Light Chain Escape
For some Intact Immunoglobulin Multiple Myeloma (IIMM) patients in remission, relapse is accompanied by a marked rise in production of monoclonal serum free light chains (FLC) with no associated increase in intact immunoglobulin concentrations. A phenomenon termed 'light chain escape' or 'light chain breakthrough'. It is important to detect light chain escape early as it is associated with an increased tumour growth rate, disease progression and a worse prognosis (Brit J. Haematol. 1969; 16: 207, Haematologica 2007; 92: 143).
For the majority of IIMM patients at relapse, synthesis of both monoclonal FLC and intact immunoglobulin is likely to occur simultaneously. However in a proportion of IIMM patients, relapse may be indicated first by intact monoclonal immunoglobulins or serum FLC measurements (BJH 2004; 126: 348, BJH 2005; 127: 405 - 406).
There has been general awareness of light chain escape within the haematology community for several decades. The term was first defined by Prof. J. R. Hobbs who reported the preliminary findings of the first MRC trial in 1969 (Brit J. Haematol. 1969; 16: 207). By monitoring patients using urine electrophoresis Prof. Hobbs identified light chain escape in 15 out of 60 patients at relapse.
Anecdotal evidence suggests the incidence of light chain escape may be around 10% - 20%. This incidence is thought to be on the increase with longer patient survival, the use of new biological therapies and improved detection using the serum FLC assay (Haematologica 2007; 92: 143). Several variants of light chain escape have been described. "True" light chain escape may be defined as rising FLC concentrations at relapse with stable or falling intact immunoglobulin concentrations and "Partial" light chain escape defined as rising FLC and intact immunoglobulins at relapse, where the rise in FLC is visibly greater.
When monitoring IIMM patients for light chain escape the serum FLC assay is a more sensitive technique than urinary BJP analysis. The kidney has a substantial reabsorption capacity for FLC, and as a result, urinary BJP only appears after this capacity has been overwhelmed, leading to overflow proteinuria. Serum FLC analysis allows determination of increased monoclonal FLC production without waiting for overflow proteinuria.
Use of the serum FLC assay to identify light chain escape was first reported by Kühnemund and colleagues (Onkologie 2005; 28: 165), and more recently by Dawson et al. (Haematologica 2007; 92: 143). The latter article presents three cases of light chain escape, with all patients demonstrating increases in monoclonal serum FLC with no associated increase in intact immunoglobulin concentrations. The authors concluded: "Whilst it is premature to suggest that all patients with IIMM should be followed with serial sFLC measurements our cases...serve to highlight the role of sFLC assays in monitoring patients with IIMM".
Recent insight into a possible biological basis of light chain escape has been provided by Ayliffe et al. who performed double immunofluorescence staining of bone marrow aspirates (Haematologica 2007; 92: 1135). Dual plasma cell clones were present in a proportion of IIMM patients producing either intact immunoglobulin and FLC, or FLC alone. It is an intriguing possibility that at relapse, these separate clones may proliferate at different rates, leading to light chain escape, illustrated in Figure 1.
In summary, monitoring IIMM patients with both intact immunoglobulin and serum FLCs will result in the earliest possible identification of relapse. 
Figure 1: A model of light chain escape
A hypothetical patient with intact immunoglobulin multiple myeloma. Dual plasma cell subsets are present 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 true 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.
Dr. Josie Hobbs
Scientific Affairs Manager
Binding Site Ltd
