Kurzfassung: Introduction: SMM is an asymptomatic plasma cell disorder with heterogeneous clinical behavior. Both the Spanish Myeloma and ECOG Groups have demonstrated that patients (pts) at high risk of progression to active MM have prolonged time-to progression upon receiving early treatment with R-based regimens. Our next step was to perform a phase 2, single arm trial, focusing on the same population, but aiming at abrogating the risk of progression through the achievement of sustained minimal residual disease negativity (MRD-ve) at 3 and 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 criteria) or ifonly one criterion was present, pts should have & gt;95%of aberrant PCs within the total PCsBM compartment by immunophenotyping plus immunoparesis (Spanish criteria). Induction therapy consisted of six 4-weeks cycles of KRd in which K was given at dose of 36 mg/m 2 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/m 2 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 ASCT and MRD-ve rate maintained at 3 and 5 years after ASCT. Results: Between June 2015 and June 2017, 90 high-risk SMM pts were recruited and 70 pts (78%) have completed the treatment protocol. The reasons for early discontinuations were: IC withdrawal (4 pts), adverse events (8 pts) or biological progression (BP), either biochemical or because of MRD conversion from negative to positive (1 pt during induction and 7 pts during maintenance). Thirty-one pts (34%) shared at least one of the biomarkers considered as myeloma defining events that currently reclassify SMM into active MM. In the intent-to-treat (ITT) pts' population, after induction, the ≥CR rate was 41% and increased to 65% after HDT-ASCT and 72% after consolidation. During maintenance therapy, 7 pts experienced biological progression (2 pts conversion from MRD-ve into +ve and 5 pts biochemical progression) and the ≥CR rate at the end of treatment was 63.3%. In the ITT population, MRD-ve rates at 10 -5 were observed in 40% of pts after induction, 63% after HDT-ASCT, 68% after consolidation and 52% after maintenance therapy. Among MRD-ve patients after maintenance therapy that had MRD assessed one year after, 67% showed sustained MRD-ve. After a median f/u of 55 months (range: 6.2-71), only three patients progressed to symptomatic disease and the three had at baseline anyone of the biomarkers defining myeloma-defining events. At 5 years, 94% of pts remain alive and progression-free and 95% of pts alive (Figure 1). Overall, twenty-six pts (29%) have experienced biological progression (19 of them were conversion of MRD-ve into +ve), 8 of them during treatment phase (1 during induction and 7 during maintenance) and 16 pts during the follow-up period. The only factors predicting biological progression was failure to achieve MRD-ve at the end of treatment and unsustained MRD-ve at 1 year after finalizing maintenance. 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 10 6/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. Seven pts had to discontinue maintenance therapy due to: G3-4 hematological toxicity (4 pts), SPM (2pts) and cardiac arrest (1pt). One additional patient withdrew the IC. Conclusions: These results suggest that early treatment with intention to abrogate risk of progression in transplant candidate high risk SMM patients is associated with a 94% PFS at 55 months and a sustained MRD negative rate at 1 year post treatment of 67%. Figure 1 Figure 1. Disclosures Mateos: Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: 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; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; 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; GSK: Honoraria; Oncopeptides: Honoraria. Rodríguez-Otero: Celgene-BMS, Janssen, Amgen, Sanofi, GSK, Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria. Gonzalez-Calle: BMS, Janssen, Amgen: Honoraria. Oriol: Celgene: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. de la Rubia: Takeda: Consultancy; Amgen, Bristol Myers Squibb,: Honoraria, Speakers Bureau; GSK: Consultancy; Celgene, Takeda, Janssen, Sanofi: Honoraria; Ablynx/Sanofi: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations; Celgene: Consultancy; AbbVie: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Sanofi: Membership on an entity's Board of Directors or advisory committees. De Arriba: Amgen: Consultancy, Honoraria; Glaxo Smith Kline: Consultancy, Honoraria; BMS-Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Ocio: MSD: Honoraria; Sanofi: Consultancy, Honoraria; Karyopharm: Consultancy; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Pfizer: Consultancy; Secura-Bio: Consultancy. Paiva: Bristol-Myers Squibb-Celgene, Janssen, and Sanofi: Consultancy; Adaptive, Amgen, Bristol-Myers Squibb-Celgene, Janssen, Kite Pharma, Sanofi and Takeda: Honoraria; Celgene, EngMab, Roche, Sanofi, Takeda: Research Funding. Puig: Celgene, Janssen, Amgen, Takeda: Research Funding; Celgene: Speakers Bureau; Amgen, Celgene, Janssen, Takeda: Consultancy; Amgen, Celgene, Janssen, Takeda and The Binding Site: Honoraria. Cedena: Janssen, Celgene and Abbvie: Honoraria. Lahuerta: Celgene: Other: Travel accomodations and expenses; Celgene, Takeda, Amgen, Janssen and Sanofi: Consultancy. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, Takeda: Consultancy, Other: Advisory board.

