Abstract: In patients with myeloma, thalidomide significantly improves outcomes but increases the risk of thromboembolic events. In this randomized, open-label, multicenter trial, we compared aspirin (ASA) or fixed low-dose warfarin (WAR) versus low molecular weight heparin (LMWH) for preventing thromboembolism in patients with myeloma treated with thalidomide-based regimens. Patients and Methods A total of 667 patients with previously untreated myeloma who received thalidomide-containing regimens and had no clinical indication or contraindication for a specific antiplatelet or anticoagulant therapy were randomly assigned to receive ASA (100 mg/d), WAR (1.25 mg/d), or LMWH (enoxaparin 40 mg/d). A composite primary end point included serious thromboembolic events, acute cardiovascular events, or sudden deaths during the first 6 months of treatment. Results Of 659 analyzed patients, 43 (6.5%) had serious thromboembolic events, acute cardiovascular events, or sudden death during the first 6 months (6.4% in the ASA group, 8.2% in the WAR group, and 5.0% in the LMWH group). Compared with LMWH, the absolute differences were +1.3% (95% CI, −3.0% to 5.7%; P = .544) in the ASA group and +3.2% (95% CI, −1.5% to 7.8%; P = .183) in the WAR group. The risk of thromboembolism was 1.38 times higher in patients treated with thalidomide without bortezomib. Three major (0.5%) and 10 minor (1.5%) bleeding episodes were recorded. Conclusion In patients with myeloma treated with thalidomide-based regimens, ASA and WAR showed similar efficacy in reducing serious thromboembolic events, acute cardiovascular events, and sudden deaths compared with LMWH, except in elderly patients where WAR showed less efficacy than LMWH.

Abstract: Introduction: The phase 3 GIMEMA-MMY-3006 trial comparing bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation (ASCT) for newly diagnosed multiple myeloma (MM) provided the first demonstration of increased CR rate, the primary study endpoint, and prolonged PFS with VTD (Cavo M et al, Lancet 2010). However, updating trial results with longer follow-up than earlier reported is needed to assess the effects of treatment interventions on OS and to identify factors predicting for favorable long term outcomes. Aims: We performed a post-hoc analysis of that study to evaluate long term results and construct a prognostic index of survival. Methods: 474 patients were enrolled, 236 randomized to VTD and 238 to TD. Median follow-up for surviving patients was 124 months (IQR: 117-131). Analyses were performed on an intention-to-treat basis. Semi-parametric Cox regression analysis was used to construct the prognostic index. To assess the evolution of prognosis over time, conditional survival CS(t|s) estimate for PFS was calculated as the probability of surviving without progression a further 2 (t) years (yrs) after having already survived s yrs. Results: Estimates of PFS and OS at 10 yrs for the VTD arm were 34% (HR=0.62; 95% CI=0.50-0.77; p 〈 0.001) and 60% (HR=0.68, 95% CI=0.51-0.90; p=0.007), respectively, compared with TD (corresponding values, 17% and 46%), representing a 38-32% reduction in the risk of progression and death with VTD. Outcome benefits with VTD were seen for patients with high-risk cytogenetic abnormalities (HCRA), including t(4;14) and/or del(17p) by FISH, (PFS: 17% vs 3% at 10 yrs, HR=0.45, 95% CI=0.30-0.69; p 〈 0.001; OS: 42% vs 22% at 10 yrs, HR=0.54, 95% CI=0.34-0.88; p=0.011) and lacking HRCA (PFS: 40% vs 20%, HR=0.60, 95% CI=0.46-0.79; p 〈 0.001; OS: 67% vs 52%, HR=0.66, 95% CI=0.46-0.95; p=0.025). On multivariate Cox regression analysis, randomization to VTD predicted for both prolonged PFS (HR=0.60, 95% CI=0.48-0.76; p 〈 0.001) and OS (HR=0.68, 95% CI=0.50-0.91; p=0.010). Specific multivariate regression analysis not including therapy revealed that the leading factors adversely affecting PFS were the presence of HRCA (HR=1.86, 95% CI=1.45-2.38; p 〈 0.001), ISS stage II+III (HR=1.38, 95% CI=1.10-1.74; p=0.006), and failure to achieve CR as time-dependent variable (HR=2.01, 95% CI=1.59-2.53; p 〈 0.001). The three variables were used to build a scoring system that stratified patients into three risk groups with divergent clinical outcomes: low-risk (LR) (22%, none of the 3 adverse variables), intermediate-risk (IR) (39%, 1 adverse variable), and high-risk (HR) (39%, 2 or 3 adverse variables). Estimated 10-yr PFS rates were 44% for patients in LR, 28% for IR, and 9% for HR (p 〈 0.001). Estimated 10-yr OS rates were 76%, 58%, and 32%, respectively (p 〈 0.001). Consensually, the prognostic score identified three groups with statistically different PFS and OS within the TD and VTD arm (p 〈 0.001). On VTD, the 10-yr PFS and OS rates were 51% and 79% for LR, 41% and 62% for IR, 13% and 43% for HR, respectively. Randomization to receive VTD was associated with longer PFS for the IR (41% vs 15% at 10 yrs, HR=0.50, 95% CI=0.34-0.73; p 〈 0.001) and HR (13% vs 7% at 10 yrs, HR=0.66, 95% CI=0.47-0.92; p=0.015) subgroups compared with TD. Moreover, HR patients assigned to VTD had significantly