Management of AKI in Myeloma:
Novel Approaches
Dr Colin A Hutchison
Consultant Nephrologist, Hawke’s Bay DHB, NZ
Senior Lecturer, University of Birmingham, Birmingham, UK

Why are nephrologists interested inmyeloma kidney?
• Myeloma accounts for about 2% ofpatients on ESRD programmes• It feels as though it should be a fixable
problem (AKI – often with limited fibrosis)• Patients do…. badly

Severe Renal Failure and Myeloma –Oxford 1997

Survival of patients with AKI and multiple myeloma

Median survival 10.2 monthHaynes et al NDT 2009Chemotherapy: Improving myeloma outcomes (theBeaumont experience (Ireland))

Dialysis dependent
N-44

Murphy et al, BJH 2014

Chemotherapy: Improving myeloma outcomes (theBeaumont experience (Ireland))All patients
N-262

Murphy et al, BJH 2014

AKI and myeloma
Key areas to improve patient outcomes:
1. Rapid diagnosis
2. New chemotherapy agents
3. Novel supportive strategies

Combined care
(Laboratory, Nephrology, Haematology)

Rapid diagnosis
Of myeloma causing AKI((Free light chains))
Education to: ED teams
General Medicine(hopefully less so Renal)

Freelite: A quantitative serum FLC assay
exposed surface
exposed surface

Kappa

hidden surface

Previously
hidden surface
heavychain

Lambdalight chain

Assessment of 1877 patients with plasma cell dyscrasias
SPE and FLC only sensitivity:• 100% of MM• 99.5% of SMM• 98% of AL amyloid• 96% of Plasmacytoma

142 patients with new dialysis
dependent renal failure
41 with myeloma

Screening for MM in AKI
Same day result

Cockwell P+ Hutchison CA Current Opinion in Nephrology and Hypertension 2010

Free light chain assays
Established polyclonal assays(Freelite – The Binding Site)
Vs
New monoclonal assays(Siemens)

Correlation of lambda assays

Freelite lambda (mg/L)

Management of myeloma kidney

Time to target FLCs??

Reductions in serum FLCs improves
renal outcomes in myeloma kidney

Leung et al, Kidney International, 2008

Probability of renal recovery from castnephropathy
For 80% of thepopulation to haverenal recovery there
most be a 60%
reduction in sFLCs
39 patients with castnephropathy:
Birmingham + Mayo

Hutchison CA et al, J Am Soc Nephrol 2011

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

Dose modification in renal impairment

Thalidomide

Degree of renal impairment

Dose adjustment

Any

Not required

Mild RI (CrCl 50-80mL/min)

25mg (full dose) every 24 hours

Moderate RI (CrCl 30-49mL/min)

10mg every 24 hours

Severe RI (CrCl <30mL/min)

15mg every 48 hours

Severe RI (requiring dialysis)

15mg three times per weekAny

Not required

Lenalidomide

Bortezomib

RI – renal impairment; CrCl – creatinine clearance.

Novel agents: Bortezomib
Attractions to use in severe AKI / MM:• Not renal excreted– Liver– No need to dose reduce• Highly protein bound – limited dialysis
removal• Acts within 1 hr – 72hrs• Myeloma response rapid (2-3 cycles)• 68 patients with MM and AKI (GFR<50)• Treated with Bortezomib, Dexamethasone and Doxorubicin• Tumor response in 84% of patients• Renal response in 62%• Only 3 of 9 dialysis dependent patients recovered renal function•Cohort of patients with renal impairment and MM•Treated with Bortezomib and Dexamethasone•59% of patients had a degree of renal recovery•Median time to renal recovery – 11 days
•Only 2 of 9 dialysis dependent patients had renal recovery

Management of myeloma kidney:
reducing FLCs
Is chemotherapy alone enough??

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

Why remove FLCs - kinetics in renal
failureKappa (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
failureKappa (shaded)
Lambda (clear)
RR 60-70%

As kidneys fail serum
half-lives increase

Both: P<0.01

Hutchison et al, cJASN 2008

Why remove FLCs - kinetics in renal
failureKappa (shaded)
Lambda (clear)

