ALBERT

Description: Background: Waldenström's macroglobulinemia (WM) is a rare immunoproliferative neoplasia with indolent characteristics that shows important variability, involving three different stages of presentation: IgM Monoclonal Gammopathy of Undetermined Significance (IgM-MGUS), asymptomatic WM (AWM), and Symptomatic WM (SWM). Whole-genome sequencing and some specific approaches have identified MYD88 L265P (90%) and CXCR4 (29%) mutations as the most recurrent somatic mutations in WM. However, other genetic abnormalities under as well as the mechanisms responsible for this clinical heterogeneity still remain to be clarified. Therefore, our aim was to analyze the genomic landscape of WM, distinguishing between the three stages of the disease, by using a targeted next generation sequencing (NGS) strategy. Methods: In this study, we performed a comprehensive mutation analysis of genes previously described as frequently involved in Waldenstrom Macroglobulinemia in a large and well characterized cohort of WM patients with the aim to dissect relationships between genotype and clinical and biological characteristics to integrate somatic mutations into a clinical/molecular prognostic model. Twelve genes of interest (ARID1A, CD79A, CD79B, TP53, MYBBP1A, TRAF2, TRAF3, RAG2, HIST1H1B, HIST1H1C, HIST1H1D, and HIST1H1E) were analyzed by high throughput sequencing (Illumina MiSeq, San Diego, CA) with a novel custom amplicon-based panel in a cohort of 61 patients (pts) diagnosed according to WHO classification as follows: 14 MGUS, 23 AWM and 24 SWM. DNA was extracted from bone marrow separated CD19+ B-cells and sequenced in a MiSeq (Illumina) using 150-bp paired-end reads and a mean depth of 2000X. Bioinformatics analysis was carried out with Illumina VariantStudio 2.2. Results were correlated with biological and clinical data of the patients. MYD88 and CXCR4 mutation status, available in all cases, was assessed by ASO-PCR and Sanger Sequencing, respectively. Results: Apart from MYD88 L265P mutations (present in 90% of cases) and CXCR4WHIM (21% of cases), 23 non-synonymous mutations were found, corresponding to 18/61 (30%) patients. Only one patient with MGUS demonstrated one additional mutation (7%), while seven of the AWM (30%), and 10 of the SWM (42%) demonstrated additional mutations (p

Description: In AL, a small PC clone synthesizes a misfolded light-chain that forms amyloid fibrils causing organ dysfunction. Significant progress was made regarding the characterization of the amyloid fibrils, but little attention has been paid to the molecular features of clonal PCs; this is most likely explained by the low tumor burden in AL, often masked by a polyclonal PC background. Here, we investigated the phenotypic, transcriptomic and genomic profile of clonal PCs from a total of 22 patients with newly-diagnosed AL. Through multidimensional (12-color) flow cytometry (MFC) combining the evaluation of 10 antigens plus cyκ/cyλ (thus confirming clonality of aberrant phenotypes), we detected clonal PC in all 22 (100%) patients (median 0.76%; range: 0.01% - 30%). Clonal PCs mainly differed from normal PCs by down-regulation of CD19 (100% of cases), CD27 (50%), CD38 (41%), CD45 (50%) and CD81 (50%); CD117, CD28 and CD56 were aberrantly bright positive in 32%, 50% and 64% of patients, respectively. Principal component analysis showed overlapping immunophenotypic expression profiles between clonal PC from AL vs multiple myeloma (MM) and MGUS patients. Using patient-specific aberrant phenotypes, we then sorted clonal PCs (purity ≥97%) by MFC for subsequent molecular studies. Gene expression profiling (GEP) was performed (HumanGene1.0ST) on extracted RNA from clonal PCs of 10 of the 22 AL patients, and compared to FACS-purified PCs from 7 healthy donors. Overall, clonal PCs showed deregulation (SAM Excel add-in with a FDR q-value25 consecutive imbalanced markers per segment, 〉100Kb length and

Description: Introduction High-throughput sequencing studies have rendered seminal knowledge in monoclonal gammopathies such as multiple myeloma (MM) and Waldenström's macroglobulinemia (WM). Unfortunately, the low incidence of AL amyloidosis and its typically low tumor burden, often masked by a polyclonal plasma cell (PC) background, account for the limited information on its tumor cell biology. Thus, it remains unknown if AL amyloidosis harbors a unifying mutation as occurs in WM or if, in its absence, there are recurrent mutations and if these overlap with those observed in MM. With this background , the aim of this study is to perform a whole exome sequencing (WES) in a series of