Kurzfassung: 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 long-term results of the trial, five 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 70.6 months, VTD resulted in a significantly longer PFS when compared with TD and VBMCP/VBAD/B (56.1 vs 29.2 vs 39.9 months, p=0.005) (Figure 1). The estimated overall survival (OS) at 8 years was 60% 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 (15.7 vs. 44.3 months, p=0.003). 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 (8.9 vs 32.8 months, p=0.04 in TD group; 14.1 vs. 43.3 months, p=0.05 in VBMCP/VBAD/B group). However, there was no significant difference in the VTD arm (23.6 vs 56.1 months, p=0.2). Patients with high-risk cytogenetics had a significantly shorter OS in the overall series (median 42.1 months vs not reached, p=0.00001) and this was observed in the three treatment arms: VTD median 37.1 months vs not reached (p=0.001), TD median 54.2 months vs not reached (p=0.06), VBMCP/VBAD/B median 30.2 months vs not reached (p=0.007). The achievement of a deeper response at the end of induction was associated with a longer PFS and OS. Thus, patients achieving CR at the end of induction had a significantly longer PFS than patients achieving a lower degree of response (median 62 vs. 28 months, p=0.00001), irrespective of the treatment arm. Furthermore, on an intention to treat basis, patients who were in postrasplant CR had a significantly longer PFS (p 〈 0.00001) and OS (p 〈 0.00001) than those who did not reach CR after ASCT (p 〈 0.001). In the overall series the OS after progression was 30.5 months and was not significantly different among the 3 arms (VTD 25.4 months, TD 50 months, VBMCP/VBAD/B 30.2 months, p=0.4). Patients with high-risk cytogenetics had a significantly shorter OS after relapse in the overall series (13.3 months vs. 37.5 months, p=0.001), in the VTD arm (13.3 vs 33.9, p=0.01) and in the VBMCP/VBAD/B arm (8.5 vs 38 months, p=0.01). 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 had a worse outcome even with the use of novel drugs. Finally, the PFS of 56 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: PFS according to the induction arm Figure 1:. PFS according to the induction arm Disclosures Rosiñol: Janssen: Honoraria; Celgene: Honoraria. Oriol:Celgene Corporation: Consultancy. De La Rubia:Janssen: Honoraria; Celgene: Honoraria. Gutierrez:Janssen: Honoraria; Celgene: Honoraria. Martinez-Lopez:Janssen: Honoraria; Celgene: Honoraria. Alegre:Janssen: Honoraria; Celgene: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Janssen: Honoraria; Celgene: Honoraria.

