Abstract: Background and objective. Anthracycline-induced cardiotoxicity is a major issue in the treatment of elderly patients with diffuse large B-cell lymphoma (DLBCL). The use of non pegylated liposomal doxorubicin (Myocet®)has been associated with less cardiotoxicity as compared to conventional doxorubicin in breast cancer, but its benefit in DLBCL has been investigated mostly in retrospective and single-arm prospective studies. The objective of this study was to evaluate the benefit, in terms of cardiac toxicity, of the substitution of conventional doxorubicin as part of R-CHOP therapy by the non pegylated liposomal doxorubicin (Myocet®, R-COMP arm) in older patients (≥60 years) with de novo DLBCL or grade 3b follicular lymphoma (FL). Methods. This is a prospective randomized phase 2 trial (ClinicalTrials.gov Identifier: NCT02012088) of newly diagnosed patients with DLBCL or grade 3b FL ≥60 years old with baseline left ventricular ejection fraction (LVEF) 〉 55%. Patients were randomized to R-COMP or R-CHOP (in both cases every 21 days for a total of 6 cycles, with a dose of conventional doxorubicin or Myocet® of 50 mg/m2/cycle). The primary end-point was to evaluate the differences in subclinical cardiotoxicity between the two arms of treatment, defined by a decrease in LVEF to ≤ 55% at the end of treatment (measured by echocardiography at 1 and 4 months after the last cycle of chemotherapy). Secondary objectives were efficacy, safety and differences in the variations of cardiac biomarkers (troponin and N-terminal pro B-type natriuretic peptide [NT-proBNP]) through therapy in both arms of treatment. Results. Patient characteristics. A total of 91 patients from 15 Spanish hospitals were included, with a median age of 75 years (range 60-86), 49 (54%) were females. ECOG performance status was 2 in 15 (16%), stage III-IV in 68 (76%) and IPI 3-5 in 56 (63%). A total of 46 patients received R-COMP while 45 were treated with R-CHOP, without significant differences between arms regarding baseline characteristics. Subclinical cardio-toxicity: No differences between arms were observed in the number of patients with LVEF ≤55% determined at the end of treatment or at 4 months (6 [15%] in those treated with R-COMP and 5 [14%] in the R-CHOP arm, p=0.966). However, a higher number of patients in R-CHOP arm increased troponin levels at cycle 6 of treatment (17 out of 24 evaluable patients [71%] in R-COMP group vs. 25 out of 25 evaluable patients [100%] in R-CHOP group, p=0.004) or at the end-of-treatment visit (13 out of 21 evaluable patients [62%] in R-COMP group vs. 20 out of 23 evaluable patients [87%] in R-CHOP group, p=0.05). No differences between both groups were observed in variations of NT-proBNP levels through treatment period and follow-up. Serious adverse events (SAEs): With a median follow-up of 16 months (range 0.7-34), a total of 59 SAEs were reported in 37 patients (39 in 21 patients from R-COMP group and 20 in 16 patients from R-CHOP group), including 18 infections (12 in R-COMP and 6 in R-CHOP), and 14 episodes of febrile neutropenia (9 in R-COMP and 5 in R-CHOP). Four patients showed cardiovascular events: atrial fibrillation (n=1, R-COMP group), supraventricular tachycardia (n=2, R-CHOP group), and myocardial infarction (n=1, R-CHOP group). Efficacy: Overall response (OR) and complete remission (CR) were observed in 72 (96%) and 54 (72%) patients, respectively, without differences between R-COMP group (OR and CR rates of 97% and 72%) and R-CHOP group (OR and CR rates of 94% and 72%) (p=0.775). Conclusions. R-COMP is a feasible immunochemotherapy schedule for patients with de novo DLBCL older than 60 years. However, in our series, the use of non-pegylated doxorubicin instead of conventional doxorubicin was not associated with less decrease in LVEF measured by echocardiography, although the differences in troponin levels merits the need for further evaluation with a higher number of evaluable patients and longer follow-up. Disclosures Sancho: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion, Inc: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees. González-Barca:Roche: Honoraria; Gilead: Honoraria; Servier: 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; Sanofi: Membership on an entity's