patients with AL amyloidosis and to compare mutational profiles in AL amyloidosis vs MM and analyze the copy number variation in this series of patients. Methods A total of 27 patients with confirmed diagnosis of AL were included. WES was performed in 56 paired samples of FACSorted bone marrow tumor plasma cells and peripheral blood mononucleated cells. Each tumor sample was captured in triplicate using Agilent's SureSelect Human All Exon V6 + UTR kit and sequenced on the Illumina NextSeq 500 platform. Data was analyzed with Strelka software to discard germinal mutations, ANNOVAR for functional annotation, and a data reduction strategy to identify candidate variants. The mutational signature was analyzed with Mutational Signatures in Cancer (MuSiCa) software. We used the MMRF CoMMpass dataset (895 patients) to compare the mutational landscape of MM vs AL. We also determined immunoglobulin gene rearrangements in AL by next generation sequencing. Besides, we analyzed the copy number variation (CNV) with CNVkit program. Results The mean depth coverage for control and tumor samples was 64x and 186x, respectively. A total of 1983 somatic SNV and 133 INDEL were identified, with an average of 71 (20-281) SNV and 5 (0-25) INDEL per patient. Overall, the most frequently mutated genes in this series were IGLL5 and MUC16 (recurrence of 17% each). When compared to MM (average of 66 SNV and 2,5 INDEL), we observed a similar mutational load. However, none of the most frequently mutated genes in MM (i.e. KRAS, NRAS, FAM46C, BRAF, TP53, DIS3, PRDM1, SP140, RGR1, TRAF3, ATM,CCND1, HISTH1E, LTB, IRF4, FGFR3,RB1, ACTG1, CYLD, MAX, ATR) were recurrently mutated in patients with AL. The only genes commonly mutated in AL amyloidosis and MM were MUC16 (recurrence of 17% and 8%, respectively) and IGLL5 (recurrence of 17% each).Most patients with AL harbored between 1 and 8 mutational signatures, implying that multiple mutational processes are operative. The most frequent mutational signature were (signatures 6, 15 and 20) associated with mismatch repair protein deficiency (MMR) and high microsatellite instability (93%), mutational signature 2 (89%), related with the aberrant activity of APOBECs, a family of proteins that enzymatically modify single-stranded DNA and mutational signature 1 (81%), profile that appear in all types of cancers and has been correlated with the age of cancer diagnosis. The signature 2 is also representative of MM. Regarding the immunoglobulin gene repertoire, we noted that 26% of patients with AL harbored more than one clone; this extent in clonal heterogeneity being similar to that found in MM (23%).The most frequent IGH gene involved was IGHV3-30 in both AL (recurrence of 10%) and MM (recurrence of 12%).Regarding CNV, recurrent gains included chromosomes 1q (29%), 5 (38%), 6p (14%), 7 (43%), 9 (43%), 15 (24%), 18 (14%) and 19 (43%). Recurrent losses affected chromosome 13 (33%), 6q (14%) and 16q (19%). Conclusions This is the first WES study performed in a series of patients with AL. We demonstrated the lack of a common driver mutation in this disease and unveiled that recurrently mutated genes in AL amyloidosis do not overlap with those observed in MM. We also confirm the existence of numerous chromosomal alterations in patients with AL. The frequencies of aberrations and alterations detected by NGS are comparable with those describe in previous studies by copy number array analysis, but here we show some novel recurrent chromosomal aberrations as gain of chromosome 7 (43%) and losses of chromosome 18 (14%). Overall, these results may have significant impact in our understanding of the pathogenesis of AL amyloidosis and its differential diagnosis vs other monoclonal gammopathies. Disclosures Ocio: BMS: Consultancy; Novartis: Consultancy, Honoraria; Sanofi: Research Funding; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy; AbbVie: Consultancy; Janssen: Consultancy, Honoraria; Pharmamar: Consultancy; 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. 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. Puig:Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding. Lahuerta:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Mateos: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; 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; 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; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. San-Miguel:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Roche: Honoraria. Martinez Lopez:Novartis: Research Funding, Speakers Bureau; Jansen: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau.