Kurzfassung: Abstract 334 Introduction: The Spanish Myeloma Group (PETHEMA/GEM) conducted a randomized phase III trial comparing induction with thalidomide/dexamethasone (TD) vs. bortezomib/thalidomide/dexamethasone (VTD) vs. VBMCP/VBAD/Bortezomib (VBMCP/VBAD/B) in patients 65 years-old or younger with newly diagnosed symptomatic MM and ASCT with MEL-200 followed by maintenance with thalidomide/bortezomib (TV) vs. thalidomide (T) vs. alfa-2b-interferon (alfa2-IFN). The induction part of the study has been recently published and the maintenance results are reported here. End-points: The primary end-point was progression-free survival (PFS) and the secondary end-points were increase of response rate, overall survival (OS) and safety. Patients and Methods: The maintenance treatment consisted of TV (thalidomide 100 mg daily plus one cycle of bortezomib at 1.3 mg/m2 on days 1, 4, 8 and 11 every 3 months) versus T (single agent thalidomide at a dose of 100 mg daily) versus alfa2-IFN (subcutaneous alfa2b-IFN at a dose of 3 MU three times per week). The planned maintenance duration was three years or until disease progression or toxicity. From February 1, 2007 to January 27, 2011 266 patients were randomized to maintenance therapy (TV: 89; T: 87, alfa2-IFN: 90). Response and survival were evaluated on an intention-to-treat basis. Responses, relapses and progressions (EBMT criteria) were monitored by an external contract research organization and centrally reassessed. Results: Patient's characteristics at diagnosis such as age, M-protein type, ISS stage, cytogenetics and presence of extramedullary plasmacytomas as well as induction regimen (VTD, TD and VBMCP/VBAD/Bortezomib) and diagnosis-randomization interval were similarly distributed among the 3 arms. The response status at the time of randomization for maintenance after ASCT was CR: 51%, nCR: 12%, PR: 34%, MR 2% and SD: 1% and was well balanced in the three groups. The CR rate with maintenance was improved by 19% with TV, 15% with T and 17% with alfa2-IFN (p=NS). After a median follow-up of 34.9 months, the PFS was significantly longer with TV compared with T and alfa2-IFN (figure 1, p=0.0009). However, OS was not significantly different among the 3 arms. Grade 3 and 4 hematological toxicity was similar (22.2% vs. 16% vs. 21.8%). No peripheral neuropathy (PN) was observed with alfa2-IFN being its frequency similar with TV (12.2%) and T (10.1%). No grade IV PN was observed. Dose reductions for TV, T and alfa2-IFN were required in 33.3%, 33.7% and 19.5% of the patients, respectively. The discontinuation rate due to progressions was not significantly diferent among the three arms (35% vs 24% vs 20%, p=NS). The discontinuation rate due to toxicity was higher with thalidomide compared with TV (30.3% vs. 15.6%, p= 0.08) and with alfa2-IFN (30.3% vs. 18.3%, p=0.17). Patients with high-risk cytogenetics [t(4;14), t(14;16) and/or del 17p] had a trend towards a shorter PFS (p=0.1) and a significantly shorter OS (p=0.03). The incorporation of bortezomib was not able to overcome the poor impact of high-risk cytogenetics. Conclusion: The addition of bortezomib to thalidomide maintenance resulted in a significantly longer PFS when compared with thalidomide alone or with single agent alfa2-IFN with no increased toxicity. However, the addition of bortezomib did not overcome the poor impact of high-risk cytogenetics. Disclosures: Rosiñol: Janssen, Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Oriol:Janssen: Honoraria; Celgene: Honoraria. De La Rubia:Celgene, Janssen: Consultancy, Speakers Bureau. Granell:Janssen: Honoraria; Celgene: Honoraria. de Arriba:Jansen: Honoraria; Celgene: Honoraria. Alegre:Janssen: Honoraria; Celgene: Honoraria. Cibeira:Janssen: Honoraria; Celgene: Honoraria. Mateos:Janssen: Honoraria; Celgene: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Janssen: Honoraria; Celgene: Honoraria; Onix: Honoraria; Novartis: Honoraria. Bladé:Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria.

