ALBERT

Description: Background: The randomized PETHEMA/GEM phase III trial GEM05menos65 (www.clinicaltrials.gov NCT00461747) demonstrated that pretransplant induction therapy with VTD resulted in a significantly higher CR rate both, pretransplant and postransplant and in a significantly longer progression-free survival (PFS) when compared with thalidomide/dexamethasone (TD) and combination chemotherapy plus bortezomib (VBMCP/VBAD/B) (Rosiñol et al, Blood 2012). We report here the definitive results of the trial, ten years after the last patient was included. Methods: From April 6, 2006 to August 5, 2009, 386 patients younger than 65 years with newly diagnosed symptomatic multiple myeloma (MM) were randomized to receive three different induction regimens: six 4-week cycles of TD (thalidomide 200 mg daily; dexamethasone 40 mg on days 1-4 and 9-12) vs. six 4-week cycles of VTD (TD at identical doses plus i.v. bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11) vs. combination chemotherapy plus bortezomib (4 cycles of alternating VBMCP and VBAD chemotherapy followed by two cycles of i.v. bortezomib at the usual dose of 1.3 mg/m2 on days 1,4,8,11 every 3 weeks). The duration of the induction therapy was 24 weeks in all arms. All patients were planned to undergo ASCT with high-dose melphalan at 200 mg/m2 followed by maintenance therapy with thalidomide/bortezomib (TV) vs. thalidomide (T) vs. alfa-2b-interferon (alfa2-IFN) for 3 years. One-hundred and thirty patients were allocated to VTD, 127 to TD and 129 to VBMCP/VBAD/B. Seventy out of the 330 patients (21%) with cytogenetic studies had high-risk cytogenetics [t(4;14), t(14;16) and/or 17p deletion]. Patient characteristics at diagnosis and prognostic factors such as ISS, cytogenetics and maintenance arm were similarly distributed in the 3 arms. Results: After a median follow-up of 115 months for alive patients, VTD resulted in a significantly longer PFS when compared with TD and VBMCP/VBAD/B (52 vs 28 vs 32 months, p=0.01) (Figure 1). The median overall survival (OS) was 128 vs 99 vs 93 months, respectively, with no significant differences among the 3 arms. In the overall series, the PFS was significantly shorter in patients with high-risk cytogenetics compared with patients with standard-risk (15 vs. 42 months, p=0.001). In the TD and in the VBMCP/VBAD/B arm patients with high-risk cytogenetics had a significantly shorter PFS than patients with standard-risk (7 vs 32 months, p=0.029 in TD group; 13 vs. 38 months, p=0.027 in VBMCP/VBAD/B group). However, there was no significant difference in the VTD arm (23 vs 52 months, p=0.125). Patients with high-risk cytogenetics had a significantly shorter OS in the overall series (median 38 months vs 114, p=0.0001) and this was observed in the three treatment arms: VTD median 36 months vs not reached (p=0.0001), TD median 52 months vs 113 (p=0.017), VBMCP/VBAD/B median 29 months vs 93 (p=0.01). The achievement of a negative MRD after transplant was associated with a longer PFS and OS. Thus, on an intention to treat basis, patients who had MRD negative after transplant had a significantly longer PFS (59 vs 38 months, p=0.0001) and OS (median not reached vs 102 months, p=0.001) than those who remained MRD positive after ASCT. Of interest, there are no significant differences in PFS (41 months vs 60 months, p=0.367) or OS (114 moths vs not reached, p=0.329) between patients with high-risk or standard risk cytogenetics who achieved negative MRD after transplant. By contrast, in patients with MRD positive after transplant, the PFS ( 16 months vs 38 months, p=0.006) and OS (29 months vs 113 months, p=0.001) was significantly shorter in patients with high-risk cytogenetics compared with patients with standard-risk cytogenetics. Conclusions: Our long-term results confirm that induction with VTD results in a significantly longer PFS when compared with TD and VBMCP/VBAD/B. Patients with high-risk cytogenetics who achieved postransplant MRD negative had a similar outcome than patients with standard-risk cytogenetics, while patients with high-risk cytogenetics who remain MRD positive had a dismal prognosis. Finally, the PFS of 52 months achieved with VTD is the longest ever reported in the first line treatment of younger patients with MM elegible for ASCT and support the use of VTD as the standard of care for pretransplant induction therapy. Figure 1. Figure 1. Disclosures Rosinol Dachs: Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Oriol:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Blanchard:Janssen: Honoraria. Granell:Janssen: Honoraria; Celgene: Honoraria. Mateos:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Martinez-Lopez:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Vivia: Honoraria; Pfizer: Research Funding; BMS: Research Funding; Novartis: Research Funding. Alegre:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Lahuerta:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. San-Miguel:BMS: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Blade:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria.

