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Henry Bence Jones. Free light chain (FLC) production by plasma cells. Lambda. Kappa. exposed surface. Kappa. exposed surface. hidden surface. antigen. Previously. hinge region. binding. hidden surface. sites. heavy chain. and antibody. target. carbohydrate. Lambda. light chain.

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slide5

exposed surface

Kappa

exposed surface

hidden surface

antigen

Previously

hinge region

binding

hidden surface

sites

heavy chain

and antibody

target

carbohydrate

Lambda

light chain

slide6

l FLC (mg/L)

k FLC (mg/L)

slide7

1000

SPEP

Total

k & l

CZE

100

sIFE

Light chain concentration (mg/L)

UPEP

10

Normal range in serum

uIFE

Normal range in urine

1

sFLC

Sensitivity of Assays forLight Chains

slide9

50,000

50,000

5,000

5,000

500

2,000

Urine FLC (mg/L)

Serum FLC (mg/L)

250

100

1,000

NR urine

NR serum

10

10

0

6

12

18

24

30

Time (months)

slide10

Patient 1

Patient 2

Serum kappa concentration (mg/L)

Serum lambda concentration (mg/L)

Urinary kappa excretion (g/24h)

Urinary lambda excretion (g/24h)

months

months

Patient 3

Patient 4

Urinary kappa excretion (g/24h)

Serum kappa concentration (mg/L)

Serum kappa concentration (mg/L)

Urinary kappa excretion (g/24h)

months

months

SERUM

URINE

slide11

Amyloidosis (AL) 10% (106)

Lymphoma 5% (50)

Asymptomatic myeloma 4% (39)

Multiple Myeloma 18% (185)

Solitary or extramedullary plasmacytoma 3% (27)

Chronic lymphocytic leukaemia 2% (21)

Waldenström’s macroglobulinaemia 2% (20)

MGUS 56% (578)

slide12

Biclonal (1%)

IgA (21%)

IgE (0.01%)

Nonsecretory myeloma (3%)

Bence Jones myeloma - free light chain (15%)

IgD (1%)

IgG (59%)

slide13

l FLC (mg/L)

k FLC (mg/L)

Blood.2001: 97: 2900-02

in intact immunoglobulin multiple myeloma

In intact immunoglobulin multiple myeloma

Serum free light chains are abnormal in 95% of patients

slide15

l FLC (mg/L)

k FLC (mg/L)

Br J Haem.2003: 122: 78-84

in multiple myeloma
In multiple myeloma
  • 1. FLCs and immunoglobulins are independent markers of disease
  • 2. FLCs can indicate early relapse
  • 3. FLCs can identify residual disease
  • 4. FLCs relate to disease stage
  • 5. FLCs can be nephrotoxic
  • 6. FLCs respond faster to treatment
slide17

l FLC (mg/L)

Total IgG in 120 IgG l myeloma patients (g/L)

Br J Haem.2003: 122: 78-84

in multiple myeloma1
In multiple myeloma
  • 1. FLCs and immunoglobulins are independent markers of disease
  • 2. FLCs can indicate early relapse
  • 3. FLCs can identify residual disease
  • 4. FLCs relate to disease stage
  • 5. FLCs can be nephrotoxic
  • 6. FLCs respond faster to treatment
slide19

l FLC (mg/L)

k FLC (mg/L)

in multiple myeloma2
In multiple myeloma
  • 1. FLCs and immunoglobulins are independent markers of disease
  • 2. FLCs can indicate early relapse
  • 3. FLCs can identify residual disease
  • 4. FLCs relate to disease stage
  • 5. FLCs can be nephrotoxic
  • 6. FLCs respond faster to treatment
plasma exchange trials of myeloma patients in acute renal failure
Plasma exchange trials of myeloma patients in acute renal failure
  • Zucchelli et al., 1988. Italy. 29 patients either on (1) peritoneal dialysis or (2) haemodialysis and plasma exchange. 13 of 15 in plasma exchange group vs. 2 of 14 in control group regained renal function and survival was better (P<0.01).
  • Johnson WJ et al., 1990 (Mayo Clinic). 21 patients with renal impairment randomised to plasma exchange or not. No difference in renal function outcome, which was related to myeloma cast formation.
  • Clark et al., 2005. Canada. 97 patients on dialysis randomised to plasma exchange or not. No benefit.
slide23

Gambro HC1100 –6 hour dialysis

Serum free lambda (mg/L)

FLC in dialysate (mg/L)