Description: Background: MM and AL are the two most common malignant monoclonal gammopathies. Both diseases result from the accumulation of clonal PCs, but their clinical behavior is significantly different suggesting fundamental differences in disease biology. Previous attempts to identify genetic hallmarks that could explain such differences have been unsuccessful. Furthermore, it is unknown if MM and AL arise from the same or different normal PC counterparts. Aim: To define a transcriptional atlas of the normal PC development in peripheral blood (PB) and bone marrow (BM) for comparison with the transcriptional programs of clonal PCs in MM and AL. Methods: A total of 93 subjects were studied. In 7 healthy adults (HA), PB PCs were phenotypically sorted according to heavy-chain isotypes (IgG, IgA and IgM). In addition, 5 different BM PCs subsets were isolated based on the differential expression of CD19, CD39, CD81 and CD56, due to their ascribed role in dissecting unique BM PC differentiation states. Clonal PCs from patients with MM (n=38) and AL (n=41) were isolated by FACS according to patient-specific aberrant phenotypes. Due to small numbers of PCs sorted from each subset in HA and clonal PCs in AL patients, we used an RNAseq method optimized for limited cell numbers. Differential expression across all pairwise comparisons between groups was analyzed with Deseq2 R package followed by k-means clustering of genes in R. Single-cell RNAseq (scRNAseq, 10xGenomics) was performed in a total of 35,910 PCs from 3 HA, 2 MM and 2 AL. We used Seurat R package to remove batch effect followed by canonical correlation to perform an integrated analysis of all single PCs from HA, MM and AL subjects. Results: Principal component analysis of RNAseq data unveiled two major clusters of normal PCs: those in PB and those in BM (with some transcriptional diversity between CD19+ and CD19- PCs), whereas the CD19+CD39+CD81+CD56- BM subset co-localized with PB and CD39- BM PCs (Panel A). Clonal PCs from MM and AL patients clustered together, and both displayed some transcriptional variance related to the spatial location of normal PCs (i.e. PB or BM). In total, 2174 genes were found significantly deregulated after cross-comparing the 10 PC groups (adj.p-value1) and semi-supervised k-means clustering unveiled 8 transcriptional modules (Panel B). Namely, the transition from PB into BM PCs was characterized by genes related to proliferation (clusters 1 & 2), whereas CD39+ and CD39- BM PC subsets differed on the expression of genes associated with proliferation, homing, and metabolism (1, 2, 4 & 6). Thus, CD19+CD39+CD81+CD56- BM PCs emerged as a novel subset that bridges new-born PB with long-lived (CD39-) BM PCs. Interestingly, clonal PCs from MM and AL shared transcriptional programs related to quiescence (5 & 6) with long-lived BM PCs; however, skewing of polyclonal immunoglobulin gene expression (3) and active gene transcription (8) emerged as hallmarks of the neoplastic transformation from normal, long-lived PCs into clonal PCs. That notwithstanding, the later displayed expression levels of the proliferation and homing transcriptional modules (1 & 4) similar to new-born PB and CD39+ BM PCs. Of note, a small transcriptional cluster of genes related to ribosome biogenesis (7) was significantly more expressed in MM than AL. These findings led us to integrate scRNAseq profiles of normal and clonal BM PCs from MM and AL patients, to define PC clusters based on their transcriptional program rather than their normal vs malignant status (Panel C). This strategy unveiled 11 different PC clusters with unequal distribution between groups. Thus, more than half of clonal PCs in MM and AL were assigned to a cluster that is also predominant in normal PCs (1). By contrast, other clusters with a transcriptional program similar to that of new-born PCs (2 & 5) became rarer in MM and AL. Furthermore, a cluster of PCs with an immature-like phenotype (6) was detectable in MM but almost absent in AL. Conclusions: This is the first integrated analysis of the transcriptional programs of normal PC subsets and clonal PCs in MM and AL, both at the bulk and single-cell levels. Our results unveil shared and exclusive transcriptional states in