Abstract: Purpose: Primary plasma cell leukemia (pPCL) is a rare and very aggressive form of plasma cell dyscrasia. To date, no information on microRNA (miRNA) expression in pPCL has been reported. This study aimed at investigating the involvement of miRNAs in pPCL and their possible relationship with higher tumor aggressiveness. Experimental design: Global miRNA expression profiles were analyzed in highly purified malignant plasma cells from 18 pPCL untreated patients included in a prospective clinical trial. MiRNA expression patterns were evaluated in comparison with a representative series of multiple myeloma patients, in relation to the most recurrent chromosomal abnormalities (as assessed by fluorescence in situ hybridization and single-nucleotide polymorphism-array analysis), and in association with clinical outcome. MiRNA expression was also integrated with gene expression profiles in pPCL and multiple myeloma samples. Results: We identified a series of deregulated miRNAs in pPCL (42 upregulated and 41 downregulated) in comparison with multiple myeloma. Some of them, on the basis of their reported functions and putative target genes computed by integrative analysis, might have a role in the pathobiology of pPCL. As regards chromosomal aberrations, the expression of some miRNAs mapped to hotspot altered regions was associated with DNA copy number of the corresponding loci. Finally, 4 miRNA (miR-497, miR-106b, miR-181a*, and miR-181b) were identified as having expression levels that correlated with treatment response, and 4 (miR-92a, miR-330-3p, miR-22, and miR-146a) with clinical outcome. Conclusions: Overall, our study provides insights into the possible contribution of miRNAs in the pathogenesis of pPCL and suggests targets for future therapeutic investigations. Clin Cancer Res; 19(12); 3130–42. ©2013 AACR.

Abstract: Introduction: The multicentre, randomized, open-label, phase 3 EMN02/HO95 study for patients with newly diagnosed multiple myeloma (NDMM) included two randomization stages (1:1) to (R1) intensification therapy with either upfront ASCT or bortezomib-melphalan-prednisone (VMP), and thereafter to (R2) consolidation therapy or no consolidation, followed by lenalidomide maintenance in both arms. Results of the final analysis from R1 (M. Cavo et al. Lancet Haematol. 2020, 7, e456-68) showed that at a median follow-up of 60.5 months progression-free survival (PFS), the primary study endpoint, was significantly improved with ASCT compared with VMP (median, 57 versus 42 months; HR 0.73, 95% CI 0.62-0.85, adjusted p=0.0001). However, no difference between these groups was found in terms of overall survival (OS), a secondary endpoint (HR 0·90, 0·71-1·13, adjusted p=0·35). Methods: We performed an updated analysis of the study with longer-term follow-up. Efficacy endpoints included OS, PFS on next-line therapy (PFS2), and time to next treatment (TTnT). Analyses were restricted to patients randomized to either ASCT (n=702) or VMP (n=495). Clinical outcomes of patients randomized to upfront ASCT or receiving ASCT at the time of progression after primary randomization to VMP (delayed ASCT) were also explored. Results: At an extended median follow-up of 75 months (IQR 67-84), patients randomized to ASCT had a significantly longer OS than those randomized to VMP (Figure). Median OS was not reached in both arms, and the 75-month survival estimate was 69% (95% CI 65-73) in the ASCT group versus 63% (95% CI 59-68) in the VMP group (HR 0.81, 95% CI 0.66-0-98, adjusted p=0.034). Patients who benefited the most from randomization to ASCT were those with unfavourable prognostic characteristics at baseline, including ISS disease stage 2-3 (HR 0.78, 95% CI 0.61-0.99, p=0.047), R-ISS stage 2-3 (HR 0.79, 95% CI 0.62-0.99, p=0.042), and the presence of at least one of the following cytogenetic abnormalities on FISH analysis: t(4;14) and/or t(14;16) in ≥10% CD138-positive plasma cells, and/or del(17p) in ≥20% enriched plasma cells. Overall, the 75-month OS estimate for patients with a high-risk cytogenetic profile was 54% with ASCT versus 39% with VMP (HR 0.61, 95% CI 0.42-0.89, p=0.010). The magnitude of OS benefit with ASCT, as measured by the HR value, was the highest for patients with del(17p) positivity (HR 0.49, 95% CI 0.28-0.86, p=0.013). PFS2 from R1 was significantly longer for patients in the ASCT arm than for those in the VMP arm. The 