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NEOPLASIA
Effects of paraprotein heavy and light chain types and free light chain load on
survival in myeloma: an analysis of patients receiving conventional-dose
chemotherapy in Medical Research Council UK multiple myeloma trials
Mark Drayson, Gulnaz Begum, Supratik Basu, Sudhaker Makkuni, Janet Dunn, Nicola Barth, and J. Anthony Child
While investigating 2592 patients enrolled in multicenter myeloma trials, we
found light chain–only (LCO) patients
had worse median survival times (1.9
years) than patients with IgA and IgG
paraproteins (2.3 and 2.5 years, respectively) (P < .001). However, IgA and IgG
patients with levels of LC excretion similar to those of LCO patients also had
poor survival times because of renal
failure, resulting in worse survival during induction therapy and at relapse
with no difference in progression-free
survival between LCO and IgG patients.
LC excretion was higher for ␭ than for ␬
types, but there was no difference in
survival between the 2 LC types when
stratified for level of LC excretion, indicating that care of renal function is vital
to improving the survival of any patient
with LC excretion. LCO patients were
younger (P ⴝ .001), had worse performance status (P ⴝ .001), and had more
lytic lesions (P < .001), perhaps reflecting late and missed diagnoses in
younger and older LCO patients, respec-
tively. No differences were observed
between IgA and IgG patients in presentation characteristics, response, or survival from disease progression. The
worse survival of IgA patients was attributed to shorter progression-free survival (median, 1.2 vs 1.6 years; P < .001),
which is important for maintenance
therapy. (Blood. 2006;108:2013-2019)
© 2006 by The American Society of Hematology
Introduction
Multiple myeloma (MM) results from the proliferation of a
neoplastic clone of plasma cells in bone marrow and accounts
for 10% of hematologic malignancies.1 The disease is heterogeneous in severity and manifestations, which variably include
skeletal disease (70%), renal impairment (20%), anemia (40%),
and impaired humoral immunity (80%).1-4 This study assesses
whether that heterogeneity of disease is linked to the type of
monoclonal immunoglobulin proteins (paraproteins) the malignant plasma cells secrete.
Immunoglobulin consists of 2 identical heavy chain regions,
variable and constant, which are encoded on chromosome 14,
and 2 identical light chains also consisting of variable and
constant regions. The light chains are either ␬ encoded on
chromosome 2 or ␭ encoded on chromosome 22. Rearrangement
of immunoglobulin variable region gene segments, during
B lymphopoiesis, dictates the specificity for antigen binding.5
Variable regions of immunoglobulin are specific to the B cell
that makes it and to any neoplastic clone that may arise from its
progeny. Immunoglobulin secreted by myeloma plasma cells
exhibits mutations in the germline variable region gene segments, indicating that their precursor cell, at some stage of
ontogeny, has undergone the physiological site-directed hypermutation process typically seen in germinal center centroblasts.6,7
Virgin B cells use ␮ and ␦ gene segments to make the
constant regions of their heavy chains and thus express surface
IgM and IgD. After antigen stimulation, they may use other ␥, ␣,
or ⑀ heavy chain constant region gene segments, a process that
requires cognate interaction with an antigen-specific T cell.7,8
This immunoglobulin class switch is more likely to be to IgG in
immune responses to antigen entering through skin and to IgA in
immune response to antigen entering through mucosal surfaces.
In MM, the immunoglobulin class is most commonly IgG and
then IgA. Evidence indicates that IgA myeloma is different from
IgG myeloma in terms of disease characteristics.3,9-11 In an
international study of staging in myeloma, 2375 IgA patients
had a median overall survival of 40 months compared with 49
months for 5894 IgG patients; the reason for this difference was
not explored.12
This international study also noted a median overall survival
time of 35 months for 1035 light chain–only (LCO) patients but
did not explore the significance of light chain (LC) excretion in
patients with IgG or IgA paraproteins.12 Normal plasma cells
produce more free light chain (flc) than heavy chain. The flc is
secreted into the blood, filtered at the renal glomeruli, and
reabsorbed by the renal tubule cells. In two thirds or more of
MM patients, the excess of flc production exceeds renal tubular
reabsorption capacity, and flc is easily detected in the urine.1,3 In
many patients, flc is nephrotoxic, and the consequent renal
impairment is associated with worse survival.1,13-17 In some
patients the dysregulation in heavy, and light chain production is
From the Division of Immunity and Infection, the Cancer Research UK Clinical
Trials Unit, and the Department of Haematology, Royal Wolverhampton NHS
Trust and Division of Cancer Studies, University of Birmingham, Birmingham,
United Kingdom; and the Clinical Trials Research Unit, University of Leeds,
Leeds, United Kingdom.
