Abstract: Abstract 309 Background: Novel insights into the biology of myeloma cells have led to the identification of relevant prognosis factors. CA has become one of the most important prognostic factors, and the presence of t(4;14), t(14;16) or del(17p) are associated with poor prognosis. DNA ploidy is another important prognostic factor with non-hyperdiploid cases being associated with a poor outcome. There are some controversies about whether or not bortezomib-based combinations are able to overcome the poor prognosis of CA. In the VISTA trial, bortezomib plus melphalan and prednisone (VMP) appeared to overcome the poor prognosis of CA in terms of response rate (RR) and survival; however, the number of patients with CA was rather small. Here we report a subanalysis, in a series of elderly newly diagnosed myeloma patients included in the Spanish GEM05MAS65 trial, in order to evaluate the influence of CA by FISH as well as DNA ploidy status on RR and survival. Patients and methods: Patients included in this study were randomized to receive 6 cycles of VMP vs bortezomib, thalidomide and prednisone (VTP) as induction therapy consisting on one 6-week cycle of bortezomib using a bi-weekly schedule (1·3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29 and 32) plus either melphalan 9 mg/ m2 on days 1 to 4 or oral daily thalidomide 100 mg, and prednisone 60 mg/ m2 on days 1 to 4; this first cycle was followed by five 5-week cycles of once-weekly bortezomib (1·3 mg/ m2 on days 1, 8, 15 and 22) plus the same doses of MP and TP. After induction therapy, patients were subsequently randomised to maintenance therapy with VP or VT, consisting of one convencional 3-week cycle of bortezomib (1·3 mg/ m2 on days 1, 4, 8 and 11) every 3 months, plus either prednisone 50 mg every other day or thalidomide 50 mg/day, for up to 3 years. FISH analysis for del(13q), t(11;14), t(4;14), t(14;16) and del(17p) was performed at diagnosis according to standard procedures using purified plasma cells, and DNA ploidy status was analysed following induction therapy by multiparametric FCM using propidium Iodide and specific markers for discrimination between myelomatous and normal cells. Result: In 231 out of the 260 patients included in the trial, FISH analysis at diagnosis were available and two groups were identified: high-risk group (n= 44 patients with t(4;14) and/or t(14;16) and/or del(17p)) and standard-risk group (n=187 patients without CA, and/or del(13q) and/or t(11;14)). There weren't differences in the rates of CA according to the treatment arm. RR was the same in the high-risk vs standard-risk groups, both after induction (21% vs 27% CR) and maintenance (39% vs 45% CR). However, high-risk patients showed shorter PFS as compared to standard risk both from first (24 versus 33 months, p=0·04, HR 0·6, 95% IC 0·4-0·9) and second randomization (17 versus 27 months, p=0·01, HR 0·5, 95% IC 0·2-0·8). This also translated into shorter OS for high risk patients (3-year OS rate: 55% versus 77% from first randomization, p=0·001, HR 0·4, 95% IC 0·2-0·7) and 60% versus 85% from second randomization, p 〈 0·001, HR 0·2, 95% IC 0·1-0·5). This adverse prognosis applied to either t(4;14) or del(17p), without differences in terms of PFS from the first (24 months for del(17p) patients and 20 months for t(4;14)) and second randomization (16 months for both CA); in addition, the outcome was not modified by the treatment scheme used. When we analyzed the influence on survival of the DNA ploidy status (224 patients) by comparing patients with hyperdiploid (132 patients) versus non-hyperdiploid DNA content (92 patients) assessed by FCM, it was found that the former group showed longer OS (77% versus 63% at 3 years, p=0·04), and this difference was more evident in patients treated with VTP (77% versus 53% at 3 years, p=0·02), while no significant differences were observed in the VMP arm. Conclusion: The present schema, particularly after month sixth (using maintenance with bortezomib every 3 