Myeloma cast nephropathy
Frank Bridoux, Nelson Leung, Colin A. Hutchison
Departments of Nephrology, Poitiers France, Mayo Clinic, Rochester
MN, USA, Birmingham, UK
13th IMW, Paris, May 4, 2011
Conflict of Interest
Dr Bridoux Research funding Celgene
Dr Leung - Travel grant from Binding Site
Dr Hutchison Research funding Gambro
1
Renal insufficiency in multiple myeloma
· Frequency
- 25-50% of patients during the course of MM
- 20-40% at presentation, 10% requiring dialysis
· Causes
- Mostly-LC related :
· Myeloma cast nephropathy : ~ 75% of all causes of AKI
· AL amyloidosis, LCDD (possible associations)
- Other :
· Glomerular deposition of monoclonal entire Ig/heavy chain
· Dehydration, hypercalcemia, infections, nephrotoxic drugs....
· Prognosis
- Recovery of renal function : ~ 50% of patients (< 20% if dialysis)
- Persistent RI associated with poor patient survival
Rota S. Medicine (Baltimore) 1987; 66: 126
Alexanian R. Arch Intern Med 1990; 150: 1693
Bladé J. Arch Intern Med 1998; 158: 1889
Light chains filtered
AL amyloidosis
(MW ~ 22 kDa)
500 mg/day
LCDD
Tamm-Horsfall
protein
mTAL
Myeloma cast
nephropathy
Cubilin/megalin
Fanconi
tandem endocytic
syndrome
receptors
2
Renal insufficiency and myeloma: Diagnosis
Urine protein electrophoresis
Alb
Albuminuria >40% (>1g/day)
Glomerular disorders
Other renal
Extra-renal symptoms
biopsy
Extra-renal symptoms
- AL amyloidosis (lambda LC ++)
- Type I cryoglobulinemia
Kidney biopsy
- LCDD
Characteristics of the monoclonal Ig...
(kappa LC ++)
- Immunotactoid GP
- Proliferative GN with
monoclonal Ig deposits ...
Renal insufficiency and myeloma: Diagnosis
Urine protein electrophoresis
Alb
Albuminuria < 30-40%
(<1g/day)
Tubulo-interstitial disorders
Fanconi syndrome
Other tubulo-interstitial disorders
Myeloma cast nephropathy
3
Myeloma cast nephropathy (MCN) : clinical features
· Clinical characteristics
- High tumor mass MM
- Light chain MM
- or LC (no correlation with LC isotype)
- Acute RI, often reveals MM
- Proteinuria : often > 2g/day (> 70% LC, albumin < 1g/d)
- Negative urine dipsticks
· Precipitating factors
· Hypercalcemia
· Dehydration
· Infection
· Contrast media
· Nephrotoxic drugs : NSAIDs, furosemide, aminoglycosides, ACEI,
angiotensin 2 receptor antagonists
· Acidic urine pH
Myeloma cast nephropathy (MCN): diagnosis
· Clinical context
· Urine protein electrophoresis
· Kidney biopsy indicated if:
· Significant albuminuria
· None or multiple precipitating factors
· Dialysis-dependent RI
4
Light green X 400
Anti-lambda X 200
5
Myeloma cast nephropathy : Pathophysiology
Urine LC output
the main culprit, but no direct
relation with MCN
LC intrinsic nephrotoxicity
- hydrophobicity, electric charge,
glycosylation ...
- LC interact with THP through their
variable domain
Local conditions
facilitating the interaction between LC and
THP
Sander s PW et al. J Clin Invest 1990; 85: 570
Huang ZQ et al. J Clin Invest 1997; 99/ 732
Ying WZ et al. Am J Pathol 2001; 2001; 158: 1859
Cast nephropathy : mechanisms of acute kidney injury
Excessive LC endocytosis in PT cells :
Oxidative stress
Activation of Nf-B+ MAP kinases
Production of inflammatory cytokines
cellular
toxicity
Morphological changes
for proximal
tubule cells
FLCs + THP
interaction LC-
myeloma cast
Urgent therapy !
LC and LC-THP
tubule obstruction
Tubulo-interstitial
inflammation fibrosis
Renal response : may take
several weeks
Wang PX, Sanders PW. J Am Soc Nephrol 2010
Ying WZ et al. Blood 2010
6
Treatment of myeloma cast nephropathy
· Principles:
1.
Prevention
2.