Description: Background: The international criteria for definition CR, requires, among other parametres, a negative IF both in serum and urine; however, urine IF is not always performed. In the belief that this lack could bias the comparison between trials, the First Trial Independent Response Adjudication Committee (FTIRAC) recommended that patients who met all CR criteria except the availability of a urine IF should be classified as VGPR (Blood 2014; 124 [abstract 3460]) but this criteria is not always applied which may translate into differences in CR rates between trials. However, it is unknown (1) if this conversion has a real clinical basis, (2) if urine IF results alter the clinical meaning of CR, or (3) on the contrary, if patients in CR with and those without a documented negative urine IF have a similar prognosis, in which case this rule would underestimate the CR rates, increasing the biases and magnifying the problem that was intended to improve. Aim: To determine the value of urine negative IF in the definition of CR. Methods: 459 patients were enrolled into the GEM2012MENOS65phase3 trial and treated with 6 induction cycles of bortezomib, lenalidomide, and dexamethasone, HDT/ASCT and 2 consolidation courses. Evaluable patients were enrolled in a maintenance trail (NCT02406144). Excluding 6 patients who discontinued early, 453 were evaluable. At diagnosis, the M-component was detected exclusively in serum in 173 of these patients and in serum and urine in 212 patients; 68 patients had pure Bence-Jones M-protein (BJMM). The protein studies were performed in each cycle. At the time of negative IF, bone marrow aspirates were analysed for count of PCs and monitoring minimal residual disease (MRD) following EuroFlow SOPs (median limit of detection of 3x10-6).The response classifications were made according to the IMWG criteria, but we applied the FTIRAC criteria, and, patients with

Description: BACKGROUND: Older patients with acute myeloid leukaemia (AML) who are unsuitable for standard induction therapy have limited treatment options. While DNMT3A, TET2, IDH1/2 and TP53 mutations have been previously associated to better response to hypomethylating agents, there are no molecular biomarkers for low-dose cytarabine (LDAC)-based regimens. AIMS: To predict outcome in AML older patients at diagnosis based on mutation status in the context of FLUGAZA trial. FLUGAZA trial was focus on 〉65 years AML de novo patients comparing azacytidine vs. fludarabine and LDAC (FLUGA Scheme). METHODS: We analyzed bone marrow (BM) samples at diagnosis from 209 out of 285 AML patients treated according Flugaza trial (NCT02319135), azacytidine-arm (n=97) and FLUGA-arm (n=112). In this trial, patients were randomized to receive 3 induction cycles with fludarabine and cytarabine (FLUGA) followed by 6 consolidation cycles with reduced intensity FLUGA, vs 3 induction cycles with 5-azacytidine (AZA) followed by 6 consolidation cycles with AZA. Median age at diagnosis was 75 years (65-90). Both treatment groups were balanced for age, leucocytes count, baseline BM blasts, karyotype risk (ELN), and FLT3-internal tandem duplication and NPM1 gene mutations. Mutational profile analysis was carried out by NGS targeted gene sequencing (Ion Torrent S5XL System-Thermo Fisher Scientific) using a 43 genes custom panel implicated in leukemia prognosis. RESULTS: We detected 893 variants, 247 Indels and 646 SNVs. 206 (23.1%) of them were included as pathogenic or like-pathogenic by clinvar database. Ninety-five percent of patients (n=203) had at least one detectable mutation, and the median number of mutations was 4 (range = 0-8 mutations). The most common gene mutations were TET2 (N=55), FLT3 (n=52), SRSF2 (n=49), TP53 (n=45), DNMT3A (n=45), ASXL1 (n=45), RUNX1 (n=43), IDH2 (n=36), IDH1 (n=34), NPM1, (n=33) and NRAS (n=23). This mutational landscape is different to previous published in younger patients (Grimwade, Blood 2016), with higher number of patients with mutations in TP53 (21.5 vs 8%), SRSF2 (23.9 vs 2%), IDH1 (16.3 vs 7%) and IDH2 (17.2 vs 9%) and lower number of patients with mutation in NMP1 (15.8 vs 33%). The median OS of global series was 6 months (range 0-40). Multivariate Cox regression in the global series showed that NRAS and TP53 mutations predict reduced OS (Table 1). Distribution of mutations between both arms was not homogeneous (Figure 1) and NRAS (p=0.012) was more frequent among patients randomized to the FLUGA-arm. However, TP53 mutation frequency distribution was homogeneous: 23.7% in AZA-arm and 19.6% in FLUGA-arm (p=NS). In the AZA-arm, patient´s age was the only variable associated with not achieving composite complete remission (CR plus CR with incomplete recovery) and TET2 and EZH2 mutations were predictors to achieve composite CR. In the FLUGA-arm, TP53 and NRAS mutations were associated with not reaching composite CR (table 2). In the AZA-arm, cytogenetic was the only variable associated with risk of early death. In the FLUGA-arm, leucocyte count, TP53 and NRAS mutations were associated with risk of early death (table 3). In the AZA-arm, BCORL1 mutations (4.1%) were the only variable associated with high risk of relapse. In the FLUGA-arm, BCOR (7.1%) and TP53 (19.6%) mutations were associated with high risk of relapse (table 4). CONCLUSION The mutational profile of AML in elderly patients is different from the previously published in young patients. We have confirmed that a molecular pattern can identify patients with poor prognosis in elderly AML patients. NRAS and TP53 mutations confer a poor prognosis in LDAC (FLUGA-arm) patients, but this effect disappeared in the AZA-arm. BCOR and BCORL1 mutations were associated to a reduced DFS. These results confirm that azacytidine could be more efficacious than LDAC treatment for older patients with AML and mutations in TP53, NRAS, TET2 and EZH2. The percentage of patients who presented mutations in these genes amounted to 77% in this AML series. The study is registered at www.ClinicalTrials.gov as NCT02319135. This study was supported by the Subdirección General de Investigación Sanitaria (ISCIII, Spain) grants PI13/02387 and PI16/01530. Disclosures Salamero: Celgene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Daichii Sankyo: Honoraria. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; unrestricted grants from Celgene, EngMab, Sanofi, and Takeda; and consultancy for Celgene, Janssen, and Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. Fernandez:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Description: BACKGROUND AND OBJECTIVES: Chemosensitization using plerixafor combined with FLAG-IDA (PLERIFLAG regimen) showed promising results (48% CR/CRi) in a phase 2 trial for primary refractory and early relapsed (duration of first CR

Description: Refractory or relapsed diffuse large B-cell lymphoma (DLBCL) often associates with the activated B-cell-like (ABC) subtype and genetic alterations that drive constitutive NF-κB activation and impair B-cell terminal differentiation. Here, we show that DNA damage response by p53 is a central mechanism suppressing the pathogenic cooperation of IKK2ca-enforced canonical NF-κB and impaired differentiation resulting from Blimp1 loss in ABC-DLBCL lymphomagenesis. We provide evidences that the interplay between these genetic alterations and the tumor microenvironment select for additional molecular addictions that promote lymphoma progression, including aberrant coexpression of FOXP1 and the B-cell mutagenic enzyme activation-induced deaminase, and immune evasion through major histocompatibility complex class II downregulation, PD-L1 upregulation, and T-cell exhaustion. Consistently, PD-1 blockade cooperated with anti-CD20-mediated B-cell cytotoxicity, promoting extended T-cell reactivation and antitumor specificity that improved long-term overall survival in mice. Our data support a pathogenic cooperation among NF-κB-driven prosurvival, genetic instability, and immune evasion mechanisms in DLBCL and provide preclinical proof of concept for including PD-1/PD-L1 blockade in combinatorial immunotherapy for ABC-DLBCL.

