National Amyloidosis Centre
(NAC, London, United Kingdom) between 1988 and 2006, were identified
retrospectively from the NAC database.
The presence of amyloid was confirmed by characteristic Congo red
staining of a tissue biopsy and/or by a diagnostic 123I-labeled serum
amyloid P component scintigraphy (SAP) scan in all cases. AL-type
amyloidosis was confirmed by immunohistochemical staining that
included a panel of antibodies against known amyloid fibrils proteins11
and exclusion of hereditary amyloidosis by demonstration of wild-type
sequence for the genes encoding known hereditary amyloidogenic
proteins.12 Myeloma and MGUS were defined according to previously
published criteria.13 IgM MGUS was defined according to the criteria
described by Baldini et al.6
All patients underwent protocolized assessments scheduled at 6 monthly
intervals until 6 months after the end of chemotherapy and then at 6 to
12 monthly intervals as clinically indicated. Assessments included a
comprehensive clinical examination, blood and 24-hour urine studies,
monitoring of whole body amyloid load with serial 123I-SAP scintigraphy,14
electrocardiogram (ECG) and echocardiography, and measurement of
monoclonal immunoglobulins in serum and urine. From 2001, additional
blood samples were requested at monthly intervals during administration of
chemotherapy and 2 monthly thereafter for measurement of serum FLCs

Submitted February 11, 2008; accepted July 8, 2008. Prepublished online as payment. Therefore, and solely to indicate this fact, this article is hereby
Blood First Edition paper, August 15, 2008; DOI 10.1182/blood-2008- marked ‘‘advertisement’’ in accordance with 18 USC section 1734.
02-138156.

The publication costs of this article were defrayed in part by page charge © 2008 by The American Society of Hematology

BLOOD, 15 NOVEMBER 2008 䡠 VOLUME 112, NUMBER 10 4009

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4010 WECHALEKAR et al BLOOD, 15 NOVEMBER 2008 䡠 VOLUME 112, NUMBER 10

using the Freelite assay (The Binding Site, Birmingham, United Kingdom). Table 1. Presenting features
FLCs were also assayed retrospectively on serum samples that had been Median No. of patients
obtained at each visit and routinely archived for patients first seen at the (range) (%)
NAC before the routine introduction of this assay in 2001.
Age, median, y 65 (46-88)
Approval for retrospective analysis and publication was obtained from
Sex, male-female ratio 1.7:1
the institutional review board of Royal Free Hospital ethics committee
IgM paraprotein, g/L 8 (IF-60) 103 (100)
(Royal Free Hospital, London, United Kingdom), and written consent for
Monoclonal light chain type
publication of anonymous material was obtained from all patients in
␬ 48 (46)
accordance with the Declaration of Helsinki.
␭ 55 (54)
Hemoglobin, g/L 12.3 (8.2-17.7)
Outcome measures Total white cell count, ⫻ 109/L 7.0 (0.5-23.4)

Outcome measures comprised overall patient survival (OS), hematologic Platelets, ⫻ 109/L 287 (18-757)

response to treatment, amyloidotic organ response, and the course of whole Creatinine, ␮M 103 (49-ESRD)

body amyloid burden by serial 123I-SAP scintigraphy.14 Hematologic Albumin, g/L 35 (14-52)

response was assessed by serum and urine electrophoresis and immunofix- Bilirubin, mM 9 (4-225)

ation and also by FLC assay. FLC response is a strong predictor of survival Alkaline phosphatase, IU/L 103 (52-3488)

in AL amyloidosis3 but its significance in IgM-related disorders has been 24-hour proteinuria, g/24 h 1.0 (⬍ 0.1-21)

little studied. Conventional responses for patients were defined using the Creatinine clearance, mL/min 56 (ESRD-152)

consensus criteria from the second Waldenström workshop.15 FLC values ECOG performance status

were considered interpretable for assessing response if the pretreatment 1 or less 26 (25)

FLC ␬/␭ ratio was outside the 95% reference range (0.3-1.2)16 and the 2 50 (49)

concentration of the light chain class (ie, ␬ or ␭) containing the monoclonal 3 or more 27 (26)

component (also called monoclonal class) was 100 mg/L or more, except in Organ involvement

patients with renal failure in whom only the ␬/␭ ratio was used. A FLC Liver, consensus criteria 15 (14)

partial response (PR) was defined as a 50% or higher fall in the monoclonal Liver, SAP scintigraphy 39 (38)

class; a FLC complete response (CR) was defined as normalization of the Renal, consensus criteria 55 (53)

