Serum Free Light Chain (SFLC) Concentration Kinetics in Patients Receiving Bortezomib: Temporary Inhibition of Protein Synthesis and Early Biomarker for Disease Response.

Monoclonal intact immunoglobulin is detectable in the serum of approximately 80% of myeloma patients while SFLC are found to be abnormal in the serum of greater than 90% of patients. One advantage of monitoring SFLC is that they have a half-life of clearance from the serum of 2–6 hours, compared with 20 days for IgG, and can therefore reveal the response to treatment more rapidly. The aim of this study is to determine whether SFLC measurements allow earlier assessment of response to treatment with bortezomib with possible implications to the design and cost of treatment strategy.Patients & Methods Serial serum samples were collected for simultaneous measurement of SFLC and serum paraprotein. Data from 8 patients receiving 2–6 cycles of bortezomib, on compassionate basis, to treat multiply treated myeloma at various stages of relapse are presented. Bortezomib was administered at a dose of 1.3mg/m² on days 1,4,8 and11. Samples were kept frozen until thawed for SFLC measurement (using Freelite kits; Binding Site, UK on an Olympus Chemistry analyser).

Results & Discussion Six of 8 patients showed a response to treatment by EBMT/Blade criteria (>25% fall in paraprotein). In 3 of these patients the tumour SFLC showed a fall and rapid recovery within 10–20 days of a treatment cycle. These patients were monitored over multiple treatment cycles and showed repeated falls in SFLC co-incident with treatment and recovery in between. This appears to correspond with the mechanism of action and biological half life of proteosome inhibition. Recovery of SFLC when seen is rapid (doubling in <10 days). This pattern of tumour response would only be observable with frequent sampling and a tumour marker rapidly cleared from the serum and we believe this is the first reported observation in myeloma patients. In comparison to SFLC, the intact immunoglobulin monoclonal protein did not show the same peaks and troughs. It is likely that the pattern of initial SFLC response is an early indication of tumour response or resistance. Generally the SFLC levels indicated disease response earlier than the immunoglobulin assays. In two of these patients, the response was seen significantly earlier (30 and 70 days). In one remaining patient, serum paraprotein showed disease response whereas SFLC showed no response and subsequently disease progression.

Conclusion: We conclude that monitoring SFLC provides a unique opportunity to follow the kinetics of tumour kill, which is obscured by the slow clearance of intact immunoglobulin monoclonal proteins. The pattern of fluctuation in the SFLC levels could suggest a temporary inhibition of tumour protein synthesis rather than tumour kill and re-growth. While extension of this study is ongoing, it does indicate that SFLC can be used as a biomarker to assess response to treatment significantly earlier allowing relevant changes of treatment strategy. This also may have major bearing on cost of treatment and utilisation of resources.