longer OS in comparison with the same group of patients on TD (43% vs 23% at 10 yrs, HR=0.65, 95% CI=0.43-0.97; p=0.033). Assessment of conditional survival revealed that the probability of surviving without progression a further 2 yrs improved progressively after 36 months, being 65% and reaching the 91% at 96 months (p value for trend=0.009). The conditional PFS became superimposable after 78 months for the LR and IR (87% and 86%, respectively), while resulted significantly lower in the HR (62.5%) (p=0.008). Conclusions: With a follow up of 10 yrs, the final analysis of the GYMEMA MMY-3006 trial comparing VTD versus TD showed a persistent PFS benefit translating into extended OS for the VTD arm. A prognostic model based on cytogenetic, ISS stage and achievement of CR, identified three risk groups with statistically different long-term survival probabilities. Both IR and HR groups significantly benefited from VTD. A PFS time of 78 months predicted for long term survival outcomes in the LR and IR groups. Disclosures Tacchetti: Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Di Raimondo:Takeda: Honoraria, Research Funding; Celgene: Honoraria. Zamagni: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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: 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. Bringhen:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Consultancy. Offidani:Celgene: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board. Montefusco:Celgene: Other: Advisory Board; Amgen: Other: Advisory Board; Janssen: Other: Advisory Board. Cavo: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, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: 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; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Abstract 3562 Aim of the present study was to evaluate the clinical outcome of a large series of younger patients with symptomatic multiple myeloma (MM) who were enrolled in two subsequent clinical trials of thalidomide-dexamethasone (thal-dex) incorporated into double autologous stem-cell transplantation (ASCT) to support high-dose melphalan (200 mg/m2). In both studies, thal (100 mg/day for the first 14 days and then 200 mg/day) and pulsed dex (between 480 and 160 mg per cycle), were administered from the onset until the second ASCT. The analysis was performed on an intention-to-treat basis on a total of 593 patients who were followed for a median of 36 months. The best VGPR and CR rates were 69% and 35%, respectively. The median duration of CR was 66 months. Median TTP and PFS were 53 and 44 months, respectively. The 5-year projected rates of TTP and PFS were 46% and 38%, respectively, while the corresponding value for OS was 67%. More than 80% of the patients were screened at diagnosis for the presence of cytogenetic abnormalities by FISH analysis. Forty-five percent of patients had del(13q), while t(4;14) and del(17p) were found in 16 % and 7 % of patients, respectively. The presence of del(17p) and/or t(4;14) was associated with a significantly shorter 5-year projected TTP, PFS and OS in comparison with the absence of these abnormalities, indifferently from the presence or absence of del(13q) (TTP: 30% vs 53%, respectively P=0.0000; PFS: 28% vs 45%, respectively, P=0.0000; OS: 53% vs 69%, respectively, P=0.0000). OS and PFS curves of patients carrying del(13q) alone were almost superimposable to those of patients without cytogenetic abnormalities, while TTP was significantly shorter for patients with del(13q) alone (5-year projected rates: 40% vs 53%, respectively, P=0.04). Patients carrying del(17p) in the absence of t(4;14) had similar 5-year projected TTP and PFS as compared with t(4;14) positive but del(17p) negative patients. However, OS was significantly shorter for the subgroup with del(17p) and absence of t(4;14) in comparison with that of patients carrying t(4;14) without del(17p) (5 year projected rates: 18% vs 70%, respectively, P=0.03). In a multivariate analysis, presence of del(17p) and high beta2-m at baseline were the most important variables adversely influencing TTP (HR: 2.3, P=0.001 and HR: 1.8, P=0.002, respectively), PFS (HR: 2.0, P=0.001 and HR: 1.9, P=0.001, respectively), and OS (HR: 3.9, P=0.000 and HR: 2.0, P=0.005, respectively). Additional variables predicting for shorter TTP and PFS were the presence of t(4;14) (HR: 1.8, P=0.004) and of del(13q) (HR: 1.6, P= 0.009). Also the quality of best response to the overall treatment program influenced clinical outcomes. In particular, patients achieving CR had a significantly longer PFS and OS than those achieving a VGPR (PFS: median 68 vs 40 months, respectively, P=0.007; 5-year projected OS rates: 84% vs 70%, respectively, P=0.01). In conclusion, incorporation of thal-dex into double autotransplantation failed to overcome the poor prognosis conferred by del(13 q), t(4;14) and del(17p). In a multivariate Cox regression analysis, del(17p) and high levels of serum beta2-m at diagnosis were the strongest variables adversely influencing PFS and OS. In comparison with the presence of t(4;14) but absence of del(17p), patients carrying del(17p) without t(4;14) had a significantly shorter OS, possibly due to their worst outcome after relapse. Presence of del(13q) alone conferred a significantly shorter TTP, but did not have an adverse impact on OS due to the favorable role of effective salvage therapies incorporating either bortezomib or lenalidomide. Disclosures: Off Label Use: use of first line thalidomide in preparation for ASCT. Cavo:Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, no; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, no; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, no.