FLC ratio and both light chain classes, unless there was renal failure Renal, SAP scintigraphy 49 (47)

(defined as creatinine clearance ⱕ .5001 mL/s [30 mL/min]) causing poly- Cardiac, any involvement 36 (35)

clonal retention of FLC, in which case the ratio alone was used. Patients Cardiac, IVS 15 mm or more 4 (3)

who could not be classed as achieving FLC-PR or FLC-CR were Lymph nodes 22 (21)

categorized as nonresponders. The response was assessed as the best Peripheral neuropathy 4 (3)

achieved response at least 6 months after completion of chemotherapy, or Autonomic neuropathy 8 (7)

the best achieved before any further therapy was given. Soft tissue 14 (13)

Amyloidotic organ involvement and response were defined according to Gastrointestinal tract 5 (4)

the international consensus criteria.17 Heart, liver, kidneys, gastrointestinal Respiratory 4 (3)

tract, nerves (autonomic and/or peripheral), lungs, and soft tissue (lymph Total no. of organs, international

node, tongue, muscles, factor X deficiency, or any other) were counted as consensus criteria

individual organs. Since lymph node involvement was a prominent feature 1 organ 47 (46)

of the current series, these were also reported separately. All organ 2 organs 35 (34)

responses (as defined by the international consensus criteria)17 were 3 or more organs 21 (20)

assessed 6 months following initial chemotherapy or before the patient Total no. of organs, SAP scintigraphy

received another regimen. All patients underwent SAP scintigraphy, and 1 organ 6 (5)

serial studies were used to quantitatively measure whole body amyloid 2 organs 61 (60)

load, as previously described.14 Labeled SAP studies were interpreted by a 3 or more organs 36 (35)

single physician (P.N.H.) with experience of more than 5000 SAP scans.
Organ involvement and responses by SAP scintigraphy were documented
and analyzed separately. Performance status was according to Eastern
Cooperative Oncology Group (ECOG) criteria.18
Statistics
Statistical analysis was undertaken using the SPSS 14 software package
(SPSS, Chicago, IL) and Minitab version 14 (State College, PA). Survival
was assessed by the method of Kaplan and Meier and compared by log-rank
test. Categoric variables were compared with chi-square or Fisher tests as
appropriate. All P values were 2 sided with a significance level of .05.
Multivariate analysis was by Cox or binary logistic regression as appropriate.
Results
One hundred three patients with a solitary IgM paraprotein
underlying AL amyloidosis were assessed at the NAC between
1988 and 2006, accounting for 6% of all patients with confirmed
AL amyloidosis during this time. Presenting features are summa-
rized in Table 1. Median age at presentation was 65 years (range,
46-88 years). Median number of organs involved by amyloid was
IF indicates immunofixation positive only; and ESRD, end-stage renal failure.
2. Renal, cardiac, and lymph node involvement were present at the
diagnostic evaluation in 55 (53%), 36 (35%), and 22 (21%)
patients, respectively. Six (5%) patients had isolated lymph node
involvement. These 6 patients have been excluded from the
response analysis, and only 1 of these patients received chemo-
therapy and has also not been included in the response analysis.
None of these cases progressed to disseminated systemic disease.
Liver involvement was present in 15 (14%) patients by consensus
criteria, and was identified by SAP scintigraphy in 24 (24%)
additional patients. Ten patients (9%) were dialysis dependent at
first assessment. Among the 36 (35%) patients with cardiac
involvement by consensus criteria, only 4 (3%) had interventricular
septal thickness of 15 mm or more on echocardiography, which is
widely regarded to represent severe cardiac amyloidosis. Serum
bilirubin was more than 20 mM in 11 (10%) patients, serum
albumin was less than 30 g/L in 31 (30%) cases, and platelet count
was raised in 23 (22%) cases, in many probably reflecting
hyposplenism.19 Overall, 2 or more organs were involved by
consensus criteria in 56 (54%) patients, and SAP scintigraphy
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BLOOD, 15 NOVEMBER 2008 䡠 VOLUME 112, NUMBER 10 AL AMYLOIDOSIS ASSOCIATED WITH IgM PARAPROTEINEMIA 4011