Reprints: Mark T. Drayson, Division of Immunity and Infection, Medical School,
University of Birmingham, Vincent Drive, Birmingham, B15 2TT, United
Kingdom; e-mail: [email protected].
Submitted March 9, 2006; accepted May 9, 2006. Prepublished online as Blood
First Edition Paper, May 25, 2006; DOI 10.1182/blood-2006-03-008953.
BLOOD, 15 SEPTEMBER 2006 䡠 VOLUME 108, NUMBER 6
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
© 2006 by The American Society of Hematology
2013
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BLOOD, 15 SEPTEMBER 2006 䡠 VOLUME 108, NUMBER 6
DRAYSON et al
so extreme that only free light chains are secreted in detectable
quantities, commonly called Bence-Jones or light chain–only
(LCO) myeloma. It is uncertain whether, in addition to the
nephrotoxicity of flc, the extreme dysregulation in heavy and
light chain production is associated with different or worse
disease for LCO myeloma patients.
Patients receiving conventional dose chemotherapy in the
multicenter Medical Research Council (MRC) United Kingdom
myelomatosis trials from 1980 to 2002 were the subjects of this
study, in which paraprotein type and levels were monitored by
central laboratory analysis. We assessed for differences in
clinical presentation and in overall and progression-free survival among the 3 main groups of patients (IgG, IgA, and LCO
myeloma) and by light chain type. We have compared survival
between patients with IgG or IgA myeloma and patients with
LCO myeloma stratified by level of urinary light chain excretion.
Patients, materials, and methods
Patients with IgG, IgA, and LCO myeloma enrolled in the IV, V, VI, and
VIII MRC UK myelomatosis trials between 1980 and 2002 (2592 total
patients) were eligible for this study. Approval was obtained by local
ethics committees of the participating hospitals’ institutional review
boards. Informed consent was provided according to the Declaration
of Helsinki.
Our diagnostic criteria were consistent with the recently agreed
criteria for symptomatic myeloma as defined and published by the
International Myeloma Working Group.18 The characteristics of these
trials are listed in Table 1. Patients were assigned to standard dose
melphalan-based chemotherapy (822 patients) or melphalan-based conventional dose combination chemotherapy (1712 patients) as exemplified by doxorubicin, carmustine, cyclophosphamide, and melphalan
(ABCM).19-21 Fifty-eight patients with thrombocytopenia received cyclophosphamide therapy. Twenty-six patients in the VI trial received
melphalan 140 mg without stem cell rescue. Analysis did not include the
Myeloma VII Trial because half these patients received high-dose
chemotherapy with autologous hematopoietic stem cell rescue.22 Little
difference was observed in survival, and no significant difference was
observed in the distribution of paraprotein types between the trials or
between the treatment arms within individual trials. Serum creatinine,
␤-2 microglobulin (S␤2m), paraprotein type and levels, and urine
creatinine and light chain levels were measured by central laboratory
investigation in Birmingham. Participating centers provided clinical
details, information on skeletal disease–related events, full blood count
(FBC), serum albumin and urea, and plasma cell infiltration of bone
marrow. Follow-up serum and urine samples were assessed at 3-month
intervals, and clinical details were recorded. Disease response and
progression were defined according to trial protocol criteria. A final
report to ascertain the cause of death and a summary of the clinical
course was recorded in the event of a death.
Statistical analysis
Differences in patient characteristics and causes of death by paraprotein
class group were investigated using Pearson ␹2 test. The primary end
point for analysis was survival defined as date of entry to date of death or
date last seen. Survival curves were constructed using the Kaplan-Meier
method,23 and the log-rank test24 was used to assess differences between
paraprotein class groups. Relapse-free interval or duration of first
plateau was calculated from the date of plateau to the date of disease
progression, or it was censored at the date of death for patients who died
without disease progression or at the date a patient was last seen alive
without disease progression.