RR 30%

RR 60-70%

As kidneys fail serum
half-lives increase

Both: P<0.01

Hutchison et al, cJASN 2008

Direct removal of FLCs from the serum:
Plasma exchange – a logical treatment

••••

14 patients
7 new presentation
Median 8 Plex
86% partial renal response

Largest RCT of plasma exchange:
no renal benefit, no survival benefit

ClarkAnn I Med 2005

Why does plasma exchange not work??
Mathematical model:• Two compartment model to evaluate the kinetics(movement) of FLCs in patients with MM and AKI
Plasma exchange:• Effectively clears the intra-vascular volume• But short duration therapy• Therefore extra-vascular compartment is not cleared• FLCs are 80% extra-vascular• Therefore total body load of FLCs is not significantly reducedExtended removal of FLCs from theserum is required:
Extended treatment will allow:
Extra-vascular FLCs
Intra-vascular

Removed

Haemodialysis:– Safely undertaken over extended periods of time
– Unsuccessful with conventional dialysers because ofthe small pore size
– In-vitro we assessed FLC removal by ‘super-flux’
dialysers– Only the Gambro HCO 1100 could effectively remove
monoclonal FLCs

Pore Sizes of High Cut-Off (HCO) Membranes
in comparison to HighFlux and plasmafiltration
membranesHighFlux

HighFluxHigh Cut-Off

Plasmafilter

1,0n/no [-]0,8HCO
0,60,40,2

Plasmafilter

0,00,001

0,010,1pore size [ｵm]1Courtesy of Dr Storr, Hechingen, Germany

HCO Membrane
Increased permeability for middle molecules

Convective permeability

Gambro HCO 1100 – 6 hour dialysis
800

Serum free lambda (mg/L)

9000

Serum free lambda

Dialysate free lambda

700

8000
600
7000
500

6000
5000

400

4000

300

3000
200
2000

Lambda in dialysate (mg/L)

10000

100

1000
000306090120

150

180210

240

270

300

330

Time (mins)

Hutchison et al. JASN March 2007

Pilot Study of FLC removal by HCO-HD
Aim: Evaluate the removal of FLCs by extended HD inpatients with biopsy proven cast nephropathy + dialysis
dependent acute renal failure
Combination of chemotherapy and HCO-HD:• Chemotherapy: high dose dexamethasone andthalidomide 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 andchemotherapy
P<0.01

Hutchison et al cJASN 2009

Recovery of renal function

14 of 19 patients

Hutchison et al cJASN 2009

Renal recovery rates in study population anda case matched control population

17 Study patients

P<0.001

17 Control patients

Hutchison et al, EDTA 2008.

Study population’’s survival relates torecovery 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 – HCO 1100
Percentage of patients who recovered
renal function• 67 patients treatedacross Europe andAustralia• Median 12 sessions• 63% had renal recovery

Percentage FLC reduction

Benefit of FLC removal in relation to degreeof renal impairment

Residual renal
function(ml/min/1.73m2)
03
6
1524

FLC exposure (g/day)without FLC
with FLC
removalremoval
418
117
314
106
251
97
157
77
114
64

Additional reduction achieved
with FLC removal (%)
7266
6150
44

ANZSN Oral Mini-Poster Session 2012Randomised and controlled
90 Patients recruitedRandomisation

Control Arm HD

Research Arm HD

45 Patients
Standard high-flux HD

45 Patients
Extended HD on HCO 1100

‘Modified PAD regimen’ Chemotherapy(P) VELCADE™ (bortezomib)
iv
1.0 mg/m2(A) Adriamycin (Doxorubicin)(D) Dexamethasone

iv
oral

9.0 mg/m240 mg

primary outcome = independence of dialysis at 3 months

EuLITE Recruitment
706050403020100• 15 UK centres• 4 German centres

45 patients

MYRE – A French RCT
How to manage renal impairment in MM:
Part 1 – Moderate renal impairment and newMM:• 200 patients randomized to CBD or BD
Part 2 – Severe renal impairment and newMM:• 90 patients with biopsy proven myeloma
kidney randomized to FLC removal HD orstandard care

If EuLITE/MYRE return positive
results – who should be treated?
MM patients with severe renal failure Cast nephropathy
 High serum FLC levels
 Suitable for chemotherapyMultiple Myeloma: Light chain kinetics and recovery from dialysis

Serum lambda (mg/L)

3000

Dexamethasone

2500

Bortezomib
2000
1500
1000
500
0051015Days

202530Combined Care in Myeloma Kidney Summary
1. Rapid diagnosis is essential - Freelite
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 – 2013
2. MYRE – 2013/14

Acknowledgements& Disclosures
Acknowledgements
EuLITE Investigators

IKMG members

University Hospital Birmingham:

Grant 05-007– Dr Paul Cockwell– Dr Mark Cook
University of Birmingham:– Prof A.R. Bradwell
The University of Tubingen:– Dr Nils Heyne

The Mayo Clinic:- Dr Nelson Leung