detected at least 1 additional organ involvement in 31 (30%)
patients. Twenty-seven (26%) patients had an ECOG performance
status of 3 or more at first assessment. The median follow-up was
36 months (range, 6-167 months) with a median 6 assessments at
the NAC.
The bone marrow was reported to be abnormal in 77 (74%)
cases. The infiltrate was reported as lymphoplasmacytoid in
42 (41%) patients, and was mainly lymphoid in 24 (23%) cases and
plasma cells in 10; no infiltrate was seen in 11 and no information,
in 16 cases. The bone marrow information is limited due to the
retrospective nature of this review spanning 18 years and the lack
of availability of the source material for a full lymphoid antibody
panel to be performed retrospectively—even though this may not
have been sensitive enough to identify low-level clonal infiltration.
Immunophenotyping details were available in 16 (38%) of 42 cases
with a lymphoplasmacytoid morphology and all were light chain
restricted (9 lambda and 7 kappa) and positive for IgM, CD19, and
CD20 and negative for CD10, CD5, CD23, or CD138 expression.
Immunophenotyping details were available in 6 (25%) of 24 cases
with a lymphoid morphology that was positive for CD19 and CD20
and light chain restricted (4 lambda and 2 kappa) but negative for
CD10, CD5, or CD23 in all but 3 cases. One case each had typical
chronic lymphocytic leukemia, follicular lymphoma, and mantle
cell lymphoma (including the appropriate translocations for the
latter 2). The rest of the patients did not have any other manifesta-
tions of lymphoma or myeloma. Similarly, apart from the 2 cases
with follicular and mantle cell lymphoma, all other lymph node
biopsies showed replacement with amyloid and no features diagnos-
tic of lymphoma. Median percentage of the lymphoid cells or
lymphoplasmacytoid cells in the bone marrow was 12% (range,
1%-70%). Among 10 patients with a bone marrow plasma cell
infiltrate (median, 4%; range, 2%-44%), only 1 had clearly
documented multiple myeloma. The other 9 had less than 10%
plasma cells and no other features of myeloma and may represent a
more mature end of the lymphoplasmacytoid spectrum. The
median IgM paraprotein concentration at presentation was 8 g/L
(range immunofixation positive, 60 g/L) and only 12 (11%) pa-
tients had more than 20 g/L serum paraprotein (Figure 1). Serum
FLC measurements were available before chemotherapy was
administered in 87 patients, yielding an abnormal ratio in 77 (88%)
cases. Median kappa and lambda concentrations, for patients with
IgM kappa and IgM lambda, respectively, were 28 mg/L (range,
5-2330 mg/L) and 38 mg/L (range, 1-3019 mg/L), respectively
Table 2. Hematologic response according to chemotherapy
regimen
Regimen No. of patients Hematologic response (%)
Chlorambucil 22 6 (27)
VAD 9 4 (44)*
IDM 8 1 (12)
Oral melphalan 6 1 (16)
Oral cyclophosphamide 6 0 (0)
CVP 3 1 (33)
R-CVP 2 1 (50)
CHOP 2 2 (100)*
CTD 3 1 (33)
FCR 3 2 (66)*
Fludarabine or cladribine 2 2 (100)
Others† 11 3 (27)*
VAD indicates vincristine-adriamycin-dexamethasone; IDM, intravenous melpha-
lan (25mg/m2); CVP, cyclophosphamide-vincristine-prednisone; R-CVP, rituximab-
cycophosphamide-vincristine-prednisone; CHOP, cyclophosphamide-doxorubicin-
vincristine-prednisone; CTD, cyclophosphamide-thalidomide-dexamethasone; and
FCR, fludarabine-cyclophopshamide-rituximab.
*Organ response; each symbol denoted 1 patient.
†Others indicates R-CHOP, single-agent rituximab, intravenous cyclophospha-
mide, thalidomide-dexamethasone, lomustine-idarubicin-dexamethasone, single-
agent dexamethasone, fludarabine-cyclophosphamide, idarubicin-dexamethasone,
and stem cell transplantation in 1 patient each.
(Figure 1). The overall level of the abnormal FLC component
appears to be rather low and only 24 (31%) of 77 with creatinine
clearance more than .5001 mL/s (30 mL/min) had an aberrant FLC
concentration of more than 100 mg/L.
Treatment and response
Hematologic response to first-line chemotherapy was evaluable in
77 (75%) patients, in 75 cases by conventional means and in
22 patients by FLC assay. Eight patients were not treated, and
insufficient data were available to determine response in
18 patients. FLCs were not evaluable in 55 of 77 patients due to
either a pretreatment aberrant FLC concentration of less than
100 mg/L or a normal ratio.
A variety of chemotherapy regimens were used and are listed in
Table 2. Patients received a median of 4 cycles (range, 2-9 cycles)
of chemotherapy. Twenty-one (27%) patients without bone marrow
plasma cell infiltrate received a regimen typically used for treat-
ment of plasma cell disorders with only 3 patients having a partial
response (2 treated with VAD and 1, with CTD). The hematologic
responses are shown in Table 3. Using conventional paraprotein
measurements, 25 (32%) (18 with lymphoplasmacytoid infiltration
and 7 with other) of the 77 evaluable patients achieved a PR, but
none achieved a CR. The number of responding patients is too
small to allow for meaningful statistical subgroup analysis by the
underlying clonal disease type. FLC criteria in the 22 evaluable
cases indicated PR in 9 (41%) patients and CR in a further 3 (14%)
such patients; 2 patients with a FLC response did not have a