Results
Patient characteristics
IgA and IgG patients were alike in all presentation characteristics with the exception of corrected calcium, with hypercalcemia
Table 1. Characteristics of patients enrolled in IV, V, VI, and VIII MRC Multiple Myeloma trials
Trial, dates (patient ages),
and induction treatment
No.
patients
Median
OS, y
Median
DP, y
IgG, %
IgA, %
LCO, %
IV, 1980-1982 (under 80 y)
MP
254
2.3
1.1
59
29
12
MPV
251
2.2
1.5
57
24
19
V, 1982-1986 (under 75 y)
C-weekly-plts ⬍ 80
58
1.8
1.7
53
28
19
M7
291
2.0
1.4
56
29
15
ABCM
293
2.7
1.6
56
27
17
HDM (M140)
12
2.5
2.5
59
33
8
HDMP
14
5.0
1.9
71
29
0
ABCM
322
2.7
1.5
58
28
14
ABCM-P
328
2.5
1.4
58
29
13
271
2.6
1.4
58
28
14
VI (under 75 y)
1986-1991
1991-1993
NR ABCM
VIII, 1993-2002 (at least 65 y, or under 65 y*)
ABCM to plateau
135
3.1
1.4
69
25
6
ABCM ⫻3 then C-weekly
140
3.1
1.5
56
36
8
NR
223
1.2
1.3
63
24
13
Total
2592
NA
NA
58
28
14
IgG, 1513 patients; IgA, 718 patients; LCO, 361 patients.
MP indicates melphalan, prednisolone; MPV, melphalan, prednisolone, vincristine; C-weekly plts, cyclophosphamide weekly for low platelets; M7, melphalan; ABCM,
doxorubicin, carmustine, cyclophosphamide, melphalan; NR, nonrandomized; C-VAMP, cyclophosphamide, vincristine, doxorubicin, methylprednisolone; OS, overall survival;
DP, duration of plateau; IgG, immunoglobulin G; IgA, immunoglobulin A; LCO, light chain only; and NA, not applicable.
*If high-dose therapy (HDT) contraindicated.
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BLOOD, 15 SEPTEMBER 2006 䡠 VOLUME 108, NUMBER 6
EFFECT OF MYELOMA PARAPROTEIN TYPE ON SURVIVAL
2015
Table 2. Patient characteristics by paraprotein class
Paraprotein class, no. (%)
Factor and grouping
IgG
IgA
LCO
Male
880 (58)
413 (58)
188 (52)
Female
632 (42)
305 (42)
173 (48)
Under 65
744 (49)
334 (47)
215 (60)
65 or more
767 (51)
383 (53)
146 (40)
Asymptomatic
193 (14)
69 (10)
19 (6)
Minimal symptoms
516 (37)
257 (38)
111 (33)
Restricted activity
544 (39)
273 (41)
166 (49)
Bedridden
151 (11)
69 (10)
41 (12)
Under 30
375 (33)
153 (28)
19 (7)
30 to 35
371 (33)
206 (38)
55 (21)
Above 35
383 (34)
185 (34)
188 (72)
Under 20
290 (25)
116 (22)
75 (26)
20 to 50
532 (46)
231 (43)
107 (38)
Above 50
326 (28)
190 (35)
103 (36)
10 or less
455 (67)
214 (64)
118 (60)
Above 10
220 (33)
121 (36)
78 (40)
4 or less
431 (29)
171 (24)
63 (18)
4 to 8
608 (41)
291 (42)
98 (28)
Above8
438 (30)
237 (34)
188 (54)
Less than 7.5
138 (10)
84 (13)
50 (15)
7.5 to 10
467 (33)
242 (36)
100 (30)
Above 10
797 (57)
344 (51)
184 (55)
24 (2)
18 (3)
11 (4)
␹2
P
4.52
.15
16.88
.001
26.68
.001
149.03
⬍ .001
14.76
.005
3.86
.14
General characteristics
Sex
Age, y
Performance status
Serum albumin, g/L
Tumor burden/activity
Bone marrow plasma cells, %
C-reactive protein, mg/L
Serum ␤-2 microglobulin, mg/L
76.38
⬍ .001
Hemopoietic function
Anemia, Hb g/dL
Thrombocytopenia, platelets ⫻109/L
Less than 80
80 to 150
Above 150
141 (11)
103 (16)
44 (14)
1169 (88)
521 (81)
256 (82)
81 (6)
45 (7)
11 (3)
Neutrophils, ⫻109/L
Less than 1.8
1.8 to 3
384 (29)
204 (32)
61 (19)