Symptomatic care as an emergency
3. Rapid initiation of efficient chemotherapy (tailored to
reduced GFR)
4. Consider efficient removal of serum FLCs
Survival of Myeloma Patients by Renal
Function
Scr < 130, 130-200, >200 mol/L
Scr > 177 mol/L
Knudsen et al. Eur J Haematol. 2000
Blade et al. Arch Int Med 1998
7
Survival of Dialysis Dependent Myeloma
Patients
USRDS data 2 year mortality rates
Myeloma 58%
All others 31%
ERA-EDTA (median OS)
Myeloma 0.91 year
All others 4.46 years
Dimopoulos et al. JCO 2010
Effects of Renal Impairment on Survival
More advanced disease
DS III
44% (normal serum creatinine)
87% (Scr 2 mg/dl or 177 mol/L)
Less chemotherapy responsive
39% vs 56.4%, p <0.01
Less chemotherapy (melphalan/prednisone, VAD era)
Patients on dialysis had a significantly higher 2 month mortality
(29% vs 7.2%)
Blade et al. Arch Int Med 1998
8
Creatinine is an Independent Predictor
of survival from -2-microglobulin
MP/ MPT/ D/ VAD/ ASCT
Kleber et al. Euro J Hematol 2009
Renal Recovery Improves Survival in
Myeloma Patients
Blade et al. Arch Int Med 1998
9
Possible Benefits of Renal Recovery
Responsiveness to therapy
Removes limitations on medications
Renal dosing
Renal toxicity
Decreases toxicity
Immunosuppression
Mucositis
Decreases Infections
Restores eligibility for clinical trials
Dimopoulos et al. JCO 2009
International Myeloma Working Group
Consensus Statement
Renal Response Criteria
Response
Baseline eGFR*
Best eGFR* Response
CRenal
< 50
>60
PRenal
< 15
30 59
MRenal
<15
15 29
15 29
30 59
*ml/min/1.73m2 by MDRD
Dimopoulos et al. JCO 2010
10
Targeting sFLC for Cast Nephropathy
sFLC
Involved with pathogenesis
Freely filtered
Ig's are not
M-spike may not represent
sFLC load
Threshold
Response
Sanders and Booker J Clin Invest 1992
Leung et al. Kidney Int 2005
Hutchison et al. Clin JASN 2009
sFLC and Cast Nephropathy
14
12
10
tsne 8
tia
fP
6
o#
85
4
2
0
0-50
51-100
101-200
201-500
501-1000
>1000
sFLC (mg/dL)
Leung et al. Kidney Int 2005
Hutchison et al. Clin JASN 2009
11
Reduction of FLC vs. Renal Response
p = 0.05
12
> 50% reduction
11
6 Non-responders
< 50% reduction
3 - LCDD
10
1 DN/ATN
8
1 CN precipitated by iv
8
contrast 1 month earlier
tsn
6
1 CN with atypical
e
6
ti
tubulointerstitial nephritis
and fibrosis
Pa
4
3
3 Responders
1 AL
2
1 LCDD
0
1 not biopsied
Renal Non
Renal
Responders
Responders
Leung et al. Kidney Int 2008
HCO Dialyzer
Hutchison et al. Clin JASN 2009
12
Probability of Renal Response by Depth
and Speed of sFLC Reduction
Hutchison et al. J Am Soc Nephrol In Press
chemotherapy
Not renally cleared
Not nephrotoxic
Bortezomib
Thalidomide
Steroids
13
Bortezomib
SUMMIT and CREST
10/256 had CrCl 30 ml/min
Overall response
Grade 3 Toxicity
PR- 2
Thrombocytopenia - 4
MR - 1
Neutropenia 3
SD - 1
Peripheral neuropathy - 3
Fracture 2
Arthralgia - 2
Jagannath et al. Cancer 2005
VISTA
VMP
MP
Normal
RI
Normal
RI
ISS III
21%
62%
22%
54%
30 ml/min
84%
80%
Overall Response
72%
68%
29%
46%
CR
30%
31%
3%
5%
30 ml/min
37%
13%
First response
1.4m
1.0m
4.9m
3.4m
Median TTP
NE