Table 3. Clonal response to chemotherapy by serum FLC assay, by

conventional immunofixation electrophoresis (IFE), and by
combined FLC plus IFE
FLC response, Conventional Combined
Response n ⴝ 22 response, n ⴝ 77 response, n ⴝ 77

CR (%) 3 (14) 0 (0) 0 (0)

PR (%) 9 (41) 25 (32) 25 (32)
Figure 1. IgM levels for patients with a quantifiable paraprotein (g/L), free Total response (%) 12 (55) 25 (32) 25 (32)
kappa, and free lambda levels (mg/L) in cases with abnormal ratios. The boxes
represent the 25th to 75th percentiles; the horizontal line is at the median and the Numbers in rows do not add up as patients are overlapping or in different
vertical line defines the range. response categories for FLC and conventional responses.
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4012 WECHALEKAR et al BLOOD, 15 NOVEMBER 2008 䡠 VOLUME 112, NUMBER 10

response according to conventional criteria. It appeared that

combination chemotherapy (VAD, CHOP, CVP, R-CVP) or purine
analogues or rituximab (or combinations) (fludarabine, cladribine,
FCR, rituximab) showed higher responses compared with oral
agents (chlorambucil, oral melphalan, and oral cyclophosphamide)
(responses in 13 [59%] of 25 vs 8 [21%] of 37 cases, respectively;
P ⫽ .003) but these numbers are limited and need interpretation
with appropriate caution. Thirty-four (33%) cases received a
second-line treatment with a further 14 (41%) patients achieving at
least a partial clonal response. A total of 3 cases in the current series
underwent an autologous stem cell transplantation (1 as first line
and 2 as second line) with complete response in 2 cases and very
good partial response in 1.
Amyloidotic organ responses (according to the consensus
criteria) occurred in a total of 4 patients—2 (12%) of 25 conven-
tional hematologic responders, and additionally in both of the
patients who achieved an FLC but not a conventional response.
Amyloidotic organ function remained stable in 17 (68%) of
25 responders, and worsened in 6 (30%). There were 2 renal
responses, comprising 55% and 62% decreases in proteinuria, and
3 hepatic responses each comprising improvement in liver function
tests. None of the patients with lymph node involvement showed
any decrease in nodal size after treatment, although among the
partial responders nor was there any further nodal enlargement.
Of these 4 patients with conventional organ response, serial
SAP scintigraphy demonstrated regression of hepatic amyloid in
2 patients and of bone amyloid in 1 patient.

