Abstract: Introduction In the first weeks of the Covid-19 pandemic when healthcare systems in many areas were overstretched, we documented that hospital mortality in multiple myeloma (MM) patients infected by Sars-Cov-2 was 50% higher than in age matched Covid-19 patients without cancer. In the following months, the pressure on healthcare systems in Spain continued although it did not reach the extreme levels of the first weeks of the pandemic. In this study, we proposed to determine if the severity of Covid-19 outcomes in MM patients has changed over the first year of the pandemic. Patients and methods The Spanish MM Collaborative Group (Pethema-GEM) conducted a survey at national level on plasma cell disorder patients infected by SARS-Cov-2 between March 2020 and February 2021. Sixty-six (69%) out of 96 contacted healthcare centers, from all 17 regions in Spain, reported 502 patients. Data on Covid-19 acute and post-acute phase outcomes (hospitalization, oxygen requirements, severity of symptoms and mortality) were reported first in May 2020 (Martinez-Lopez et al, BCJ 2021) and updated in February 2021. In this study, we compared outcome occurrence between two study periods: P1, a period of extreme stress for the healthcare system in Spain, from March to mid-June 2020; and a second period, P2, up to mid-February 2021 with a sustained but lower burden on the national health care system. Results Among the 451 patients with plasma cell disorders and a Sars-Cov-2 infection documented with an rRT-PCR positive test, 377 (84%) were MM patients, 15 SMM (3%), 40 MGUS (9%) and 19 amyloidosis (4%). The number of MM weekly reported cases was 57% (95%CI, 48-65) lower in P2 (188 cases in 35 weeks) compared to P1 (189 cases in 15 weeks), p & lt;0.001. The mean (SD) age and the proportion of men did not differ between P1 and P2, respectively 69.8 (10.9) vs 68.6 (11.0) years, p=0.6, and 53.3% vs 59.6%, p=0.2. MM patients with active or progressive disease at time of Covid-19 diagnosis were 24% in P1 and 34% in P2, p=0.05; patients on active treatment were more frequent in P1, 89%, than in P2, 79%, p=0.01. MM treatment was withheld in 78% and 82% of patients, p=0.4. Covid-19 treatment changed over time: MM inpatients received more remdesivir and corticoids in the second period (3% vs 31% p & lt;0.001, and 49% vs 73%, p & lt;0.001, respectively). In P1, 90% of the reported MM patients were hospitalized compared to 71% in P2, p & lt;0.001. Thirty-one and 41% of patients did not require oxygen support during P1 and P2, respectively; non-invasive ventilation in 19% and 14%, and mechanical ventilation in 7% and 8%, p=0.12. Overall, acute clinical Covid-19 severity was reduced from P1 to P2: 75% to 51%, p & lt;0.001: moderate/severe pneumonia was reduced from 68% to 36%, p & lt;0.001 but severe distress syndrome increased from 7% to 15%, p=0.03. However, mortality in all reported patients was 30.7% in P1 vs 26.1% in P2, p=0.3; and no differences in mortality were observed in hospitalized patients, 32.2% in P1 and 35.3% in P2, p=0.6. We performed a multivariable adjustment with the predictors identified in our previous study (BCJ 2021) and confirmed that inpatient mortality was similar in both study periods, odds ratio (OR) 0.99 (95%CI 0.59-1.66). Independently of the study period, an increased mortality was observed in men (OR 1.81, 1.08-3.05), patients over 65 (OR 2.40, 1.33-4.36), and patients with active or progressive disease (OR 2.12, 1.24-3.62). The severity of Covid-19 clinical outcomes -besides mortality, was associated with increased age but not with active or progressive disease. Conclusions Although COVID-19 clinical severity has decreased over the first year of the pandemic in multiple myeloma patients, mortality remains high with no change between the initial weeks of the pandemic and the following months. Prevention and vaccination strategies should be strengthened in this vulnerable population, particularly in patients with active or progressive disease at time of Covid-19 diagnosis. Disclosures Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy; Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Mateos: Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Sanofi: 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; Celgene - Bristol Myers Squibb: 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; Bluebird bio: Honoraria; GSK: Honoraria; Oncopeptides: Honoraria. López-Muñoz: Amgen: Consultancy. Sureda: GSK: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Mundipharma: Consultancy; Bluebird: 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, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. Lahuerta: Celgene, Takeda, Amgen, Janssen and Sanofi: Consultancy; Celgene: Other: Travel accomodations and expenses. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, Takeda: Consultancy, Other: Advisory board.

