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Background The emergence of highly active novel agents has led some to question the role of autologous haematopoietic stem-cell transplantation (HSCT) and subsequent consolidation therapy in newly diagnosed multiple myeloma. We therefore compared autologous HSCT with bortezomib-melphalan-prednisone (VMP) as intensification therapy, and bortezomib-lenalidomide-dexamethasone (VRD) consolidation therapy with no consolidation.Methods In this randomised, open-label, phase 3 study we recruited previously untreated patients with multiple myeloma at 172 academic and community practice centres of the European Myeloma Network. Eligible patients were aged 18-65 years, had symptomatic multiple myeloma stage 1-3 according to the International Staging System (I S S), measurable disease (serum M protein >10 g/L or urine M protein >200 mg in 24 h or abnormal free light chain [FLC] ratio with involved FLC >100 mg/L, or proven plasmacytoma by biopsy), and WHO performance status grade 0-2 (grade 3 was allowed if secondary to myeloma). Patients were first randomly assigned (1:1) to receive either four 42-day cycles of bortezomib (1.3 mg/m 2 administered intravenously or subcutaneously on days 1, 4, 8, 11, 22, 25, 29, and 32) combined with melphalan (9 mg/m(2) administered orally on days 1-4) and prednisone (60 mg/m(2) administered orally on days 1-4) or autologous HSCT after high-dose melphalan (200 mg/m(2)), stratified by site and ISS disease stage. In centres with a double HS CT policy, the first randomisation (1:1:1) was to VMP or single or double HSCT. Afterwards, a second randomisation assigned patients to receive two 28-day cycles of consolidation therapy with bortezomib (1.3 mg/m(2)either intravenously or subcutaneously on days 1, 4, 8, and 11), lenalidomide (25 mg orally on days 1-21), and dexamethasone (20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12) or no consolidation; both groups received lenalidomide maintenance therapy (10 mg orally on days 1-21 of a 28-day cycle). The primary outcomes were progression-free survival from the first and second randomisations, analysed in the intention-to-treat population, which included all patients who underwent each randomisation. All patients who received at least one dose of study drugs were included in the safety analyses. This study is registered with the EU Clinical Trials Register (EudraCT 2009-017903-28) and ClinicalTrials.gov (NCT01208766), and has completed recruitment.Findings Between Feb 25, 2011, and April 3, 2014, 1503 patients were enrolled. 1197 patients were eligible for the first randomisation, of whom 702 were assigned to autologous HSCT and 495 to VMP; 877 patients who were eligible for the first randomisation underwent the second randomisation to VRD consolidation (n=449) or no consolidation (n=428). The data cutoff date for the current analysis was Nov 26, 2018. At a median follow-up of 60.3 months (IQR 52. 2-67. 6), median progression-free survival was significantly improved with autologous HSCT compared with VMP (56.7 months [95% CI 49.3-64.5] vs 41.9 months [37.5-46.9]; hazard ratio [HR] 0.73, 0.62-0.85; p=0.0001). For the second randomisation, the number of events of progression or death at data cutoff was lower than that preplanned for the final analysis; therefore, the results from the second protocol-specified interim analysis, when 66% of events were reached, are reported (data cutoff Jan 18, 2018). At a median follow-up of 42.1 months (IQR 32.3-49.2), consolidation therapy with VRD significantly improved median progression-free survival compared with no consolidation (58.9 months [54.0-not estimable] vs 45.5 months [39.5-58.4]; HR 0.77, 0.63-0.95; p=0.014). The most common grade >= 3 adverse events in the autologous HSCT group compared to the VMP group included neutropenia (513 [79%] of 652 patients vs 137 [29%] of 472 patients), thrombocytopenia (541 [83%] vs 74 [16%]), gastrointestinal disorders (80 [12%] vs 25 [5%]), and infections (192 [30%] vs 18 [4%]). 