Kurzfassung: Abstract 3962 Introduction: In April 2006, the Spanish Myeloma Group (PETHEMA/GEM) activated a randomized phase III trial comparing induction with TD vs. VTD vs. VBMCP/VBAD/Bortezomib (VBMCP/VBAD/B) in patients 65 years-old or younger with newly diagnosed symptomatic MM and ASCT with MEL-200 followed by maintenance with thalidomide/bortezomib (TV) vs. thalidomide (T) vs. alfa-2b-interferon (alfa2-IFN). Primary end points : response rate after induction and after ASCT and time to progression. Patients and Methods: The maintenance program consisted of TV (thalidomide 100 mg daily plus one cycle of bortezomib-1.3 mg/m2 on days 1, 4, 8 and 11 every 3 months) versus T (single agent thalidomide at a dose of 100 mg daily) versus alfa2-IFN (subcutaneous alfa2b-IFN at a dose of 3 MU three times per week). The planned maintenance duration was three years or until disease progression or toxicity. From February 1, 2007 to January 27, 2011 266 patients were randomized to maintenance therapy (TV:90; T: 89, alfa2-IFN: 87). Response and survival were evaluated on an intention-to-treat basis. Responses and progressions reported by the investigators were centrally reassessed. Results: the patient's characteristics at diagnosis such as age, ISS stage, cytogenetics and presence of extramedullary plasmacytomas as well as induction regimen (VTD, TD and VBMCP/VBAD/Bortezomib) and diagnosis-randomization interval were similarly distributed among the 3 arms. The response status at the time of randomization after ASCT was CR: 51%, VGPR: 23%, PR: 24% and SD: 2% and was well balanced in the three groups. The CR rate with maintenance was improved by 23% with TV, 11% with T and 19% with alfa2-IFN (p=NS). After a median follow-up of 24 months, the PFS was significantly longer with TV compared with T and alfa2-IFN (PFS at 2 yrs: 78% vs. 63% vs. 49%, p=0.01). However, OS was not significantly different among the 3 arms. Grade 3 and 4 hematological toxicity was similar (22.2% vs. 16% vs. 21.8%). No peripheral neuropathy (PN) was observed with alfa2-IFN being its frequency similar with TV (12.2%) and T (10.1%). No grade IV PN was observed. Dose reductions for TV, T and alfa2-IFN were required in 33.3%, 33.7% and 19.5% of the patients, respectively. The discontinuation rate due to toxicity was significantly higher with thalidomide compared with TV (30.3% vs. 15.6%, p= 0.08) and with alfa2-IFN (30.3% vs. 18.3%, p= 0.17). Conclusion: the addition of bortezomib to thalidomide maintenance resulted in a significantly longer PFS when compared with thalidomide alone or with IFN with no increased toxicity. Disclosures: Rosiñol: Janssen: Honoraria; Celgene: Honoraria. Cibeira:Janssen: Honoraria; Celgene: Honoraria. Mateos:Janssen: Honoraria; Celgene: Honoraria. Martinez:Janssen: Honoraria; Celgene: Honoraria. de la Rubia:Janssen: Honoraria; Celgene: Honoraria. Díaz-Mediavilla:Janssen: Honoraria; Celgene: Honoraria. Alegre:Janssen: Honoraria; Celgene: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Blade:Janssen: Honoraria; Celgene: Honoraria.

Kurzfassung: Background: Autologous stem-cell transplantation (ASCT) is the standard of care for younger patients with multiple myeloma (MM). The degree of tumor reduction after ASCT is the crucial factor associated with a prolonged PFS and OS, being the M-protein decrease at the time of transplant the most important predictor of residual disease after ASCT. While there is an agreement that bortezomib and dexamethasone associated to a third drug is the induction of choice, which should be the third drug (thalidomide, lenalidomide, doxorubicin or cyclophosphamide) and the optimal number of cycles remain unknown. The results of phase 3 PETHEMA study GEM05menos65 showing a CR rate of 35% increasing overtime during the 6 induction cycles of VTD (Rosiñol et al, Blood 2012) prompted us to study the kinetics of response to VTD and TD in this study and in similar historic data with the VD regimen in phase 2 PETHEMA VELCA/DEXA trial (Rosiñol et al, JCO 2007). Objective: To study the kinetics of response by cycle during the 6 cycles of induction with VTD, TD and VD using a random effects model methodology. Patients and Methods: In GEM05menos65 study patients were randomized to receive 6 induction cycles of either VTD or TD followed by ASCT. One hundred and thirteen patients were treated with TD (thalidomide 200 mg daily; dexamethasone 40 mg on days 1-4 and 9-12) and 122 with VTD (TD at identical doses plus bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11) (Rosiñol et al, Blood 2012) and had complete data set for this analysis. In VELCA/DEXA study 40 patients received 6 induction cycles of bortezomib and dexamethasone on an