months) doesn't overcome the negative prognosis of high-risk cytogenetics in terms of PFS and OS in elderly myeloma patients, and this applied to either patients with t(4;14) or del(17p), and it was independent of the induction treatment arm. Our data also show that non-hyperdiploid cases displayed worse outcome than hyperdiploid patients, particularly under VTP induction treatment. These results suggest that continuous efforts are still required in order to overcome the dismal prognosis of high-risk patients. Disclosures: Mateos: Janssen Cilag: Honoraria; Celgene: Honoraria. Off Label Use: VTP is not approved for the treatment of elderly newly diagnosed myeloma patients. VT and VP are not approved for maintenance therapy. Gutierrez:Janssen Cilag: Honoraria; Celgene: Honoraria. Oriol:Janssen Cilag: Honoraria; Celgene: Honoraria. Martínez-López:Janssen Cilag: Honoraria; Celgene: Honoraria. Garcia-Laraña:Janssen Cilag: Honoraria; Celgene: Honoraria. Palomera:Janssen Cilag: Honoraria. Hernández:Janssen Cilag: Honoraria. García-Sanz:Janssen Cilag: Honoraria; Celgene: Honoraria. Cibeira:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lahuerta:Janssen Cilag: Honoraria; Celgene: Honoraria. Blade:Janssen cilag: Honoraria; Celgene: Honoraria. San Miguel:Janssen Cilag: Honoraria; Celgene: Honoraria.

Abstract: Abstract 1910 The outcome of multiple myeloma (MM) patients has markedly improved in the last decade. Thus, overall response rates between 85%-95%, with 30%-50% complete remission (CR) rates are now being reported in young patients treated with novel agents plus high-dose therapy/autologous stem cell transplantation (HDT/ASCT). A similar scenario is also emerging in the elderly (non-transplant candidates) population. Accordingly, more sensitive techniques are needed to assess patients’ response; these may contribute to compare the efficacy of different treatment schemas, to monitor minimal residual disease (MRD) and for prognostication. In the present study we have assessed the frequency and the prognostic value of IR by multiparameter flow cytometry in a total of 516 newly diagnosed MM patients included in three consecutive PETHEMA/GEM Spanish trials: two designed for transplant candidate patients - GEM 2000 (n=157) and GEM2005 〈 65y (n=206) - and one for elderly patients - GEM2005 〉 65y (n=153). The GEM2000 trial was based on 6 induction cycles of VBMCP/VBAD followed by HDT/ASCT; the GEM2005 〈 65y included three arms with 6 cycles each (Thalidomide/Dexamethasone -TD-, Bortezomib/Thalidomide/Dexamethasone -VTD- and, VBMCP/VBAD with Bortezomib in the two final cycles -VBMCP/VBAD/Bortezomib) followed by HDT/ASCT; and the GEM2005 〉 65y compared 6 cycles of Bortezomib/Melphalan/Prednisone -VMP- vs. Bortezomib/Thalidomide/Prednisone -VTP-. All three trials had in common that patients received 6 induction cycles and IR was evaluated at this time point. In addition, IR was assessed on day +100 after HDT/ASCT in the first two trials. Patients were defined to be in IR when myelomatous plasma cells (MM-PCs) were undetectable by MFC or when less than one phenotypically aberrant PC was detected among 104 cells analyzed. Patients were referred for MRD studies if they were mainly in CR or VGPR. The IR rates reported here were calculated on intention to treat analysis. Figure 1 summarizes the IR rates after induction. The lowest IR rates corresponded to the VBMCP/VBAD and TD schemes (5% and 6%, respectively) while with the bortezomib-based regimens an approximately 3-fold increment in the IR rates was observed: VTP (12%), VBMCP/VBAD/Bortezomib (15%), VMP (16%) and VTD (17%). After HDT/ASCT, IR rates were found to be significantly increased (p 〈 .001) in the GEM2000 protocol (14%) and in all arms of the GEM2005 〈 65y trial: TD (18%), VBMCP/VBAD/Bortezomib (30%) and VTD (34%). Thus, a minimum 2-fold increment of IR rates was further achieved after HDT/ASCT. In addition, IR rates achieved after HDT/ASCT in patients included in all three arms of the GEM2005 〈 65y trial were