AL Amyloidosis and renal complications

Alex Legg PhDScientific Affairs Manager

The Binding Sitealex.legg@bindingsite.com

Distributor in Poland BIOKOMbeata.olsz@biokom.com.pl

Why are FLCs associated with kidney disease?

In plasma cell dyscrasias toxic monoclonal FLCs are produced:

Light chain physico-chemical

properties

organisation oflight chain aggregates Characteristic

organ/tissue injury

Location of deposits

Acute tubular necrosisFanconi’s syndromeAL amyloid

LCDD

868 AL Amyloidosis patients

Kidney involvement 72%Nephrotic syndrome 52%Renal failure (creat >2mg/dL) 18%

Merlini, G. et al. 2008. 2(1): p. 287 - 293.

AL

Cast nephropathy

CN

AL Amyloidosis DiagnosisMonoclonal Protein Investigations

Serum electrophoresis: SPE + sIFE

+

Urine electrophoresis: UPE + uIFE

and/or?

Serum FLC assay

AL AmyloidosisAL Amyloidosis

Lachmann H. et al. BJH 2003; 122 :78-84

IFE sensitivity -

- SPE sensitivity

Diagnostic Performance in AL Amyloidosis (n = 110)

Assay % Positive

FLC κ/λ ratio 91

Serum IFE 69

Urine IFE 83

Serum IFE + urine IFE 95

FLC κ/λ ratio + serum IFE 99

FLC κ/λ ratio + serum IFE + urine IFE 99

Katzmann et al. Clin Chem 2005; 51: 878-881

‘Urine IFE did not add any additional information.’

Diagnostic Performance in AL Amyloidosis (n = 115)

Assay % Positive

FLC κ/λ ratio 76

Serum IFE 80

Urine IFE 67

Serum IFE + urine IFE 96

FLC κ/λ ratio + serum IFE 96

FLC κ/λ ratio + serum IFE + urine IFE 100

Palladini et al. Clin Chem 2009; 55: 499-503

All three assays are complementary

Publication Screening

IMWG for sFLC analysisDispenzieri, A., et al. Leukemia, 2009. 23(2): p. 215-24.

sIFE + sFLC + uIFE

BCSH AL Amyloidosis guidelinesBird, J.M., et al. Br J Haematol, 2004. 125(6): p. 681-700.

sIFE + sFLC + uIFE

AL Amyloidosis Guidelines SummaryScreening

Polyclonal sFLC increase as GFR decreases

Hutchison Clin J Am Soc Nephrol 3: 1684–1690, 2008

Kappa FLCLambda FLC

/ ratio increases as GFR decreases

Hutchison Clin J Am Soc Nephrol 3: 1684–1690, 2008

New renal reference range for ratio: 0.37 – 3.1

Can sFLC assays be used to diagnose multiple myeloma in

patients with renal failure?

• Audit of 142 patients with new dialysis dependent acute renal failure

• 41 / 142 patients with multiple myeloma

Hutchison et al. BMC Nephrology 2008, 9:11

New reference range for / ratio

for renal impairment

0.1

1

10

100

1000

10000

100000

0.1 1 10 100 1000 10000 100000

Serum kappa FLC (mg/L)

Ser

um

lam

bd

a F

LC

(m

g/L

)

1,000100.1

1,000

10

Normal / ratio

0.26 – 1.65

Proposed renal range

/ = 0.37 – 3.1

ARF - Myeloma ()

ARF - Myeloma ()

ARF - No MG

Normal sera

Hutchison et al. BMC Nephrology 2008, 9:11

0.1

1. Interpret sFLC results in the context of clinical findings and other laboratory tests… including renal function

2. If patient has renal impairment, then renal reference range (/ = 0.37 – 3.1) may be applicable

3. Renal reference range improves diagnostic specificity without changing diagnostic sensitivity

New reference range for / ratio for renal impairment

Serum amyloid P scans: Reduction of AL deposits in the liver and spleen after one year of chemotherapy

AL Amyloidosis Treatment

AL amyloidosis: BD response

Kastritis Haematologica 2007; 92: 1351 - 1358

Progressive disease

“..at least a 50% reduction occurred in all [responding] patients within two courses of treatment.”