normal and clonal PCs, together with unique differences between clonal PCs in MM and AL. Thus, we provide here a fundamental resource to understand normal PC development and the cellular origin of both malignant monoclonal gammopathies. Figure Figure. Disclosures Puig: Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Ocio:Pharmamar: Consultancy; AbbVie: Consultancy; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy; BMS: Consultancy; 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. Oriol:Janssen: 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; 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. Martinez Lopez:Bristol Myers Squibb: Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau. Mateos: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; 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; 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; 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. 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. 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.

Description: Key Points MFC is a valuable biomarker to discriminate “true” SBP patients from those with “occult” BM clonal PCs and high-risk of progression to MM.

Description: Key Points Benign (ie, IgM MGUS and smoldering WM) clonal B cells already harbor the phenotypic and molecular signatures of the malignant WM clone. Multistep transformation from benign (ie, IgM MGUS and smoldering WM) to malignant WM may require specific copy number abnormalities.

Description: Background: Chromosome 14q32 rearrangements involving the immunoglobulin heavy chain gene (IGH) affect less than 5% of chronic lymphocytic leukemia (CLL) patients. Their clinical course is aggressive and the outcome, worse than other CLL subtypes (Cavazzini et al, 2008; Gerrie et al, 2012). However, the biology of CLL showing IGH rearrangements (CLL-IGHR) is not completely defined. The identification of novel recurrent mutations in CLL by next generation-sequencing (NGS) has offered a more comprehensive view into the genomic landscape of the disease and improved the prognostication of CLL. Thus, mutational analysis might be especially useful in those patients with uncertain prognosis, such as those carrying IGH rearrangements. Aim: To analyze the mutational profile of CLL-IGHR patients by targeted NGS in order to improve our understanding of the genetic underpinnings of this subgroup. Methods: The study was based on 899 CLL patients, well characterized at cytogenetic, biological and clinical level, forty-two of them (4.7%) showing IGH rearrangements. Targeted NGS was performed in 231 CLL samples: 117 with 13q deletion, 27 with 11q deletion, 26 trisomy 12, 42 showing IGH rearrangements and the remaining 19 without any cytogenetic alteration. CD19+ B cells were isolated and DNA extracted. SureSelectQXT targeted enrichment technology and a custom-designed panel (MiSeq, Illumina), including 54 CLL-related and recurrent mutated genes, was carried out. The panel yielded 100x or greater coverage on 97% of the genomic regions of interest and the mean coverage obtained was 600x. Mutations were detected down to 3% allele frequency. Results: The mutational analysis of CLL-IGHR patients identified a total of 72 mutations in 32 genes. Seventy-one percent of patients (30/42) harbored at least one mutation. The most frequently mutated genes in this cohort were NOTCH1 (28.6%), POT1 (14.3%), TP53 (9.5%), SF3B1 (7%), BRAF (7%), EGR2 (7%), IGLL5 (7%) and MGA (7%), followed by BCL2, HIST1H1E and FBXW7 (4.8%), uncommonly mutated genes in CLL at these frequencies (Table 1). In fact, mutations in NOTCH1, BRAF, EGR2, BCL2, HIST1H1E and FBXW7 were significantly associated with CLL-IGHR patients (p=0.013, p=0.003, p=0.021, p=0.038, p=0.038 and p=0.021 respectively). In terms of time to the first therapy (TFT), CLL-IGHR had an intermediate-negative impact (median TFT=24 months) compared to the presence of cytogenetic alterations associated with good prognosis such as 13q deletions (median TFT〉120 months; p