Abstract: Abstract 861 The high rate of complete response (CR) effected by novel agents as induction and consolidation/maintenance therapy in multiple myeloma (MM) has renewed interest in the evaluation of minimal residual disease (MRD) after these combined treatment strategies. For this purpose, a useful molecular marker is represented by the immunoglobulin heavy-chain (IgH) rearrangement which can be carefully detected by means of polymerase chain reaction (PCR). We designed a molecular sub-study to the phase 3 GIMEMA trial of bortezomib-thalidomide-dexamethasone (VTD) vs. thalidomide-dexamethasone (TD) incorporated into double autologous stem cell transplantation (ASCT) for newly diagnosed MM. By study design, patients randomized at diagnosis to VTD or TD as induction therapy before ASCT received two 35-day cycles of consolidation therapy with VTD or TD starting 3 months after ASCT(s), independently from prior response. Doses of study drugs were the following: V, 1.3 mg/m2 once weekly; T, 100 mg/d through d 1 to 70; D, 320 mg/cycle. Aim of the molecular study was to compare the activity of VTD consolidation with that of TD by qualitative and quantitative PCR analysis. Patients who were planned to receive consolidation with either VTD or TD and who were in confirmed CR or near CR before the start of consolidation therapy were eligible for entry into the molecular study. A qualitative and quantitative PCR analysis with patient-specific primers was performed on bone marrow samples collected at day 0 and at day +70 after the two preplanned cycles of either VTD or TD. At this time, 84 patients were included in the study; of these, 67 patients were analyzed for MRD detection based on the availability of: 1) a molecular marker (e.g. IgH rearrangement) assessed at diagnosis; 2) both pre- and post-consolidation bone marrow samples. According to randomization at diagnosis, 35 out of 67 patients received VTD consolidation, while TD consolidation was given to 32 patients. Qualitative PCR analysis performed on bone marrow samples collected at day 0 showed that MRD before the start of VTD consolidation therapy was undetectable in 15 out of 35 patients, or 43%; the corresponding value before the start of TD consolidation was 37.5% (or 12 out of 32 patients). In comparison with the pre-consolidation status, analysis of bone marrow samples collected at day +70 revealed an upgrade in PCR-negativity from 37.5% to 52% with TD consolidation and from 43% to 67% with VTD consolidation (p=0.05, according to McNemar's test). By using the Fisher's exact test, the proportion of patients with post-consolidation PCR-negativity was significantly higher with VTD vs. TD consolidation (p=0.05). These data were furtherly extended by a Real-time quantitative PCR analysis, which could be performed in 45 out of the 67 patients initially included in the study (22 in the TD arm and 23 in VTD). In comparison with residual tumor mass at day 0, quantitative PCR analysis of bone marrow samples collected at day +70 revealed a median 1 log reduction in tumor burden with TD consolidation vs. a median 5 log reduction with VTD consolidation. By using the Wilcoxon test, the overall reduction in residual tumor burden effected by VTD consolidation therapy was statistically significant (p=0.05). In conclusion, in comparison with TD consolidation, two 35-day cycles of consolidation therapy with VTD following double ASCT significantly increased the rate of molecular remissions and significantly reduced the burden of residual myeloma cells persisting after ASCT. Superior activity of VTD over TD consolidation was retained although prior exposure to the same regimen given as induction therapy in preparation for ASCT. Additional data on molecular follow-up analyses of bone marrow samples collected after day +70 and comparisons of the prognostic relevance of PCR-negativity with PCR-positivity, as well as of PCR-negativity induced by VTD with that induced by TD will be presented during the meeting. Supported by: Progetto di Ricerca Finalizzata Orientata (to M.C), BolognAIL, Fondazione del Monte di Bologna e Ravenna. Disclosures: Baccarani: NOVARTIS: Honoraria; BRISTOL MYERS SQUIBB: Honoraria. Cavo:jansen-cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, no; celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, no; novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, no.