alternating basis (Rosiñol et al, JCO 2007). Linear random effects models were employed to analyze the tumor response kinetics using the absolute decrease value of the serum M-protein after each cycle. Because the nonlinearity in the change of the M-protein overtime, a piecewise linear model was used to estimate mean changes in M-protein in each of the 6 cycles. Results: Three different comparisons were made: 1) the decrease of the M-protein by cycle within each treatment group, 2) the total M-protein decrease at the end of induction with VTD compared to TD and VD and 3) the decrease by cycle comparing VTD vs TD and VTD vs VD. Concerning the M-protein decrease by cycle within each arm, statistically significant decreases versus the previous cycle were observed in the first 5 cycles of VTD, the first 3 of TD and the first 4 of VD. The serum M-protein reduction at the end of the 6 induction cycles was significantly higher with VTD when compared with TD (p 〈 0.0001) and VD (p 〈 0.0001). Finally, when comparing the serum M-protein decrease between VTD and TD by cycle, the M-protein reduction was significantly higher with VTD in the first 5 cycles and the same analysis between VTD and VD showed that the serum M-protein decrease was significantly higher with VTD in the first 3 cycles (Tables 1 and 2). Conclusions: In the cycle by cycle analysis VTD continued to improve M-protein reduction significantly in the first 5 cycles. When compared with TD and VD, the M-protein decrease at the end of induction was significantly higher with VTD. Furthermore, in the cycle by cycle comparison there was a significantly higher efficacy of VTD over TD in the first 5 cycles and over VD in the first 3 cycles. Our results suggest a synergistic rather than only an additive effect between thalidomide and bortezomib supporting the use of an IMiD as the drug of choice to be combined with bortezomib and dexamethasone. Finally, our study supports an induction period beyond 3 or 4 cycles when using a bortezomib/IMiD regimen in order to maximize the induction efficacy. Table 1. Comparison between VTD versus TD by cycles overtime. Serum M-protein (g/dl) Change (VTH-TH) Estimate SE 95% CI P-value C1 – Baseline -3.0747 0.3461 (-3.7539, -2.3954) 〈 .0001 C2 – C1 -1.1343 0.1294 (-1.3883, -0.8802) 〈 .0001 C3 – C2 -0.4474 0.09586 (-0.6356, -0.2593) 〈 .0001 C4 – C3 -0.2140 0.08224 (-0.3753, -0.05257) 0.0094 C5 – C4 -0.1339 0.07550 (-0.2821, -0.01428) 0.0765 C6 – C5 0.01862 0.05395 (-0.08725, 0.1245) 0.7300 Table 2. Comparison between VTD versus VD by cycles overtime. Serum M-protein (g/dl) Change (VTH-VD) Estimate SE 95% CI P-value C1 – Baseline -3.1553 0.2243 (-3.5957, -2.7150) 〈 .0001 C2 – C1 -1.3748 0.2279 (-1.8223, -0.9272) 〈 .0001 C3 – C2 -0.4266 0.2354 (-0.8887, 0.03552) 0.0703 C4 – C3 -0.05473 0.2439 (-0.5337, 0.4242) 0.8225 C5 – C4 -0.02217 0.2530 (-0.5189, 0.4745) 0.9302 C6 – C5 0.06493 0.2908 (-0.5060, 0.6358) 0.8234 Disclosures Rosiñol: Janssen: Honoraria; Celgene: Honoraria. Oriol:Janssen: Honoraria; Celgene: Honoraria. De La Rubia:Janssen: Honoraria; Celgene: Honoraria. Gutierrez:Janssen: Honoraria; Celgene: Honoraria. Mateos:Janssen: Honoraria; Celgene: Honoraria. Martinez-Lopez:Janssen: Honoraria; Celgene: Honoraria. Alegre:Janssen: Honoraria; Celgene: Honoraria. Feng:Janssen: Employment. van de Velde:Janssen: Employment. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Janssen: Honoraria; Celgene: Honoraria. Blade:Janssen: Honoraria; Celgene: Honoraria.

Kurzfassung: Abstract 307 Introduction: In April 2006, the Spanish Myeloma Group (PETHEMA/GEM) activated a randomized phase III trial comparing TD vs. VTD vs. VBMCP/VBAD/Bortezomib (VBMCP/VBAD/B) in patients 65 years-old or younger with newly diagnosed symptomatic MM followed by ASCT with MEL-200. Primary end points: response rate after induction and after ASCT and time to progression. Patients and Method: TD consisted of thalidomide 200 mg daily (escalating doses in the first cycle) and dexamethasone 40 mg on days 1–4 and 9–12 at 4-week intervals for 6 cycles. The VTD regimen was identical to TD plus bortezomib 1.3 mg/m2 on days 1,4,8,11 of each cycle. Combination chemotherapy plus bortezomib consisted of 4 cycles of VBMCP/VBAD on an alternating basis followed by 2 cycles of bortezomib (1.3 mg/m2 on days 1,4,8, and 11 every 3 weeks). The duration of the induction therapy was 24 weeks in all arms. From April 6, 2006 to August 5, 2009 the 390 planned patients entered the study. Four patients failed the eligibility criteria. 