Board of Directors or advisory committees. Martín:Janssen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sevier: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (alloSCT) is the only curative strategy for relapsed/refractory T cell lymphoma (T-NHL). In the past ten years, there have been several improvements in conditioning regimens and graft versus host disease prophylaxis (GVHD), which have contributed to lower transplant-related mortality (TRM). Also, selective and low toxicity therapies, might improve response quality in some T-NHL Recently, haploidentical stem cell transplantation (Haplo) with post-transplant cyclophosphamide is a new option for those patients who do not have an HLA-identical sibling or a suitable unrelated donor, but also it has shortened the time for urgent cases. METHODS: This study analyzes overall outcomes of 211 consecutive patients diagnosed with T-NHL who received an alloSCT from 1995 to 2018 in GELTAMO/GETH centers. Previous therapies (chemotherapies and autologous stem cell transplantation) and baseline diagnostic parameters were recorded. RESULTS The median age at alloSCT was 47 years (range, 17-69). (see table 1). Forty-nine (23%) had primary extranodal disease. Disease status pre alloSCT was available in 202 patientes: 54% were in complete response (CR), 30% in partial response (PR) and 16% with stable/progressive disease (PD). Since 2013 BV was used as a bridge therapy in ≥ 3rd line in 25 patients with CD30+ tumor expression, it was effective in 20 (CR 68% (n=17), PR 12% (n=3) PD 16% (n=4), not assessed in 1 case). The use of BV was not associated with a better response probability pre alloSCT compared with other regimens used after third line and it did not impact on post alloSCT outcomes. Reduced intensity conditioning (RIC) was the most frequent (76%, n=156). (see table 2) GVHD prophylaxis were Methotrexate + CsaA or Tacrolimus (n=72, 35,8%), sirolimus-tacrolimus (n=37; 18,4%), Cy-post based (n=44, 21,9%; used in Haplo setting n= 29). The median follow-up of all cohort was 22.5 months (range, 0-280). The two year overall survival (OS) and disease free survival (DFS) were 60% (CI95%, 53-67%) and 76.7% (CI95%, 69.3-82.5%) (Figure 1A) We observed a significant improvement in alloSCT outcomes since 2011 (OS 〈 2011 51.4% vs ≥2011 64.8%, p=0,04).(Figure 1B) Disease status was the only pre alloSCT variable that impacts 2 years - OS: CR 72.8% (CI95%, 63-80.4%), PR 52%(38.7-63.7%), PD 43.8 (26.5-59.8%) (p=0.002) (Figure 1C). Forty-three (21%) cases relapsed after alloSCT. To analyze the impact of GVHD on OS and DFS we selected landmark time point at day +100 and +1 year after alloSCT for acute (aGVHD) and chronic GVHD (cGVHD) respectively, which allowed us to capture the majority of events that could interfere with the analysis. A landmark analysis (day +100) showed a 2 year OS for grade 3-4 aGVHD was 18% and for 1-2 aGVHD 54,6% (p 〈 0,001). The severity of aGVHD had no impact on DFS. Different grades of cGVHD did not impact OS nor DFS significantly. Cumulative incidence of acute GVHD at 90 days was 51.6% (CI95%, 43.9-58.2%) being 27% grade 3-4. Chronic GVHD at 6 months was 53.9% (46.1-60.5), 54% of cases were grade 3-4). The 2 years non relapse mortality (NRM) was 30.2% (CI95%, 23.3-36.5%); the main causes contributing to NRM were GVHD (40%) and infections (44%) Haploidentical (Haplo) alloSCT was introduced in 2012 (29 of 128). With a median follow up of 13 months (range, 0-60) we found that outcomes in terms of 1 year OS (Haplo 60.7% vs. others 67,5%), 1 year DFS (Haplo 74.8% vs. others 83.8%) and 1 year NRM (Haplo 29.7% vs. 26%) are similar to other alloSCT modalities (Figure 1D). Not additional analysis could be estimated due to the low number of population at risk for each category. CONCLUSION Overall outcomes of alloSCT for T-NHL have improved over time. Complete response pre alloSCT is the only determinant for OS. Haploidentical alloSCT is not significantly different from other approaches and should be considered as an alternative. Disclosures Sierra: Novartis: Honoraria, Research Funding, Speakers Bureau; Astellas: Honoraria; Pfizer: Honoraria; Daiichi-Sankyo: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Roche: Honoraria; Jazz Pharmaceuticals: Honoraria.