239 (34%) of 702 patients in the autologous HSCT group and 135 (27%) of 495 in the VMP group had at least one serious adverse event. Infection was the most common serious adverse event in each of the treatment groups (206 [56%] of 368 and 70 [37%] of 189). 38 (12%) of 311 deaths from first randomisation were likely to be treatment related: 26 (68%) in the autologous HSCT group and 12 (32%) in the VMP group, most frequently due to infections (eight [21%]), cardiac events (six [16%]), and second primary malignancies (20 [53%]).Interpretation This study supports the use of autologous HSCT as intensification therapy and the use of consolidation therapy in patients with newly diagnosed multiple myeloma, even in the era of novel agents. The role of high-dose chemotherapy needs to be reassessed in future studies, in particular in patients with undetectable minimal residual disease after four-drug induction regimens including a monoclonal antiboby combined with an immunomodulatory agent and a proteasome inhibitor plus dexamethasone. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

Background: Lenalidomide (R) plus dexamethasone (d) triplet combinations have been indicated by ESMO guidelines as standard of care in first relapse for lenalidomide sensitive multiple myeloma (MM) patients (pts) (Dimopoulos et al, 2021). Meta-analysis of randomized clinical trials (RCT) shows better outcome with the combination of Daratumumab + Rd (DaraRd) over other Rd-based combinations (carfilzomib+Rd (KRd), elotuzumab+Rd (EloRd), Ixazomib+Rd (IxaRd). There are few real-life studies focusing on the pattern of utilization and outcome of different Rd triplets in first relapse MM. Aims: To explore performances of market-approved Rd-based triplets in unselected MM pts in first relapse. Patients and methods: After ethics committee approval, we review data of 366 MM pts in first relapse consecutively addressed to Rd-based triplets according to market-approved schedule after 2017. Rd-based therapies was distributed as follows: DaraRd 51.6% (189 pts), KRd 36.1% (132 pts), EloRd 8.7% (32 pts), IxaRd 3.6% (13 pts). Given the limited number of pts treated with IRd and EloRd, the analysis is focused only on DaraRd and KRd group after further excluding 51 pts (13%) addressed to salvage autologous stem cell transplant (ASCT) after daraRd (n=9)/KRd(n=42) fixed induction. Few pts in both groups were previously exposed to R/K/Dara (respectively 12 pts (3%), 8 (2%), 0). Treatment choice was influenced by market approval, with KRD regimen used more commonly in the IQR 2017- 2019, while DaraRd more commonly in the IQR 2018-2020. To limit the bias of a retrospective observation, we calculated a propensity score and we used it (after trimming of 5% of observations) to re-weight the data, according to the Inverse Probability of Treatment method (IPTW analysis). For the estimation of the propensity score, we used: age at Rd-triplet starting, ISS stage, presence of high-risk FISH, previous exposure to Bortezomib, previous ASCT, good response at first-line therapy (≥VGPR), time between diagnosis and relapse, myeloma defining events at diagnosis, type of relapse (symptomatic/biochemical), center. Details of these characteristics are reported in table1. Of note, pts addressed to DaraRd were slightly older (68,7 vs 63,4 years in KRd, p Conclusions: Our real-life study shows that DaraRd represents the most commonly received regimen at first relapse followed by KRd triplet. After propensity score matching, DaraRd and KRd combinations proved to be both effective with similar outcomes when used early in the treatment history, after one line of therapy. This study, in addition, points out the possible gap of outcome between RCT and clinical practice. Figure 1 Figure 1. Disclosures Mangiacavalli: BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; GSK: Honoraria. Galli: BMS, Celgene, Janssen, Sanofi, Takeda: Honoraria. Belotti: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; GSK: Membership on an entity's Board of Directors or advisory committees. Fazio: Janseen: Honoraria. Petrucci: Celgene: Honoraria, Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; GSK: Honoraria, Other: Advisory Board; Karyopharm: Honoraria, Other: Advisory Board.