Description: Clonal evolution is considered as a hallmark of progression in chronic lymphocytic leukemia (CLL). Next-generation sequencing technologies have expanded our knowledge of genetic abnormalities in CLL and enabled to describe marked clonal changes. The acquisition of driver mutations accompanied by selectively neutral passenger changes may be essential to understand the transformation from diagnosis to later more aggressive stages. However, the role of genetic mutations and clonal evolution during the clinical progression prior any therapy is still largely unknown. Longitudinal studies analyzing CLL patients repeatedly before intervening treatment are currently scarce. Patients and methods: We examined the exomes from 35 CLL patients in 2 time-points. Two groups of patients were characterized: (i)patients with progression (n=26) in which we analyzed samples taken from an early stable stage (inactive disease) and during clinical progression (active disease), but before treatment (median of time to first treatment=2.7 years); (ii)patients without progression with a stable inactive disease until last follow-up (n=9) (median follow-up=5.25 years). We also compared patients that gained new cytogenetic aberration detected by FISH in the 2nd time-point with those who did not. Sequencing libraries were prepared using TruSeq Exome Enrichment and sequenced by Illumina HiSeq1000 (84X). Somatic mutation calling was performed by a standardized bioinformatics pipeline. Thereafter, driver mutations were identified using the Cancer Genome Interpreter (https://www.cancergenomeinterpreter.org), a novel tool that identifies variants that are already validated as oncogenic and predicts the effect of the mutations of unknown significance. Results: We identified 397 somatic mutations in 364 different genes, ranging from 4 to 26 mutations per patient. Among them, 58 driver mutations were identified, being SF3B1 (6/35, 17.1%), TP53 (4/35, 11.4%) and NOTCH1 (4/35, 11.4%) the most common mutated genes. Comparing progressive vs. stable group, CLL patients with clinical progression showed a higher intra-tumoral heterogeneity than cases without progression (median of somatic mutations=14[4-26] vs. 9[5-14]). Comparing both tumoral time-points in the same patient, we identified a total of 11 acquired driver mutations and 7 mutations increasing its allele frequency in more than double in the 2nd time-point respect to the 1st one. All of them were detected in patients with clinical progression. Interestingly, TP53 and BIRC3 exhibited recurrently acquired mutations (detected each one in 2 cases). Three driver mutations in cancer genes not yet known for CLL (DHX9, GNAQ and HDAC2) were also acquired. Within CLL progressive patients (n=26), we observed clonal evolution characterized by acquired cytogenetic aberration in 9 cases. In patients with progression but no cytogenetic aberration gained at the 2nd moment (n=17), we detected that almost half of them (7/17) showed clonal evolution by acquired or doubled driver mutations. In the remaining patients with clinical progression but without any clonal evolution (n=10), 6 cases showed a driver mutation of CLL genes associated with bad prognosis (SF3B1, TP53, NOTCH1 or RPS15) already at first time-point. In the stable group (n=9), none acquired or doubled mutation was detected. However, clonal evolution characterized by acquired cytogenetic aberration was observed in 4/9 stable patients: two of them acquired 13q- whereas the other two acquired 11q-. Within stable patients without clonal evolution (n=5), we detected one case with a driver mutation in SF3B1 already at 1st time-point (follow-up=5 years). Conclusion: Clonal evolution represents a central feature of tumor progression in CLL. Our data show that the disease is evolving during time even in stable patients without any clinical signs of disease activity. In progressive patients, the disease evolution is accompanied by new appearance or accumulation of driver mutations and cytogenetic aberrations. Moreover, progressive patients that showed less or no changes during time bore typical CLL drivers at the first time-point. Funding: Seventh Framework Programme (NGS-PTL/2012-2015/no.306242); Ministry of Education, Youth and Sports (2013-2015, no.7E13008; CEITEC 2020 (LQ1601)); AZV-MZ-CR 15-31834A-4/2015 and TACR (TEO2000058/2014-2019); PI15/01471; Junta de Castilla y León (MHS). Disclosures No relevant conflicts of interest to declare.