Abstract: 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 〈 5% BM PCs and negative serum IF but with unavailable urine IF (or vice versa for patients with BJMM) were classified as VGPR. For the purpose of this study, we called these uncertain CR (uCR). Stringent Complete Responses were classified as CR.Median follow-up was 40 months. Results: Overall, 3774 protein evolution studieswere performed: 691 (18%) in CR, 802 (21%) in uCR and 868 (23%)in VGPR.In all patients with M-component exclusively in serum at diagnosis butwith negative serum IF after treatment, and available urine IF (174 patients, 1476 protein studies), the urine paraprotein IF detection rate was 0%. In patients with a positive M-component in both serum and urine at diagnosis, but with negative serum IF after treatment, and available urine IF (212patients, 1763 protein assessment), 11 protein evaluations in 6 patients (2.8%) tested positive in urine; in other words: in 97,2% of the patients a negative serum IF predicts for negative urine.Since MRD is a robust subrogate of depth of responses (J ClinOncol. 2017;35:2900-10), we compared MRD-verates in patients achieving CR, uCR and VGPR. Interestingly, there were no significant differences in the post-consolidation MRD-verates among patients in CR vsthose in uCR (68% vs 77%, P=.1), whereas significant differences were seen when comparing CR and uCRvs VGPR (23% in the latter; P≤.0001). Accordingly, a landmark analysis performed at HDT/ASCT, - time pointselected to improve the PFS observation time- , showed 2-year PFS rates of 88%, 87% and 77% inpatients in CR, uCR and VGPR, no differences in 2-year PFS rates between patients in CR vsuCR (P=.6) while patients in VGPR showed inferior PFS compared with those in uCR (P=.04). With this landmark, the MRD-negativity ratios are similar to those described after consolidation. Conclusions: In MM patients with M-component exclusively in serum at diagnosis, urine IF follow-up is unnecessary, while in patients with paraprotein in both serum and urine,a negative serum IF response is accompanied by a negative urinary IF in 97.8% of patients. Moreover, patients with CR but without available IF in urine display similar MRD-veand PFS rates compared withthose in CR. By contrast, MRD-veand PFS values in these patients are significantly superior to those in VGPR. Thus, our results suggest that, except for those with pure BJMM, patients fulfilling CR criteria but with unavailable urine IF should be classified as CR instead of VGPR. This data discourages the application of the FTIRAC conversion criteria. Also, the IMWG criteria for CR should be reviewed. Disclosures Rosinol: Janssen, Celgene, Amgen, Takeda: Honoraria. Puig:Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding. Garcia-Sanz:Affimed: Research Funding. 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. Rios:Amgen, Celgene, Janssen, and Takeda: Consultancy. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. Mateos: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; 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; 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; 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. San-Miguel:Brystol-Myers Squibb: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Amgen: Consultancy; MSD: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees. Bladé:Celgene: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Lahuerta: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; 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.