Above 3
851 (65)
390 (61)
245 (77)
2.63 or less
812 (72)
296 (55)
177 (69)
Above 2.63
311 (28)
245 (45)
80 (31)
512 (34)
259 (36)
131 (36)
12.64
.01
17.67
.001
25.73
⬍ .001
51.55
⬍ .001
Skeletal disease
Corrected calcium, ␮M
Bone pain
Present
Absent
174 (12)
75 (10)
36 (10)
No information
827 (55)
384 (53)
194 (54)
468 (31)
214 (30)
125 (35)
Fractures
Present
Absent
587 (39)
261 (36)
120 (33)
No information
458 (30)
243 (34)
116 (32)
None
382 (25)
166 (23)
36 (10)
Isolated
100 (7)
43 (6)
22 (6)
Multiple
867 (57)
421 (59)
266 (74)
No information
164 (11)
88 (12)
37 (10)
66 (18)
30 (17)
13 (15)
0.99 to 1.5
233 (64)
117 (67)
50 (56)
Above 1.5
63 (17)
28 (16)
26 (29)
Lytic lesions
.74
6.54
.16
45.23
Serum phosphate, ␮M
Less than 0.99
1.99
7.90
⬍ .001
.10
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BLOOD, 15 SEPTEMBER 2006 䡠 VOLUME 108, NUMBER 6
DRAYSON et al
Table 2. Continued
Paraprotein class, no. (%)
Factor and grouping
IgG
IgA
LCO
936 (64)
436 (62)
128 (36)
␹2
P
170.52
⬍ .001
98.17
⬍ .001
Renal disease
Serum creatinine, ␮M
Less than 130
130 to 199
330 (23)
151 (22)
81 (23)
Above 199
193 (13)
113 (16)
149 (42)
Less than 6.5
760 (51)
363 (51)
122 (34)
6.5 to 10
454 (30)
195 (28)
85 (24)
Above 10
280 (19)
150 (21)
154 (43)
Blood urea, ␮M
in 45% of IgA patients compared with 28% of IgG patients
(Table 2). However, there was no difference in the rates of bone
fractures, bone pain, or lytic lesions between these 2 groups of
patients, and the increased hypercalcemia levels in IgA patients
might have been artifactual. Presentation characteristics of
patients with LCO myeloma were unlike those of IgA or IgG
patients. Sixty percent of LCO patients were younger than 65
years of age, whereas the rate was 48% in IgA and IgG patients
(P ⫽ .001). Sixty-six percent of IgA and IgG patients had serum
albumin concentrations lower than 35 g/L compared with 28%
of LCO patients (P ⬍ .001), but this might partly have reflected
a compensation for high total serum protein levels attributable
to paraprotein. Despite their younger age, LCO patients had
poorer performance status; 61% had restricted activity or worse
compared with 51% of IgA patients and 50% of IgG patients
(P ⫽ .001). LCO patients had a higher incidence of renal
impairment with elevated serum creatinine (42% had serum
creatinine greater than 199 mM compared with 16% of IgA and
13% of IgG patients; P ⫽ .001). LCO patients also had a higher
incidence of elevated S␤2m (54% had levels greater than 8
mg/L compared with 34% and 30% of IgA and IgG patients,
respectively). An increased incidence of multiple lytic bone
lesions (P ⬍ .001) was observed in LCO patients compared with
IgG and IgA patients but was not apparent in bone pain or
fractures (Table 2).
Overall survival by paraprotein class
IgG patients had the longest overall survival (median, 2.5 years;
95% CI, 2.3-2.7 years) followed by IgA patients (median, 2.3
years; 95% CI, 2.1-2.6 years; P ⫽ .01). LCO patients had the
shortest overall survival (median, 1.9 years; 95% CI, 1.5-2.3
years; P ⬍ .001; Figure 1).
