Light Chain
Deposition Disease
Nelson Leung, MD
Mayo Clinic Rochester
Rochester MN
MN, USA
USA
Light Chain Deposition Di
Disease
One of several diseases characterized by
the tissue deposition of immunoglobulin
pg
components resulting in organ dysfunction
AL amyloidosis
y
Cryoglobulinemia
Fibrillary and Immunotactoid glomerulonephritis
Monoclonal Immunoglobulin Deposition
Disease (MIDD)
Non-amyloid deposits
Granular or amorphous (Randall-type)
Nl
Nomenclature
Monoclonal Immunoglobulin Deposition
Disease
Light Chain Deposition Disease- (LCDD)
Light Heavy Chain
Chain Deposition
Deposition Disease
Disease-
(LHCDD)
Heavy Chain Dep
yposition Disease- (HCDD)
()
History
1957- Kobernick and Whiteside noted non-
amyloidotic kidney disease resembling diabetic
glomerulosclerosis in non-diabetic myeloma
patients
LCDD vs. Di b
a t
e itic N h
ep
l
rosc
i
eros s
History
1957- Kobernick and Whiteside noted non-
amyloidotic kidney disease resembling diabetic
glomerulosclerosis in myeloma non-diabetic
patients
1973- Antonovych et al. described light chain
deposits in a multiple myeloma patient in an
abstract
1976- Randall et l
a .
b
pu li
bli h
s d
e 2 cases of li h
g t
chain deposition disease with systemic
involvement
Incid
ident of LCDD
LCDD
Unknown
Autopsy study of myeloma patients
LCDD 5% (LCDD + AL, LCDD + MCN)
()
MCN 30%
AL 9%
Renal biopsy of
of patients with monoclonal
monoclonal
gammopathy
LCDD 11.6%
LHCDD 4.1%
MCN 10.7%
AL 10.7%
Paueksakon et al. Am J Kidney Dis. 2003
Ivanyi. Arch Pathol Lab Med 1990
Prevalence of LCDD
LCDD by Age
30%
25%
20%
15%
10%
5%
0%
<19 20-29 30-39 40-49 50-59 60-69 70-79 80+
Age
Dist irb
ibutition of LCDD by Sex
70.00%
63.50%
60.00%
50.00%
36.50%
40.00%
5
00%
30.00%
20.00%
10.00%
0.00%
Fem
Fe a
m le
a
Mal
Ma e
Hematologic Diagnoses in LCDD
LCDD
65%
70%
60%
50%
32%
40%
30%
20%
3%
10%
0%
Myeloma
LPD
Idiopathic
Pozzi et al. Am J Kid Dis. 2003; 42: 1154-1163
Pf
Presence of a Monoclonal Protein
100%
90%
90%
76%
80%
e
70%
iv
60%
it
50%
osP 40%
%
30%
20%
6%
10%
0%
Serum
Urine
None
Pozzi et al. Am J Kid Dis. 2003; 42: 1154-1163
Serum Free Light Chains
The use of sFLC assay can further
increase the sensitivity
: ratio
Sensitivity 99%
Diagnosis of LCDD
Immunofluorescence
TBM 97%
GBM 82%
Glomerular nodules 40%
Electron microscopy
Overall 77%
GBM 74%
TBM 56%*
Vascular wall
wall 34%
*2 negative by IF were positive by EM
Pt
Pa h
thogenesis
Light chain
Quality not quantity
Light chain bias
Distribution of Light Chains in
LCDD
24.8%
75.2%
Pozzi et al. Am J Kid
Kid Dis. 2003
Heilman et al. Am J Kid Dis. 1992
Tubbs et al. Am J Med. 1981
Lin et al. J Am Soc Neph. 2001
Royer et al. Kid Int. 2004
Pt
Pa h
thogenesis
Light chain
Quality not quantity
Light chain bias
Light Chain Subtypes bias
,
I
IV
Light chain characteristics
Myatt- ability to form multimers
Carbohydrates
Exposed hydrophobic segments
Mutation analysis
CDR >> J region
Vidal et al. Am J Path. 1999
Myatt et al. PNAS 1994
cis-proline8
edge
cis-proline8
edge
Forces Involved in the Stabilization
Stabilization
of the Pentadecamer
Disruptions to the -edge
severely hinders the
multimeric formation
The interaction is
thermodynamically
yy stable
in the native state
No folding or unfolding is
required
Pt
Pa h
thogenesis in th
the Gl
Glomerulus
Specific surface
receptor
Induces phenotypic
changes
Increase production
of collagen and
ti
tenascin (nodules)
Decrease in MMP's
Md
Me i
diated by TGF
TGF
Keeling & Herrera Kid Int 2005
Cli i
n
l
ca P
t
resen t
a ition
Renal manifestations
35% have extrarenal
Nearly ubiquitous
manifestations
Renal insufficiency
Heart
96%
Lung
52% acute or
or rapid
rapid
GI/Liver
progressive
Muscle
Proteinuria
Salivary gland
40% nephrotic
gland
Hypertension
Carpel tunnel
63%-90%
Neuropathy
Brain
Buxbaum & Gallo. Hem/Onc Clin N Am. 1999
Extrarenal Sites of Symptomatic
LC Deposition
Pozzi et al. Am J Kid Dis. 2003
Prognosis of LCDD
LCDD
Renal outcome
Poor
Median time to ESRD is
is 2 7
. years
years
ESRD free Survival at 5 years is 37%
Overall survival
Variable
18 months to > 5 years
OS of 4.1 years was reported in 63 patients
Pozzi et al. Am J Kid Dis. 2003
Pozzi et al. Clin Neph. 1995
Heilman et al. Am J Kid Dis. 1992
Patitient Survival in LCDD
Pozzi et al. Am J Kid Dis. 2003
Survival f
o MIDD vs MIDD + MCN
Patients with MIDD and
MCN were more likely to
have MM
MM (91%
(91% vs 39%, p
= 0.025)
Presence of myeloma
y
did
not negatively impact
survival
(36 m vs 42 m, p = 0 74)
.