Time (mins)

in multiple myeloma3
In multiple myeloma
  • 1. FLCs and immunoglobulins are independent markers of disease
  • 2. FLCs can indicate early relapse
  • 3. FLCs can identify residual disease
  • 4. FLCs relate to disease stage
  • 5. FLCs can be nephrotoxic
  • 6. FLC respond faster to treatment than intact immunoglobulins because of their short serum half-life.
slide25

Total IgG

kFLC (mg/L)

Intact IgG (g/L)

Monoclonal IgG

Days after high-dose melphalan

Leuk & Lymph. 2006: 47: 21-28

k

FLC

slide26

k/lratio

Total IgG (g/L)

Time (days)

Courtesy of Dr M Das & E. Liakopoulou

slide27

Amyloidosis (AL) 10% (106)

Lymphoma 5% (50)

Asymptomatic myeloma 4% (39)

Multiple Myeloma 18% (185)

Solitary or extramedullary plasmacytoma 3% (27)

Chronic lymphocytic leukaemia 2% (21)

Waldenström’s macroglobulinaemia 2% (20)

MGUS 56% (578)

slide28

l FLC (mg/L)

k FLC (mg/L)

dispenzieri a gertz ma kyle ra blood november 2004 104 2991 4

“The introduction of the free light chain assay has revolutionised our ability to assess haematological responses in patients with low tumour burden”

Dispenzieri A, Gertz MA, Kyle RA.

Blood: November 2004; 104: 2991-4

slide30

l FLC (mg/L)

k FLC (mg/L)

Courtesy of H. Lachmann

slide31

Normal FLC ratio (K/L 0.26-1.65)

Abnormal FLC ratio (K/L <0.26 or > 1.65)

Percent

0 10 20 30 40 50 60

0 5 10 15 20 25 30

Years

Blood 2005: 106: 812-817

slide32

Lambda

Normal

Kappa

Relative Risk of Progression

0.5 1.0 5.0 10.0 50.0 500.00

0.01 0.10 0.26 1.0 1.65 10.00 100.00

Free Light Chain Ratio

Blood 2005: 106: 812-817

suggested mgus guidelines
Suggested MGUS Guidelines

Low risk - reassurance and discharge

Review MGUS when attending for other illnesses. For younger patients - follow-up as intermediate risk.

Intermediate risk - annual follow-up*

No benefit from more frequent early monitoring following diagnosis.

High risk - 6 month follow-up*

*Increased risk associated with rising and more abnormal FLC ratios. High FLC concentrations associated with greater risk of renal impairment.

FLC MGUS is a new, potentially high risk group

slide35

Screening of symptomatic patients for B-cell lymphoproliferative disorders

slide36

100000

10000

SPE Sensitivity

1000

Normal sera

Kappa LCMM

Lambda LCMM

100

Serum Lambda (mg/L)

IIMM

High pIgG

AL Amyloidosis

10

Renal impairment

NSMM

1

IFE Sensitivity

IFE Sensitivity

0.1

0.1

1

10

100

1000

10000

100000

Serum Kappa (mg/L)

screening symptomatic patients with serum flc and capillary protein electrophoresis cze
Screening symptomatic patients with serum FLC and capillary protein electrophoresis(CZE)
  • 1003 consecutive unknown samples studied
  • 33 had abnormal serum FLC ratios
  • 16/33 were normal by electrophoresis
  • 9/16 confirmed lymphoproliferative disorders:
  • 3x CLL, 2x LCMM, lymphocytosis, atypical lymphoma, IgMl + aplastic anaemia, NSMM
screening with serum flcs and serum protein electrophoresis
Screening with serum FLCs and serum protein electrophoresis
  • Adding FLC to screening protocol increased tumour detection rate by 56%
  • Bakshi et al. Am J Clin Pathol: August 2005.
slide39

l FLC (mg/L)

k FLC (mg/L)

serum free light chain immunoassays for screening symptomatic patients
Serum free light chain immunoassays for screening symptomatic patients
  • More sensitive than other serum and urine tests for free light chains (Clin Chem 2001)
  • More precise than SPE for free light chains (CAP 2005)
  • Clinically more accurate and sensitive for light chain diseases (Lancet 2003; Br J Haem 2004)
  • Identifies 50% more patients (Am J Clin Path 2005)
  • Allows risk stratification for MGUS (Blood 2005)
  • Should be used in combination with SPE
acknowledgements

Acknowledgements

J Katzmann, R Kyle, Mayo Clinic.

H Lachmann, P Hawkins, UK, AL Centre.

David Keren, Ann Arbor University.

M Nowrousian, Essen University.

M Drayson, Birmingham University, UK

H Carr-Smith, G Mead, P Showell,

J Overton, S Reid, The Binding Site.