Myeloma and Renal impairment:
The role of plasmapheresis
G.Gaskin, D.Samson, N Iggo, G Jackson,
M Drayson, J Behrens
1
What is the scale of the problem?
Severe renal failure is an important
complication of myeloma
20- 30% at presentation have renal
impairment at presentation
50% at some time
2- 5% of myeloma patients require
long-term dialysis
Increased risk of early mortality
2
Why do patients with myeloma present
with renal failure?
Light chain damage
Hypercalcaemia
Dehydration
Nephrotic drugs ­ particularly NSAIDS
Infection
Hyperuricaemia
Renal vein thrombosis
Plasma cell infiltration
Amyloid
3
How do light chains damage the kidneys?
Cast formation in the distal tubules
Damage to the proximal tubule with crystal formation
and aquired fanconi's syndrome
Immunoglobulin deposition disease
Amyloid
4
Irreversible renal failure
Irreversible renal damage ­renal cast formation with
light chains and Tamm-Horsfall protein +/- interstitial
tubular damge
Light chain damage
Volume of protein delivered to distal tubule
Iso-electric point
Kapppa v lambda
Co-precipitant
5
Fractured
casts
6
Giant cell reaction
Disrupted tubular basement
membrane
7
MERIT; Myeloma and Renal Impairment Trial
A new multicentre randomised controlled phase III
trial of adjunctive plasma exchange in patients with
newly diagnosed multiple myeloma and acute renal
failure
Gill Gaskin, Judith Behrens, Neil Iggo, Graham Jackson,
Mark Drayson
Sue Bell, Gill Eddison, Julia Brown, Kim Hawkins, Diana
Samson,
For the Renal Association and the UK Myeloma Forum
Funded by the Leukaemia Research Fund and Cancer
Research UK.
Included in the National Cancer Research Network Trials
Portfolio
8
The Hypothesis
Plasma exchange has
potential to reduce rate
of permanent renal
failure by RAPID
REDUCTION of
I
Immunoglobulin light
chains delivered to the
kidney
9
Primary Question
Does the addition of plasma exchange to chemotherapy
increase the rate of renal recovery in patients presenting
with acute renal failure and newly diagnosed multiple
myeloma?
10
Secondary aims
To determine whether addition of plasma exchange to
chemotherapy affects overall survival
To assess the impact of the addition of plasma
exchange to chemotherapy on patients' quality of life
To assess the value of renal histology in predicting
recovery of renal function
To assess the value of serum free light chain assay in
determining response of the myeloma to chemotherapy
and recovery of renal function in patients with renal
failure.
11
What is the current evidence?
Conflicting evidence in existing literature
Initial reports from early seventies proposed
that plasma exchange combined with
hydration, diuresis and chemotherapy could
reverse renal failure due to multiple myeloma
12
What is the current evidence?
Non-controlled study by Pozzi et al (1987)
Plasma exchange combined with hydration,
diuresis and chemotherapy could reverse
renal failure in 61%
Recovery of 27% in those not plasmapheresed
13
What is the current evidence?
Zucchelli et al 1988
Small RCT - 29 patients with 19 newly diagnosed
All received same chemotherapy
Group1 5 x plasma exchanges +/- 2 more
haemodialysis
Group 2 Peritoneal dialysis
14
What is the current evidence?
Group 1
Group 2
p
Number
15
14
On Dialysis at
13
11
start
Off dialysis at
11
2
<0.01
the end
Deaths within 2
1
5
NS
months
Serum
2.6 +/- 2.1
7.7 +/-1.9
<0.001
creatinine mg/dl 11.16 +/- 3.34
9.23 +/- 2.35
Survival at 1yr
66%
28%
15
What is the current evidence?
Johnson et al 1990
Small RCT - 21 patients with newly diagnosed disease
All received same chemotherapy
Group 1 forced diuresis + haemodialysis
Group 2 as above plus plasmaphersis 3 x weekly for 1-4
weeks
It is worth noting that the interval between diagnosis of
renal impairment with myeloma and dialysis was 1.21
months +/- 2.04 months (range 0-7) months
16
What is the current evidence?