significantly superior (p≤.008) to cases treated according to the GEM2000 protocol, indicating that induction regimens with novel agents improved post-transplantation rates of IR. Moreover, bortezomib-based regimens vs. TD were associated with increased IR rates not only before but also after HDT/ACSCT (p=.06 and p=.02 for VBMCP/VBAD/Bortezomib and VTD, respectively). We further compared the impact of achieving an IR after induction and at day+100 after HDT/ASCT in the progression-free (PFS) and overall survival (OS) within the three protocols. Patients in IR status after an induction regimen according to the GEM2000, GEM2005 〈 65y and GEM2005 〉 65y protocols showed significantly longer (p 〈 .001) 3-year PFS rates (100%, 100% and 90%, respectively) compared to patients in a no-IR status (61%, 59% and 35%, respectively). Similarly, 3-year OS rates were significantly longer (p=.01) in IR vs. no-IR patients status (100%, 100% and 94% vs. 84%, 90% and 76% for the GEM2000, GEM2005 〈 65y and GEM05 〉 65y protocols, respectively). Likewise, an IR vs. no-IR status after HDT/ASCT in both the GEM2000 and GEM05 〈 65y trials was also associated with significantly increased 3-year PFS (p 〈 .001) and OS (p=.007) rates. In summary, this study demonstrates that the achievement of an IR is a strong prognostic factor regardless of the type of treatment; thus, higher IR rates may help to identify optimal therapeutical schemes. In this sense, HDT/ASCT is able to markedly increase IR rates after induction even in the era of novel agents, and this translates into extended survival. Disclosures: Off Label Use: VTP is not approved for the treatment of newly diagnosed myeloma patients and VT and VP are not approved for maintenance therapy. None of the combinations proposed, VBCMP/VBAD plus bortezomib, VT and VTD are approved as induction therapy in newly diagnosed myeloma patients. Mateos:Janssen Cilag: Honoraria; Celgene: Honoraria. Rosiñol:Janssen-Cilag: Honoraria; Celgene: Honoraria. Cibeira:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Oriol:Janssen-Cilag: Honoraria; Celgene: Honoraria. de Arriba:Janssen-Cilag: Honoraria; Celgene: Honoraria. Palomera:Janssen Cilag: Honoraria. De La Rubia:Janssen-Cilag: Honoraria; Celgene: Honoraria. Díaz-Mediavilla:Janssen-Cilag: Honoraria; Celgene: Honoraria. Garcia-Laraña:Janssen Cilag: Honoraria; Celgene: Honoraria. Sureda:Janssen-Cilag: Honoraria; Celgene: Honoraria. Alegre:Janssen-Cilag: Honoraria; Celgene: Honoraria. Blade:Janssen cilag: Honoraria; Celgene: Honoraria. Lahuerta:Janssen-Cilag: Honoraria; Celgene: Honoraria. San Miguel:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Cytogenetic abnormalities (CAs) such as t(4;14), t(14;16) or del(17p), and nonhyperdiploidy are associated with poor prognosis in multiple myeloma. We evaluated the influence of CAs by FISH and DNA ploidy by flow cytometry on response and survival in 232 elderly, newly diagnosed multiple myeloma patients receiving an induction with weekly bortezomib followed by maintenance therapy with bortezomib-based combinations. Response was similar in the high-risk and standard-risk CA groups, both after induction (21% vs 27% complete responses [CRs]) and maintenance (39% vs 45% CR). However, high-risk patients showed shorter progression-free survival (PFS) than standard-risk patients, both from the first (24 vs 33 months; P = .04) and second randomization (17 vs 27 months; P = .01). This also translated into shorter overall survival (OS) for high-risk patients (3-year OS: 55% vs 77%; P = .001). This adverse prognosis applied to either t(4;14) or del(17p). Concerning DNA ploidy, hyperdiploid patients showed longer OS than nonhyperdiploid patients (77% vs 63% at 3 years; P = .04), and this was more evident in patients treated with bortezomib, thalidomide, and prednisone (77% vs 53% at 3 years; P = .02). The present schema does not overcome the negative prognosis of high-risk CAs and nonhyperdiploidy. This trial was registered with www.ClinicalTrials.gov as NCT00443235.