386 patients (median age: 56 yrs; M: 207, F: 179; IgG: 233, IgA: 85, light chain: 57, IgD: 9, Ig M: 2) were analyzed. The stage according to the ISS was I in 147 patients, II in 160, III in 75 and unknown in 4 and 66 patients (17%) had extramedullary soft-tissue plasmacytomas (EMP). Seventy out of the 330 patients (21%) with cytogenetic studies had high-risk cytogenetics (t(4;14), t(14;16), and/or 17p deletion). One-hundred and thirty patients were allocated to VTD, 127 to TD and 129 to VBMCP/VBAD/B. Prognostic factors, including cytogenetics, were similar in the 3 arms. Response, survival and toxicity were evaluated on an intention-to-treat basis. Responses reported by investigators were centrally reassessed. Result: The IFE negative CR rate was significantly higher with VTD (35%) compared to TD (14%) and VBMCP/VBAD/B (22%) (p=0.0001 and p=0.01, respectively). The progressive disease (PD) rate during induction was significantly lower with VTD than with TD (7% vs. 23%, p=0.001). In patiens with high-risk cytogenetics, the CR rate was significantly greater with VTD when compared with TD (35% vs. 0%, p=0.002) and with VBMCP/VBAD/B (35% vs. 22%, p=0.02). The CR rate to VTD in patients with 17p deletion was 58% while none of the patients with this cytogenetic abnormality responded to TD or to VBMVP/VBAD/B (p=0.03 and p=0.02, respectively). Of interest, the CR rate in patients with t(11;14) was significantly lower than in patients lacking this abnormality (11% vs. 27%, p=0.01). This low CR rate in patients with t(11;14) was similar in the 3 arms. In the overall series, PD was significantly higher in patients with EMP (24% vs. 11%, p=0.01) with a significantly higher PD rate for TD as compared to VTD (40% vs. 12%, p=0.02). The incidence of thrombotic events was 2%, 6% and 5% for VTD, TD and VBMCP/VBAD/B, respectively (p=NS). The frequency of grade ≥ 3 peripheral neuropathy was 12% with VTD compared to 1% in both the TD and the VBMCP/VBAD/B arms (p= 0.0002). Treatment was discontinued due to toxicity en 16 patients (VTD:9, TD:4, VBMCP/VBAD/B:3). Nine patients died during the induction period (3 in each arm). On an intention to treat basis, the post-ASCT CR rate was higher in the VTD arm compared with TD (46% vs. 24%, p=0.004) and VBMCP/VBAD/B (46% vs. 38%, p=0.1). The estimated overall survival (OS) at 4 years was 76% with no significant differences among the 3 arms. After a median follow-up of 27 months, the progression-free survival (PFS) was not reached with VTD while it was 27 and 38 months with TD and VBMCP/VBAD/B, respectively (p=0.006). In the overall series, patients with high-risk cytogenetics had a significantly shorter OS (p=0.00007) and PFS (p=0.004). In addition, when compared with the good-risk group, patients with high-risk cytogenetics showed a trend towards a shorter PFS either after induction with VTD (median not reached vs. 17 months, p=0.05) and with TD (median 28 vs. 15 months, p=0.09). Conclusion: Induction with VTD resulted in a significantly higher CR rate in both the overall series and in patients with high-risk cytogenetics. The post-ASCT CR rate was also significantly higher with VTD than with TD and there was a trend when compared with VBMCP/VBAD/B. Finally, VTD resulted in a significantly longer PFS. However, longer follow-up is required to establish whether or not VTD will overcome the poor prognosis of patients with high-risk cytogenetics. Disclosures: Rosiñol: Janssen-Cilag: Honoraria; Celgene: Honoraria. Off Label Use: Bortezomib and Thalidomide are not approve for first line in Spain. Cibeira:Janssen-Cilag: Honoraria; Celgene: Honoraria. Mateos:Janssen-Cilag: Honoraria; Celgene: Honoraria. Oriol:Janssen-Cilag: Honoraria; Celgene: Honoraria. García-Laraña:Janssen-Cilag: Honoraria; Celgene: Honoraria. De La Rubia:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sureda:Janssen-Cilag: Honoraria; Celgene: Honoraria. Díaz-Mediavilla:Janssen-Cilag: Honoraria. Alegre:Janssen-Cilag: Honoraria; Celgene: Honoraria. Lahuerta:Janssen-Cilag: Honoraria; Celgene: Honoraria. San Miguel:Janssen-Cilag: Honoraria; Celgene: Honoraria, Speakers Bureau. Blade:Janssen-Cilag: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.