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Henry Bence Jones

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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Henry Bence Jones

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  1. Henry Bence Jones

  2. Free light chain (FLC) production by plasma cells Lambda Kappa

  3. exposed surface Kappa exposed surface hidden surface antigen Previously hinge region binding hidden surface sites heavy chain and antibody target carbohydrate Lambda light chain

  4. l FLC (mg/L) k FLC (mg/L)

  5. 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

  6. 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)

  7. 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

  8. 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)

  9. Biclonal (1%) IgA (21%) IgE (0.01%) Nonsecretory myeloma (3%) Bence Jones myeloma - free light chain (15%) IgD (1%) IgG (59%)

  10. l FLC (mg/L) k FLC (mg/L) Blood.2001: 97: 2900-02

  11. In intact immunoglobulin multiple myeloma Serum free light chains are abnormal in 95% of patients

  12. l FLC (mg/L) k FLC (mg/L) Br J Haem.2003: 122: 78-84

  13. 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

  14. l FLC (mg/L) Total IgG in 120 IgG l myeloma patients (g/L) Br J Haem.2003: 122: 78-84

  15. 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

  16. l FLC (mg/L) k FLC (mg/L)

  17. 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

  18. 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.

  19. Gambro HC1100 –6 hour dialysis Serum free lambda (mg/L) FLC in dialysate (mg/L) Time (mins)

  20. 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.

  21. Total IgG kFLC (mg/L) Intact IgG (g/L) Monoclonal IgG Days after high-dose melphalan Leuk & Lymph. 2006: 47: 21-28 k FLC

  22. k/lratio Total IgG (g/L) Time (days) Courtesy of Dr M Das & E. Liakopoulou

  23. 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)

  24. l FLC (mg/L) k FLC (mg/L)

  25. “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

  26. l FLC (mg/L) k FLC (mg/L) Courtesy of H. Lachmann

  27. 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

  28. 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

  29. Risk stratification incorporating three important predictive factors

  30. 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

  31. Screening of symptomatic patients for B-cell lymphoproliferative disorders

  32. 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)

  33. 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

  34. 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.

  35. l FLC (mg/L) k FLC (mg/L)

  36. 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

  37. Clinical sensitivity of serum tests versus urine tests for FLCs

  38. 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.

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