19.9m
18.0m
16.1m
Median OS
NE
NE
NE
31.9m
* Serum Cr 2.0 mg/dL
Dimopoulos et al. JCO 2009
14
Renal Response
VMP
MP
Overall Response
51%
44%
CRenal
44%
34%
PRenal
50%
MRenal
42%
67%
GFR 30 < 50 ml/min
46%
39%
GFR 30 ml/min
37%
7%
Time to RR
2.1m
2.4m
< 50% reduction in M-protein
26%
17%
50% reduction in M-protein
48%
42%
Dimopoulos et al. JCO 2009
Safety
AE's, SAE's and discontinuation were
lower in patients with reversible renal
impairment
VMP
AE's (8% reversible vs 15% irreversible)
SAE's (43% reversible vs 60% irreversible)
Discontinuation (6% reversible vs 24% irreversible)
MP
AE's (10% reversible vs 13% irreversible)
Discontinuation (8% reversible vs 24% irreversible)
Dimopoulos et al. JCO 2009
15
Phase II Trial with bortezomib doxorubicin
dexamethasone (BDD) in patients with acute
renal failure
Inclusion criteria
Treatment
Bortezomib 1.3 mg/m2 on Day
eGFR < 60 ml/min/1.73m2
1,4,8,11
ARF must occurred <4 weeks
Doxorubicin 9 mg/m2 Day
Excluded
1,4,8,11
2 - AL
Dexamethasone 40 mg on Day
1 elevated liver function tests
1,4,8,11
1 eGFR
After first 5 patients,
doxorubicin was given only on
Not evaluated
Day 1 and 4 and bortezomib
7 died < 2 cycles
was reduced to 1.0 mg/m2
1 discontinued after 1 cycle due
to toxicity
1 progression
1 incomplete data
Ludwig et al. JCO. 2010
Responses of 58 patients to BDD
Hematologic
Renal
CR/nCR - 38%
CRenal 31%
VGPR -
15%
PRenal 7%
PR -
13%
MRenal 24%
MR -
6%
Overall 62%
Overall -
72%
Ludwig et al. JCO. 2010
16
Renal Response by Hematologic
Response
Final eGFR by
hematologic response
>VGPR 59.5 ml/min/1.73m2
PR/MR 38.9 ml/min/1.73m2
SD/PD 16.8 ml/min/1.73m2
Ludwig et al. JCO. 2010
Upfront Thalidomide Dexamethasone
Induction Before Double ASCT
31 patients
Renal impairment = CrCl < 50 ml/min by
Cockcroft Gault
52% < 30 ml/min
23% were dialysis dependent
Tosi et al. Biol Blood Marrow Transplant. 2010
17
Response and Adverse Events
Hematologic
AE
response
DVT 9.6%
CR 29%
Skin 1
> VGPR 42%
PN 1
Constipation 2
Lethargy - 1
Tosi et al. Biol Blood Marrow Transplant. 2010
Renal Response
Improved RF
> 50 ml/min
<PR
37.5%
25%
>PR
82.6%
65%
VGPR (69% CR)
84.6%
Overall renal response rate 74%
Tosi et al. Biol Blood Marrow Transplant. 2010
18
Lenalidomide and Dexamethasone in
Patients with Renal Impairment
MM-009 and MM-010
RD vs D
353 patients randomized to RD
Renal function calculated by Cockcroft Gault equation
Scr cutoff for the studies was < 2.5 mg/dl
Treatment
Median dose for patient with CrCl > 30 ml/min = 25 mg/d
Median dose for patient with CrCl < 30 ml/min = 15 mg/d
Dimopoulos et al. Cancer 2010
Outcome
Dimopoulos et al. Cancer 2010
19
Toxicity of RD in Renally Impaired Patients
Dimopoulos et al. Cancer 2010
Improvement in Renal Function
Overall renal response rate 72%
Dimopoulos et al. Cancer 2010
20
Hematologic and Renal Response by
Therapy
Hematologic
Renal
OR/> VGPR
MP/VAD/VCMP
39%
26%
MP
35%/4%
34%
VMP
71%/30%
44%
BDD
72%/53%
62%
RD
55%/29%
72%
TD + ASCT
74%*/42%
74%
Management of myeloma kidney:
reducing FLCs
How do we reduce serum FLC levels?