Abstract: Assessing measurable residual disease (MRD) has become standard with many tumors, but the clinical meaning of MRD in multiple myeloma (MM) remains uncertain, particularly when assessed by next-generation flow (NGF) cytometry. Thus, we aimed to determine the applicability and sensitivity of the flow MRD-negative criterion defined by the International Myeloma Working Group (IMWG). PATIENTS AND METHODS In the PETHEMA/GEM2012MENOS65 trial, 458 patients with newly diagnosed MM had longitudinal assessment of MRD after six induction cycles with bortezomib, lenalidomide, and dexamethasone (VRD), autologous transplantation, and two consolidation courses with VRD. MRD was assessed in 1,100 bone marrow samples from 397 patients; the 61 patients without MRD data discontinued treatment during induction and were considered MRD positive for intent-to-treat analysis. The median limit of detection achieved by NGF was 2.9 × 10 −6 . Patients received maintenance (lenalidomide ± ixazomib) according to the companion PETHEMA/GEM2014MAIN trial. RESULTS Overall, 205 (45%) of 458 patients had undetectable MRD after consolidation, and only 14 of them (7%) have experienced progression thus far; seven of these 14 displayed extraosseous plasmacytomas at diagnosis and/or relapse. Using time-dependent analysis, patients with undetectable MRD had an 82% reduction in the risk of progression or death (hazard ratio, 0.18; 95% CI, 0.11 to 0.30; P 〈 .001) and an 88% reduction in the risk of death (hazard ratio, 0.12; 95% CI, 0.05 to 0.29; P 〈 .001). Timing of undetectable MRD (after induction v intensification) had no impact on patient survival. Attaining undetectable MRD overcame poor prognostic features at diagnosis, including high-risk cytogenetics. By contrast, patients with Revised International Staging System III status and positive MRD had dismal progression-free and overall survivals (median, 14 and 17 months, respectively). Maintenance increased the rate of undetectable MRD by 17%. CONCLUSION The IMWG flow MRD-negative response criterion is highly applicable and sensitive to evaluate treatment efficacy in MM.

Abstract: Background: Since survival in AL mainly depends on the extent of organ involvement of patients at presentation, early diagnosis and risk stratification are key to improve patients' outcome. Therefore, together with surrogates of organ involvement, biomarkers identifying patients with MGUS or MM at greater risk of developing AL would be highly valuable to prevent organ damage, to maximize therapeutic efficacy and to improve outcomes in AL. Aim: To investigate the value of multidimensional flow cytometry (MFC) for simultaneous fast diagnostic screening of plasma cell (PC) clonality and risk stratification, as well as to identify immunophenotypic markers useful for the selection of patients with monoclonal gammopathies candidates for monitoring of pre-symptomatic organ damage related to AL. Methods: We used MFC to characterize a large series of patients with newly-diagnosed (ND) AL (N=94) vs MGUS (N=20) and NDMM (N=52), as well as age-matched healthy adults (HA, N=30). For each patient with AL, automated risk stratification was performed using principal component analysis (PCA) based on the relative frequency of bone marrow (BM) PCs, plus the percentage of clonal and normal PCs within the whole BM PC compartment, vs a database containing information on the same three parameters from a total of 1,774 patients, including 497 MGUS and 1,227 NDMM. In parallel, immunophenotypic protein expression profiles (iPEP) of AL patients were clustered using t-SNE, and the comparison between the iPEP of clonal PCs from patients with AL vs MGUS and MM cases was performed using