Intact Immunoglobulin Multiple Myeloma (IIMM)

96% of IIMM patients have abnormal light chain concentrations or kappa/lambda ratio

Some 82% of patients with Multiple Myeloma produce a detectable monoclonal protein of intact immunoglobulin heavy chain type G, A, M, D or E and either light chain kappa or lambda. This paraprotein can be used as a serum marker for diagnosis and levels can be monitored during treatment to assess efficacy.

Measurement of serum free light chains with Freelite has shown that 96% of patients with Intact Immunoglobulin Multiple Myeloma also have abnormal light chain concentration or abnormal kappa/lambda (κ/λ) ratios in addition to the intact immunoglobulin.1

 

Graph 5

Concentrations of serum free light chains in 314 patients with IgG Myeloma compared with 282 normal sera.

Graph 6

Concentrations of serum free light chains in 142 IgA, 36 IgD and 5 IgE Myeloma patients compared with 282 normal sera.

Image 1

Monitoring of one of the 17 Myeloma patients using IgGκ and free κ. Electrophoresis gels are shown for each sample. CVAMP = cyclophosphamide, vincristine, adriamycin, melphalan, prednisolone: HDM: high dose melphalan and stem cell transplant.1

Serial samples from 17 IIMM patients were also studied1.

"Reductions in the concentrations of the intact immunoglobulins and the FLC occurred in parallel in all patients. The extent of change in the FLC concentrations was, however, greater than that of the total intact immunoglobulin in all but one patient. The range of FLC reduction was 2.1-1678-fold (mean 219-fold) whereas the range of total, intact immunoglobulin reduction was 1.5-88-fold (mean 14.6-fold)."

FLC readily pass through the glomeruli, with a serum half-life of 2-6 hours. In contrast the serum half-life of intact immunoglobulin IgG is 20-25d.

Another study2 analysed the changes in serum FLC after autologous peripheral blood stem cell transplantation (PBSCT) in 19 patients.

"The half-life of serum FLC adds only a few hours to the true picture of the tumor killing rate. The rate of fall and range of reduction of FLC varied between individual patients indicating different tumor killing rates and chemosensitivity. By contrast, the concentrations of total and monoclonal immunoglobulin were continuing to fall even after leaving hospital, reflecting the long half-life of serum immunoglobulins."

Serum FLC measurement showed a good degree of correlation with bone marrow assessments of myeloma.3

 
Bone Marrow
 
Normal
Abnormal
Serum Free Light Chains
Normal
22
7
 
Abnormal
10
66
 
Urine Free Light Chains
Normal
25
31
 
Abnormal
7
42
 
Serum Immunofixation
Normal
14
6
 
Abnormal
18
67

 

Results of the comparison between serum free light chains, urine free light chains, serum immunofixation and bone marrow assessment. The number of patients who had abnormal bone marrows but normal urine FLC illustrates the increased sensitivity of serum FLC measurements.

Light Chain Escape

The serum free light chain assay can be used to detect disease progression in Intact Immunoglobulin Multiple Myeloma patients who at relapse switch to production of light chains only.

For some Intact Immunoglobulin Multiple Myeloma (IIMM) patients in remission, relapse is accompanied by a marked rise in monoclonal serum free light chains (sFLC) with no associated increase in intact immunoglobulin concentrations. This phenomenon is known as light chain (LC) escape or Bence-Jones escape.4

 

Graph 5

A model of light chain escape in a hypothetical patient with IIMM. Dual plasma cell subsets are present at diagnosis producing either monoclonal intact immunoglobulin and FLC or FLC alone. In response to chemotherapy, intact immunoglobulin and serum FLC concentrations fall (FLC fall more rapidly due to their shorter half life). Disease relapse with light chain escape is associated with proliferation of the light chain only plasma cell clone but not the intact immunoglobulin producing clone. This leads to a marked rise in serum FLC but no associated change in the intact immunoglobulin concentration.

FLC = Free Light Chain

Why is it important to detect light chain escape early?

Light chain escape and its detection may increase with:

Measurement of serum immunoglobulin concentrations will fail to identify LC escape. Without Freelite, LC escape is only detectable by urine Bence Jones protein (BJP) measurement. Mead et al. examined 11 patients identified as showing light chain escape; this was corroborated by urine results in 5 of the patients. However, in the other 6 patients the urine free light chains were unmeasurable.7

Summary

 

* In the USA diagnostic use of this product is restricted to those stated in the product insert

 

References

  1. G. P. Mead, H. D. Carr-Smith, M. T. Drayson, G. J. Morgan, J. A. Child and A. R. Bradwell.
    "Serum free light chains for monitoring multiple myeloma"
    BJH 2004;126:348-354

    Reference: MKG228 Quantity:

  2. GP Mead, S Reid, B Augustson, MT Drayson, AR Bradwell, JA Child
    Comparison of serum and urine free light chain measurements with bone marrow assessments in multiple myeloma
    haematologica / the hematology journal 2005;90(s1):108(PO.407)

  3. Hobbs JR.
    Growth Rates and Responses to Treatment in Human Myelomatosis
    British Journal of Haematology 1969;16:607-17

  4. Ayliffe et al.
    Demonstration of changes in plasma cell subsets in multiple myeloma.
    Haematologica 2007;92:1135-8

  5. Mark A. Dawson, Sushrut Patil, Andrew Spencer
    "Extramedullary relapse of multiple myeloma associated with a shift in secretion from intact immunoglobulin to light chains"
    haematologica 2007; 92:143-144

    Reference: MKG346 Quantity:

  6. Mead et al
    Incidence of light chain escape in myeloma patients at relapse
    British Journal of Haematology 2008;141:98a