75-month PFS2 estimate was 57% in the ASCT group and it was 49% in the VMP group (HR 0.76, 95% CI 0.64-0.90, adjusted p=0.002) (Figure). Patients randomized to ASCT had a significantly longer TTnT in comparison with those who were randomly assigned to VMP. Median TTnT values for these groups were 66 versus 47 months, respectively (HR 0.71, 95% CI 0.60-0.82, adjusted p & lt;0.001) (Figure). Demographic and clinical characteristics at baseline of patients in the delayed ASCT group were comparable with those of patients who were randomized to upfront ASCT. PFS2 and TTnT in the upfront ASCT group were significantly longer than in the delayed ASCT group. Median PFS2 values were 85 versus 51 months, respectively (HR 0.52, 95% CI 0.40-0.66, p & lt;0.001). Median TTnT values were 59 versus 29 months, respectively (HR 0.32, 95% CI 0.26-0.40, adjusted p & lt;0.001). At the time that this analysis was performed, the rate of events of death was 30% in the upfront ASCT group versus 46% in the delayed ASCT group. In both the ASCT and VMP arms of the study, lenalidomide maintenance at the dose of 10 mg orally on day 1-21 of 28-day cycles was planned until progressive disease or undue toxicity. The median duration of lenalidomide treatment was 34 (IQR 13-63) months; 28% of patients were still on treatment at 60 months after start of lenalidomide and 31% discontinued due to treatment-related adverse events (27%) or second primary malignancies (4%). At a median follow-up of 70 (IQR 60-77) months from start of maintenance therapy, median PFS with lenalidomide was 56 months in the ASCT arm and 42 months in the VMP arm (HR 0.77, 95% CI 0.65-0.91, adjusted p=0.002). OS curves started to diverge at 5 years, and the 70-month estimate was 74% in the ASCT arm versus 69% in the VMP arm, suggesting that longer-term follow-up analysis is required. Conclusions: Upfront ASCT significantly prolonged OS, PFS2 and TTnT in comparison with VMP in NDMM patients. Figure Disclosures Cavo: Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Gay:AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; GSK: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Beksac:Janssen & janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Deva: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Petrucci:GSK: 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; BMS: 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; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zweegman:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zamagni:Amgen: 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, Other: Travel, Accommodations, Expenses, Speakers Bureau; Takeda: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau. Palumbo:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Galli:BMS: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Maisnar:Janssen, Takeda, Amgen, BMS/Celgene, The Binding Site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hansson:Amgen, Celgene, Takeda, Janssen Cilag: Consultancy. Belotti:Celgene: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Offidani:Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Zambello:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Liberati:Verastem: Research Funding; Janssen: Honoraria, Research Funding; Takeda: Research Funding; Morphosys: Research Funding; Novartis: Research Funding; GSK: Research Funding; Incyte: Honoraria; Oncopeptides: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Research Funding; Onconova: Research Funding; Pfizer: Research Funding; Karyopharm: Research Funding. Broyl:Janssen, Celgene, Takeda, Amgen: Honoraria. Musto:Amgen: Honoraria; Celgene: Honoraria. Ludwig:Seattle Genetics: Other: Advisory Boards; Takeda: Research Funding; Sanofi: Other: Advisory Boards, Speakers Bureau; Bristol Myers: Other: Advisory Boards, Speakers Bureau; Amgen: Other: Advisory Boards, Research Funding, Speakers Bureau; Janssen: Other: Advisory Boards, Speakers Bureau; Celgene: Speakers Bureau. Hajek:Roche: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria, Research Funding; Pharma MAR: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Waage:Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy; Shire: Honoraria. Mellqvist:Janssen. Celgene, Amgen: Honoraria. Boccadoro:Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding. Sonneveld:Karyopharm: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.