Description: Introduction: Recent studies have shown that young to middle-aged adults who receive a pediatric-inspired chemotherapy regimen for treatment of Ph-neg ALL do not appear to require an alloHSCT if they achieve good response on MRD testing after induction and/or consolidation therapy. Patients (pts) who are not good MRD responders achieve better outcomes with alloHSCT than their counterparts who do not receive alloHSCT. However, it is not clear if this approach can specifically apply to adult ALL pts with HR features at baseline. The aim of the prospective ALL-HR-11 trial (NCT01540812) from the Spanish PETHEMA Group was to evaluate response of HR Ph-neg adult ALL patients to a different post-induction therapy (chemotherapy or alloHSCT) according to MRD levels (centrally assessed by 8-color flow cytometry [FCM]) at the end of induction (week 5) and consolidation therapy (week 17).. Patients and methods: HR ALL included one or more of the following parameters at baseline: age 30-60y, WBC count 〉30x109/L for B-cell precursor ALL or 〉100x109/L for thymic T-ALL, pro-B, early or mature T-ALL, 11q23 or KMT2A rearrangements or complex karyotype. Induction therapy included vincristine, prednisone, daunorubicin and asparaginase (E coli native or PEG according to center availability) for 4 weeks (Induction-1). FLAG-Ida was administered as intensified induction (Induction-2) in pts not achieving CR or in those in CR with MRD≥0.1% at the end of induction. For pts in CR and MRD

Description: Next-generation sequencing (NGS) has revealed new insight into the complexity of clonal and subclonal architecture of multiple myeloma (MM). The introduction of targeted studies allows the detection of mutations with very low allele frequencies at affordable price. However, there is few information about the prognostic impact of this mutational profile in series of homogeneously treated MM patients. In this study, we analyzed the most frequently mutated genes in MM from patients included in a randomized clinical trial applying the highest read depth to date. We performed a correlation study between our results and cytogenetics aberrations and clinical outcomes. We used Ampliseq Library Kit 2.0 to target 77 genes (M3Pv2.0 panel) related to critical pathophysiological pathways, associated to drug resistance or targetable with molecular drugs in MM. We sequenced DNA (15ng) from CD138+ purified plasma cells from 80 MM patients at diagnosis included in GEM2010MAS65 clinical trial. We sequenced at an average read depth of 1500X and using Ion Proton sequencer (Thermo Fisher, USA, PaloAlto, CA). We used Ion Reporter software applying in-house modifications in call variants process. We also sequenced DNA from CD138 negative population in 30% of patients in order to filter out potential artifacts and stablish conditions for excluding germline variants. We first fitted a cox-proportional hazard model to predict survival and a second approach using a penalized regression LASSO. We identified 137 gene mutations in the 80 patients analyzed, 54 mutations were predicted pathogenic by Shif and Poliphen and 65 have been described in COSMIC database. 85% of patients harbored at least 1 mutation. The most frequently mutated genes were KRAS (16%), DIS3 (15%), NRAS (13%), BRAF (6%), and TP53 (5%), accounting for the 54% of the total number of mutations. The most frequently mutated pathways were RAS and NFKB in 34% and 28% of patients respectively. Mutational allele frequency for KRAS, BRAF and TP53 was, in all cases, lower than 50% while DIS3 showed mutations in a broad range (from 2 to 85%). Only one patient presented one mutation in NRAS at 73 % of allele frequency. For patients with more than one mutation, two different scenarios have been found. Some patients showed several genes mutated in a similar allele frequency values. On the contrary, a complex subclonal structure was confirmed in 3 patients, with mutations at very different clonal frequency. CD138 negative fraction was sequenced to confirm that these mutations were exclusive of plasma cells. The first of them had two mutations in DIS3 at 8 and 53% of allele frequency, second in KRAS and DIS3 at 13 and 63% respectively and the third in NRAS and IFNGR2 at 5 and 37% respectively. We found no differences in the survival based on pathway, mutational allele frequency or number of mutations. We also investigated pairwise associations between events and we not found significant correlations (Figure 1). Cox-proportional hazard model only showed a negative impact in survival of patients with TP53 mutations. This ultra-deep targeted sequencing strategy is able to detect mutations in most of patients, at very low allele frequency and using a minimal amount of DNA. Despite of its huge capacity to detect mutations, we have not identified new prognostic factors in MM patients treated with highly efficient therapies. However, this study again confirms the complexity of the genomic landscape of MM and the great heterogeneity between patients. The role of theses mutations at relapse as well as in the subsequent treatment effectiveness remains unknown and should be preferably investigated in larger cohorts of homogeneously treated MM patients. Figure 1 Figure 1. Disclosures Martínez-López: Novartis: Honoraria, Speakers Bureau. Oriol:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: 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. Stewart:celgene: Consultancy.

