Introduction All symptomatic multiple myeloma (MM) patients are virtually preceded by a precursor disease (PD). However, the PD is rarely known at the time of diagnosis of MM. Several PD can progress to MM: monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM) and solitary plasmacytoma (SP). Sigurdardottir et al have recently demonstrated that only 2.7% in a series of 14798 MM patients had prior knowledge of MGUS. This group had better overall survival (OS), stressing the importance of clinical follow-up in MGUS and suggesting that earlier treatment of MM leads to better OS. Nonetheless, we have recently shown that diagnostic delay in MM have a paradoxical effect on OS. Furthermore, little is known about the outcome of MM with prior knowledge of other PD. Methods All symptomatic MM patients diagnosed between January 1993 and July 2015 in our MM population-based registry, excluding palliative patients, were selected. Information about any prior PD was checked, as well as baseline common prognostic factors such as age, sex, lactate dehydrogenase (LDH), creatinine (Cr), International Staging System (ISS), high-risk FISH, and diagnostic delay. Comparisons among groups were made with the χ2-testfor categorical and t-test for quantitative variables. OS was estimated in months (m) by the Kaplan-Meier method in patients with or without specific PD or any PD as a whole. Log-rank test was used to compare curves. A Cox proportional hazard model was used to assess the simultaneous impact on survival of prior PD and other predictors. Results 473 MM patients fulfilled the inclusion criteria. 383 of them (81%) had available data concerning prior PD. There were 233 men and 240 women (50.7%), median age 67 years (12-87). 19 patients (5%), 10 (2.6%) and 5 (1.3%) had prior MGUS, SP and SMM, respectively. The group without prior PD had significantly higher values of serum Cr (2.09 vs 1.09 mg/dL, p<0.001), LDH (317.3 vs 256.2 U/L, p=0.09), ISS3 (49.6% vs 22.2, p=0.02), but less delay (5.6 vs 10.9 m, p=0.002). Median OS of patients with prior MGUS was 87.7 m (57.1-118.2) vs 34.4 (27.8-41.1)(p=0.112), with prior SP 88 m (46.9-129) vs 34.9 (28.4-41.5)(p=0.101) and prior SMM 104.1 m vs 36 (29.9-42.1)(p=0.102). Median OS of any PD (Fig 1) was 88 m (82.6-93.3) vs 32.7 (26.2-39.2)(p=0.006). In the multivariate model, age, LDH and Cr are significantly associated with survival. The presence of prior PD, when adjusting for these factors, is also significantly associated with survival, acting as a protective factor. When ISS is added to the model, prior PD remains only marginally significant. Conclusion Prior knowledge of PD is infrequent at the moment of MM diagnosis. MM with any previously documented PD seems to have better outcome. The reason for this finding is not an earlier diagnosis, but rather a better prognostic profile. However, we cannot rule out other underlying biological mechanisms. More and larger studies are warranted to confirm our results. Disclosures No relevant conflicts of interest to declare.