Survival

There was no significant difference in the overall survival of

patients with a lymphoid, lymphoplasmacytoid, plasma cell, or
normal/unknown infiltrate in the bone marrow (median Kaplan-
Meier estimate of 47 months, 49 months, 51 months, and
39 months, respectively; log rank: P ⫽ .9). Only one of the deaths
was directly due to the underlying lymphoma (high-grade transfor-
mation). The Kaplan-Meier estimated median OS for the whole
cohort from diagnosis was 49 months (Figure 2A). Although the
difference did not attain statistical significance, potentially reflect-
ing the relatively small numbers of patients, the estimated 10-year
survival for nonresponders was less than 10% compared with more
than 50% for responders, with the survival curves diverging at
approximately 50 months (Figure 2B). The Kaplan-Meier esti-
mated OS was 44 months for the 26 patients who were not treated
or were not evaluable for treatment response. Estimated median
survival for patients with single-organ involvement was 84 months
compared with 26 and 19 months, respectively, for those with 2 or
3 involved organs (log rank, P ⫽ .003). The estimated 10-year
survival among patients with ECOG performance status of 1 or
lower before treatment was more than 90% (Figure 2C). The
various factors associated with survival are detailed in Table 4, of
which on univariate analysis, ECOG performance status, number
of organs involved by amyloid, and presence of amyloid deposits in
the heart or liver were significant. On multivariate analysis, only
performance status and liver involvement were significant
(P ⬍ .001, RR 3.7 and P ⫽ .018, RR 2.2, respectively).

Discussion Figure 2. Overall survival, effect of treatment, and performance at diagnosis on

overall survival. (A) Overall survival from diagnosis (all patients). (B) Overall survival
according to clonal response or no response to initial treatment. (C) Overall survival
We report the presenting features, response to treatment, and stratified by the ECOG performance status at diagnosis.
clinical outcome in the largest series to date of patients with AL
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BLOOD, 15 NOVEMBER 2008 䡠 VOLUME 112, NUMBER 10 AL AMYLOIDOSIS ASSOCIATED WITH IgM PARAPROTEINEMIA 4013

Table 4. Factors affecting overall survival

Factor Univariate significance (odds ratio; 95% CI) Multivariate significance (odds ratio; 95% CI)

No. of organs .0001 (1.8; 1.3-2.4)

Performance status* .0001 (4.0; 2.5-6.5) .0001 (3.7; 2.2-6.2)
Cardiac involvement .026 (2.3; 1.0-3.7) 0.072 (3.8; 0.8-2.5)†
Liver involvement (consensus criteria) .0001 (3.2; 1.6-6.4) .018 (2.2; 1.1-4.5)
Renal involvement (consensus criteria) 0.28 (1.3; 0.76-2.5)
Amyloid load on SAP scan 0.28 (1.03; 0.97-1.1)
Hematologic response 0.42 (0.8; 0.3-1.6)
Age 0.15 (1.02; 0.9-1.05)
IgM level 0.54 (0.9; 0.9-1.2)
Abnormal FLCs 0.41 (1.6; 0.4-5.3)

Bold face numbers in columns 2 and 3 indicate significant P values.

*ECOG performance status 2 or less or more than 2.
†Not significant.

amyloidosis associated with IgM paraproteinemia, and for the first
time analysis of serum FLCs in this clinical setting.
IgM paraproteinemias account for 17% to 20% of patients with
MGUS,5,20 and although Waldenström macroglobulinemia (WM)
and other lymphomas have been described in association with
systemic and localized AL amyloidosis,7,10,21-30 the largest reported
series of IgM-associated amyloidosis is 50 patients from the Mayo
Clinic in whom treatment outcomes have not been clearly re-
ported.7 The current series of 103 patients accounted for 6% of
patients with confirmed AL amyloidosis seen at the NAC between
1988 to 2006, similar to the 5% frequency at the Mayo Clinic.4 In
our series, 54% of patients had 2 or more organs involved by
amyloid, most frequently the kidneys (53%) followed by the heart
(35%), similar to the large previous Mayo series of patients with
AL associated with non-IgM monoclonal proteins.4 Lymph node
involvement is uncommon in AL amyloidosis associated with
non-IgM paraproteins4 but was evident in 21% of patients in our
series (Figure 3). Conversely, peripheral neuropathy was less
common at presentation, in just 3%, than in previously reported
non-IgM series.4,31 None of our patients had lymphoma related “B”
symptoms or hyperviscosity syndrome, likely reflecting the ob-
served low clonal burden of their B-cell disorder.