Description: Cytogenetic analysis is still an important and mandatory component of Acute Myeloid Leukemia (AML) diagnosis and prognosis. Pretreatment cytogenetic and molecular genetic findings are one of the major independent prognostic markers in AML, and they determine chemotherapy response and outcome. However, cytogenetic does not provide alternative treatments when a patient have a high cytogenetic risk, and requires relatively long time until obtaining the results despite the treatment of these patients should begin as soon as possible. The aim of this study is providing data about the utility of a new AML Precision Medicine (PM) Test as a complementary tool to conventional cytogenetic to overcome the main obstacles this later has. For this purpose, AML bone marrow from 111 patients were received at the laboratory 24h from extraction and incubated for 48h in 96-well plates containing single drugs or combinations, representing up to 31 different treatments that are currently given in the clinical practice. The analyses were performed in the automated flow cytometry PharmaFlow platform and the test results can be sent to the hematologists 72h after the extraction of the sample. Pharmacological responses were calculated using pharmacokinetic population models. Induction response was assessed according to the Cheson criteria (2003). Patients attaining a complete remission (CR) or CR with incomplete blood count recovery (CRi) were classified as responders and the remaining as resistant, excluding early deaths. The probability of being resistant or non-responder was modeled using binary logistic generalized additive models (GAM) with Cytarabine (CYT) and Idarubicin (IDA) area under the curve (AUC) data and over the cytogenetic risk (favorable/intermediate/adverse). The empirical ROC curves were calculated for the probabilities of being non-responder from each GAM. Final scores and treatments ranking are based on a therapeutic algorithm that integrates ex vivo activity of single drugs, quantified by the AUC and synergism, referred as α parameter, using a surface interaction model. Clinical and cytogenetic risk data of the patients were monitored and collected. A simple logistic model of the probability of being non-responder over the cytogenetic risk (favorable/intermediate/adverse) explained less variability (29.4%) than the GAM over the AUC values (40.8%) in the subset of 111 patients in whom the cytogenetic risk was informed. Figure 1 shows the results of the clinical correlation of cytogenetics vs PM Test in the cohort of 111 patients analyzed. In both approaches prediction of sensitive patients (Negative Prediction Value, NPV) is better than resistant patients (Positive Predictive Value, PPV), being the PM Test slightly better in predicting the sensitive patients (NPV=93% vs 88%), while the cytogenetics shows a 20% improvement in the prediction of resistant patients (PPV= 76% vs 56% with PM Test). The correlation achieved by the PharmaFlow PM test was 80% that is almost similar than the correlation obtained with the cytogenetic data using the same cut off point (86%). Figure 1 (right) also shows an example of the classification of AML treatments with the PharmaFlow PM Test in a patient sample according to a color scale from higher (green) to lower (red) ex vivo activity. In summary, despite the PharmaFlow PM Test and cytogenetics provide similar information, results from cytogenetic risk are available typically in 10-14 days, and thus after patient treatment, while results from this novel PM Test are available in 48-72h, prior to treatment. Hence, this novel approach provides information to hematologist with higher predictive value than risk factor (deviance explained 40.8% vs 29.4%) and ahead of treatment, and thus represent a valuable in-time prior to treatment decision making. In addition, the PM Test can provide alternative treatments to AML patient in a basis of their ex vivo activity. Disclosures Ballesteros: Vivia Biotech: Employment. Martinez Lopez:Novartis: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau. Hernandez:Vivia Biotech: Employment. Primo:Vivia Biotech: Employment. Gorrochategui:Vivia Biotech: Employment. Rojas:Vivia Biotech: Employment. Montesinos:Novartis: Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Speakers Bureau.

