Abstract: VRD was effective and well tolerated before ASCT; 33.4% complete response/28.8% minimal residual disease–negative after 6 induction cycles. Responses deepened with VRD throughout induction and over the course of treatment with few discontinuations due to toxicity.

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

Abstract: Introduction: SMM is an asymptomatic and heterogeneous plasma cell disorder. Both Spanish Myeloma and ECOG Groups have demonstrated that pts at high risk of progression to active MM benefit from early treatment with R-based regimens. Our next step was to design this phase 2, single arm trial, focusing on the same population, but with the potential goal of cure, defined by sustained minimal residual disease negativity (MRD-ve) at 5 years after HDT-ASCT. Patients and methods: Ninety SMM pts at high-risk of progression ( & gt;50% at 2 yrs), younger than 70 years and transplant candidates were included. The high risk was defined by the presence of both ≥PC 10% and MC ≥3g/dL (Mayo) or ifonly one criterion was present, pts must & gt;95%of aberrant PCs within the total PCsBM compartment by immunophenotyping plus immunoparesis (Spanish). Induction therapy consisted on six 4-weeks cycles of KRd in which K was given at dose of 36 mg/m2 twice 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/m2 followed by ASCT was given as intensification therapy followed by two KRd consolidation cycles and maintenance with R at dose of 10 mg plus dexamethasone at dose of 20 mg weekly for up to 2 yrs. The primary end-point was to evaluate the MRD-ve rate by next generation flow (NGF) after induction and ASCT and our aim was to increase the MRD -ve rate from 34% (reported in NDMM pts after VTD and ASCT) to at least 50%. Results: Between June 2015 and June 2017, 90 high-risk SMM pts were recruited. Twenty-eight pts (32%) shared at least one of the new biomarkers predicting imminent risk of progression to MM. On February 4th, 2019, 71 pts were already receiving maintenance treatment; 7 pts had finalized the treatment and there were 11 early discontinuations (4 biochemical relapses during maintenance, 2 Informed Consent refusal, 3 adverse events and two deaths). After a median follow-up of 32 months (8-128), 93% of pts remain alive and free of progression and 98% of them alive. In the intent-to-treat pts' population, after induction, the ≥CR rate was 41% and increased to 59% after HDT-ASCT and to 70% after consolidation. In the same analysis, MRD-ve rate was observed in 30% of pts after induction, 52% after HDT-ASCT and 57% after consolidation. If we focus on the 83 pts who completed induction, HDT-ASCT and consolidation, the ≥CR/undetectable MRD rates were 42%/31%, 64%/56% and 76%/63% after each step, respectively. Concerning toxicity, during induction, G3-4 neutropenia and thrombocytopenia were reported in 5 (6%) and 10 pts (11%), respectively. G3-4 infections were reported 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 pts reported hypertension (G2 in two and G3 in one). In all but two of the pts, PBSC collection was successful with a median of 4.10 x 106/Kg CD34 cells collected. All pts engrafted but one patient developed late graft failure. During consolidation, 2 pts developed G3-4 neutropenia, 3 pts G3-4 infections and 1 pt skin rash. Maintenance treatment is ongoing and one patient had to discontinue due to a second primary malignancy (lung cancer) and other due to sustained thrombocytopenia. Conclusions: The primary end point of the trial was met, and 56% of the pts who completed induction and HDT-ASCT achieved MRD-ve. This "curative strategy for high risk SMM" continues being encouraging and 93% of pts remain alive and progression-free at 30 months and 98% of pts alive. Disclosures Mateos: GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: 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; 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; EDO: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rodriguez Otero:Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; Takeda: Consultancy; BMS: Honoraria; Kite Pharma: Consultancy. Oriol:Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy; Takeda: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau. 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. Rosinol Dachs:Janssen, Celgene, Amgen and Takeda: Honoraria. Amor:Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Puig:Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria; The Binding Site: Honoraria. De La Rubia:AMGEN: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; AbbVie: Consultancy. De Arriba:Takeda: Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Lopez Jimenez:GILEAD SCIENCES: Honoraria, Other: Education funding. Ocio:Celgene: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Mundipharma: Research Funding; AbbVie: Consultancy; Sanofi: Research Funding; Seattle Genetics: Consultancy; Array Pharmaceuticals: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Pharmamar: Consultancy. Bladé:Jansen, Celgene, Takeda, Amgen and Oncopeptides: Honoraria. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria.

Abstract: MRD monitoring is one of the most relevant prognostic factors in elderly MM patients, irrespective of age or cytogenetic risk. Second-generation MFC immune profiling concomitant to MRD monitoring also helped to identify patients with different outcomes.

