Management of renal failure in Myeloma patients.

1
Management of renal failure in Myeloma
patients.
MERIT update

• Dr Judith Behrens
• St Helier Hospital
• Carshalton

2
OVERVIEW

• Background.
• The challenge of renal impairment in myeloma
  patients.
• MERIT.
• Design
• History
• Results so far
• Implications

3
What is the extent of the problem?

• Renal impairment occurs in
• 25- 30 of patients at presentation
• (Knudsen 1994, Kyle RA, 1975, Eleutherakis-Papaia
  kovou V et al, 2007).
• 50 of patients at some stage of the illness
• (Alexanian, Barlogie and Dixon, 1990).
• 3-12 patients require dialysis or other major
  intervention
• (Clark, Shetty and Soutar, 1999).

4
Why do patients with myeloma get renal damage?

• Light chain toxicity
• Hypercalcaemia
• Dehydration
• Nephrotic drugs particularly NSAIDS
• Infection
• Hyperuricaemia
• Plasma cell infiltration

Immunoperoxidase staining showing proximal
tubules stuffed with light chains
5
Importance of SFLC in IIMM

• FLCs are abnormal in 95 at disease presentation.
  
• concentrations are gt1,000mg/L in 10- 15 of IgG
  and IgA cases with IIMM
• characteristic of IgD multiple myeloma

6
Urinary flc excretion and renal failure by
paraprotein class

• IgG, 1367 patients IgA, 649 patients LCO, 310
  patients.
• Urinary flc excretion, Patients with renal
  failure no ()
• g/g creatinine 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)
• Blood 2006 108 2013 19
• Effects of paraprotein heavy and light chain
  types and free light chain load on survival in
  myeloma
• Mark Drayson, Gulnaz Begum, Supratik Basu,
  Sudhaker Makkuni, Janet Dunn, Nicola Barth, and
  J. Anthony Child

7
Importance of SFLC in LCMM

• LCMM can be missed by conventional techniques.
• SPE demonstrates a monoclonal band in 50 cases,
• IFE demonstrates monoclonal bands in most cases
  but may be misinterpreted
• Urine needed for identification and quantitation
  but urine tests may never arrive in the lab.
• Serum Freelite assay pos 100 cases.
• Quantititative

8
What is the effect of renal failure on outcome?

• 1973 MRC IV th trial median survival
• ureagt 13mmol/l 2 months
• urea lt 6.5 37 months
• 1995 median survival with renal impairment
• (Torra, Blade et al BJH 1995)
• 20 -24 months

9
Impact of renal impairment on survival in myeloma
patients

• 30 patients die in the first 60 -100 days
  (c.f. 10 overall)
• However those surviving the first 60 days have
  similar overall survival to patients without
  renal failure.
• Normally IgG and IgA myeloma patients have longer
  survival than LCOM but in patients having the
  same quantity of BJP survival is the same for
  all isotypes
• The degree of renal impairment predicts survival
• Drayson et al. Analysis of MRC patients in 1Vth
  Vth V1th and V111th UK MRC trials
• Blood June 2006
• Thus rescuing the kidney is key

10
What is the likelihood of renal recovery?

• Until last decade widely quoted to be 10 once
  dialysis dependent
• Blade 2005

11
Renal out come of Patients admitted to SW Thames
Renal Unit 2000 -2007
12
Renal out come of Patients admitted to SW Thames
Renal Unit 2000 -2007

• Of 47 New patients
• 14 (30) early death (including 4 considered too
  unfit for active treatment)
• 13 (28) on long term dialysis
• 20 (42) avoided or became dialysis independent
  
• 38 reversal of dialysis dependency
• Of 15 Relapsed patients
• 27 early death
• 6.6 long term dialysis
• 66.6 dialysis avoided or reversed
• 88 reversal of dialysis dependency

13
Overall survival for myeloma patients has
improved in the last decade since the use of high
dose steroid containing regimes and novel
therapies
Projected median survival in patients entered in
to Myeloma 1X is 6-7 years Morgan et al IMW 2009
The goal must be to ensure that patients with
renal impairment and myeloma have access to this
longer survival
Overall survival gt 2000 ? 12 mths
Newly diagnosed MM (1971-2006) n 2981
Kumar ASH 2007 abstract 3594 Kumar et al. Blood
2008 Mar 1111(5)2516-20
14
Treatment of patients with myeloma renal failure
by reducing the SFLC