Abstract: In May 2006, the Italian Myeloma Network GIMEMA initiated a multicenter, randomized phase III study comparing VTD (arm A) with TD (arm B) incorporated into ASCT for newly diagnosed MM. Both VTD and TD were planned to be administered before (induction) and after (consolidation) double ASCT with melphalan 200 mg/m2 (MEL-200). In both arms, induction therapy consisted of three 21-d courses [63 days (d)]. The VTD regimen included Vel, 1.3 mg/m2 on d 1, 4, 8, and 11, plus Dex, 40 mg on each day of and after Vel administration; Thal was given at 200 mg/d from d 1 to 63. Patients randomized to TD received Thal as in arm A and Dex 40 mg/d on d 1–4 and 9–12 of every 21-d cycle. Primary study end point was complete response [either immunofixation negative (CR) or immunofixation positive (nCR)] to induction therapy. Secondary study end points included CR+nCR to consolidation therapy, time to progression, event-free survival, overall survival and toxicity. An interim analysis was planned to be performed after one year from study initiation to assess efficacy and toxicity of induction therapy. As of May 30, 2007, 234 patients entered the study and 187 were evaluated for response to induction therapy and adverse events (AEs). Of these patients, 92 were randomly assigned to receive VTD and 95 to receive TD. Efficacy and toxicity analyses were performed on an intention-to-treat basis. The rate of CR+nCR to VTD was 38% vs 7% to TD (P 〈 0.001); 60% of patients in VTD arm and 25% of patients in the control group attained at least a very good partial response (P 〈 0.001). Patients who failed at least a partial response to VTD were significantly less than those who failed on TD (7% vs 21%, respectively; P=0.004). Grade ≥ 2 and grade ≥ 3 AEs were similar in both arms, with the exception of grade ≥ 3 skin rash (6.5% in VTD arm vs 1% in TD arm; P=0.04). Grade 3 peripheral neuropathy was reported in 8% of patients randomly assigned to VTD and in 2% of patients treated with TD (P=0.07). All patients received acyclovir prophylaxis against reactivation of varicella zoster virus (VZV). VZV infection occurred in 2% of patients in VTD arm and in 1% of patients in the control group. Treatment discontinuation due to AEs was required in a single patient in each of the two treatment arms. No patient died for any cause during the induction phase. In a subgroup of patients with longer follow-up response to first ASCT was also evaluated. The rate of CR or CR+nCR to MEL-200 was significantly higher in VTD arm than in the control group (P=0.02 for CR comparison and P=0.05 for CR+nCR comparison between the two treatment arms). Preliminary analysis of this study provides demonstration that VTD is a highly active and well tolerated induction regimen, resulting in a significantly higher CR or CR+nCR rate compared to TD both before ASCT and after the first autologous transplantation with MEL-200.