Description: Background:Novel insights into the biology of myeloma cells have led to the identification of relevant prognosis factors.Cytogenetic abnormalities (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. Although there are some reports indicating that 1q gains may be considered as a poor-risk feature, the information is not uniform. Furthermore, there are important controversies about whether or not novel agents-based combinations are able to overcome the poor prognosis of CA. In the relapse setting, the combinations including proteasome inhibitors and immunomodulatory drugs have shown to improve, and some of them to overcome, the outcome of patients with high-risk CA. Here we report a preplanned analysis, in a series of elderly newly diagnosed myeloma patients included in the Spanish GEM2010 trial and receiving VMP and Rd, in a sequential or alternating approach, in order to evaluate the influence of CA by FISH on the response rate and outcome. Patients and methods: 242 pts were randomized to receive a sequential scheme consisting of 9 cycles of VMP followed by 9 cycles of Rd or the same regimens in an alternating approach (one cycle of VMP alternating with one Rd, up to 18 cycles. VMP included the IV administration of weekly bortezomib (except in the first cycle that was given twice weekly) at 1.3 mg/m2 in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2once daily on days 1-4. Rd treatment consisted on lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly. FISH analysis for t(4;14), t(14;16), del(17p) and 1q gains was performed at diagnosis according to standard procedures using purified plasma cells. Results: In 174 out of the 233 patients evaluable for efficacy and safety, FISH analysis at diagnosis were available and two groups were identified: high-risk group (n= 32 patients with t(4;14) and/or t(14;16) and/or del(17p)) and standard-risk group (n=142 patients without high-risk CA). The rates of CA was similar in both treatment arms. Response Rates (RR) were no different in the high-risk vs standard-risk groups, both in the sequential (74% vs 79% RR and 42% vs 39% CR) and alternating arms (69% vs 86% RR and 39% vs 38% CR). After a median follow-up of 51 months, high-risk patients showed shorter PFS as compared to standard risk in the alternating arm (24 versus 33 months, p=0.03) and this also translated into a significantly shorter OS (38.4m vs not reached, p=0.002). However, in the sequential arm, high-risk and standard-risk patients showed similar PFS (29.5 months vs 31.5 months, p=0.9) and OS (46m vs 63m, p=0.1). This beneficial effect observed in the sequential arm applied to both t(4;14) or del(17p). As far as 1q gains is concerned, 151 patients had 1q information and 76 of them had 1q gains (50.3%), defined as the presence of more than 3 copies in at least 10% of plasma cells. The rate of 1q gains was well balanced in both sequential and alternating arms. The ORR was similar in patients with or without 1q gains (83% vs 80%) as well as the CR rate (45% vs 31%), and no differences were observed between sequential and alternating arms. Patients with or without 1q gains had a similar PFS (36 months vs 29 months) and 4-years OS (63% vs 68%) in the whole series and no differences were observed between the sequential and alternating arms. This effect has been observed in patients with 1q gains as isolated CA and the outcome was slightly but not significantly worse when 1q gains were present plus either t(4;14) and/or del17p. Conclusions: The total therapy approach including VMP and Rd administered in a sequential approach is able to overcome the poor prognosis of the presence of high-risk CA in elderly patients with newly diagnosed MM. The presence of 1q gains has no impact in the PFS and OS of elderly patients treated with VMP and Rd. Disclosures Mateos: Janssen, Celgene, Amgen, Takeda, BMS: Honoraria. Martínez-López:Novartis: Honoraria, Speakers Bureau. Oriol:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Paiva:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; EngMab: Research Funding; Amgen: Honoraria; Binding Site: Research Funding.