Figure 3. 123I-labeled SAP scan from a patient with

IgM-associated AL amyloidosis showing uptake of
the radiotracer within the involved right cervical
lymph node (arrow) in addition to some splenic
uptake. There is a normal blood pool tracer signal from
the heart and liver.
 From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
4014 WECHALEKAR et al
In a series of 382 patients reported from the M. D. Anderson
Cancer Center (Houston, TX), IgM paraproteinemia was associated
with lymphoplasmacytic lymphoma (LPL)/WM in 58%, chronic
lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)
in 20%, and other lymphoproliferative disorders in 20% of cases.32
The same variability is likely to exist in IgM-associated amyloid-
osis patients—there was a suggestion that lymphoplasmacytoid
morphology was the most common followed by lymphoid, but this
will need further prospective study for confirmation. However, it is
important to recognize this marked variability of the underlying
clonal disorder in these cases—which contrasts from those with AL
amyloidosis in general where the underlying clonal cell population
is usually a plasma cell dyscrasia—a fact that is not widely
recognized outside of specialized centers. IgM amyloidosis pa-
tients often do not undergo full immunophenotyping to character-
ize the lymphoid clone—investigations instead are focused on
characterizing the plasma cell disorder; this is also seen in the
current series and hence, in some cases, leads to less than
appropriate treatment selection. Immunophenotyping by multipa-
rameter flow cytometry is critical for all cases with IgM-associated
AL (ideally in every AL case) to accurately diagnose the underlying
clonal disorder. In other respects, the situation in the current series
was analogous to the typical situation of AL amyloidosis. Most
patients in the current series had low-level bone marrow infiltration
that was associated with a median circulating IgM paraprotein
concentration of 8 g/L. Among 364 non-IgM AL amyloidosis
patients seen at NAC over a similar period, in whom a paraprotein
was detectable, the median paraprotein concentration was 7 g/L,
and in 10% of IgM and non-IgM AL patients assessed in our center
who have had monoclonal protein the median was more than
20 g/L (NAC, unpublished observations).
Measurement of serum FLCs (Freelite) is the most sensitive
method for detecting, quantifying, and monitoring the underlying
clonal disease in patients with AL amyloidosis.3 This assay has,
however, been little studied in IgM-associated lymphoid disorders
or IgM-associated amyloidosis, the first reported series comprising
6 patients with AL complicating non-Hodgkin lymphoma (NHL) in
whom abnormal FLC values were recorded in each case.10 Al-
though the frequency of abnormal FLC results was high in our
series, at 88%, the concentration of the clonal FLC class was
generally low and exceeded 100 mg/L, the currently defined lower
limit for assessing treatment response in the international consen-
sus criteria,17 in only 27% of patients. This is much lower than the
AL in general where the FLC levels are assessable for response
(⬎ 100 mg/L) in approximately 65% of patients with non–IgM-
associated AL amyloidosis (NAC, unpublished data, 2008); al-
though the current series has a selection bias since it was a cohort
defined by the presence of a detectable whole paraprotein, which is
often absent in AL patients generally. The kappa bias in the current
series (as opposed to the usual lambda bias in AL amyloidosis)
remains unexplained and may either be due to the nature of the
underlying clone or simply reflect patient referral bias. An interna-
tional registry of patient with IgM amyloidosis would be a step
toward gathering accurate information about this condition. The
presence and concentration of abnormal FLCs in this cohort is,
however, comparable to that reported in a series of individuals with
uncomplicated IgM MGUS in whom FLCs were abnormal in 74%
of cases, with the clonal FLC concentration usually less than
50 mg/L.17 This and the present findings suggest that low-grade
