Management of renal failure  in Myeloma patients.

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OVERVIEW. Background. The challenge of renal impairment in myeloma patients.MERIT.Design HistoryResults so farImplications. What is the extent of the problem? . Renal impairment occurs in 25- 30% of patients at presentation (Knudsen 1994, Kyle RA, 1975, Eleutherakis-Papaiakovou V et al, 20

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Management of renal failure in Myeloma patients.

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1. Management of renal failure in Myeloma patients. 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-Papaiakovou 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

5. Importance of SFLC in IIMM FLCs are abnormal in 95% at disease presentation. concentrations are >1,000mg/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 urea> 13mmol/l= 2 months urea < 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

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 <30 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.

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 St Georges Healthcare Trust St Helier Hospital University Hospital Coventry and Warwickshire NHS Trust Victoria Royal Infirmary Western General Hospital, Edinburgh York District Hospital

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