Group 1
Group 2
p
Plasmapheresis
Number
10
11
On Dialysis at
5
7
start
On dialysis at
5
4
NS
the end
Serum
570 +/- 240
880 +/- 260
NS
creatinine mg/dl -340
-620
Survival at 1yr
No difference
No diffference
Around 70%
Around 70%
17
What is the current evidence?
Clark et al 2005 PO.513
RCT - 97 patients with newly diagnosed disease
All received same chemotherapy
Group 1 39 pts standard care
Group 2 58 plus plasma exchange x 5-7
18
What is the current evidence?
Clark et al 2005 PO.513
Primary composite end-point death, dialysis
dependence or crcl <30
Group 1 61.5% standard care
Group 2 68.6% plus plasma exchange x 5-7
19
What is the current evidence?
Does reversibility depend on the severity of
cast formation?
Both Pozzi and Johnson suggest that non-reversibility is
likely with degree of cast formation even with plasma
exchange.
20
Why now?
Diversity of current practice in the UK
centre-centre variation: 0-100% of patients receive plasma
exchange
unnecessary costly treatment or avoidable renal failure & dialysis?
Enthusiasm for a trial
strong patient and specialist society support
60 UK centres have expressed interest in participation
21
Why now?
With improved survival and prospects of
better treatments for myeloma, more
important than ever patients not
burdened by consequences of established
renal failure
22
Main eligibility criteria
Newly diagnosed myeloma
Acute renal failure (creatinine >500mmol/l,
urine output <400 ml/d or requiring dialysis)
Aged 18 years or over
Written informed consent
No previous chemotherapy for myeloma
No significant intrinsic renal disease unrelated
to myeloma
23
Design overview
New diagnosis of myeloma
Acute renal failure
Two of:
Attributed to myeloma
>10% plasma cells in bone marrow,
At least one of: Creatinine >
serum/urine paraprotein,
+
500µmo/l, oliguria, need for dialysis.
lytic skeletal lesions,
Unresponsive to rehydration
renal biopsy consistent with myeloma.
& treatment of hypercalcaemia.
Stratification (age, need for dialysis) & randomisation
Recommended chemotherapy:
Plasma exchange
No plasma
Dexamethasone days 1-4, 9-12; VAD x 4
x 7
exchange
cycles, beginning days 17, 38, 59, 80
in 1st 14 days
Alive and dialysis independent at day 100?
24
Add-on scientific studies
Serum free light chain analysis
serum free light chains (flc) assay will allow comparison
of flc changes in exchanged and non-exchanged groups
flc concentrations will be compared with bone marrow
appearance as marker of disease response
Renal biopsy
not mandatory; expected to be performed for clinical
indications in 2/3 patients
Initial renal biopsy appearances will be correlated with
renal outcome
25
Patient numbers & recruitment
plan to recruit 286 patients.
3000 new myeloma / yr in UK;
150 / yr with Creat > 500,
goal of 50-60 / yr to recruit in five years
26
Sample size
286 patients over a five year recruitment period
designed to detect an absolute improvement in
recovery of renal function of 20% (from 20% in the no
plasma exchange group to 40% with plasma exchange).
27
Current status
Opened to recruitment in January 2004
First patient randomised 05/02/2004
Over 30 centres have enrolled on study
Some delays in 2004 due to demands of EEC trials
directive
To date 16 patients entered
28
Recruitment and publicity
We hope to collaborate with other national
myeloma groups to encourage participation in
the trial.
Interest has been shown by groups from New
Zealand and Australia.
29
Practical details
LREC packs are available from the Clinical Trials
Research Unit at the University of Leeds.
Sue Bell
(Senior Trial Coordinator)
Gill Eddison (Senior Trial Coordinator)
Tel: 0113 343 1495
Tel: 0113 343 1492
CTRU, University of Leeds,
17 Springfield Mount, Leeds,
LS2 9NG.
Fax: 0113 343 1471
30
Conclusions
Renal failure remains a very important issue in
patients with multiple myeloma.
Optimisation of renal function is important to
allow patients to benefit maximally from new
innovations in the treatment of myeloma
Evidence that plasma exchange is important
needs to be confirmed
31