However, IgA patients had significantly shorter durations of
plateau than IgG and LCO patients (median, 1.2; 95% CI,
1.1-1.3; P ⬍ .001; Figure 2.)
Survival from first disease progression
Survival from disease progression was worse for LCO patients.
Median survival from disease progression for IgA and IgG
patients was 1.3 years (95% CI, 1.2-1.5 years) compared with
0.9 years for LCO myeloma patients (95% CI, 0.7-1.1 years;
P ⬍ .001; Figure 3).
Effect of free light chain (flc) excretion on survival
Twenty-eight percent of IgA and IgG myeloma patients did not
have significant urinary flc excretion, and within this group only
2% had renal impairment (Table 4). Eleven percent of IgG and
13% of IgA patients had high levels of urine flc excretion
(greater than 12 g/g creatinine), and 48% of these patients had
renal impairment; this compares to a 54% rate of renal
impairment in LCO patients with greater than 12 g/g creatinine
flc excretion. There was no difference between IgG, IgA, and
LCO myeloma in the probability of renal impairment for a given
level of flc excretion (Table 4). No differences in overall
survival between paraprotein classes stratified by level of
urinary light chain excretion were detected (Figure 4). No
differences in survival were identified between the ␬ and ␭ light
chain types for patients with LCO myeloma when stratified by
levels of urinary light chain excretion (Figure 5). Evidence
suggested superior survival in patients with IgA/IgG ␬ light
chain type compared with survival in patients with IgA/IgG ␭
light chain. This was only apparent in patients with detectable
Early death and failure to reach plateau
LCO myeloma was associated with early death, with 19% of LCO
patients dying within 100 days compared with 11% of patients with
IgA and 12% with IgG myeloma; this increase in early deaths was
primarily attributable to renal failure (P ⫽ .01; Table 3). LCO
patients were less likely to achieve plateau than IgA or IgG patients
(48% compared with 56%; P ⫽ .008).
Duration of first plateau phase by paraprotein class
Little difference in duration of plateau was observed between
LCO and IgG patients (P ⫽ .08). Median durations of plateau
were 1.6 years (95% CI, 1.5-1.8 years) for IgG patients and 1.5
years (95% CI, 1.3-1.8 years) for LCO myeloma patients.
Figure 1. Overall survival by paraprotein class.
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BLOOD, 15 SEPTEMBER 2006 䡠 VOLUME 108, NUMBER 6
EFFECT OF MYELOMA PARAPROTEIN TYPE ON SURVIVAL
2017
Table 3. Causes of early death
Cause of death
IgG, %
IgA, %
LCO, %
␹2
Progressive tumor
36
39
31
NS
Infection, tumor under control
28
18
13
NS
Mainly renal
Died of other cause
6
8
19
15.94*
30
36
37
NS
Early death was defined as death within 100 days of entry.
IgG, n ⫽ 185 of 1513 (12%) patients; IgA, n ⫽ 80 of 718 (11%) patients; LCO, n ⫽
70 of 361 (19%) patients.
NS indicates not significant.
*P ⫽ .01.
Figure 3. Survival from the time of disease progression.
Table 4. Urinary flc excretion and renal failure by paraprotein class
Urinary flc excretion,
g/g creatinine
Patients with renal failure, no. (%)
IgG
IgA
LCO
0 g/g
28 (2)
29 (3)
0 (0)
Less than 4 g/g
48 (8)
46 (11)
22 (18)
4-12 g/g
13 (29)
12 (28)
18 (38)
More than 12 g/g
11 (48)
13 (48)
60 (54)
IgG, 1367 patients; IgA, 649 patients; LCO, 310 patients.
Figure 2. Duration of plateau by paraprotein class.
urinary light chain excretion; patients with IgA/IgG ␬ light
chain had a median survival of 2.4 years (95% CI, 2.2-2.7 years)
compared with 2.0 years (95% CI, 1.7-2.2 years) in patients with
IgA/IgG ␭ light chain (P ⫽ .007; Figure 6). This probably
reflected higher levels (greater than 4 g/g creatinine) of flc
excretion in ␭ (30% of ␭ patients) than in ␬ (21% of ␬ patients)
light chain (P ⬍ .001). Increasing levels of urinary flc are only
associated with worse survival if they are associated with renal
impairment at presentation. In patients with serum creatinine
lower than 100 ␮M, light chain levels did not influence the
percentage of patients achieving plateau (P ⫽ .86) or survival in
the first 3 years (P ⫽ .48).