Abstract: The achievement of complete response (CR) after high-dose therapy/autologous stem cell transplantation (HDT/ASCT) is a surrogate for prolonged survival in multiple myeloma; however, patients who lose their CR status within 1 year of HDT/ASCT (unsustained CR) have poor prognosis. Thus, the identification of these patients is highly relevant. Here, we investigate which prognostic markers can predict unsustained CR in a series of 241 patients in CR at day +100 after HDT/ASCT who were enrolled in the Spanish GEM2000 (n = 140) and GEM2005 〈 65y (n = 101) trials. Twenty-nine (12%) of the 241 patients showed unsustained CR and a dismal outcome (median overall survival 39 months). The presence of baseline high-risk cytogenetics by FISH (hazard ratio 17.3; P = .002) and persistent minimal residual disease by multiparameter flow cytometry at day +100 after HDT/ASCT (hazard ratio 8.0; P = .005) were the only independent factors that predicted unsustained CR. Thus, these 2 parameters may help to identify patients in CR at risk of early progression after HDT/ASCT in whom novel treatments should be investigated.

Abstract: Abstract 630 The achievement of CR after high-dose therapy/ASCT (HDT/ASCT) is a surrogate for prolonged survival in MM. While this is well accepted, the long-term clinical outcome of MM patients achieving CR is still heterogeneous and a small fraction of patients unexpectedly lose their CR status early on after HDT/ASCT and experience a dismal survival. In fact, survival of patients with unsustained CR is even poorer than that of those not achieving CR. Herein we sought to identify prognostic markers predictive of unsustained CR after HDT/ASCT. The study included a total of 241 patients achieving CR at day+100 after HDT/ASCT treated in two consecutive GEM/PETHEMA trials: GEM2000 (VBMCP/VBAD, n=140) and GEM2005 〈 65y (randomized induction with the same chemotherapy plus bortezomib in the last two cycles or thalidomide/dexamethasone or bortezomib/thalidomide/dexamethasone followed by HDT/ASCT; N=101). All cases were referred for MRD assessment by MFC at day+100 after HDT/ASCT; baseline FISH analysis were available in 110 of the 241 patients. We first investigated which of the most relevant disease characteristics had prognostic influence in patients in CR at day+100 after HDT/ASCT. In this cohort some markers with consistent influence in unselected MM populations such as patient age, ISS stage, serum β2-microglobulin, BMPC burden and % of PC in S-phase were not significantly predictive. In contrast, the presence of baseline anemia was a significant prognostic marker for OS (P=.01). Regarding cytogenetics, 16% of CR patients were considered with high-risk disease at presentation and showed a significantly inferior TTP (3-years, 40% vs 79%; P=.001) and borderline OS (3-years, 73% vs 96%; P=.07) compared to cases with standard-risk. In addition, MFC immunophenotyping showed persistent MRD in 87 of the 241 (36%) CR patients, and the failure to achieve an immunophenotypic CR at day+100 after HDT/ASCT resulted in significantly inferior TTP (3-years, 58% vs 85%; P 〈 .001) and OS (3-years, 80% vs 90%; P=.001). In the multivariate analysis, the best combination of independent predictive parameters for TTP were immunophenotypic CR status (P 〈 .001;HR=7.1) and FISH cytogenetics (P 〈 .001;HR=5.6); in turn, for OS immunophenotypic CR status (P=.001;HR=7.7), FISH