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The outcome for patients with Multiple Myeloma (MM) is highly variable. Understanding the prognosis for a particular patient can help when selecting the intensity of treatment to be used and the frequency of reviews. The quantification of heavy/light chains pairs by the immunoassay Hevylite (HLC) allows us a precise measurement of monoclonal and non-monoclonal immunoglobulins of the same isotype. In this study we evaluate i) the impact of the "HLC ratio" defined as monoclonal immunoglobulin over isotype matched non-monoclonal immunoglobulin (involved/uninvolved HLC ratio or i/u HLC ratio), ii) the suppression of non-monoclonal pair denominated "HLC-matched pair suppression" and iii) the effect of "systemic immunoparesis", at diagnosis and at +100 days after autologous stem cell transplant (ASCT). Methods: 85 patients (50 M:35 F) with a median age of 70 years (56-78) were followed (35 IgGK, 18 IgGl, 17 IgAK and 15 IgAl) for a median of 19 (5-30) months. Sixteen patients (18%) presented ISS stage I, 15 (28%) stage II and 54 (64%) stage III. Thirty transplanted patients were evaluated at day +100 of ASCT. Serum free light chains (FLC) and immunoglobulin heavy/light chain pairs (HLC) were assessed by Freelite and Hevylite assays, respectively (The Binding Site, UK). FLC, HLC, b2-microglobulin, albumin, creatinine, hemogloblin, calcium, LDH, bone marrow plasma cell infiltration, presence of lytic bone lesions and ISS stage were evaluated for their impact on patient´s outcome. Statistical analysis with SPSS 23. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier method and Cox Regression. Results: The median OS of the 85 patients was 54% and 26 patients deceased during the study due to MM. The median value of i/u HLC ratio at diagnosis was 80 (31.5-319.71) and values >80 were significantly associated with worse OS (48 vs. 61%, p=0,005, fig.1A and Table 1) and shorter PFS (23% vs. 42%, p=0,006, fig.1B). Severe HLC-matched pair suppression (i.e. more than 50% below the lower reference range) was identified in 68% of the newly diagnosed patients and was associated with shorter OS (35% vs. 81%, p=0,004, fig. 1C) and PFS (21% vs. 50%, p=0,013, fig.1D). Severe (>50%) systemic immunoparesis was identified in 64% of the patients and was also significantly associated with shorter OS (32% vs. 81%, p=0,030, fig.1E) but not with shorter PFS (26% vs. 44%, p=0,306, fig. 1F). In a multivariate analysis, severe HLC-matched pair suppression and albumin were found as independent risk factors for OS whereas creatinine and i/u HLC ratio >80 were independent risk factors for PFS. In the post-ASCT evaluation of the patients (n=30), normalization of HLC Ig´k/Ig´l ratio was observed in 8 patients (27%). An altered HLC ratio was predictive of shorter PFS after ASCT (25% vs. 70%, HR: 3,42, 95%CI 1,12-11,97, p=0,039, fig. 2B) and with a trend towards a worse OS (p=0,072, fig. 2A). Severe HLC-matched pair suppression was found in 12 patients (40%) and was predictive of worse OS (0% vs 70%, HR: 10,63, 95%CI: 1,11-114,11, p=0,023, fig.2C) and shorter PFS (35% vs. 71%, HR: 8,87, 95%CI: 1,72-45,92, p=0,002, fig. 2D). The severe systemic immunoparesis observed in 17 patients (57%) was not associated with OS (p=0,644, fig.2E) or PFS (p=0,750, fig. 2F). Conclusions: Severe HLC-matched pair suppression and i/u HLC>80 are associated with worse OS and shorter PFS in MM patients suggesting a potential use of these parameters as prognostic biomarkers in newly diagnosed patients. Severe HLC-matched pair suppression is an independent risk factor for OS whereas i/u HLC>80 is independently associated with shorter PFS. In patients after ASCT, severe HLC-matched pair suppression reflects the persistence of clonal cells that is not associated with severe systemic immunoparesis. Table 1 Analysis of prognostic factors for OS and PFS in newly diagnosed MM patients. Only significant variables are shown. Table 1. Analysis of prognostic factors for OS and PFS in newly diagnosed MM patients. Only significant variables are shown. Figure 1 Newly diagnosed MM patients. OS (A) and PFS (B) by i/u HLC ratio >80; OS (C) and PFS (D) according to severe (>50%) HLC-matched pair suppression; OS (E) and PFS (F) according to severe (>50%) systemic suppression. Figure 1. Newly diagnosed MM patients. OS (A) and PFS (B) by i/u HLC ratio >80; OS (C) and PFS (D) according to severe (>50%) HLC-matched pair suppression; OS (E) and PFS (F) according to severe (>50%) systemic suppression. Figure 2 MM patients at day +100 after ASCT. OS (A) and PFS (B) by HLC ratios; OS (C) and PFS (D) according to severe (>50%) HLC-matched pair suppression; OS (E) and PFS (F) according to severe (>50%) systemic suppression. Figure 2. MM patients at day +100 after ASCT. OS (A) and PFS (B) by HLC ratios; OS (C) and PFS (D) according to severe (>50%) HLC-matched pair suppression; OS (E) and PFS (F) according to severe (>50%) systemic suppression. Disclosures Barbosa: The Binding Site: Employment. Pais:The Binding Site: Employment.

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