Abstract: Introduction: The sFLC assay was introduced in 2006 for diagnosis and monitoring of gammopathies, being currently the normalization of its ratio one of the requirements for defining stringent complete response (sCR). The new sHLC assay allows identifying the different light chain types bound to each heavy chain (i.e. separate the amount of IgG Κ from IgG λ) and may have greater prognostic value than sFLC assay. However, its advantages over immunofixation (IFE) have to be demonstrated and the sHLC assay does not work well for every light chain secretors MM. We wanted to investigate the utility and prognostic impact of serum free-light chains (sFLC) and heavy-light chains (sHLC) studies in multiple myeloma (MM) in the context of three GEM clinical trials (GEM05 〉 65y,GEM05 〉 65y and GEM2010 〉 65y). Methods and Patients: Frozen sera from patients were retrospectively analyzed for sFLC and sHLC (623 and 183 patients at diagnosis, respectively) in the context of three GEM/PETHEMA clinical trials. In addition, sHLC measurements performed in 30 healthy individuals were used for control values. After induction, regardless of the achieved response, serum samples were available in 308 cases for sFLC and 89 for sHLC. All patients in which sHLC assay was analyzed were IgG or IgA-MM. Results and discussion: In our series, around 95% of the patients had abnormal values of sFLC and sHLC ratios at the time of diagnosis. Normal values did not impact in prognosis, and even when we considered Òvery pathologicalÓ (VP) sFLCr values (0.03-32), no prognostic differences were observed [Figure 1A]. Conversely, after establishing several arbitrary cut-offs, we note that very pathological sHLC values of the ratios ( 〈 0.29 or 〉 73) at diagnosis had greater risk of progression (p=0.006) [Figure 1B], confirmed by multivariate analysis ― age [p=0,003; OR 1.04 (1.01-1.06)] ; LDH [p= 0.03; OR 0.4 (0.26-0.94)]; VP-sHLCr [p=0.01; OR 1.78 (1.14-2.78)] ; high vs low risk FISH [p=0.02; OR 1.75 (1.11-2.74)]―. sHLC non-involved pair suppression (described as a 50% reduction under de lower range limit) at diagnosis wasnÕt related to worse prognosis in our series. The HLC-involved-Ig values show a strict linear correlation with values of monoclonal protein (MP) by serum protein electrophoresis (sPE) (p= 0,000; Pearson's r=0.676) [Figure 2] and thus the high sensitivity of sHLC for IgA MP should prove useful for monitoring MP migrating within the β fractions. After treatment, as we might expect, there was a clear association between quality of response and normalization of the sFLC ratio (Pearson's χ2 p 〈 0.001). Concerning the sFLCr, among the 130 patients in CR after induction, no prognostic difference was observed between patients with a normal (0.26-1.65) vs pathological sFLCr (OS p=0.137; PFS p=0.359). No conclusive results were obtained from the normalization of sHLC in CR due to a low number of samples available for these studies. Conclusions: Very pathological ( 〈 0.29 or 〉 73) sHLC ratios at diagnosis have bad prognosis impact. However sFLC did not show any prognosis impact. Regarding response measurement sFLC and sHLC did not show any advantages over conventional methods. Additionally, sHLC values are highly related to the M component levels, thus the high sensitivity of sHLC for IgA should prove very useful for monitoring MP migrating within the β fractions. Figure 1. Impact of "very pathological" (VP) sFLC and sHLC ratios on progression free survival (PFS) Figure 1. Impact of "very pathological" (VP) sFLC and sHLC ratios on progression free survival (PFS) Figure 2. Correlation of monoclonal protein (MP) quantification by serum protein electrophoresis (sPE) and HLC-involved-Ig values Figure 2. Correlation of monoclonal protein (MP) quantification by serum protein electrophoresis (sPE) and HLC-involved-Ig values Disclosures San Miguel: Millennium, Celgene, Novartis, Janssen, Onyx, BMS, MSD: Membership on an entity's Board of Directors or advisory committees. Lahuerta:Janssen Cilag, Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Disease control at 5 years would be a desirable endpoint for elderly multiple myeloma (MM) patients, but biomarkers predicting this are not defined. Therefore, to gain further insights in this endpoint, a population of 498 newly diagnosed transplant-ineligible patients enrolled in two Spanish trials (GEM2005MAS65 and GEM2010MAS65), has been analyzed. Among the 435 patients included in this post-hoc study, 18.6% remained alive and progression free after 5 years of treatment initiation. In these patients, overall survival (OS) rate at 10 years was 60.8% as compared with 11.8% for those progressing within the first 5 years. Hemoglobin (Hb) ≥ 12 g/dl (OR 2.74, p  = 0.001) and MGUS-like profile (OR 4.18, p  = 0.005) were the two baseline variables associated with long-term disease-free survival. Upon including depth of response (and MRD), Hb ≥ 12 g/dl (OR 2.27) and MGUS-like signature (OR 7.48) retained their predictive value along with MRD negativity (OR 5.18). This study shows that despite the use of novel agents, the probability of disease control at 5 years is still restricted to a small fraction (18.6%) of elderly MM patients. Since this endpoint is associated with higher rates of OS, this study provides important information about diagnostic and post-treatment biomarkers helpful in predicting the likelihood of disease control at 5 years.