cytogenetics (P=.01;HR=5.1) and age ≥60 years (P=.03;HR=3.4) were selected. We further explored the clinical impact of the immunophenotypic CR in the context of standard-risk and high-risk disease. The best prognosis was for patients with both standard-risk cytogenetics and in immunophenotypic CR (3y: TTP, 92%; OS, 100%), while the worst outcome occurred in cases with both high-risk disease and persistent MRD (3y: TTP, 0%; OS, 32%). The two other categories had an intermediate prognosis, although it was better for patients with high-risk cytogenetics achieving an immunophenotypic CR (3y: TTP, 69%; OS, 100%) than for patients with standard-risk disease but failing to achieve an immunophenotypic CR after HDT/ASCT (3y: TTP, 57%; OS, 90%). We then investigated the parameters that could help to identify patients in CR at risk of early relapse after HDT/ASCT. Of the 241 patients, 30 (12%) progressed within 1 year after HDT/ASCT (unsustained CR) and this subgroup showed a dismal outcome, with a median OS of only 39 months (P 〈 .001). Patients with unsustained CR showed significantly higher incidence of anemia at baseline (48% vs 24%, P=.01), advanced ISS stage 2 or 3 (86% vs 55%, P=.003), high-risk cytogenetics (40% vs 10%, P=.005) and persistent MRD by MFC (63% vs 32%, P=.001) compared with the remaining cases. At the multivariate analysis, only cytogenetic abnormalities (P=.002;HR=12.5) and the immunophenotypic CR status at day+100 after HDT/ASCT (P=.001;HR=8.8) emerged as independent predictive markers for unsustained CR. Based on these two variables, we established a predictive index by assigning one point for each adverse factor. Accordingly, 3 risk groups of patients in CR after HDT/ASCT were defined, with significantly (P 〈 .001) different rates of disease progression within the first year after HDT/ASCT for patients with none, one, or both risk factors (7%, 20% and 100%, respectively; Figure). Our results show that the baseline evaluation of cytogenetic abnormalities combined with response assessment by MRD after HDT/ASCT can discriminate a subset of CR patients with a dismal outcome who should be candidates for novel treatment strategies after HDT/ASCT. Disclosures: Paiva: Celgene: Honoraria; Janssen: Honoraria. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Mateos:Janssen: Honoraria; Celgene: Honoraria. Cibeira:Janssen: Honoraria; Celgene: Honoraria. Alegre:Janssen: Honoraria; Celgene: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. Blade:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Janssen-Cilag: Honoraria; Celgene: Honoraria.

Abstract: Abstract 3949 Although in MM an optimal response to front-line therapy is a surrogate for extended survival, two class of patients fall outside this paradigm: those that after treatment show unsustained complete remission (CR) and those that not achieving CR, return into an MGUS-like signature and experience nevertheless long term disease control (LTDC). The prospective identification of the later group remains to be accomplished. Herein, we hypothesized that whole BM immunophenotypic profiling by multiparameter flow cytometry (MFC) would help to identify upfront, symptomatic MM patients with an occult MGUS-like signature (from here on named MGUS-like-MM). For this purpose, the relative frequency of plasma cells (plus the balance between clonal and normal PC), precursor and mature B-cells, T- and