The Ratio of Monoclonal to Polyclonal Immunoglobulins Assessed with the Hevylite Test Predicts Prognosis, Is Superior for Monitoring the Course of the Disease and Allows Detection of Monoclonal Immunoglobulin In Patients with Normal or Subnormal Involved Immunoglobulin Isotype

Abstract 4038

Parameters that appraise the prognosis of an individual multiple myeloma (MM) patient are essential for clinical guidance and treatment planning. Similarly important for clinical care are factors that assess variations in the course of the disease and that allow accurate measurement of residual monoclonal proteins. Presently, the International Staging System (ISS) stage, and cytogenetics are used for prognostication, EBMT or IMWG response criteria are applied for evaluation of response and of progressive disease, and conventional protein analytics including serum free light chain (FLC) measurement, serum protein electrophoresis (SPE) and immunofixation (IF) for detection of residual paraprotein. Here, we evaluate the prognostic relevance of the ratio of monoclonal to isotype matched polyclonal immunoglobulins for prognostication at start of therapy, for evaluation of response for long term follow up and for measurement of monoclonal immunoglobulin in patients with normal or below normal levels of the involved immunoglobulin isotype.

103 previously untreated patients with multiple myeloma were enrolled (35 IgGκ, 17 IgGλ, 29 IgAκ, 22 IgAλ). 39 (38%) presented with ISS stage I, 42 (41%) with stage II, and 22 (21%) with stage III disease; there was insufficient data to assign ISS in 2 cases. Median age was 67 (range: 32,86) years. Patients were enrolled from 1994 to 2007, either into a trial comparing thalidomide-dexamethasone with Melphalan-Prednisone or into a study comparing double with triple autologous transplantation after 4 cycles of VAD induction therapy. Patients were followed for a median of 13 months (range: 85 days -158 months).

Immunoglobulin heavy/light chain (HLC) pairs were assessed by using polyclonal antibodies targeted at unique junctional epitopes between heavy chain and light chain constant regions of intact immunoglobulins using the Hevylite IgA kappa, IgA lambda, IgG kappa and IgG lambda kits (HevylitêO Binding Site, Birmingham, UK) on a Siemens BN̂OII Analyzer. Concentrations of conventional parameters such as IgA, IgG, ß2-microglobulin (β2-M), FLC, immunofixation, LDH, creatinine, were assessed by standard techniques. Survival analysis and Cox proportional hazards were performed using SPSS v18 program

Median OS of the entire group was 37.9 months with 39 (37 %) of the103 (6 patients were lost to follow up) patients being alive at 4 years follow up. Univariate analysis revealed a correlation between OS and β2-M, (HR: 1.411, 95% CI: 1.369–4.248, p=0.002), the HLC ratio (HR: 1.9, 95% CI: 1.092–3.36, p=0.02), and LDH (HR:1.006, 95%CI 1.00–1.014, p=0.0396) but not with Albumin, age, and creatinine.

In multivariate analysis, β2-M (HR: 1.9, 95% CI: 1.105–3.93, p=0.028), and the HLC ratio (HR: 1.89, 95% 1.092–3.362: x-y, p=0.039), were found as the only parameters correlating with survival. A three tiered risk stratification model utilizing ß2-M >3.5mg/L and HLC >median value had a greater prognostic value than ISS (p=0.001 v p=0.09). Patients with 0 risk factors (ß2-M <3.5mg/L, HLC ratio <median) had a 50% survival time of 118 months, patients with 1 risk factor (either ß2-M >3.5mg/L or HLC ratio >median) had a 50% survival of 53 months and those with both risk factors (ß2-M >3.5mg/L and HLC ratio >median) had a 50% survival of 29 months (p=0.001).

During follow up 46 (45%) of the patients achieved normal or subnormal levels of their involved immunoglobulin isotype. Abnormal HLC ratios were identified in 35/46, interestingly 7/35 patients (IgA kappa: 2 pts, IgA lambda: 2pts. IgG kappa: 3pts) were negative by IFE, indicating that the hevylite test is more sensitive than IF in identifying residual disease. In addition in 7/35 patients HLC ratio indicated relapse when immunoglobulin levels where within normal ranges.

In conclusion, the HLC ratio is highly prognostic. Furthermore, HLC analysis improved the detection of variations in the course of the disease and increased the diagnostic accuracy in patients with normal or subnormal levels of the involved isotype and even in patients shown to ne negative in IF. Determination of the HLC ratio seems to overcome a hitherto unmet need for improvement in assessment of response and of variations in the production of the monoclonal protein.

Figure 1:

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Risk stratification model based upon ß2-M >3.5mg/L and HLC >median

Figure 1:

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Risk stratification model based upon ß2-M >3.5mg/L and HLC >median

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