Abstract: Introduction: Relapses after front-line therapy for Burkitt lymphoma/leukemia (BL) are unfrequent, and there is scarce information about the best rescue strategy for these patients. The objective of this study was to evaluate the incidence of relapse, salvage treatment and prognosis after relapse in patients with BL treated with two consecutive Spanish protocols. Patients and methods: Retrospective study of patients diagnosed with BL in 40 Spanish hospitals betwen January 1997 and October 2014 treated with first line chemotherapy according to protocols PETHEMA LAL-3/97 (specific chemotherapy without rituximab) and BURKIMAB (rituximab plus specific chemotherapy). The demographic, clinical and biological characteristics were collected at the time of diagnosis and at relapse, as well as the salvage treatment and outcomes. Results: 233 patients were diagnosed with Burkitt lymphoma (n=150) or leukemia (n=83) and received first-line therapy according to PETHEMA LAL-3/97 (n=53) and BURKIMAB (n=180) protocols. Baseline characteristics at diagnosis are described in Table 1. A total of 26 patients relapsed, 11 (28%) treated with PETHEMA LAL-3/97 protocol and 15 (10%) with BURKIMAB protocol (p=0.009). The cumulative incidence of relapse at 10 years was 27% (95% CI, 12%-42%) in PETHEMA LAL-3/97 protocol vs.16% (95% CI, 4%-28%) in BURKIMAB protocol (p= 0.013) (Figure 1). Time to relapse was shorter in PETHEMA LAL-3/97 protocol (median of 3.7 months) vs. BURKIMAB protocol (6.3 months), but it was not significant (p=0.506). No differences were observed in relapse incidence between Burkitt leukemia and Burkitt lymphoma in PETHEMA LAL-3/97 protocol (6/31 vs. 5/22, p=1) and BURKIMAB protocol (7/41 vs. 8/107, p=0.124). Out of 15 patients in whom rescue treatment strategy was evaluable, 12 received chemotherapy with high-dose methotrexate and/or cytarabine (4 of the them followed response, CR in 2, followed by SCT in the 2 patients achieving PR [autologous in one and allogeneic SCT in the other]), and the remaining 3 patients received DA-EPOCH-R (n=1, achieving CR), R-ICE (n=1, no response) and paliative care (n=1). At the time of the analysis, only 3 patients are alive. Median overall survival after relapse was 3 months (95% CI, 0.9-5.1) for PETHEMA LAL-3/97 relapsed group and 3.6 months (95% CI, 0.1-7.1) for BURKIMAB relapsed patients group. Conclusions: Patients with Burkitt leukemia/lymphoma treated with specific immunochemotherapy have lower probability of relapse compared with those treated with specific chemotherapy without rituximab. In our series, the most frequent regimens administered for the treatment of relapsed patients were based in high-dose methotrexate and/or cytarabine. The prognosis of relapsed Burkitt leukemia/lymphoma is poor, independently of the type of rescue therapy. Supported by grants RD12/0036/0029 (RTICC, FEDER), Instituto Carlos III, Spain. Disclosures No relevant conflicts of interest to declare.

Abstract: Introduction: To discriminate different outcomes among patients in CR, the International Myeloma Working Group (IMWG )introduced more stringent CR (sCR) criteria by adding to the pre-existing CR parameters 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 cytometrycriteria were included as alternative methodology to IHC to define sCR. Aim: To validate the preliminary data of our previous study (Blood 2015. 126:858-62) regarding the lack of influence of an abnormal sFLCr in the outcome of MM patients, through the analysis of a more extensiveseries of newly diagnosed multiple myeloma (NDMM) patients in CR or sCR. Patients and Methods: This study is based on 459 NDMM patients who were transplant candidates and enrolled in the GEM2012MENOS65phase 3trial;evaluable patients were enrolled in a subsequent maintenance trial (NCT02406144).CR and sCR was defined according to the IMWG criteria. Agreeing to the protocol, patients with 〈 5% BM PCs and negative serum immunofixation (IF) but with unavailable urine IF should have been classified as VGPR, but after the results of recent analysis conducted by our group showing that these patients had the same outcome of those in CR (unpublish information), these patients were reclassified