PS1352 DISSECTING THE BONE MARROW IMMUNE MICROENVIRONMENT IN THE COMPLETE SPECTRUM OF MONOCLONAL GAMMOPATHIES: POTENTIAL IMPLICATIONS IN DISEASE PATHOGENESIS

Abstract

Background: To discriminate different outcomes among patients in CR the IMWG introduced a more stringent CR (sCR) criteria by adding to the pre-existing CR criteria the requirement of a normal free-light chain ratio (sFLCr) plus the absence of clonal plasma cells (PCs) in bone marrow (BM) by immunohistochemistry (IHC). In 2011, the low-sensitivity cytometry was included as alternative methodology to IHC to define sCR. However, the prognostic significance of the kappa/lambda ratio values is not clear. Aims: To verify the conclusion of our previous study (Blood 2015. 126:858–62) regarding the lack of influence in the prognosis of abnormal serum free light chain ratios (sFLCr) in a more extensive series of newly diagnosed multiple myeloma (NDMM) patients in CR or sCR Methods: NDMM patients aged ≤65 years enrolled in GEM2012MENOS65 (NCT01916252). Of 458 patients, 8 discontinued early and were not evaluable. The definition of CR and sCR was made according to the IMWG criteria. SFLCr (FREELITE assay) was classified as normal (0.26–1.65) or abnormal (<0.26 if the patient was λ; >1.65 if the patient was κ). MRD was assessed using next-generation flow cytometry. The median limit of detection was of 3x10–6. All the CR with normal sFLCr and absence of clonal PCs by MFC with a sensitivity of 10–2 were considered sCR. Median follow-up was 47.5 months. Results: After induction, 425 patients were evaluable for response; 201 (47%) reached ≥CR. Data from sFLCr and MRD was available in 192 and 193 patients, respectively. In the CR evaluable patients for sCR assessment (n = 184), the rate of sCR was 64% (n = 117). In a landmark from the end of induction (median follow-up 39 months), sCR didn’t show significantly differences in PFS (2 years-PFS 89% vs 87%; P = .7) (fig 1a) neither in OS (2 years-OS 94% vs 94%; P = .9). Interestingly, patients with abnormal (n = 67) vs normal (n = 125) sFLCr showed superimposable PFS (2 years-PFS 88% vs 87%; P = .9) (fig 1b) and OS (2 years-OS 96% vs 94%; P = .8).By contrast, the few patients (n = 3) in whom BM clonality was detected by the low-sensitivity IHC-adapted MFC method had significantly worse PFS (2 years-PFS 89% vs 67%; P = .03) (fig 1c) and OS (2 years-OS 95% vs 67%; P = .8) than patients in whom BM clonality was undetectable or detected at levels below the threshold proposed for IHC assessment. On using our traditional MRD method, persistent MRD (>10–4) was detectable among 39 of the 193 (20%) patients who, compared with MRD-negative cases, had significantly inferior PFS (2-years PFS 91% vs 80%; P = .01) (fig 1b) and OS (2 years-OS 96% vs 87%; P = .01).As validation, we reproduced the analysis in the ASCT end-point. Of the 395 evaluable patients; 238 (60%) reached ≥CR. Once again, in the landmark analysis, sCR didn’t show significantly differences in PFS in respect to CR (P = .3) neither in OS (P = .6). Patients with abnormal (n = 51) vs normal (n = 173) sFLCr showed superimposable PFS (P = .9) and OS (P = .6). Patients with persistent MRD (>10–4), had significantly inferior PFS (P = .003) but similar OS (P = .2).Summary/Conclusion: These results confirm our previous analysis based on GEM05menos65/ GEM10mas65 clinical trials. For MM patients in CR, the stringent CR criteria does not predict a different outcome. If this essential criterion in the definition of sCR lacks for the prognosis connotations, it is not justified to maintain a response category whose real significance depends on the combination of the traditional CR criteria with a negative MRD status based on very low (IHC) or low resolution (<104) levels, today outdated.