Abstract: Background. High-dose melphalan followed by autologous stem cell transplantation is a standard of care in transplant-eligible newly diagnosed multiple myeloma (NDMM) patients and is also an option at relapse. Therefore, since the minimum number of CD34+ cells required to ensure adequate bone marrow recovery after myeloablative chemotherapy is 2x10^6/kg, an adequate upfront stem-cell collection is necessary in MM patients. Approximately 5-15% of MM patients mobilized with granulocyte colony-stimulating factor (G-CSF) or G-CSF+cyclophosphamide (G-CSF/CY) fail stem-cell collection ( & lt;2x10^6/kg CD34+). Plerixafor in combination with G-CSF or G-CSF/CY increases stem-cell yield and lowers the rate of poor mobilizers (PM). Here we present preliminary results of the prospective, observational MOZOBL06877 study (partially supported by Sanofi investigation funds) to evaluate the performance of stem-cell mobilization with G-CSF/CY plus on-demand plerixafor in NDMM patients treated with novel agents. Methods. NDMM patients undergoing stem-cell mobilization with cyclophosphamide (2-4 g/m2) and G-CSF (5-10 mcg/kg/day), with on-demand plerixafor according to clinical practice ( & lt;20 CD34+/ul on first count day or & lt;1×106 CD34+ cells/kg collected on first apheresis day), could be enrolled and were observed for 30 days after mobilization. The primary endpoint was the PM rate (patients collecting & lt;2×106 CD34+ cells/kg); secondary endpoints were the number of patients requiring plerixafor, the stem-cell yields with or without plerixafor, the identification of predictive factors for the use of plerixafor and adverse events (AEs) during study treatment. Results. At the data cut-off (09 June 2020), a total of 252 patients had been enrolled: of these, 192 patients (59, 29-72 years) were available for the analysis. The median number of induction cycles before mobilization was 4 (range 1-7); median time from diagnosis to mobilization was 6 months (IQR 5-8). Induction therapy consisted of a bortezomib-based regimen in 171 (90%), carfilzomib/lenalidomide-based regimen in 14 (7%), lenalidomide-based regimen in 3 patients (2%). 187/192 (97%) patients successfully collected ≥2 x 10^6/Kg CD34: of these, 153/192 (80%) collected with G-CSF/CY, 29/192 (15%) required the administration of plerixafor. The PM rate was 5/192 (2.5%): of these, 3/5 did not receive plerixafor in addition to G-CSF/CY, while 2/5 failed stem-cell collection despite the use of plerixafor. The median number of CD34 collected was 9.8x10^6/Kg (6.7-14.2). The median number of CD34/Kg collected with or without plerixafor was 5.1 (4.3-9.1) and 10.6 (8.1-14.4), respectively. The median number of apheresis days was 1 (IQR 1-2), with a stem-cell collection efficiency (CD34 number collected/ days of apheresis) equal to 7.7 x10^6 CD34/kg/day. The median number of apheresis days was 1 without plerixafor and 2 with plerixafor, with a stem-cell collection efficiency (CD34 number collected/ days of apheresis) equal to 8.8 without plerixafor and 3 with plerixafor. In patients who received plerixafor, the median number of CD34/ul pre-apheresis was 16 (10-19.5); after the administration of plerixafor, the median number of CD34/ul pre-apheresis increased to 46 (21-81). Non hematological AEs within 30 days after mobilization occurred in 8% of patients (grade 3-4: 2%); all grade and grade 3-4 infections occurred in 2% of patients each. In a multivariate analysis, main factors predicting the use of plerixafor were ISS 3 (vs. 1, OR 4.43; p=0.008), bone marrow plasma cells at diagnosis & gt;60% (OR 3.85; p=0.006), white blood cell (WBC) count pre-mobilization (OR 6.66; p & lt;0.001) and lenalidomide-based therapy (OR 3.85; p=0.03). Conclusion. "On-demand" plerixafor combined with G-CSF/CY is a safe and effective rescue strategy for stem-cell collection in MM, reducing the PM rate to 2.5%. Extensive bone marrow plasmacytosis, ISS 3 disease at diagnosis, use of lenalidomide during induction and a low WBC count pre-mobilization predicted the use of plerixafor. Thus, pre-emptive administration of plerixafor in patients presenting one or more risk factors for poor mobilization might help in further reducing the PM rate. Disclosures Mina: Amgen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Petrucci:Celgene: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: 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; Janssen: 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. Lemoli:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BerGenBio ASA: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Offidani:BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Musto:Amgen: Honoraria; Celgene: Honoraria. Corradini:F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; Incyte: Consultancy; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; KiowaKirin: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; BMS: Other; Sanofi: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Kite: Consultancy, Honoraria. Cavo:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, 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; AbbVie: 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, Other: Travel accomodations, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Honoraria. Boccadoro:GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; AbbVie: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Larocca:Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; 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; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of patients with multiple myeloma (including cyclophosphamide, G-CSF and plerixafor).