canonical-correlation analysis (CCA). To identify additional immunophenotypic hallmarks of AL, the BM cellular composition in HA, MGUS, AL and MM patients was compared using 2-dimensional minimum spanning tree (MST) force-directed classification to determine the distance among individual cases. Results: PC clonality was detected by MFC in 93/94 (99%) AL patients, whereas an M-component was detectable in 96% of cases by electrophoresis, immunofixation and sFLC. PCA as defined above, identified AL patients displaying an MM-like (n=6) and an MGUS-like (n=38) signature, as well as 49 cases with an intermediate signature between the MGUS and MM reference datasets. Multivariate analysis of baseline prognostic factors for survival, including patients' age, number of organs involved, Mayo staging, the percentage of BM PCs based on cytomorphology and eligibility for ASCT, showed that having an intermediate- or an MM-like profile had an independent adverse effect on patients' progression-free (PFS) and overall survival (OS) (HR:3.4; P≤.02). t-SNE based on the iPEP of clonal PCs revealed two major clusters of AL patients with significantly different PFS, defined by opposite patterns of expression for CD45, CD56 and CD138 (P≤.02). CCA of tumor iPEP showed partial overlap between AL vs MGUS and MM, with progressively higher percentages of cases with a CD38lo, CD45-ve, CD81-ve and CD138lo iPEP being observed from MGUS to AL and MM. In contrast, AL patients displayed significantly lower reactivity for CD56 (P≤ .03). Further characterization of the BM cellular composition allowed the systematic assessment of 16 cell populations and 18 phenotypic parameters that, by MST, mapped AL in between MGUS and MM. Of note, while AL patients displayed a predominantly-clonal PC compartment in the absence of an MM-like tumor PC expansion, the percentage of B-cell precursors was consistently lower in AL patients than in HA, MGUS and MM (P=.004). Thus, using optimal cut-off values to discriminate between AL vs MGUS and MM, we built a scoring model based on the presence of 〈 100% CD56+ve clonal PCs, 〈 0.1% B-cell precursors, 〉 80% clonal PCs within total BM PCs and 〈 2% BM PCs. Overall, a significant (P 〈 .001) association was found between a progressively higher score and the diagnosis of AL, with a 74% accurate classification based on ROC analysis (AUC of 0.74; 95% CI = 0.66 - 0.82; P 〈 .001) of the performance of the scoring model. Conclusions: We demonstrate the value of MFC for fast diagnostic screening of PC clonality in AL and simultaneous automated patient risk-stratification, based on the BM tumor burden and PC phenotype. In addition, our results also provide new immunophenotypic markers for the identification of patients with monoclonal gammopathies that are candidates for monitoring of pre-symptomatic organ damage related to AL. Disclosures Puig: Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding. Ocio:Array Pharmaceuticals: Research Funding; Sanofi: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Pharmamar: Consultancy; BMS: Consultancy; AbbVie: Consultancy; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy; Mundipharma: Research Funding; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Oriol:Takeda: 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; Amgen: 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. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. Martinez Lopez:Janssen: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau. Mateos: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; 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; 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. Lahuerta:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria.