Discussion
The paraprotein class and degree of dysregulation between
heavy and light chain production reflect differences in original
immune response and biology of the malignant cells. Whether
the 3 main paraprotein types of multiple myeloma—IgG, IgA,
and light chain only (LCO)—are associated with significantly
different disease at presentation and subsequent survival is
relevant to prognosis and clinical management. An international
study of staging in myeloma noted median survival for IgG,
IgA, and LCO patients to be 49 months, 40 months, and 35
months, respectively.12 However, this study did not explore why
IgA patients fared worse than IgG patients, nor did it explore the
significance of LC excretion in IgG and IgA patients or whether
the extreme dysregulation in heavy and light chain production
was associated with different or worse disease for patients with
LCO myeloma. This study assesses presentation characteristics
and survival in 2592 patients receiving conventional dose
chemotherapy in the IV, V, VI, and VIII MRC myeloma trials
over 22 years. Most (822) patients received standard dose
melphalan-based chemotherapy or melphalan-based-conventional dose combination chemotherapy (ABCM; 1712 patients).
Paraprotein types and levels were assessed by central laboratory
analysis (Table 1).
We found no differences in the presentation characteristics of
IgG and IgA myeloma patients, with the exception of a higher
Figure 4. Survival by paraprotein class stratified by urinary light chain excretion.
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BLOOD, 15 SEPTEMBER 2006 䡠 VOLUME 108, NUMBER 6
DRAYSON et al
Figure 5. Survival by type for patients with light chain myeloma stratified by urinary light chain excretion.
incidence of hypercalcemia in IgA patients (45% vs 28%;
P ⫽ .001; Table 2). This higher incidence of hypercalcemia was
not associated with any increased incidence of bone pain, lytic
lesions, or fractures, and we are investigating whether it might
reflect an interference of IgA paraproteins with the measurement
of corrected serum calcium levels. We found no difference
between IgG and IgA patients with respect to early deaths (12%
and 11%), percentages of patients achieving plateau phase
(56% for both groups), or survival from disease progression
(Figure 3). The difference in overall survival was wholly
attributable to a shorter duration of plateau phase for IgA
compared with IgG patients (1.2 vs 1.6 years; P ⬍ .001; Figure
2). This clinically important difference should be taken into
account when considering maintenance therapy and in the
interpretation of results of trials of maintenance therapy. The
biologic cause for this difference in the duration of the plateau
phase might reflect susceptibility to the translocation of genes
into IgG versus IgA switch regions. IgA patients have been
shown to have a higher incidence of t(4;14) and associated early
disease progression,25 but we did not have cytogenetic data in
our study.
Evidence that light chain disease is a variant of myeloma
dates from the 1941 report of Gutman et al,26 who described a
patient with myeloma, hypoproteinemia, and Bence-Jones proteinuria. Light chain myeloma accounts for 10% to 20% of all
cases of myeloma, and it is well established that LCO myeloma
is associated with a higher incidence of renal impairment and
worse survival.1-4,13-17 Whether this worse survival is attributable solely to light chain nephrotoxicity or also reflects a
biologically more aggressive disease is unclear, and the importance of LC excretion to survival of IgG and IgA patients also
requires clarification.
LCO myeloma patients were younger than IgG and IgA
patients. Only 40% of LCO myeloma patients were older than
65 years compared with 52% of IgG and IgA patients (P ⫽ .002;
Table 2). This might have reflected biologic differences, failure
to diagnose LCO myeloma in older patients, or failure to enter
them into trials. Despite their younger age, LCO patients had
worse performance status (P ⫽ .001) and greater incidence of
multiple lytic lesions at diagnosis that might have reflected the
biology of the disease or a delay in diagnosis because of the lack
of a serum paraprotein, emphasizing the need to assess urine for
flc and indicating that failure to send urine to the laboratory can
delay the diagnosis of myeloma; assay of serum for flc may
mitigate this problem. Paraproteins cause high total serum
protein levels and a compensatory reduction in albumin concentration, so it was not surprising that twice as many LCO patients
(72%) as IgG and IgA patients (34%) had normal serum albumin
levels, a factor that might have confounded the use of albumin
as a prognostic marker. LCO patients had a 3-fold higher
incidence of renal impairment and elevated levels of S␤2m at
presentation than IgG/IgA patients (P ⫽ .001).