as CR. SFLCr (FREELITE assay) was stratified as normal (0.26-1.65) or abnormal ( 〈 0.26 if the patient was λ; 〉 1.65 if the patient was κ). BM aspirates were assessed for morphological enumeration of PCs and monitoring of minimal residual disease (MRD) using next-generation flow (NGF) according toEuroFlow SOPs. The median limit of detection was of 3x10-6. We classified as sCR all patients in CR with normal sFLCr and absence of clonal PCs by NGF with a reduced threshold of sensitivity to 10-4.The median follow-up was 40 months. Results: After ASCT,392 patients were evaluable for response; 239 (61%) reached ≥CR. Data from sFLCr and MRD was available in 225 and 221 patients, respectively. In 153 out of a total of 203 (74%) patients in CR in which complete information about FLC and MRD was available were categorized as sCR. The remaining 55 patients were consider in CR because of failure to accomplish 1 of the 2 criteria: abnormal sFLCr (n=49) or MRD+veby low sensitivity flow (n=11); 5patientsshared both criteria.In a landmark from ASCT, with a follow up of 27 months, sCRdidn't show significantly differences inPFS (2 years-PFS 90% vs 83%; P=.2) neither in OS (2 years-OS 96% vs 98%; P=.6) as compared to CR patients.Interestingly, patients with abnormal (n=51) vs normal (n=174) sFLCr showed superimposable PFS (2 years-PFS 86% vs 88%; P=.6) and OS (2 years-OS 95% vs 100%; P=.2).By contrast, in the 11 patients (out of the 221, 5%) with persistent MRD ( 〉 10-4) the PFS was significantly poorer as compared with MRD-ve cases (2-yearsPFS 91% vs48%; P=.001)but the OS was similar (2 years-OS 98% vs 96%; P=.3).As validation, we reproduced the analysis in the consolidation-2 end-point (figure 1), where375patients were evaluable for response assessment,267 of them (71%) reached ≥CR. Once again, in the landmark analysis, sCR didn't show significantly differences in PFS with respect to CR patients (2 years-PFS 88% vs 84%; P=.2) neither in OS (2 years-PFS 96% vs 90%; P=.3); moreover, patients with abnormal (n=55) vs normal (n=195) sFLCr showed superimposable PFS (2 years-PFS 84% vs 87%; P=.4) and OS (2 years-OS 89% vs 96%; P=.2).In the MRD analysis, patients with persistent MRD, had significantly inferior PFS (2-years PFS 87% vs 72%; P=.04 for 〉 10-4 MRDsensitivity). If we increase the sensitivity of the MRD to 10-6, the differences in PFS at 2 years are more evident (2 years-PFS 94% vs 67%; P 〈 .000001 for 〉 10-6 sensitivity). Conclusion: These results confirm our previous findings based on GEM05menos65/ GEM10mas65 clinical trials, indicating that for MM patients stringent CR criteria does not predict a different outcome as compared to standard CR. Specifically, the sFLCr doesn't identify patients in CR at distinct risk. If this essential criterion in the definition of sCR lacks connotations for the prognosis, is it 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 ( 〈 10-4) levels, which is outdated. Figure 1. Figure 1. Disclosures Martinez Lopez: Janssen: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau. Rosinol:Janssen, Celgene, Amgen, Takeda: Honoraria. Puig:Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Oriol:Celgene: 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; 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. Ocio:Pharmamar: Consultancy; AbbVie: Consultancy; Seattle Genetics: Consultancy; BMS: Consultancy; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. Rios:Amgen, Celgene, Janssen, and Takeda: Consultancy. Mateos:Janssen: 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; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: 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; Celgene: Consultancy, Honoraria, 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; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. San-Miguel:Sanofi: Consultancy; Takeda: Consultancy; Novartis: Consultancy; MSD: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Brystol-Myers Squibb: Consultancy; Amgen: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees. Bladé:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Lahuerta: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; 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.