Haematological Response Criteria

Complete response

Serum and urine negative immunofixation

Free light chain ratio normal

Marrow <5% plasma cells

Partial response

If serum M component > 5g/L, a 50% reduction

If light chain in urine with visible peak and >100 mg/day and 50% reduction

If serum iFLC >100 mg/L and 50% reduction

Gertz et al., Am J Hematol, 2005: 79, 319-328

Definition of treatment Response

Gertz et al., Curr Opin Oncol 2007. 19; 136-141

AL amyloidosis: Outcome

Publication Monitoring

IMWG for sFLC analysisDispenzieri, A., et al. Leukemia, 2009. 23(2): p. 215-24.

sFLC essential(Recommended for LCDD)

BCSH AL Amyloidosis guidelinesBird, J.M., et al. Br J Haematol, 2004. 125(6): p. 681-700.

sFLC recommended

International Consensus OpinionGertz, M.A., et al., Am J Hematol, 2005. 79(4): p. 319-28.

sFLC recommended

AL Amyloidosis Guidelines SummaryMonitoring

Light chain deposition disease2 large published studies:1) Mayo Clinic n = 19 abnormal sFLC ratio 89%

2) NAC n = 17 abnormal sFLC ratio 88%Katzmann J. et al. Clin Chem 2002; 48: 1437 - 1444Wechalekar A. et al. Haematologica 2005; 90: 1414

Utility in

monitoring:Brockhurst I. et al. Nephrol Dial Transplant 2005; 20: 1251 - 1253

Gregorini, et al. 2008. Haematologica. 2(2): E41

Serum FLC

Number of AL amyloidosis/ LCDD diagnoses

Myeloma and renal insufficiency

• 10 – 20% myeloma patients present with acute renal failure

• 10% remain dialysis dependent long term– There is a high mortality rate– Chemotherapy and transplantation are hazardous

Cast Nephropathy:

Light chain removal strategies for cast nephropathy

1.Plasma exchange

• Used since 1980s

2.Haemodialysis

• New treatment strategy

Challenges:

1. >80% of FLCs are extravascular.

2. PE procedures are of limited frequency & duration (typically 6 x 1.5 hour sessions over 2 weeks)

Plasma exchange to remove sFLCs

Typical recovery rates: 10 - 20%.

Randomised control trial of plasma exchange

Cum

ulat

ive

surv

ival

100 %

0 %

80 %

60 %

40 %

20 % ControlPlasma exchange

0 1 2 3 4 5 6

Time to death (months)

Clark et al. Ann Intern Med 2005 143:777 – 84

• 7 dialysers evaluated in vitro for filtration efficiency

• The Gambro HCO 1100* was the most efficient at removing FLC

* Available in Poland

Haemodialysis to remove sFLCs

Hutchison, CA. et al. JASN 2007; 18: 886-895

pore size [µm]

0,001 0,01 0,1 1

n/no

[-]

0,0

0,2

0,4

0,6

0,8

1,0

pore size [µm]

0,001 0,01 0,1 1

n/n o

[-]

0,0

0,2

0,4

0,6

0,8

1,0HighFlux Plasmafilter

High Cut-Off

High Flux

PlasmaFilter

Size of albumin

Pore size [m]

Distribution of filter pore sizes

0

500

1000

1500

2000

2500

3000

0 5 10 15 20 25 30

Days

Ser

um

lam

bd

a F

LC

(m

g/L

)

Dexamethasone

Pre-dialysis FLC

Post-dialysis FLC

Velcade

Patient 3:

