P900: involved/uninvolved serum free light chain ratio is a stronger predictor of diagnostic/risk factors in light chain compared to heavy chain monoclonal gammopathies

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Light chain (LC) monoclonal gammopathy of undetermined significance (MGUS) is not well characterized. It is primarily considered a precursor of LC multiple myeloma (MM) and amyloidosis and diagnostic criteria include an abnormal free light chain (FLC) ratio, increase in involved LC, and the absence of a M-protein on immunofixation. No risk criteria for MM progression have been developed independently for LC monoclonal gammopathies (MG) and there is a need for evaluating established and new risk factors specifically for LC-MG. Flow cytometry may be useful in clinical assessment of LC-MG as it can both identify and quantify phenotypically aberrant plasma cells (abPC). Aims: To evaluate the association between FLC ratio and subsequent smoldering MM (SMM) diagnosis and established risk factors for SMM in individuals with LC-MG vs non-IgM heavy chain (HC) MG. Methods: Participants in the Iceland Screens, Treats, or Prevents MM study (iStopMM) with either non-IgM M-protein or abnormal serum FLC ratio and absence of a M-protein in screening sample were included. Next-generation flow cytometry (NGF) was used to assess the percentage of normal and abPC in bone marrow (BM) samples. BM plasma cell (BMPC) percentage was assessed by morphology. FLC levels were measured using the Freelite assay (used as involved/uninvolved ratio). Receiver operating characteristic (ROC) curve analysis was used to evaluate the discriminatory ability of FLC ratio for categories of BMPC count and NGF results. Samples from individuals with LC-MG were grouped according to the previously suggested cutoffs in FLC ratio of <8 and >20 and the observed cutoff in FLC ratio for detection of abPC by NGF. Results: A total of 254 individuals were included. At diagnosis of LC-MG (n=48), 20 had LC-MGUS, 21 LC-SMM, and 7 LC-MM (median FLC ratio: 2.6, 21.8, and 184.6). At diagnosis of HC-MG (n=206), 102 had MGUS, 84 SMM, and 20 MM (median M-protein: 1.0, 6.0, and 12.0 and FLC ratio: 1.7, 3.7, and 18.4). 544 paired FLC and BMPC, and 372 paired FLC and NGF results were used. FLC ratio was significantly more predictive of >10% BMPC (area under the curve (AUC): 0.86 vs 0.66) and >20% BMPC (AUC: 0.85 vs 0.63) by morphology, and the detection of abPC (AUC: 0.97 vs 0.83) and >95% abPC/total PC (AUC: 0.93 vs 0.73) by NGF in LC-MG vs HC-MG samples (p<0.001 for all). The cutoffs in FLC ratio (sensitivity, specificity) of 8.7 (93%, 71%), 22.7 (85%, 71%), 3.2 (95%, 92%) and 17.8 (85%, 71%) were found to optimally discriminate between LC-MG samples according to these factors, respectively. In LC-MG samples, the median percentage of BMPC (4, 8, 13, and 26%; p<0.001) and abPC by NGF (0.0, 0.3, 1.6, and 3.8%; p<0.001) increased progressively with greater FLC ratio (<3.2, 3.2-8, 8-20, and >20 FLC ratio) (Table). Summary/Conclusion: We found FLC ratio to be significantly more associated with having >10% BMPC, and the SMM risk factors of >20% BMPC and >95% abPC/total PC in LC-MG vs HC-MG samples. This is likely due to low or absent FLC involvement in proportion of HC-MG cases. Furthermore, observed cutoffs in FLC ratio for LC-MG were close to suggested <8 FLC ratio (vs 8.7) for deferral of BM biopsy in LC-MGUS and the >20 FLC ratio (vs 22.7 and 17.8) used in the 2/20/20 risk criteria, respectively. FLC ratio was highly predictive of abPC detection by NGF in LC-MG samples where low detection rate was observed at <3.2 FLC ratio (3/14 samples), indicating that false-positive diagnosis of LC-MGUS might be frequent at slightly elevated FLC ratio according to current diagnostic criteria. Altogether, these results indicate that FLC ratio is a stronger predictor of risk factors in LC-MG than HC-MG and suggest that NGF could be particularly useful in clinical assessment of LC-MG. Utilizing these markers together could lead to improved prediction of risk in LC-MG.Keywords: Plasma cells, Monoclonal gammopathy, Flow cytometry, Serum free light chains