Abstract: Introduction : Cytogenetic abnormalities by fluorescence in situ hybridization (FISH) are clinically relevant prognostic factors in MM. Data in transplant ineligible patients treated with bortezomib or lenalidomide in first-line therapy for high-risk (HiR) patients is limited. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. This sub-analysis evaluates the impact of cytogenetics on outcomes in transplant-ineligible patients with newly diagnosed MM (NDMM) treated with bortezomib-based induction (BORT) or lenalidomide-based (LEN) treatment. Methods : In the GIMEMA-MM-03-05-trial, patients were randomized to bortezomib-melphalan-prednisone-thalidomide for 9 cycles followed by maintenance with bortezomib-thalidomide (VMPT-VT) vs VMP for 9 cycles, without maintenance. In the EMN01-trial, patients were randomized to melphalan-prednisone-lenalidomide (MPR) or cyclophosphamide-prednisone-lenalidomide (CPR) or lenalidomide plus low-dose dexamethasone (Rd) for 9 cycles, followed by maintenance with lenalidomide alone or plus prednisone continuously. Results of these studies have previously been reported (Palumbo A et al JCO 2010 and 2014; Magarotto V et al Blood 2016 127(9)). Cytogenetics were assessed using FISH. Patients were categorized into cytogenetic risk groups according to International Myeloma Working Group criteria. HiR cytogenetics included del(17p), t(4;14), and t(14;16); all other patients were categorized as standard risk (StR). Subgroup analyses were performed to determine the consistency of treatment effects of BOR vs LEN in the different subgroups using interaction terms between treatment and FISH, ISS, age, sex, Karnofsky PS and LDH. The different effect of BORT vs LEN in cytogenetic subgroups was confirmed by one sensitivity analysis where the follow-up of the BORT study was reduced to make the follow-up times similar; and by another sensitivity analysis with multiple imputation method for missing cytogenetic value. Results : 902 of 1165 patients from the intent-to-treat population had available cytogenetic profiles, with 243 (27%) patients in the HiR group and 659 (73%) in the StR group. In the BORT vs LEN groups, median age was 71 vs 73 years (p & lt;0.001), ISS3 20% vs 27% (P=0.65), HiR patients were 29% vs 26%, StR patients were 71% vs 74% (p=0.32) and the median follow-up was 72.3 and 63.6 months, respectively. In the subgroup analysis, a significant difference was found in the cytogenetic subgroup with a superior advantage of BORT versus LEN in HiR group, whereas no significant difference was found between BORT and LEN in the other subgroups analyzed (ISS, age, sex, Karnofsky PS and LDH) (interaction-p=0.01) (Fig. 1 B). BORT treatment resulted in a reduced risk of death or progression compared with LEN in patients with HiR. In HiR patients, median PFS was 30.8 with BORT compared with 14.8 months with LEN (HR: 0.54; 95% CI: 0.41-0.72); in StR, median PFS was 29.1 with BORT compared with 22.1 months with LEN (HR: 0.87; 95%; CI: 0.72-1.05) (Fig. 1 A). Considering the standard of care VMP and Rd, in the HiR group (n=95) VMP resulted in a 48% reduced risk of death or progression compared with Rd (HR: 0.53; 95% CI: 0.34-0.83), whereas no significant difference in PFS was found in the StR group (n=273) (HR: 1.00; 95% CI: 0.75-1.33), interaction-p=0.02. BORT treatment resulted in a reduced risk of death in patients with HiR cytogenetics: median OS was 62.4 months with BORT compared with 43.2 months with LEN (HR: 0.68; 95% CI: 0.47-0.96); in StR, median OS was 78.1 months with BORT and was not reached with LEN (HR: 1.06; 95% CI: 0.82-1.36), interaction-p=0.04 (Fig. 1 A). In patients with del(17p) (n=131) median PFS was 18.0 vs 12.9 months for BORT vs LEN (HR: 0.71; 95% CI: 0.49-1.04), interaction-p=0.73. In patients with t(4;14) (n=118) median PFS was 31.5 vs 15.2 months for BORT vs LEN (HR: 0.41; 95% CI: 0.27-0.62) interaction-p=0.002. In patients with t(14;16) (n=31) median PFS was 36.2 vs 9.8 months for BORT vs LEN treated patients (HR: 0.34; 95% CI: 0.16-0.76), interaction-p=0.045. Conclusions : BORT treatment resulted in a PFS and OS benefit vs LEN in patients with HiR cytogenetics. Treatment with VMP led to a significant reduction of the risk of death or progression vs Rd in HiR patients. These results support VMP induction as a standard treatment option for patients with NDMM who are ineligible for transplant with HiR cytogenetics. Disclosures Larocca: Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria. Offidani: 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. Musto: Janssen: Honoraria; Celgene: Honoraria. Patriarca: MSD Italia: Honoraria; Janssen: Honoraria. Corradini: Gilead: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Bosi: Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Petrucci: Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Boccadoro: Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Mundipharma: Research Funding; AbbVie: Honoraria.