Description: Introduction:SMM is an asymptomatic and heterogeneous plasma cell disorder. The Spanish Myeloma Group demonstrated that patients at high risk of progression benefit from early treatment with Rd. In addition, our preliminary results of the curative approach (GEM-CESAR) showed encouraging results (Mateos ASH 2017). Aim: The primary end-point was to evaluate the Minimal Residual Disease negative (MRD-ve) rate by next generation flow (NGF) after induction and ASCT and the sustained MRD-ve rate at 3 and 5 yrs after ASCT as secondary end-points. Our aim was to increase the MRD -ve rate from 34% (reported in NDMM patients after VTD and ASCT) to 50%. As all patients have completed induction and ASCT, we report the results of the primary end point, efficacy and safety after induction and ASCT. Methods: In this phase II single arm trial, 90 SMM patients at high-risk of progression (〉50% at 2 yrs), younger than 70 yrs and transplant candidates were included. The high risk was defined by the presence of both ≥PC 10% and MC ≥3g/dL (Mayo criteria) or ifonly one criterion was present, patients must have a proportionof aberrant PCs within the total PCsBM compartment by immunophenotypingof 95% plus immunoparesis (Spanish criteria). Asymptomatic MM patients with any of the three biomarkers recently included into the definition of active MM were allowed to be included. Induction therapy consisted on six 4-weeks cycles of KRd in which K was given at dose of 36 mg/m2twice per week plus R at dose of 25 mg on days 1-21 and dexamethasone at dose of 40 mg weekly. Melphalan at dose of 200 mg/m2followed by ASCT was given as intensification therapy and three months later, patients received two KRd consolidation cycles followed by maintenance with R at dose of 10 mg on days 1-21 plus dex at dose of 20 mg weekly for up to 2 yrs Results: Between June 2015 and June 2017, the 90 SMM patients at high risk of progression were recruited. Twenty-eight pts (32%) shared at least one of the new biomarkers predicting imminent risk of progression to MM. The primary end point of the trial was met, since 55% of the patients who completed induction and ASCT achieved MRD -ve by NGF (sensitivity 3 x 10-6). Upon analyzing the results after induction, 88 patients completed the 6 induction cycles and were evaluable for response (two patients early discontinued): the ORR was 98% including 41% of ≥CR (32% sCR and 9% CR) and 41% of VGPR rate. Two patients were mobilization failures and one patient rejected ASCT. Two additional patients experienced biological progression before ASCT and went off the study. Eighty-three patients, therefore, proceeded to HDT-ASCT and were evaluable at day +100: the ORR was 100% including ≥CR in 63% of the patients (51% sCR and 12% CR) and VGPR rate in 23%. The MRD-ve rate increased from 31% after induction to 55% with the ASCT. No differences in outcome have been observed according neither to the definition of high risk (Mayo or Spanish model) nor ultra high risk SMM. Concerning toxicity, during induction, G3-4 neutropenia and thrombocytopenia were reported in 5 (6%) and 10 pts (11%), respectively. G3-4 infections were the most frequent non-hematological AE observed in 16 pts (18%), followed by skin rash in 8 pts (9%). One patient reported G1 atrial fibrillation and another cardiac failure secondary to respiratory infection. Three patients reported hypertension (G2 in two and G3 in one). Thirteen patients required lenalidomide dose reduction whilst carfilzomib was not reduced in any patient. In four patients, dexamethasone was reduced. In all but two of the pts, PBSC collection was successful with a median of 4.10 x 106/Kg CD34 cells collected. All patients engrafted. Consolidation and maintenance phases are ongoing. After a median follow-up of 17 months (5-36), 94% of patients remain alive and free of progression and 97% of them alive. Three patients experienced biological progression and discontinued the study: one of them was refractory to the rescue therapies and died and the other two are receiving rescue therapies. One additional patient died early during induction due to a massive ischemic stroke unrelated to the treatment. Conclusions: Although longer follow-up is required, this "curative strategy for high risk SMM" continues being encouraging with an acceptable toxicity profile. The study has met its primary endpoint. The depth of response improved over the treatment: 63% of patients who completed induction and ASCT achieved ≥CR with a MRD-ve rate of 55%. Disclosures Mateos: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rodriguez Otero:Takeda: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Clínica Universidad de Navarra: Employment. Ocio:AbbVie: Consultancy; Pharmamar: Consultancy; Seattle Genetics: Consultancy; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS: Consultancy; Takeda: Consultancy, Honoraria; Sanofi: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding. Oriol:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rios:Amgen, Celgene, Janssen, and Takeda: Consultancy. Rosinol:Janssen, Celgene, Amgen, Takeda: Honoraria. Alegre:Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Puig:Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. García Mateo:Binding Site: Research Funding; Amgen: Honoraria; Celgene: Honoraria. Bladé:Janssen: Honoraria. Lahuerta:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. San-Miguel:Novartis: Honoraria; Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Roche: Honoraria.