Abstract: Background: Despite significant improvements in the treatment of MM, the outcome of patients with HR cytogenetics remains poor despite similar complete remission (CR) rates as compared to SR cases. Relapses among patients in CR are attributed to the persistence of MRD, but knowledge about the impact of MRD in patients with SR and HR cytogenetics, treated with modern therapies and monitored with next-generation techniques, is limited. Similarly, there is virtually no data about in vivo mechanisms of resistance in SR and HR MM; however, since MRD represents those very few cells that are resistant to treatment, it could be hypothesized that profiling MRD cells may shed light into the mechanisms of resistance in both SR and HR patients. Aim: To determine the clinical impact of MRD in MM patients with SR vs HR cytogenetics, and to identify transcriptional mechanisms determining MRD resistance by investigating the transcriptome of MRD cells in both patient subgroups. Methods: This study was conducted in a series of 390 patients enrolled in the PETHEMA/GEM2012 trial (6 induction cycles with VRD followed by ASCT and 2 courses of consolidation with VRD). FISH was analyzed on CD138 purified PCs at diagnosis. MRD was predefined to be prospectively assessed following induction, transplant and consolidation, using next-generation flow (NGF) according to EuroFlow. In 40 patients [28 with SR and 12 with HR cytogenetics: i.e., t(4;14), t(14;16) and/or del(17p)], diagnostic and MRD tumor cells persisting after VRD-induction were isolated by FACS according to patient-specific aberrant phenotypes. Due to the small number of sorted MRD cells (median of 25,600) we used a 3' end RNAseq method optimized for generating libraries from low-input starting material (MARSeq). Differential expression analyses were performed with DESeq2 R package. Results: At the latest time-point in which MRD was assessed, MRD-positive rates progressively increased (p =.006) from SR patients (148/300, 49%) to cases with t(4;14) (24/42, 57%) and del(17p) (29/38, 76%). Furthermore, MRD levels were significantly superior in patients with del(17p) compared to SR FISH (0.02% vs 0.006%, p =.009), while MRD levels in patients with t(4;14) (0.004%) were similar to those in SR MM. Only 10 patients had a t(14;16) and 4 were MRD-positive. Among patients achieving MRD-negativity ( 〈 2x10-6), 3-year progression-free survival (PFS) rates were similar for those with SR FISH, t(4;14) and del(17p) (90%, 100% and 89%; p 〉 .05). Conversely, 3-year PFS rates for MRD-positive patients decreased from those having SR FISH to those with t(4;14) and del(17p) (59%, 46% and 24%, respectively), with statistically significant differences between the first and the latest subgroups (p 〈 .001). Since clearance of MRD notably lowered the risk of relapse and persistence of MRD significantly shortened the PFS in each cytogenetic group (p ≤.001), we investigated the unique features of MRD cells persisting after VRD-induction by comparing their transcriptome to that of patient-matched tumor cells at diagnosis (n=40). Accordingly, MRD cells showed 763 genes significantly deregulated (Padj 〈 .05), including a cluster of proteasome subunits and proteasome related genes (i.e. PSMB5, PSMC3IP, BTRC, HUWE1, FBXL20 and TRIM69). Gene set enrichment analysis unveiled biologic determinants of MRD resistance such as the IL6-JAK-STAT signaling pathway in SR patients and the ROS pathway in HR patients (FDR 〈 0.1). Interestingly, the number of genes deregulated in MRD cells of SR patients was 9-fold higher than HR cases suggesting that, whereas in SR MM, a few tumor cells with specific gene regulatory networks may have higher probability to persist VRD induction, the presence of HR cytogenetic alterations is associated per se, with a transcriptional program that allows a few MRD cells to persist treatment. Conclusions: This is one of the largest studies integrating patients' cytogenetics and MRD status. Our results, based on intensive treatment and MRD monitoring using NGF, unveil that achieving MRD-negativity may overcome the poor prognosis of HR cytogenetics. By contrast, persistent MRD significantly reduces PFS rates, particularly in patients with del(17p). Interestingly, MRD cells from SR and HR patients may have different transcriptional mechanisms leading to VRD resistance, and further understanding of these could provide knowledge on how to eradicate MRD in both patient subgroups. Disclosures Puig: Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Garcia-Sanz:Affimed: Research Funding. Martinez-Lopez:BMS: Research Funding; Pfizer: Research Funding; Vivia: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Research Funding. Oriol:Celgene: 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; 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. Rios:Amgen, Celgene, Janssen, and Takeda: Consultancy. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. Mateos:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, 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; 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; 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. Lahuerta:Janssen: 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; 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. Bladé:Janssen: Honoraria. San-Miguel:Amgen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria.