Abstract: Abstract 620 Background. The combination of bortezomib-melphalan-prednisone (VMP) is a new standard of care for elderly newly diagnosed multiple myeloma. This phase 3 study compared the 4 drug combination bortezomib-melphalan-prednisone-thalidomide followed by maintenance bortezomib-thalidomide (VMPT-VT) with VMP alone. Methods. Patients (N=511) older than 65 years were randomized to receive nine 6-week cycles of VMPT-VT (N=254; induction: bortezomib 1.3 mg/m2, d 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, d 1, 8, 22, 29, cycles 5–9; melphalan 9 mg/m2 d 1–4, prednisone 60 mg/m2, d 1–4, thalidomide 50 mg d 1–42; maintenance: bortezomib 1.3 mg/m2 every 14 days and thalidomide 50 mg/day) or VMP (N=257) alone. In March 2007, the protocol was amended: both VMPT-VT and VMP induction schedules were changed to nine 5-week cycles and bortezomib schedule was modified to weekly administration (1.3 mg/m2 d 1,8,15,22, all cycles). The primary end point was progression-free survival (PFS). Results. All patients have been evaluated in intention-to-treat. Patient characteristics were similar in both groups, median age was 71 years. The response rates were superior in the VMPT-VT group with a complete remission (CR) rate of 38% vs 24% (p=0.0008). After a median follow-up of 26.1 months, the 3-year PFS were 55% in patients receiving VMPT-VT and 38% in those receiving VMP (HR 0.65, 95% CI 0.49–0.85, P=0.002, Table). The 3-year time-to-next-therapy were 69% with VMPT-VT and 55% with VMP (HR 0.60, 95% CI 0.42–0.85, P=0.004). The 3-year overall survival was 86% with VMPT-VT and 84% with VMP (HR 0.88, 95% CI 0.53–1.45, P=0.62). The achievement of CR was a strong predictive factor of longer PFS in both groups (P=0.0001): in VMPT-VT arm, 3-year PFS was 66% in patients who obtained CR and 47% in those achieving PR; in VMP arm, it was 70% and 30%, respectively. The PFS benefit of VMPT-VT was seen consistently across different subgroups defined by creatinine clearance, LDH and bortezomib schedule; by contrast, in patients older than 75 years (HR 0.87; 95% CI 0.54–1.43, P=0.59) and in those at increased risk of disease progression, defined as presence of cytogenetic abnormalities [t(4;14) or t(14;16) or del17p] and ISS 3 (HR 1.35; 95% CI 0.45–4.06, P=0.60), VMPT-VT seemed not to add any significant PFS advantage to VMP. Grade 3–4 neutropenia (38% vs. 28%, p=0.02), cardiological events (10% vs. 5%, p=0.04) and thromboembolic events (5% vs. 2%, p=0.08) were more frequent among patients assigned to the VMPT-VT group; treatment-related deaths were 4% with VMPT-VT and 3% with VMP. In both groups, the once-weekly infusion of bortezomib significantly reduced the incidence of severe sensory peripheral neuropathy from 16% to 3% (p 〈 0.0001). One hundred and forty-nine VMPT-VT patients were assessable for maintenance treatment. After a median duration of maintenance of 14.4 months, the PR rate was 90%, including 45% CR. The 1-year landmark analysis of PFS in patients completing the 9 induction cycles, showed a 2-year PFS of 63% in the VMPT-VT group and 40% in the VMP group, demonstrating that maintenance with VT reduced the risk of disease progression of 51% (HR 0.49, 95% CI 0.33–0.72, p=0.0003, Figure). This advantage was less evident in patients older than 75 years (HR 0.97, 95% CI 0.52–1.78, P=0.91) and in those with high-risk of disease progression, defined as presence of cytogenetic abnormalities and ISS 3 (HR 1.31, 95% CI 0.22–7.85, p=0.77). Continuous therapy with VT had favourable safety profile: 3% of patients experienced grade 3–4 hematological toxicity, 5% grade 3–4 peripheral neuropathy and 7% discontinued due to adverse events. Conclusion. In summary the current results indicate that: 1. VMPT-VT prolonged PFS with an unprecedented 3-year PFS of 55% in elderly patients; 