Abstract: Abstract 351 Introduction A phase III study of melphalan (200 mg/m2)-based double autologous stem-cell transplantation (ASCT) incorporating thalidomide (T) and dexamethasone (D) with or without the addition of bortezomib (V) as first-line therapy for younger (≤65 years) patients (pts) with newly diagnosed multiple myeloma (MM) is currently being conducted by the Italian Myeloma Network GIMEMA. Patients and Methods By study design, pts were random assigned to receive three 21-d cycles of either bortezomib-thalidomide-dexamethasone (VTD) (V, 1.3 mg/m2 twice-weekly; T, 200 mg/d through d 1 to 63; D, 320 mg/cycle) or thalidomide-dexamethasone (TD) (both drugs at the same dose and schedule than in VTD) as induction therapy in preparation for ASCTs. Two 35-d cycles of either VTD or TD were given as consolidation therapy following ASCTs (V, 1.3 mg/m2 once-weekly; T, 100 mg/d through d 1 to 70; D, 320 mg/cycle). Primary study end point was the rate of high-quality responses [immunofixation negative complete response (CR) and ≥very good partial response (VGPR)] to induction therapy. Secondary study end points included response to, and toxicity of, subsequent treatment phases (including first and second ASCTs, and consolidation therapy), progression-free survival (PFS) and overall survival (OS). Analyses were intent to treat. All the 474 pts were evaluated for response to, and toxicity of, induction therapy. Responses reported by study investigators were centrally reassessed to confirm CR and VGPR; pts reported as complete responders but in whom bone marrow aspirate was not evaluable or not performed were reassessed as in VGPR. The VGPR category included the subcategories of near CR and VGPR. Results The study was closed to pts accrual after a total of 480 pts were enrolled; of these, 6 failed inclusion criteria and the remaining 474 were randomized to the VTD (n=236) or TD (n=238) arm. The mean total dose of V received in induction therapy was 14.7 mg (or 94% of that planned). Grade 3 peripheral neuropathy (PN) and skin rash (SR) were reported more frequently with VTD induction therapy than with TD (PN: 9.7% vs 2.1%, respectively; P 〈 0.001) (SR: 10% vs 1.7%, respectively; P 〈 0.001). In the VTD arm, resolution or reduction to at least grade 2 of PN was observed within a median of 26 days. Remarkably, once-weekly standard dose administration of V and reduction of T dose in VTD as consolidation therapy resulted in a dramatic decrease in the frequency of grade ≥3 PN (2%) and SR (1%). Reported rates of herpes zoster infection with VTD as both induction and consolidation therapy were 0.4% and 1%, respectively. Overall, the CR (≥VGPR) rate with VTD induction therapy was 19% (62%) vs 5% (31%) with TD (P 〈 0.001 for both CR and ≥VGPR comparisons); no pt had disease progression while on VTD, as compared to 5% of pts treated with TD (P 〈 0.001) who discontinued therapy and went off study. Progression through the subsequent treatment phases was associated with an increase in the frequency of CR and ≥VGPR up to a final value of 44% and 80%, respectively, in the VTD arm; the corresponding rates in the TD arm were 32% (p=0.02) and 65% (p=0.001), respectively. On an intention to treat basis, best responses in the VTD vs TD arm were the following: CR, 55% vs 38%, respectively (P 〈 0.001); ≥VGPR: 87% vs 69%, respectively (P 〈 0.001). Superiority of the VTD vs TD arm in terms of CR rate was confirmed in pts with high-risk cytogenetics, as defined by the presence of t(4;14) and/or del(17p) (58% vs 33%, respectively; p=0.004). Two year-projected PFS was 85% in the VTD arm as compared to 75% in TD (p=0.008). Improved PFS with VTD vs TD, both added to double ASCT, was consistent across subgroup analyses of pts with poor prognosis, including those with high-risk cytogenetic profiles (p=0.03; HR=0.42, 95% CI: 0.18 to 0.96). PFS curves for pts in the VTD arm who carried or not high-risk cytogenetics were similar (p=0.19). No difference in OS was seen between the two treatment groups, but longer follow up is required. Conclusions Incorporation of VTD into double ASCT for newly diagnosed MM resulted in a significant improvement in clinical outcomes (CR, ≥VGPR, PFS) in comparison with TD and double autotransplantation. Superior benefit with VTD and double ASCT in comparison with the control group was maintained in pts at high risk of progression or death, including those with t(4;14) and/or del(17p). Disclosures: Cavo: Celgene: Honoraria; Ortho Biotech, Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals: Honoraria; Novartis: Honoraria.