Hutchison, CA. et al. JASN 2007; 18: 886-895

Resolution of Cast Nephropathy

Basnayake et al. 2008. J Med Case Reports; 2, ePub

Renal biopsies: Haematoxylin and eosin stainA: Presentation

B: After chemotherapy/ HCO1100 treatment

Pilot study: Renal recovery rates

Hutchison, CA. et al. 2009. Clin JASN 4, 745-54

28 days

European Trial of Free Light Chain Removal by Extended Haemodialysis in Cast Nephropathy

Contact: Dr Colin Hutchisoncah692@bham.ac.uk

AL amyloidosis? Publication in press

IMWG 1 BCSH 2

International Consensus Opinion 3

Screening

Prognosis

Monitoring

+ sIFE & uIFE

1. Dispenzieri, A., et al. Leukemia, 2009. 23(2): p. 215-242. Bird, J.M., et al. Br J Haematol, 2004. 125(6): p. 681-7003. Gertz, M.A., et al., Am J Hematol, 2005. 79(4): p. 319-28

N/A

N/A-

Guidelines Summary

Conclusions

• alex.legg@bindingsite.com

FLCs in AL amyloidosis:

“The introduction of FLC assay has greatly improved the management of patients with AL amyloidosis

and is now an essential tool in the care of this disease.”

Prof. G. Merlini 5th International Symposium, Bath Assembly Rooms

Biennial Meeting, 2008

New reference range for / ratio for renal impairment

0.1

1

10

100

1000

10000

100000

0.1 1 10 100 1000 10000 100000

Serum kappa FLC (mg/L)

Ser

um

lam

bd

a F

LC

(m

g/L

)

0.1 1,000100.1

1,000

10

Normal / ratio

ARF - Myeloma ()

ARF - Myeloma ()

ARF - No MG

Normal sera

Hutchison et al. BMC Nephrology 2008, 9:11

Patient inclusion criteria

• Dialysis dependent renal failure, renal biopsy proven cast nephropathy

• Fulfils diagnostic criteria for the diagnosis of symptomatic de novo MM

• Abnormal sFLC ratio and sFLC > 500 mg/L• Informed consent • Commencement of study within 10 days of

presentation

Serum negativeUrine positive

n = 16

Serum PositiveUrine negative

n = 52

Fre

qu

ency

sFLC concentrations (mg/L

Fre

qu

ency

Monoclonal urine FLC (g/day)

Total: 219 patients

Mead, G.P., et al., Clin Lymphoma Myeloma, 2009. February: p. 153a.

AL amyloidosis: Serum FLC negative and urine positive?

Patient X: Serum FLCs before developing AL amyloidosis:

Kappa: 10 mg/ LLambda: 10 mg/ Lk/l ratio: 1

Patient X then develops a very subtle AL amyloidosis tumour

Kappa: 12 mg/ LLambda: 8 mg/ Lk/l ratio: 1.5

This patient would normally be urine negative due to normal kidney function......

Normal

Normal

Glomerulus damaged by

amyloids

Weakly positive urine

Renal Metabolism of FLC

Albumin saturates

proximal tubule

sIF + sFLC: 98%sIF + sFLC + uIF: 100%

90 Patients recruited

Randomisation

Control Arm HD45 PatientsStandard high-flux HD

‘Modified PAD regimen’ Chemotherapy (P) VELCADE™ (bortezomib) iv 1.0 mg/m2

(A) Adriamycin (Doxorubicin) iv 9.0 mg/m2

(D) Dexamethasone oral 40 mg

Assess outcome

Research Arm HD 45 Patients Extended HD on HCO 1100

Randomised and controlled

Trial time course

Day 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 onwards

Research arm HD(Hours)

√(6)

√(8)

√(8)

√(8)

√(8)

√(8)

√(8)

√(8)

√(8)

√(8)

√(8)

√(8)

√(8)

Accord. to clin need (6)

Chemo VAD

AD

AD

VAD

V

D* D* D*

V

D* D* D* D* D*

As per PAD protocol

sFLCmeasured √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √

sFLC measured • at assessment Run within 24 hours• pre dialysis• post dialysis• non-dialysis Run once /week