2. once-weekly infusion of bortezomib improved safety without affecting outcome; 3. higher dose-intensity regimens seemed to be less effective in frail patients (≥ 75 years) and 4. maintenance therapy with VT further improved PFS with a good safety profile. Disclosures: Palumbo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bringhen:Celgene: Honoraria; Janssen-Cilag: Honoraria. Patriarca:Celgene: Honoraria; Janssen Cilag: Honoraria; Roche: Honoraria; Merck: Membership on an entity's Board of Directors or advisory committees. Guglielmelli:Celgene: Honoraria; Janssen Cilag: Honoraria. Petrucci:Celgene: Honoraria; Janssen Cilag: Honoraria. Musto:Celgene: Honoraria; Janssen Cilag: Honoraria. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract: Cardio-vascular (CV) events are common in patients (pts) with myeloma (MM) and may occur as a result of age-related comorbidities, the disease itself or as a complication of anti-MM treatment, including proteasome inhibitors.Carfilzomib is a novel second generation proteasome inhibitorapproved as a single agent and in combination with lenalidomide and dexamethasone for the treatment of relapsed MM. Here, we present the results of an integrated CV safety analysis of 148 newly diagnosed, elderly or transplant-ineligible pts enrolled in 3 phase I/II studies with the combination of Carfilzomib, cyclophosphamide and dexamethasone(IST-CAR-506, IST-CAR-561, IST-CAR-601).In all trials cyclophosphamide 300 mg/m2 was administered orally on days 1, 8, 15 and dexamethasone 40 mg was administered orally once weekly. Carfilzomib was administered intravenously at the dose of 36 mg/m2 on days 1, 2, 8, 9, 15, 16 in the IST-CAR-506 trial; at 3 dose levels escalated from 45 to 70 mg/m2 on days 1, 8, 15 in the IST-CAR-561 trial and on days 1, 2, 8, 9, 15, 16 in the IST-CAR-601 trial. In all studies, after completing 9 28-day cycles, pts received 28-day maintenance cycles with Carfilzomib until disease progression or intolerance. Adverse events (AEs) were graded based on NCI-CTCAE v4. Median age was 72 years (range 55-85), 38 pts (26%) were older than 75 years. The median follow-up was 21 months. Overall, any grade CV AEs were reported in 62 pts (42%): 40/110 pts (36%) younger than 75 years and 22/38 (58%) older than 75 years (p=0.02). The more frequent events were hypertension, aggregated cardiac failure events, thromboembolic events and arrhythmia (Table 1). Grade ≥ 3 events occurred in 29 pts (30%): 17/110 pts (15%) younger than 75 years and 13/38 (34%) older than that (p=0.01). Aggregated cardiac failure events of any grade were reported in 10 pts (7%), thromboembolic events in 5 pts (3%), hypertension in 4 pts (3%) and arrhythmia 2 pts (1%). In pts younger than 75 years, the most frequent grade ≥ 3 AEs were hypertension (10 patients, 9%) and dyspnea (11 patients, 10%). In pts older than 75 years, the most frequent grade ≥ 3 AEs were hypertension and pulmonary edema (5 pts each, 13%). Importantly, 34% of pts who experienced CV AEs had hypertension at baseline or developed it during treatment compared to 14% of pts who did not experience CV AEs. Diabetes was more frequent (33%) in pts older than 75 years who developed CV AEs compared to 10% of pts older than 75 years who did not report any CV AEs or those younger than 75 years. No difference was observed among different doses or different schedules of Carfilzomib. Among pts who developed a CV AE, one third had a Carfilzomib dose reduction or discontinuation (Table 1) compared to 12-18% of pts who did not experience CV toxicity (p 〈 0.0001). Overall, the risk of CV toxicity was lower during maintenance: 21 pts of 97 who started maintenance (22%) developed any grade CV events. This improvement was evident only in pts younger than 75 years: 11/75 patients younger than 75 years (15%) had CV events compared