NK-cells, erythroblasts, monocytes, neutrophils and eosinophils was determined in 698 newly diagnosed, transplant eligible MM patients included in two consecutive GEM/PETHEMA trials: GEM2000 (VBMCP/VBAD; n=486) and GEM2005 〈 65y (randomized induction with the same chemotherapy plus bortezomib in the last two cycles or thalidomide/dexamethasone or bortezomib/thalidomide/dexamethasone followed by HDT/ASCT; n=212). In addition, we extended this analysis to 114 high-risk smoldering MM patients included in the Quiredex trial. Median follow-up was 63 months for symptomatic MM patients. Unsupervised hierarchical cluster analysis was used on the log2 transformed values of the 11 variables described above. Whole BM immunophenotypic profiling identified a cluster of 176 (25%) symptomatic MM patients “assigned as MGUS-like-MM” based on the following phenotypic features: significantly decreased median numbers of myelomatous PC together with a significant increment of eosinophils, neutrophils, monocytes, T- and NK -cells, mature B-cells and particularly normal PC. This subgroup was characterized by a favorable clinical presentation with increased (P 〈 .005) frequency of ISS stage I or II (88%), high baseline hemoglobin (116 g/L) and albumin (3.8 g/dL) values. MGUS-like-MM patients showed an increased frequency of hyperdiploid DNA content (63%; P=.001) and a lower incidence of t(4;14) (3%; P=.05). When compared to the overall population, MGUS-like-MM patients showed a markedly superior median TTP (88 vs 40 months; P 〈 .001) and OS (141 vs 61 months; P 〈 .001). Moreover, the MGUS-like signature was a strong predictor for LTDC, with 16% of these patients being disease-free at 10 years as compared to 3.5% in the overall MM population (P 〈 .001). Interestingly, while the depth of response achieved after HDT/ASCT translated into superior TTP (P=.032) and OS (P=.005) in the overall population, MGUS-like-MM patients failing to achieve CR showed non significantly different median TTP (80m vs 105m; P=.167) and OS (not reached vs 141m; P=.438) as compared to those attaining CR, respectively. Finally, it should be pointed out that this MGUS-like signature was not restricted to symptomatic MM, since we have also found a subset of high-risk smoldering MM patients with the same signature. These later patients showed a significantly lower risk of progression into symptomatic MM as compared to the rest of high-risk smoldering MM patients (data not shown). In summary, whole BM immunophenotypic profiling by MFC is capable to identify a subset of symptomatic MM patients with an occult MGUS-like signature associated with prolonged survival. Given that in this subgroup of patients the value of CR is not as important as in the rest of MM patients, the prospective identification of this signature may contribute to discriminate a sub-optimal response that require additional treatment from a residual “MGUS-like component” that may remain stable without further treatment. Disclosures: Paiva: Celgene: Honoraria; Miellenium: Honoraria; Janssen: Honoraria. Martínez-López:Celgene: Honoraria. Mateos:Celgene: Honoraria; Miellenium: Honoraria; Janssen: Honoraria. De La Rubia:Celgene, Janssen: Consultancy, Speakers Bureau. Lahuerta:Celgene: Honoraria; Millenium: Honoraria. Blade:Celgene: Honoraria; Millenium: Honoraria; Janssen: Honoraria. San Miguel:Celgene: Honoraria; Millenium: Honoraria; Janssen: Honoraria.