Death within 100 days occurred in 19% of LCO patients
compared with 12% of IgG and IgA patients (Table 3), primarily
because of renal failure attributable to higher incidence and
amounts of urinary flc in LCO patients (Table 4). Seventy-eight
percent of LCO patients had greater than 4 g/g creatinine flc
excretion compared with only 24% of IgG and IgA myeloma
patients. IgG and IgA patients with the same levels of urinary flc
excretion as LCO myeloma patients had the same incidence of
renal failure and poor survival (Table 4; Figure 4). There has
been conjecture as to whether light chain type affects survival.
In LCO patients, there was no difference in survival between ␬
and ␭ types when stratified by level of LC excretion (Figure 5).
Similarly, the inferior outcome of IgG/IgA ␭ myeloma compared with IgG/IgA ␬ is a function of the higher level of flc
Figure 6. Survival by light chain type for IgG and IgA myeloma stratified by the
presence or absence of urinary light chain excretion.
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BLOOD, 15 SEPTEMBER 2006 䡠 VOLUME 108, NUMBER 6
excretion in the former group (Figure 6). The significantly
different survival between LCO and IgG/IgA myeloma reflects
the incidence of renal failure that is a function of the incidence
and level of flc excretion associated with those paraprotein and
light chain types. In patients without renal impairment, levels of
light chain excretion do not influence early survival, reinforcing
that it is the renal impairment caused by LCs that affects
survival, not the LCs themselves.
Progression-free survival reflects the intrinsic biology of the
disease and is also an indicator of any treatment benefit. We
noted no difference in progression-free survival between IgG
and LCO myeloma patients. However, survival from progression was worse for LCO myeloma patients. Response to
treatment and relapse in LCO myeloma was conventionally
assessed by urine light chain measurements. Studies suggest that
kidneys metabolize 20 to 30 g/d flc.27,28 Free light chains are not
present in urine until their production exceeds the renal
threshold; thus, serum levels are greatly increased before flc is
detectable in the urine. Recent studies suggest urine flc measurements are relatively insensitive for assessing residual disease or
early relapse in LCO myeloma.29 The increase in mortality at
EFFECT OF MYELOMA PARAPROTEIN TYPE ON SURVIVAL
2019
relapse may, therefore, reflect a delay in diagnosing relapse and
the higher incidence of associated renal impairment. In these
patients, careful monitoring of disease in the plateau phase and
preemptive therapy early in relapse may reduce further renal
damage and thus improve survival. Newly available serum flc
analysis may prove to be a more sensitive way of monitoring
disease response and relapse in LCO myeloma.29,30
This large study demonstrates a strong association between
level of flc excretion, renal impairment, and poor survival
irrespective of paraprotein type or light chain class (␬ or ␭).
Survival is related to preservation of renal function. Supportive
measures to minimize further renal damage, including avoidance of aminoglycosides and NSAIDs and maintenance of
hydration, are important to avoid death during induction therapy
and at progression.31,32 Choice of chemotherapy and recent
expansion of therapeutic options to agents including thalidomide, lenalidomide, and bortezomib should take into account
their interaction with renal impairment and now provide a
greater potential for controlling myeloma in these patients.32-35
Comparable survival between LC secretors and nonsecretors
might be achieved.
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From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
2006 108: 2013-2019
doi:10.1182/blood-2006-03-008953 originally published
online May 25, 2006
Effects of paraprotein heavy and light chain types and free light chain
load on survival in myeloma: an analysis of patients receiving
conventional-dose chemotherapy in Medical Research Council UK
multiple myeloma trials
Mark Drayson, Gulnaz Begum, Supratik Basu, Sudhaker Makkuni, Janet Dunn, Nicola Barth and J.
Anthony Child
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