Two components:
· Effective chemotherapy novel agents
· Direct removal of FLCs from the serum
21
Why remove FLCs - kinetics in renal
failure
Kappa (shaded)
Lambda (clear)
As kidneys fail serum
half-lives increase
Both: P<0.01
Hutchison et al, cJASN 2008
Why remove FLCs - kinetics in renal
failure
RR 30%
Kappa (shaded)
Lambda (clear)
RR 60-70%
Dimopoulos MA, Clin Lymph +
Myeloma 2009
Ludwig H, J Clin Onc 2010
Both: P<0.01
Hutchison et al, cJASN 2008
22
Pore Sizes of High Cut-Off (HCO) Membranes
in comparison to HighFlux and plasmafiltration
membranes
HighFlux
HighFlux
High Cut-Off
Plasmafilter
1,0
1,
0,8
0,
HCO
[
-
] 0,60,
n
/
n
o
0,4
n
/
n
o
0,
0,2
0,
Plasmafilter
0,0
0,
0,
0 001
00
0p o,01 r e s i z e [ µ m0 ],1
1
Courtesy of Dr Storr, Hechingen, Germany
Gambro HCO 1100 6 hour dialysis
10000
800
9000
Serum free lambda
Dialysate free lambda
700
8000
600
(mg/L)
7000
(mg/L)
tea
500
s
6000
ly
mbda 5000
400
la
dia
e 4000
in
300
fre 3000
200
rum
mbda
2000
Se
La
100
1000
0
0
0
30
60
90
120
150
180
210
240
270
300
330
Time (mins)
Hutchison et al. JASN March 2007
23
Key points:
· Clearance of and
1
FLCs are comparable
·Clearance rates
dramatically increased
when 2 dialysers are
used in series
2
Clearance remains effective over extended
dialysis sessions (8 hours)
A
B
Albumin replacement is essential
24
Pilot Study of FLC removal by HCO-HD
Aim: Evaluate the removal of FLCs by extended HD in
patients with biopsy proven cast nephropathy + dialysis
dependent acute renal failure
Combination of chemotherapy and HCO-HD:
· Chemotherapy: high dose dexamethasone and
thalidomide for de novo; bortezomib for relapsing
· Daily extended (8 hours) HD using the Gambro HCO 1100
5 days
· HD then reduced to alternate days for next 21 days or until
FLC concentrations <500mg/L
Hutchison et al. cJASN 2009
Primary outcome: FLC reductions
6 Patients
Chemotherapy stopped
13 Patients continuous
combined HD and
chemotherapy
P<0.01
Hutchison et al cJASN 2009
25
Recovery of renal function
14 of 19 patients
Hutchison et al cJASN 2009
Renal recovery rates in study population and
a case matched control population
17 Study patients
P<0.001
17 Control patients
Hutchison et al, EDTA 2008.
26
Study population's survival relates to
recovery of renal function
Renal recovery (n-14)
P<0.001
No renal recovery (n-5)
Hutchison et al, EDTA 2008.
International experience with HCO-HD
Chart Audit of Renal Recovery in Multiple
Myeloma
· 67 patients treated
d
across Europe and
ree
Australia
voc
· Median 12 sessions
reoh
· 63% had renal recovery
w
tion
tsn
tie
lfunc
pa
na
re
of
getane
rc
Pe
Percentage FLC reduction
27
EuLITE
A randomized control trial of FLC removal HD
versus standard care
Inclusion criteria:
· De novo multiple myeloma
· New dialysis dependent renal failure (eGFR<15)
· Cast nephropathy on renal biopsy
Exclusion criteria:
· Chronic renal failure
· Contra-indication to chemotherapy
28
Randomised and controlled
90 Patients recruited
Randomisation
Control Arm HD
Research Arm HD
45 Patients
45 Patients
Standard high-flux HD
Extended HD on HCO 1100
`Modified PAD regimen' Chemotherapy
(P) VELCADETM (bortezomib)
iv
1.0 mg/m2
(A) Adriamycin (Doxorubicin)
iv
9.0 mg/m2
(D) Dexamethasone
oral
40 mg
primary outcome = independence of dialysis at 3 months
EuLITE recruitment
100
90
80
rs 70
be 60
50
35 patients
Series1
tnum 40
n 30
tiea 20
P 10
0
Nov-07 Jun-08 Dec-08
Jul-09
Jan-10 Aug-10 Feb-11 Sep-11
Time
· In total 20 UK centres will participate (15
active)
· 6 German centres will participate (2 active)
29
MYRE A French RCT
How to manage renal impairment in MM:
Part 1 Moderate renal impairment and new MM:
· 200 patients randomized to CBD or BD
Part 2 Severe renal impairment and new MM:
· 90 patients with biopsy proven myeloma kidney
randomized to FLC removal HD or standard
care
Frank Bridoux + Jean Paul Fermand
Improving Outcomes in Myeloma
Kidney - Summary
1. Rapid diagnosis is essential
2. Early initiation of disease specific treatment
1. High dose dexamethasone
2. Bortezomib
3. In severe kidney failure direct removal of FLCs may
be indicated
1. EuLITE 2012
2. MYRE 2012/3
30