Immunoglobulin Heavy/Light Chain Measurements Provide Prognostic Information in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation

Introduction. Both reduction in M-protein and reconstitution of the immune system are associated with increased survival in multiple myeloma (MM) patients receiving an autologous stem cell transplant (ASCT). Heavy/light chain (HLC) pair analysis allows discrimination between Igκ and Igλ and as a result allows measurement of both the monoclonal involved and polyclonal uninvolved HLC pair. Abnormal HLC ratios and suppression of the uninvolved HLC pair correlate with shorter overall survival in MM patients. We evaluated HLC analysis for predicting progression free survival in MM patients receiving an ASCT.

Methods. We prospectively evaluated 28 intact immunoglobulin MM (IIMM) patients (12 Female, 16 Male; 20 IgG, and 8 IgA; median age: 54 years; range 37-67 years) who received ASCT subsequent to high dose melphalan. Median follow up time from ASCT was 391 days (range: 61-603 days). Patient responses were assigned according to international response criteria guidelines prior to ASCT. Serum samples were analysed with Hevylite®, prior to ASCT (median: 2 days; range 0-77 days) and following ASCT (median: 50 days; range 22-119 days), on a SPAPLUS turbidimeter. HLC concentrations and ratios were compared to normal ranges (IgGk: 3.85-12.07 g/L; IgGl: 1.91-6.74 g/L; IgAk: 0.57-2.08 g/L; IgAλ: 0.44-2.04 g/L HLC ratio reference range: IgGk /IgGλ: 1.12-3.21; IgAk / IgAλ: 0.78-1.94). Progression free survival (PFS) was estimated by Kaplan Meier analysis and compared using a log rank test (Graphpad Prism).

Results. Prior to ASCT, 1 patient achieved CR, 13 obtained VGPR, 9 obtained PR, 2 obtained (MR), 2 PD and 1 patient had no response assigned. An abnormal HLC ratio (18/28 patients) prior to ASCT was associated with significantly poorer PFS (17.1 months versus median not reached p=0.036). In comparison, achievement of ≥VGPR (14/28 patients) prior to ASCT was not associated with increased PFS (p=0.74). Addition of a normal HLC ratio to the assignment of response (in 8/14 patients achieving a ≥VGPR) added significant prognostic information and was significantly associated with improved PFS (median not reached versus 11.5 months, p=0.025). Suppression of the uninvolved HLC pair only (concentration below the normal reference range) prior to ASCT (15/28 patients) had no significant impact on PFS (p=0.32). Post-ASCT, an abnormal HLC ratio (11/28 patients) was not significantly associated with poorer PFS (p=0.18). However, suppression of the uninvolved HLC pair (6/28 patients) was significantly associated with poorer PFS (10.6 months versus median not reached p=0.013).

Discussion. HLC analysis may provide early prognostic markers for PFS in MM patients receiving an ASCT. Warranting larger patient cohort studies, this preliminary data indicates that a normalised HLC ratio prior to ASCT and the absence of HLC paired suppression post-ASCT may be significant markers of improved PFS, adding prognostic information to current response criteria.

Acknowledgments: This work was partially supported by the National Science Fund (D02-35/2009).