Abstract: INTRODUCTION. Elderly patients (pts) with newly diagnosed multiple myeloma (NDMM) are a heterogeneous population. The IMWG frailty score stratifies pts ≥65 years into 3 categories (fit, intermediate-fit and frail), according to chronological age, comorbidities and functional abilities, with different prognosis. We previously reported results from the phase II EMN10-Unito study investigating 4 Ixazomib-based induction regimens followed by Ixazomib maintenance in elderly NDMM pts. Here we present a post-hoc analysis of safety and efficacy of ixazomib-based induction regimens and maintenance according to IMWG frailty score. METHODS. NDMM, transplant-ineligible pts ≥65 years were enrolled. Treatment consisted of 9 induction cycles of Ixazomib combined with dexamethasone (Id), Cyclophosphamide-dexamethasone (ICd), Thalidomide-dexamethasone (ITd) or Bendamustine-dexamethasone (IBd), followed by single-agent Ixazomib maintenance for up to 2 years. Pts were stratified into 3 groups (fit, intermediate-fit and frail) according to IMWG frailty score. The aim of this analysis was to evaluate the efficacy (TTP, PFS, PFS2 and OS) and safety of ixazomib-based induction regimens and single-agent ixazomib maintenance in the 3 patient subgroups. RESULTS. 171 pts were enrolled in the study and started treatment; of these, 75 (44%) were classified as fit, 53 (31%) as intermediate-fit and 43 (25%) as frail. As expected, the median age was higher in frail (79 years) as compared with fit (71 years) and intermediate-fit (76 years) pts, and a worse ECOG score (1-2) was reported in frail (67%) as compared with fit (46%) and intermediate-fit pts (46%). Frail pts were also more likely to have ISS 2-3 myeloma (82%) compared with fit (59%) and intermediate-fit (77%) ones. The median follow-up for the entire population was 27 months. The ORR and VGPR rates after the induction were similar in fit (71%; 42%), intermediate-fit (74%; 38%) and frail pts (76%; 40%), although fit (8%) and intermediate-fit (13%) pts were more likely to achieve a CR than frail ones (2%). No significant differences in median PFS were observed among fit (14.1 months; HR: 0.75, p=0.27), intermediate-fit (14.8, HR: 0.68, p=0.12) as compared to frail pts (12.2 months). The median PFS2 was significantly longer in fit (41.1, HR: 0.48; p=0.04) and intermediate-fit (35.6, HR: 0.47, p=0.03) in comparison with frail pts (28.6 months). OS was longer in fit pts (NR; HR: 0.36, p=0.02) and intermediate-fit (NR; HR: 0.58, p=0.15) as compared to frail ones (36.7 months). The rates of grade 3-4 adverse events (AEs) and grade 3-4 non-hematological AEs during the induction phase were higher in frail pts (47% / 37%) as compared to fit (28% / 24%) and intermediate-fit (32% / 26%) ones. Similarly, the risk of treatment discontinuation was higher in frail (21%) as compared to fit (11%) and intermediate-fit pts (9%). When comparing PFS with three- vs two-drug ixazomib-based induction, both fit (HR: 0.75) and intermediate-fit (HR: 0.69) pts benefited from the use a triplet over a doublet; whereas, no difference between three- and two-drug combinations was observed in frail pts (HR: 1.01). Overall, 102 pts (60%) completed the induction phase and proceeded to ixazomib maintenance: of these, 46 (45%) were fit, 35 (34%) intermediate-fit and 21 (21%) frail. The median PFS from start of maintenance in the overall population was 15 months, without significant differences in intermediate-fit (HR: 0.92) and frail (HR: 1.14) pts as compared to fit ones. Concerning the safety of ixazomib maintenance, grade 3-4 non-hematological AEs were infrequent, occurring in 15% of fit pts (15%), 3% of intermediate-fit and 5% of frail (5%) ones. Ixazomib dose reductions were more frequent in frail (24%) as compared to fit (13%) and intermediate-fit (11%) pts, although a similar percentage of pts discontinued ixazomib due to AEs in the three groups (fit: 11%; intermediate-fit: 15%; frail: 10%). CONCLUSIONS. Ixazomib-based regimens had similar efficacy in terms of ORR and PFS, irrespective of frailty status, although AEs, dose modifications and treatment discontinuation were more frequent in frail pts. Importantly, frail pts did not seem to benefit from the addition of a third drug over the use of a doublet induction therapy. Single-agent ixazomib maintenance was effective and well tolerated in fit, as well as in intermediate-fit and frail pts, thus representing an appealing maintenance option in elderly MM. Disclosures Mina: Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria. Larocca:Amgen: Honoraria; Bristol-Myers Squibb: 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; GSK: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Offidani:Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Galli:BMS: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria. De Sabbata:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Cavo:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Boccadoro:Mundipharma: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Bringhen:Bristol-Myers Squibb: Honoraria; Takeda: Consultancy; Janssen: Consultancy, 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; Karyopharm: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including ixazomib, dexamethasone, cyclophosphamide, thalidomide and bendamustine).