• Physical removal
• Switching off production

15
Physical removal

• Plasma exchange is theoretically beneficial in
  cast nephropathy,
• Evidence from two early small randomised trials
  conflicting
• (Zucchelli et al, 1988 Johnson et al, 1990)
• No conclusive evidence that plasma exchange
  substantially reduced a composite outcome of
  death, dialysis dependence, or glomerular
  filtration rate lt30 ml /min per 1.73 m2 at 6
  months in randomized, controlled trial conducted
  in Canada between 1998 and 2004
• (Clark et al 2005)

16
Reversibility of renal failure with high dose
steroid containing regimes

• 73 of 41 newly diagnosed patients
• Increasing to 80 with the addition of novel
  agents
• Kastritis et al Haematologica 2007

17
MERIT TRIAL DESIGN
18
MERIT
MyEloma Renal Impairment Trial
A randomised controlled trial of adjunctive
plasma exchange in patients with newly diagnosed
multiple myeloma and acute renal failure

• Inclusion Criteria
• Newly diagnosed myeloma
• Acute renal failure (creatinine gt 500mmol/l,
  urine output lt400 ml/d or requiring dialysis)
• Aged 18 years or older
• Written Informed Consent
• No previous chemotherapy for myeloma
• No significant intrinsic renal disease unrelated
  to myeloma

• Exclusion Criteria
• Pregnancy
• Inadequate contraception
• Known HIV seropositivity
• Platelet count lt50x109/l (risk of exacerbating
  thrombocytopenia by plasma exchange
• Standard contra-indications to study medication
  including allergy, abnormal liver function tests,
  known cardiac insufficiency and peptic ulcer

• Trial Endpoints
• Primary
• Proportion of patients alive and dialysis
  independent at 100 days
• Secondary
• Overall survival
• Proportion of patients alive and dialysis
  independent at 6 and 12 months
• GFR at 15 days, 100 days, 6 months and 12 months
• Change in serum-free light chain levels between
  days 0 and 15
• Response of myeloma to treatment according to
  standard criteria at 100 days, 6 months and 12
  months
• Quality of life

19
Recruitment

• 79 patients randomised January 2004 to January
  2009

20
Recruitment per centre
21
MERIT interim analysis of effect of SFLC on renal
recovery

• Malignant SFLC levels were significantly lower at
  entry in patients who were alive and dialysis
  free at 100 days
• Greater percentage reductions in FLC in the first
  two weeks are associated with a higher
  probability of renal recovery
• Maximum percentage reduction in malignant FLC
  levels in the first two weeks was variable and
  mostly achieved by 5 days.
• median 68.9 (range -78 to 99)
• ADF group mean 74.1 sd 16.4
• NADF mean 44.6 sd 44.6.
• Drayson et al Poster IMW 2009

22
It follows from MERIT data

• that patients need to be identified earlier in
  the disease so FLC load is smaller
• and
• that treatment has to be directed at the most
  effective means of reducing the SFLC

23
Current Status of Trial.

• Data cleansing.
• Your prompt return of information greatly
  appreciated.
• Meeting of TMG imminent
• Publication in 2010

24
Acknowledgements

• Patients and staff
• Aberdeen Royal Infirmary
• Addenbrookes Hospital
• Aintree Hospital NHS Trust
• Belfast Hospital
• Bradford Teaching Hospitals NHS Trust
• Glasgow Royal Infirmary/ Glasgow Western
• Hope Hospital, Salford
• Hull Royal Infirmary
• Kent and Canterbury Hospital
• William Harvey Hospital
• Queen Elizabeth the Queen Mother Hospital
• Leeds General Infirmary
• Leicester General Hospital
• Monklands Hospital, Airdrie
• Oxford Radcliffe Hospital
• Royal Cornwall Hospital
• Royal Sussex Hospital, Brighton
• Southmead Hospital, Bristol

• Trial Co-ordination and Statistics
• Sue Bell
• Gill Booth
• Sue Bourne
• Kim Cocks
• Dena Cohen
• Corrine Collett
• Central Laboratories
• MT Drayson
• A Adkins
• J Birtwistle
• N Newnham
• K Walker

Trial Management Group Dr G Gaskin Dr J Behrens,
Dr GH Jackson Dr MT Drayson Dr N Iggo NCRI
Haematological Oncology Clinical Studies
Group UK Myeloma Forum Clinical Trials
Committee Myeloma UK Funders