Description: BACKGROUND High dose therapy followed by autologous stem cell transplantation (ASCT) remains the standard of care, especially in Europe, for young and eligible multiple myeloma patients (usually younger than 65 years old). Immunoparesis is defined as a reduction (below the lower normal limit) in the levels of 1 or 2 uninvolved immunoglobulins (Ig) and it is related to a reversible suppression of B lymphocytes that correlates inversely with disease stage. B Lymphocyte reconstitution begins at 3 months after ASCT, with maximum B lymphocyte levels at 1 year after ASCT. AIMS The goal of the present study was to investigate the role of the immunoparesis recovery after ASCT as predictor of relapse or progression in multiple myeloma (MM). METHODS We reviewed medical records of MM patients who underwent to ASCT at University Hospital of Salamanca between 1992 and 2013. The primary endpoint was time to relapse or progression from ASCT. Ig (Ig G, Ig A e Ig M) were collected at the time of diagnosis, before ASCT, every 3 months during the first year after ASCT, and every year up to 5 years after ASCT among eligible patients until the relapse or disease progression. RESULTS 106 multiple myeloma patients who underwent ASCT were included in the analysis. Conventional chemotherapy was administered as induction regimen in 69 patients (65%), whereas novel agents were used in 37 patients (35%). Most patients had immunoparesis at diagnosis (91%) and at the moment of ASCT as well (94%). After a median follow-up of 62 months, median time to progression or relapse (TTP) from ASCT was 31 months (95 % CI: 24.1 - 37.1 months). MM patients with immunoparesis 1 year after ASCT had a significantly shorter median TTP as compared with patients without immunoparesis (33.5 months vs 94.2 months; HR: 2.14, 95% CI: 1.13-4.05; p=0.019). In the group of patients with reduction of both Igs, median TTP was slightly inferior than in the group with reduction of only one of them(33.5 vs 36.4 months, p=0.03). Presence of ISS 3, high-risk cytogenetics at diagnosis, less than partial response achieved before and three months after ASCT were also identified as predictors of progression. Multivariate analysis selected immunoparesis 1 year after ASCT as an independent variable for relapse or progression (HR: 5.97, 95% CI: 1.63-21.88; P=0.007). CONCLUSIONS The lack of immunoparesis recovery at 1 year after ASCT in MM patients is associated with significantly higher risk of relapse or progression and this group of patients could potentially benefit of continuous treatment after ASCT to enhance the immune recovery. Disclosures Ocio: Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy; Mundipharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; MSD: Research Funding; Pharmamar: Consultancy, Research Funding; Janssen: Honoraria. Puig:The Binding Site: Consultancy; Janssen: Consultancy. Mateos:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy; BMS: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Description: The two main criteria for risk-adapted treatment in AML are the presence of adverse cytogenetic or molecular features, and the response to induction treatment assessed by morphology, in which only failure to respond is truly informative. Therefore, more sensitive techniques are needed to evaluate the response. However, the potential value of MRD detection within different cytogenetic subgroups in AML has not yet been defined. This raises the question of whether a negative MRD result could counterbalance the adverse effect of poor-risk cytogenetics, or whether high MRD levels after induction modify the outcome of patients with otherwise favourable feature. In addition, it is not known whether the modality of intensification therapy modifies the influence of the level of MRD assessed after induction therapy. We analyzed the prognostic impact of MRD level on the BM at CR after induction therapy using MFC in 306 non-APL AML patients. First, we have validated the prognostic value of MRD thresholds we had previously proposed (≥0.1%; ≥0.01-0.1%; and