Lin et al. J Am Soc Neph 2001
Tt
Treatment
Myeloma Present
Without Myeloma
Steroids
ACE inhibition
Melphalan and
Steroids
Prednisone
Cyclophosphamide +
VAD/VAMP
Steroids
Thalidomide/
Dialysis
Lenalidomide +
Kidney
Dexamethasone
Transplantation
Bortezomib or
bi
com
ti
na on
HDM-ASCT
Kidney Transplant in LCDD
without CR
Recurrence in the
allograft ( 61% to 86%)
Md
Me i
dian titime to
recurrence = 33 months
Median allograft survival
survival
= 37 months
Not advisable unless CR
can bh
be ac i
hieved
Leung, et al. Am J Kidney Dis 2004; 43: 147-53
Tt
Treatment
Myeloma Present
Without Myeloma
Steroids
ACE inhibition
Melphalan and
Steroids
Prednisone
Cyclophosphamide +
VAD/VAMP
Steroids
Thalidomide/
Dialysis
Lenalidomide +
Kidney
Dexamethasone
Transplantation
Bortezomib or
Preserve or restore
bi
com
ti
na on
kidney function
HDM-ASCT
HDM ASCT
-
in LCDD + MM
Pozzi et al. reported on 5 patients
4 LCDD + MM, 1 LCDD
All were
were alive
alive at
at a median follow up
up of
of 44
44 months
months
1 developed ESRD
Pozzi et al. Am J Kid Dis. 2003; 42: 1154-1163
HDM SCT
-
in LCDD + MM
Royer et al. treated 11 with L(H)CDD
Durie-Salmon
Stage I
7
Stage III-
3
Idiopathic -
1
Organ involvement
< 2 - 4
= 2 - 5
> 2 - 2
Royer et al. Kidney Int. 2004; 65:642-8
Tt
Treatment Regimen
First 4 patients
Last 7 Patients
Mobilization
Mobilization
Cyclophosphamide (CTX)
GCSF
Conditioning
Conditioning
Mel 140 mg/m2
Mel 140 mg/m2
Mel 140 mg/m2
mg/m
CTX 60 mg/kg
Mel 200 mg/m2 (N = 1)
CCNU
Tandem Mel 140 (N=2)
VP16
TBI 12 gray*
*1 did not receive TBI
Rl
Resu tlts
Hematologic Response
Organ response
Complete remission 6
Heart
stage I - 4
CHF: 4/4
4/4
stage III - 2
Echocardiogram: 5/7
Very Good Partial
Arrhythmia 2/2
Response (>75%
(>75%
Liver: 2 /2
/2
reduction in M protein) - 2
Kidney
Function: 4/11
Nephrotic syndrome 3/3
Neurologic
Facial palsy 1/1
Endocrine
0/1
Tt
Treatment Outcome
Treatment related mortality
None
Treatment related toxicity
Atrial fibrillation -2
Encephalopathy -2
Acute renal failure as a result of sepsis - 2
Relapse
3 patients
1 died of progressive disease
HDM ASCT
-
in LCDD ith
w out MM
6 patients
5 had < 10% plasma
p
cells in the bone marrow
Conditioning
Mel 200 mg/m2
g
-5
Mel 140 mg/m2 1
Outcome
Hematologic CR 86%
Serum FLC
FLC normalization in all
All are alive
Weichman et al. Bone Marrow Transplant. 2006
Summary
LCDD is a complex disease involving
multiple organ
pg
systems
A multidisciplenary approach is
encouraged to provide patients with
with total
total
care
More studies are needed to determine the
optimal treatment for patients without
myeloma
Light Chain
Deposition Disease
Nelson Leung MD
Mayo Clinic Rochester
Rochester MN
MN, USA
USA