monoclonal IgM-secreting disorders may be oligosecretory for
FLCs. This low-level abnormality in FLC often makes it more
BLOOD, 15 NOVEMBER 2008 䡠 VOLUME 112, NUMBER 10
difficult for FLCs to be used as a marker to track the clonal
responses in IgM amyloidosis patients.
Literature is scanty on outcomes of treatment in IgM-associated
AL amyloidosis, and response was not examined in the 50-patient
Mayo series.8 Two of 5 patients at Memorial Sloan-Kettering
Hospital (New York, NY) responded to rituximab-based regi-
mens.10 The Mayo group recently reported favorable outcomes of
autologous stem cell transplantation in 12 patients, among whom
there was 1 treatment-related death, 7 partial hematologic re-
sponses, and 1 complete response.9 The latter, however, compares
poorly with a widely reported CR rate of 40% following stem cell
transplantation (SCT) in non-IgM amyloidosis,33 but is in keeping
with the relatively low complete response rates following SCT in
WM compared with myeloma.34,35
The wide variety of chemotherapy regimens received by our
patients reflects the lack of standardization of treatment in this
condition, and we emphasize the critical need to recognize the
distinct underlying clonal disorder in this subgroup of patients from
that of AL amyloidosis in general for selection of regimens
appropriate for a lymphoid clonal disorder rather than a plasma cell
disorder. The overall hematologic response rate to initial treatment
was poor (32%)—which may reflect, in part, the fact that 27% of
patients received regimens that are not very effective in lymphopro-
liferative disorders. The small number of responding cases in each
group limits the interpretation of response data in relation to the
underlying disorder. It was encouraging that patients who received
a combination regimen or purine analogues with/without rituximab
(defined here as combination chemotherapy such as CHOP or
similar combinations, purine analogues, or rituximab or its combi-
nation with other agents) had a 3-fold higher response rate than
those single-agent oral alkylators or thalidomide and its combina-
tions. These numbers are small and need interpretation with
caution. The response rate of 20% following oral alkylator therapy
is similar to rather poor responses also seen in non–IgM-associated
AL amyloidosis treated with oral melphalan and prednisone.36,37
The regimens with purine analogous or chemoimmunotherapeutic
combinations appear to have similar hematologic response rates to
some for the more recently described regimens in non-IgM AL
amyloidosis38-40 and merit further prospective study. The lack of
hematologic complete responses in the present IgM series was
striking, given that a fifth of patients can expect a CR following
the more recent combination chemotherapy for non-IgM amy-
loidosis. These findings are not surprising since CR is known to
be rare in WM or CLL treated with alkylators,41 single-agent
purine analogues,42,43 or single-agent rituximab.44 These find-
ings and also the fact the hematologic responses in the current
series did not translate into survival improvement identify an
urgent need to study more effective chemoimmunotherapeutic
or other novel treatment approaches.
Median overall survival for IgM amyloidosis was about 2 years
in the 1993 Mayo series,7 similar to that reported in non–IgM-
associated AL amyloidosis at the time.4 There was no significant
difference in the overall survival according to the underlying
disorder, which is in keeping with the fact that most cases had a
low-grade disorder with progressive lymphoma the actual cause of
death in only one case. Survival in AL amyloidosis in general
appears to be improving, and median survival of 600 AL patients
assessed at the NAC over the last decade has been 3.3 years (NAC,
unpublished data, 2008), a value comparable with the outcome of
the present IgM series. ECOG performance status at presentation
was the most significant single factor associated with survival in
the current cohort, and patients with single-organ involvement by
 From www.bloodjournal.org by guest on September 11, 2016. For personal use only.