Abstract: The existence of patients with multiple myeloma (MM) and light-chain (AL) amyloidosis who present with a monoclonal gammopathy of undetermined significance (MGUS)–like phenotype has been hypothesized, but methods to identify this subgroup are not standardized and its clinical significance is not properly validated. PATIENTS AND METHODS An algorithm to identify patients having MGUS-like phenotype was developed on the basis of the percentages of total bone marrow (BM) plasma cells (PC) and of clonal PC within the BM PC compartment, determined at diagnosis using flow cytometry in 548 patients with MGUS and 2,011 patients with active MM. The clinical significance of the algorithm was tested and validated in 488 patients with smoldering MM, 3,870 patients with active MM and 211 patients with AL amyloidosis. RESULTS Patients with smoldering MM with MGUS-like phenotype showed significantly lower rates of disease progression (4.5% and 0% at 2 years in two independent series). There were no statistically significant differences in time to progression between treatment versus observation in these patients. In active newly diagnosed MM, MGUS-like phenotype retained independent prognostic value in multivariate analyses of progression-free survival (PFS; hazard ratio [HR], 0.49; P = .001) and overall survival (OS; HR, 0.56; P = .039), together with International Staging System, lactate dehydrogenase, cytogenetic risk, transplant eligibility, and complete remission status. Transplant-eligible patients with active MM with MGUS-like phenotype showed PFS and OS rates at 5 years of 79% and 96%, respectively. In this subgroup, there were no differences in PFS and OS according to complete remission and measurable residual disease status. Application of the algorithm in two independent series of patients with AL predicted for different survival. CONCLUSION We developed an open-access algorithm for the identification of MGUS-like patients with distinct clinical outcomes. This phenotypic classification could become part of the diagnostic workup of MM and AL amyloidosis.

Abstract: Introduction: The GEM-CESAR trial is a potentially curative strategy for high-risk smoldering multiple myeloma (HRsMM) patients in which the primary endpoint is the assessment of bone marrow minimal residual disease negativity by next generation flow (NGF). However, alternative methods of tumor burden evaluation in serum, like Quantitative Immunoprecipitation Mass Spectrometry (QIP-MS), a polyclonal antibody-based technology to identify intact immunoglobulins, have been also evaluated. Patients and Methods: Ninety HRsMM patients included in the GEM-CESAR trial received six 4-weeks cycles of carfilzomib, lenalidomide and dexamethasone followed by high dose melphalan and ASCT and 2 further cycles of consolidation with the same regimen. All patients received maintenance with lenalidomide up to 2 years. SPEP and IFE were performed using standard procedures and MRD was analyzed by flow cytometry following EuroFlow recommendations. QIP-MS assessment has been previously described (1) and allowed us the characterization of the isotype of each Ig trough immunoprecipitation with paramagnetic beads as well as the measurement of the molecular mass of each Ig for each specific patient, with enough precision and accuracy to establish clonality. Standard response assignment was carried out as per the IMWG guidelines. Results: First, we confirmed the higher sensitivity of QIP-MS to identify the presence of a serum M-spike as compared to conventional protein immunofixation electrophoresis methods. Amongst patients in CR, QIP-MS identified the M-spike in 18/30 (60%) post-induction, 18/47(38%) post-ASCT and 25/58(43%) post-consolidation. Interestingly, similar results were obtained with MRD-NGF post-induction [17/30(57%)] and post-ASCT [15/47(32%)] although the positive rate post-consolidation [15/58(26%)] was higher with QIP-MS. Then, we analyzed the overall concordance between the results obtained with QIP-MS and MRD-NGF at the three timepoints of disease evaluation, finding an overall concordance of 81% post-induction (n=76), 70% post-transplant (n=76) and 68% post-consolidation (n=77). Thus, when compared to the results of MRD-NGF, QIP-MS demonstrated sensitivities of 100%, 79% and 77% post-induction, post-ASCT and post-consolidation, and negative predictive values (NPV) of 100%, 79% and 82% at each respective time-point. (P & lt; 0,0001; P = 0,0004; P = =,0012) Evaluation of discrepant cases showed 14 out of 22 MRD-NGF-negative patients post-induction for whom QIP-MS identified a M-spike; in some cases (i.e. IgG MM isotype) this may be related to a longer immunoglobulin half-life. There were no cases with detectable disease by NGF but QIP-MS negative. By