Kumar, S., et al., Haematologica, 2008. 2(2): p. C19

Four variables that had maximum impact on the outcome: FLCdifferencetroponin-TBNPB2M

0

2000

4000

6000

8000

10000

12000

0 1 2 4 5 6 7 8 9 11 12 13 14 15 17 18 19 20 21 22 24 25 26 27 28 30

Time (days)

Ser

um

kap

pa

(mg

/L)

1

0 5 10 15 20 25 30

2

3

Model of sFLC Removal - PE

Hutchison et al (2007) JASN 18, 886-895

1. 100% tumour kill on day 1, RES clearance only2. 10% tumour kill/day, RES clearance only3. 10% tumour kill/day with PE

0

2000

4000

6000

8000

10000

12000

0 1 2 4 5 6 7 8 9 11 12 13 14 15 17 18 19 2 0 2 1 2 2 2 4 2 5 2 6 2 7 2 8 3 0

Time (days)

Seru

m k

app

a (m

g/L

)

1

0 5 10 15 20 25 30

2

3

4

5

1. 100% tumour kill on day 1, RES clearance only2. 10% tumour kill /day, RES clearance only3. 10% tumour kill /day with PE4. 10% tumour kill /day with HD (3 x 4h /week)5. 10% tumour kill /day with HD (12h /day)

Model of sFLC Removal – HCO1100

Urine IFE +only

Serum IFE + and

Urine IFE +

Serum IFE -and

Urine IFE -

Abnormal sFLC ratio

40/ 40 34/ 37 14/18

Abraham, R.S., et al., Am J Clin Pathol, 2003. 119(2): p. 274-8

All urine IFE+ AL amyloidosis patients identified by sIFE + sFLC

Katzmann, J.A., et al., Mayo Clin Proc, 2006. 81(12): p. 1575-8.

Absolute FLC levels are prognostic in AL amyloidosis patients undergoing peripheral blood stem cell

transplantation

Higher FLC concentrationcorrelated with:

Bone marrow plasmacytosisNumber of organs involvedBeta-2-microglobulinSerum cardiac troponin T

Dispenzieri et al. Blood, 2006; 3378-3383

Higher FLC concentrationcorrelated with:

Bone marrow plasmacytosisNumber of organs involved

Beta-2-microglobulinSerum cardiac troponin T

AL amyloidosis: MP response

A.R. Bradwell: Serum Free Light Chain Analysis 5th Edition

Monoclonal Protein InvestigationsAL Amyloidosis DiagnosisSerum electrophoresis: SPE + sIFEN

um

ber

of

pat

ien

ts

SPE+ SPE-/ IFE+ SPE-/ IFE- FLCTotal

100%

53%

26%21%

SPEquantifiable

FLC 3%

98%

Lachmann H. et al. BJH 2003; 122 :78-84

Absolute FLC levels are prognostic in AL amyloidosis patients undergoing peripheral blood

stem cell transplantation

Dispenzieri et al. Blood, 2006; 3378-3383

Comparison SAP scans and serum FLCs in 127 AL amyloidosis patients before and 12 months after chemotherapy.

Lachmann, H.J., et al., Br J Haematol, 2003. 122(1): p. 78-84

Monitoring plasma exchange with sFLC

Chemotherapy:B

c

BortezomibDexamethasoneCyclophosphamideThalidomide

Ser

um

FL

C (

mg

/L)

Cre

atin

ine

(mg

/dL

)

Plasma exchanges

Cserti Transfusion 2007 47: 511 - 514

Normal plasma cell FLC production

Intravascular FLC pool

Removal by kidneys

A model of light chain production and metabolism

Removal by Reticuloendothelial system

Extravascular FLC pool

Tumour

Intravascular FLC pool

Removal by kidneys

A model of light chain production and metabolism

Removal by PE or HD

Removal by Reticuloendothelial system

Extravascular FLC pool