Abstract: The Godelieve Denys-Struyf method (GDS) is a motor learning intervention that may be applied in group or individualized sessions. Objective The study objective was to compare the effectiveness of routine physical therapy, group GDS (GDS-G) sessions, and group and individualized GDS (GDS-I) sessions. Design This was a cluster randomized controlled trial. Setting The study took place in 21 primary care physical therapy units (“clusters”) of the Spanish National Health Service (SNHS). Participants The participants were 461 people with subacute and chronic low back pain (LBP). Intervention Clusters were randomized into 3 groups. All participants received medical treatment and a 15-minute group education session on active management. Additional interventions were as follows: control (fifteen 40-minute sessions of transcutaneous electrical nerve stimulation, microwave treatment, and standardized exercises), GDS-G (eleven 50-minute group GDS sessions), and GDS-I (the same 11 sessions plus four 50-minute individualized GDS sessions). Measurements Primary outcomes at baseline and 2, 6, and 12 months later were LBP and pain referred down the leg (separate pain intensity numeric rating scales) and disability (Roland-Morris Questionnaire [RMQ]). Secondary outcomes were use of medication and self-reported health (mental and physical component summaries of the 12-Item Short-Form Health Survey [SF-12] ). Separate linear mixed models for LBP, pain referred down the leg, and disability were developed to adjust for potential confounders. Randomization, outcome assessment, and data analyses were masked. Results At 12 months, disability improved 0.7 (95% confidence interval [CI]=−0.4, 1.8) RMQ point in the control group, 1.5 (95% CI=0.4, 2.7) RMQ points in the GDS-I group, and 2.2 (95% CI=1.2, 3.2) RMQ points in the GDS-G group. There were no differences in pain. Limitations The amount of exercise was smaller in the control group, and GDS-I sessions were provided by junior physical therapists. Conclusions The improvement in disability was slightly higher with group GDS sessions than with the program routinely used in clusters within the SNHS. Adding individualized GDS sessions eliminated this advantage. Further studies should compare the GDS with other types of exercise.

Abstract: The value of minimal residual disease (MRD) status by bone marrow and imaging analysis as independent prognostic factors has been well established in multiple myeloma (MM). Nevertheless data about their potential complementarity for a more accurate assessment are limited. With this aim, we retrospectively analyzed the prediction of outcome with the combination of PET‐CT and MRD, assessed by multiparameter flow cytometry (MFC) in 103 patients with newly diagnosed MM. We confirmed the benefit in terms of progression‐free survival (PFS), linked to the achievement of negativity by MFC (hazard ratio [HR] 0.53; 95% confidence interval [CI] : 0.28‐0.98), and PET‐CT (HR 0.18; 95% CI: 0.09‐0.36) individually. By combining both techniques, patients who became MRD‐/PET‐, with a median of PFS 92 months, had significant prolonged median PFS ( P 〈  .001). This is compared with MRD+/PET‐ and PET+ patients (median PFS of 45 and 28 months, respectively). We observed a significant difference ( P = .003) in overall survival (OS) outcomes between MRD‐/PET‐ and MRD+/PET‐ patients (4‐year OS 94.2% and 100%, respectively), vs PET+ patients (4‐year OS 73.8%). All survival results were confirmed in a conditional landmark analysis. These findings support the potential complementarity between PET‐CT and MFC, and highlight their better predictive capability when improving sensitivity.