to 10/22 (45%) older than 75 years (Figure 1). The most frequent CV AE during maintenance was hypertension (12%), regardless of age. Only 5 pts (5%) reduced Carfilzomib dose during maintenance. Five (3%) CV-related deaths were documented: 4 during induction and 1 during maintenance. All of them were possibly related to Carfilzomib (atrial fibrillation, heart failure, cardiac arrest, sudden death, pulmonary embolism). The occurrence of any CV AE during induction increased the mortality for any cause by twofold, regardless of age: the 2-year overall survival was 70% in patients who experienced CV AE and 82% in those who did not (HR 2.01, 95% CI 0.99-4.07, p=0.04). The risk of CV AEs during treatment with Carfilzomib is significantly higher in pts older than 75 years and the most important risk factor, regardless of age, is hypertension. Developing CV toxicity increases the need for dose reduction or drug discontinuation with a negative impact on overall survival. Elderly pts should be carefully assessed before starting treatment with 24 hour blood pressure monitoring. During treatment, baseline vital signs should be recorded and medications of blood pressure should be targeted promptly to keep blood pressure below 140/80 mmHg. With these simple actions, these AEs may be prevented or managed proactively and pts can derive maximum benefit from their treatment with Carfilzomib. Disclosures Bringhen: Mundipharma: Other: ADVISORY BOARD; Amgen: Other: ADVISORY BOARD; Janssen-Cilag: Honoraria; Celgene: Honoraria; BMS: Honoraria; Karyopharm: Other: ADVISORY BOARD. Petrucci:Janssen-Cilag: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria. Caravita di Toritto:Janssen-Cilag: Honoraria. Ria:BMS: Speakers Bureau; BMS: Speakers Bureau; Italfarmaco: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Janssen-Cilag: Other: Advisory Board, Speakers Bureau; Binding Site: Speakers Bureau. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Foà:Janssen-Cilag: Consultancy, Speakers Bureau; Genetech: Consultancy; Roche: Consultancy, Speakers Bureau; Ariad: Speakers Bureau; Pfizer: Speakers Bureau; BMS: Consultancy; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau. Corradini:Celgene: Honoraria, Speakers Bureau; Janssen-Cilag: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Sanofi Aventis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Gentium: Honoraria, Speakers Bureau. Gaidano:Roche: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Sonneveld:Celgene: Other: Advisory board, Research Funding; Millennium: Other: Advisory board, Research Funding; Onyx: Other: Advisory board, Research Funding; Janssen-Cilag: Other: Advisory board, Research Funding. Boccadoro:Novartis: Honoraria, Research Funding; SANOFI: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Abbivie: Honoraria; Amgen: Honoraria, Research Funding; Mundipharma: Research Funding; CELGENE: Honoraria, Research Funding.

Abstract: Abstract 1835 Poster Board I-861 Five studies demonstrated the superiority of MPT over MP regimen in elderly patients with MM not eligible for transplantation. In particular, one of these studies, showed this figure in patients aged more than 75 years who represent more than one third of MM patients. Nevertheless, in this latter study 42.5% of patients withdrawn from the MPT protocol because of toxicity. Therefore, there is a wide room of improving these results in this troublesome patient population. Using ThaDD regimen, including liposomal pegylated doxorubicin, we reported low haematological and non-hematological toxicity in elderly and

Abstract: This is the first study of carfilzomib-cyclophosphamide-dexamethasone in elderly patients with newly diagnosed multiple myeloma. Carfilzomib-cyclophosphamide-dexamethasone induced high complete response rates and was associated with low toxicity.