BLOOD, 15 NOVEMBER 2008 䡠 VOLUME 112, NUMBER 10 AL AMYLOIDOSIS ASSOCIATED WITH IgM PARAPROTEINEMIA 4015

amyloid had a notably good prognosis. Only 4 patients had
advanced cardiac amyloidosis in the current cohort, which may
account for the fact that cardiac involvement was not a significant
independent prognostic factor as opposed to liver involvement—
the latter accounting for a group of patients who had advanced
multiorgan involvement, often with poor performance status.
Although it is again tempting to speculate that clonal biology may
have some role to play, this outcome likely reflects a referral bias. It
is clear that a hematologic response independently predicts for
better survival in most AL series,3,45 and the complete responders
appear to have even better outcomes especially for cases with
cardiac involvement.46 In the current series, although survival of
hematologic responders was not statistically better than nonre-
sponders, there was a distinct impression that in a small number of
responders benefit might well become evident with more prolonged
follow-up beyond 50 months. The former is likely to be accounted
by the poor overall response rate of only 32% with no complete
responses. In a small number of later cases, the Kaplan-Meier
survival curves began to diverge later—consistent with the well-
recognized phenomenon that regression of AL amyloid and clinical
benefit can occur very slowly after suppression of the underlying
clonal disorder. The poor hematologic response also led to only a
limited number of organ responses and was not enough to prevent
early deaths for those with advanced organ dysfunction—a clear
case in need of rapidly effective therapeutic approaches. However,
a majority of the surviving hematologic responders had stable
function, suggesting that the response was adequate to prevent
progression but not enough to achieve regression of amyloid
deposits. This is in keeping with earlier observations for AL in
general.3,47 The adequacy of the hematologic response for
achieving an organ response may be a complete clonal response
in some cases, although others may well achieve the same
functional improvement with a good partial response avoiding
excessive exposure to treatment-related toxicity. However, there
are no clearly defined determinants of this adequacy of hemato-
logic response, but early data indicate that functional markers
such as NT-ProBNP may well act as surrogates and plainly there
is also a need to prospectively study larger populations.
In summary, IgM-associated AL amyloidosis should be recog-
nized as a rare but distinct subtype of AL amyloidosis. Although the
presenting features of this subgroup are not vastly different from
those of non–IgM-associated AL amyloidosis, lymph node involve-
ment is more frequent. A critical distinction from non-IgM
amyloidosis patients is the possibility of a wide variety of
underlying lymphoproliferative disorders instead of the usual
culprit—a plasma cell clone. Investigations for the clonal disorder
in IgM amyloidosis should focus on accurate characterization of
the underlying clone to select an appropriate treatment regimen.
While recognizing that the current series has limitation in terms of
being retrospective and having limited numbers of patients in each
treatment group, hematologic response rates with traditional alkyla-
tor-based treatment regimens appear to be poor and clearly
regimens used for treatment of myeloma, such as standard thalido-
mide combinations or oral melphalan, are likely to be inappropriate
since there is usually an underlying lymphoid clone. There have
been significant improvements in lymphoma outcomes with chemo-
immunotherapeutic combinations and these approaches should be
considered for treatment of these patients, especially if they are not
eligible for autologous stem cell transplantation. The rarity of IgM
paraprotein-associated AL amyloidosis not only makes prospective
trials difficult but also poses a substantial challenge to studying the
phenotypic and genetic profiles of the underlying clonal disorder.
Establishment of an international registry, including a repository
for tissue and marrow samples, would be a valuable step toward
achieving these goals.
Acknowledgments
We acknowledge Ms Dorothea Gopaul for undertaking SAP
scintigraphy, Ms Dorota Rowczenio for performing all relevant
genotyping, Ms Janet Gilbertson for histology, and Ms Jean
Berkley for expert preparation of the paper. We acknowledge all of
the hematologists who took care of these patients.
This study was supported by Medical Research Council (Lon-
don, United Kingdom) Program Grant G97900510 (P.N.H.), Uni-
versity College London (United Kingdom) Amyloidosis Research
Fund, and National Health Service Research and Development
Funds.
Authorship
Contribution: A.D.W. performed research, analyzed data, and
wrote the paper; H.J.B.G. performed research and wrote the paper;
H.J.L. performed research; A.B. contributed to vital reagents for
free light chain assay reported in this paper; and P.N.H. and J.G.D.
performed research and wrote the paper.
Conflict-of-interest disclosure: A.B. has ownership interest in
Freelite, the serum free light chain assay produced by The Binding
Site, that has been reported in this paper. The other authors declare
no competing financial interests.
Correspondence: Ashutosh Wechalekar, Department of Medi-
cine, University College London Medical School (Royal Free
Campus), Rowland Hill Street, London NW3 2PF, United
Kingdom; e-mail: a.wechalekar@medsch.ucl.ac.uk.

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 From www.bloodjournal.org by guest on September 11, 2016. For personal use only.

2008 112: 4009-4016

doi:10.1182/blood-2008-02-138156 originally published
online August 15, 2008

AL amyloidosis associated with IgM paraproteinemia: clinical profile and

treatment outcome
Ashutosh D. Wechalekar, Helen J. Lachmann, Hugh J. B. Goodman, Arthur Bradwell, Philip N.
Hawkins and Julian D. Gillmore

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