contrast, post-ASCT, QIP-MS was negative in seven MRD-positive patients, two of whom became MRD-NGF-negative after consolidation; at last follow-up, none of them have progressed. On the other hand, sixteen patients with negative MRD-NGF after ASCT had a detectable M-spike by mass spectrometry. Of note, the M-spike became undetectable after consolidation in six out of these 16 patients. Post-consolidation, there were 7 patients in which MRD-NGF was positive but QIP-MS negative: MRD evaluation during maintenance is pending but none of them have so far progressed. By contrast, there were 18 patients with the M-spike detectable by QIP-MS but MRD-NGF negative: follow-up of these patients will address their outcome but, the only patient that has progressed so far had MRD-NGF negative post-induction, becoming positive post-transplant and consolidation, but the M-spike was detectable by QIP-MS throughout. Conclusions: M-spike monitoring by QIP-MS shows a moderate concordance with the MRD assessment by NGF in this group of HRsMM homogeneously treated. Longer follow-up will allow us to unravel the outcome of discordant cases and to define the specificity of QIP-MS and its complementary value to NGF. North S, Barnidge D, Brusseau S, Patel R, Haselton M, Du Chateau B, et al. QIP-MS: A specific, sensitive, accurate, and quantitative alternative to electrophoresis that can identify endogenous m-proteins and distinguish them from therapeutic monoclonal antibodies in patients being treated for multiple myeloma. Clinica Chimica Acta 2019;493:S433. Disclosures Puig: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; The Binding Site: Honoraria; Takeda, Amgen: Consultancy, Honoraria. Mateos:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; Abbvie: 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; EDO: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. 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. Rodriguez Otero:Takeda: Consultancy; Kite Pharma: Consultancy; BMS: Honoraria; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria. Oriol:Celgene, Amgen, Takeda, Jansse: Consultancy, Speakers Bureau. Rios: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. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. de la Rubia:AbbVie: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Takeda: Consultancy. De Arriba:Amgen: Consultancy, Honoraria; Takeda: Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Ocio:Mundipharma: Research Funding; Pharmamar: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; AbbVie: Consultancy; Takeda: Consultancy, Honoraria; Array Pharmaceuticals: Research Funding; Sanofi: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy; Novartis: Consultancy, Honoraria; BMS: Honoraria. Bladé:Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees; Irctures: Honoraria. Lahuerta:Takeda, Amgen, Celgene and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: 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.

Abstract: Introduction: The GEM-CESAR trial is a potentially curative strategy for high-risk smoldering multiple myeloma (HRsMM) patients (pts) in which the primary endpoint is the achievement of bone marrow minimal residual disease (MRD) negativity. However, other methods of disease evaluation in serum such as heavy+light chain (HLC) assessment, with a potential complementary value to the IMWG response criteria, have also been tested. Aim: To evaluate the performance of HLC assay in HRsMM pts at diagnosis and after consolidation, comparing the results with standard serological methods and Next Generation Flow (NGF) for the assessment of bone marrow MRD. Patients and Methods: Ninety HRsMM pts included in the GEM-CESAR trial received six 4-weeks cycles of carfilzomib, lenalidomide and dexamethasone followed by high dose melphalan and 2 further cycles of consolidation with the same regimen. All pts received maintenance treatment with lenalidomide for up to 2 years. SPEP and IFE were performed using standard procedures. Serum IgGk, IgGl, IgAk and IgAl HLC concentrations were measured using Hevylite (The Binding Site Group Ltd, Birmingham, UK) on a SPA PLUS turbidimeter. HLC concentrations and ratios were considered abnormal if they were outside the 95% reference ranges provided by the manufacturer. MRD was analyzed by flow cytometry following EuroFlow recommendations (sensitivity, 2x10-6). Standard response assignment was carried out as per the IMWG guidelines. Hevylite responses were assigned and HLC-pair suppression was defined as in Michalet et al (Leukemia 2018). Results: Out of 90 HRsMM pts, 75 had monoclonal intact immunoglobulin and samples available at diagnosis (50 IgG and 25 IgA). HLC ratio was abnormal in 98% of IgG pts and in 100% of IgA pts. Response assessment