Abstract: Abstract 3938 The incorporation of high-dose therapy/autologous stem cell transplantation (HDT/ASCT) and novel agents has significantly improved survival of MM young pts; however, the molecular heterogeneity of the disease warrants the investigation if such improvement also benefits patients harboring poor prognostic features such as non hyperdiploid (HY) karyotypes and high proliferation index. Herein, we have analyzed by MFC the DNA ploidy status and proliferation of bone marrow (BM) PC in a total of 595 newly diagnosed MM pts included in two consecutive PETHEMA/GEM trials: GEM2000 (VBMCP/VBAD followed by HDT/ASCT; N=319) and GEM2005 〈 65y (randomized induction with the same chemotherapy plus bortezomib in the last two cycles or thalidomide/dexamethasone or bortezomib/thalidomide/dexamethasone followed by HDT/ASCT; N=276). Baseline FISH analysis were performed on separated PC. DNA ploidy and cell cycle were assessed by MFC through simultaneous staining with CD38/CD138 and propidium iodide. Median follow-up of the whole series was 38 months. Of the 595 pts, 295 were classified as non-HY (49.6%) and 300 as HY (50.4%). Patients with non-HY vs HY DNA content showed significantly inferior median PFS (34 vs 44 months, P=.004) and OS (67 vs 84, P=.005). Interestingly, we have detected by MFC the presence of two different PC clones (with different DNA ploidy status) in 34 of the 595 (6%) patients, and this subgroup showed a poor outcome (median PFS and OS of 26 and 52 months respectively, P≤.005). Regarding the proliferative index, the median percentage of PCs in S-phase in the whole series was of 1.14% (0%-13%). Accordingly, pts were stratified using a cutoff of ≥1% vs 〈 1% PCs in S-phase, which translated in significantly different PFS (medians of 34 vs 43 months, P 〈 .001) and OS (medians of 66 vs 93 months, P=.001). Of note, the detection of a proliferative rate ≥3% also identified a subgroup of patients (92 of 595, 15%) with high-risk disease (median PFS and OS of 22 and 45 months respectively, P≤.001). At the multivariate analysis including other baseline prognostic factors, the presence of high-risk cytogenetics (HR=1.7;P=.007), ≥1% PCs in S-phase (HR=2.0;P 〈 .001), 〉 15% PCs by MFC (HR=1.7;P=.008) and 〉 5% normal PCs within the BM PC compartment (HR=6.6;P=.008) emerged as independent prognostic factors for PFS; in turn, for OS the presence of high-risk cytogenetics (HR=2.3;P 〈 .001), non-HY DNA content (HR=1.7;P=.02), ≥1% PCs in S-phase (HR=2.0;P=.002) and the ISS disease stage (HR=1.7;P=.03) were selected. After this analysis of the overall population, we investigated whether the incorporation of novel agents in the induction regimen previous to HDT/ASCT could abrogate the poor prognosis of patients classified as non-HY and with ≥1% PCs in S-phase. Patients with non-HY DNA status included in the GEM2005 〈 65y trial do not show significantly superior PFS (40 vs 34 months, P=.8) nor OS (not reached vs 63 months, P=.5) compared to cases enrolled in the GEM2000 protocol. Focusing on pts with ≥1% PCs in S-phase, no differences were founded for PFS (40 vs 33 months, P=.9), but OS was significantly longer for patients treated with novel agents prior to HDT/ASCT (NR vs 61months, P=.004). Finally, we wanted to gain further insight into the potential association between specific cytogenetic abnormalities and PC proliferation, as well as whether there is a difference in the proliferative rate of PCs between diagnosis and disease progression. Interestingly, pts harboring a t(11;14) showed a significantly decreased percentage of PCs in S-phase (0.7% vs 1.2%, P 〈 .001), while no differences were recorded for t(4;14), t(14;16), del(Rb) and del(17p). To address our final question, we compared the proliferative rate of PCs from 52 pts with paired BM samples at diagnosis and at relapse. Of note, 45 of the 52 (85%) pts showed an increased percentage of PCs in S-phase at relapse, with a median 2-fold difference between the proliferative rate at diagnosis vs. relapse (P 〈 .001). In summary, our results show that the evaluation of PCs DNA content by MFC immunophenotyping provides valuable clinical information, as pts with a non-HY DNA status and high proliferative rate show a poor outcome, which is not yet fully abrogated by the incorporation of novel agents prior to HDT/ASCT. Moreover, pts at relapse show an increased proliferative index; therefore, the precise mechanisms leading to PC proliferation deserves further investigations. Disclosures: Paiva: Celgene: Honoraria; Janssen: Honoraria. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Mateos:Janssen: Honoraria; Celgene: Honoraria. Alegre:Janssen: Honoraria; Celgene: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. Blade:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Janssen-Cilag: Consultancy; Celgene: Consultancy; Millennium Pharmaceuticals, Inc: Consultancy.