by Hevylite and standard IMWG criteria were available in 62 pts post-consolidation (Table 1). A good agreement was found between the two methods (kappa quadratic weighting = 0,6327 (0,4016 - 0,8638)). Among 46 pts with assigned CR as per the IMWG response criteria, there were 3 and 8 pts in PR and VGPR according to the Hevylite method, respectively. In 62 cases, paired Hevylite and MRD assessment data were available. Concordant results were found in 72.5% of cases (45/62; HLC+/NGF+ in 15 and HLC-/NGF- in 30 cases) while in the remaining 27.4% of cases results were discordant (17/62; HLC-/NGF+ in 6 and HLC+/NGF- in 11 cases). Post-consolidation, 24, 25.8 and 42.3% of the 62 samples were positive by SPEP, NGF and Hevylite, respectively. HLC-pair suppression was identified in 13/62 pts; 10 had severe HLC-pair suppression at the end of consolidation. After a median follow-up of 32 months (8-128), 93% of pts remain alive and progression-free. Three patients that have already progressed had their responses assessed post-consolidation. The first pt was assigned VGPR by the standard IMWG criteria and PR by Hevylite and was MRD positive by NGF; the second pt was assigned CR by IMWG criteria and Hevylite but had severe HLC-pair immunosuppression and was MRD positive by NGF; the third pt was in CR by IMWG and HLC criteria and was MRD positive by MFC. Conclusions: Moderate agreement was found between response assessment by Hevylite and the standard IMWG methods as well as between Hevylite and MRD assessment by NGF. Most discordances were a result of Hevylite detecting disease in samples negative by the standard methods, but longer follow-up is needed to ascertain its clinical value. HLC assessment could have anticipated the progression noted in 2 (out of 3) patients. Disclosures Puig: Takeda, Amgen: Consultancy, Honoraria; The Binding Site: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche and Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Sanofi and Takeda: Consultancy. Rodriguez Otero:Kite Pharma: Consultancy; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy. Oriol:Celgene, Amgen, Takeda, Jansse: Consultancy, Speakers Bureau. Rios: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. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. de la Rubia:Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Takeda: Consultancy; AbbVie: Consultancy. De Arriba:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Honoraria. Ocio:Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; BMS: Honoraria; Novartis: Consultancy, Honoraria; Array Pharmaceuticals: Research Funding; Pharmamar: Consultancy; Seattle Genetics: Consultancy; Mundipharma: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; AbbVie: Consultancy; Janssen: Consultancy, Honoraria. Bladé:Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees; Irctures: Honoraria. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Patients with multiple myeloma (MM) may show patchy bone marrow (BM) infiltration and extramedullary disease. Notwithstanding, quantification of plasma cells (PCs) continues to be performed in BM since the clinical translation of circulating tumor cells (CTCs) remains undefined. PATIENTS AND METHODS CTCs were measured in peripheral blood (PB) of 374 patients with newly diagnosed MM enrolled in the GEM2012MENOS65 and GEM2014MAIN trials. Treatment included bortezomib, lenalidomide, and dexamethasone induction followed by autologous transplant, consolidation, and maintenance. Next-generation flow cytometry was used to evaluate CTCs in PB at diagnosis and measurable residual disease (MRD) in BM throughout treatment. RESULTS CTCs were detected in 92% (344 of 374) of patients with newly diagnosed MM. The correlation between the percentages of CTCs and BM PCs was modest. Increasing logarithmic percentages of CTCs were associated with inferior progression-free survival (PFS). A cutoff of 0.01% CTCs showed an independent prognostic value (hazard ratio: 2.02; 95% CI, 1.3 to 3.1; P = .001) in multivariable PFS analysis including the International Staging System, lactate dehydrogenase levels, and cytogenetics. The combination of the four prognostic factors significantly improved risk stratification. Outcomes according to the percentage of CTCs and depth of response to treatment showed that patients with undetectable CTCs had exceptional PFS regardless of complete remission and MRD status. In all other cases with detectable CTCs, only achieving MRD negativity (and not complete remission) demonstrated a statistically significant increase in PFS. CONCLUSION Evaluation of CTCs in PB outperformed quantification of BM PCs. The detection of ≥ 0.01% CTCs could be a new risk factor in novel staging systems for patients with transplant-eligible MM.