Introduction Multiple myeloma (MM) patients (pts) with high-risk cytogenetic abnormalities (CA) have a shorter survival as compared to the standard-risk ones. In the FORTE study, carfilzomib-lenalidomide-dexamethasone induction/consolidation with ASCT (KRd-ASCT) significantly improved progression-free survival (PFS) vs KRd without ASCT (KRd12) or carfilzomib-cyclophosphamide-dexamethasone (KCd) plus ASCT (KCd-ASCT). KR maintenance also prolonged PFS vs R. The primary aim of this analysis was to evaluate the impact of treatment on PFS and 1-year sustained MRD negativity (1y-MRD neg) rates according to pt cytogenetic risk. Methods Pts were randomized to KRd-ASCT vs KCd-ASCT vs KRd12 and, thereafter, to KR vs R maintenance. High risk (HiR) was defined as the presence of ≥1 HiR CA [del17p, t(4;14), t(14;16), del1p and 1q gain (3 copies) or amp1q (≥4 copies)], double hit (DH) as the presence of ≥2 HiR CA, standard risk (SR) as the absence of all evaluated HiR CA. Results 396 out of 474 enrolled pts with complete fluorescence in situ hybridization (FISH) data were included in the analysis: 243 HiR, 105 DH and 153 SR pts. Among HiR pts, 60 had del17p, 65 t(4;14), 20 t(14;16), 44 del1p, 126 1q gain and 49 amp1q. SR pts benefited from intensification with KRd-ASCT vs KRd12 (HR 0.47, p=0.05) and KCd-ASCT (HR 0.38, p=0.01), with a 4-year PFS of 80%, 67% and 57%, respectively. In HiR pts, KRd-ASCT improved PFS vs KRd12 (HR 0.6, p=0.04) and KCd-ASCT (HR 0.57, p=0.01), with a 4-year PFS of 62%, 45% and 45%, respectively. The advantage with KRd-ASCT vs KRd12 (HR 0.53, p=0.07) and KCd-ASCT (HR 0.49; p=0.03) was also observed in DH pts (4-year PFS 55%, 31% and 33%, respectively). Despite the limited number of patients in each subgroup, a trend towards a PFS benefit from KRd-ASCT vs KRd12 was observed in pts with del17p (HR 0.61, p=0.3), t(4;14) (HR 0.59, p=0.2) and 1q gain (HR 0.45, p=0.02). In pts with del1p, KRd-ASCT (HR 0.24, p=0.06) and KRd12 (HR 0.33, p=0.09) showed superiority over KCd-ASCT, while amp1q pts had the worst outcome regardless of treatment (KRd-ASCT vs KCd-ASCT, HR 1.16, p=0.73; KRd12 vs KCd-ASCT, HR 1.34, p=0.45). KR improved PFS vs R in SR (3-year PFS 90% vs 73%, HR 0.42, p=0.06), HiR (3-year PFS 69% vs 56%, HR 0.6, p=0.04) and DH pts (3-year PFS 67% vs 42%, HR 0.53, p=0.1). Despite the small subgroups, a beneficial trend with KR vs R was observed in pts with del17p (HR 0.59, p=0.37), t(4;14) (HR 0.59, p=0.3), 1q gain (HR 0.54, p=0.07) and del1p (HR 0.23, p=0.08), while amp1q pts showed the worst outcome and no benefit from KR vs R (HR 0.83, p=0.7). Conclusion KRd-ASCT and KR maintenance are highly effective in SR and also in HiR and DH pts, with impressive 4-year PFS from diagnosis (KRd-ASCT: HiR 62%, DH 55%) and 3-year PFS from maintenance (KR: HiR 69%, DH 67%), thus providing an effective option in HiR pts, who still represent an unmet medical need.

BACKGROUND: Bortezomib- and lenalidomide-containing regimens are well-established therapies in multiple myeloma (MM). However, despite their extensive use, head-to-head comparisons have never been performed. Therefore, we compared bortezomib and lenalidomide in fixed-duration therapies for relapsed MM. METHODS: In this open-label, phase III study, we randomized MM patients at first relapse to receive either 9 cycles of bortezomib-cyclophosphamide-dexamethasone (VCD) or lenalidomide-cyclophosphamide-dexamethasone (RCD). The primary endpoint was the achievement of a very good partial response (VGPR) or better at six weeks after 9 treatment cycles. FINDINGS: From March 2011 to February 2015, 155 patients were randomized. The primary endpoint was met by 12 patients (15%) in the VCD arm and 14 patients (18%) in the RCD arm (p=0·70). Median progression-free survival (PFS) was 16·3 (95% CI: 12·1-22·4) with VCD and 18·6 months (95% CI: 14·7-25.5) with RCD, and the 2-year overall survival (OS) was 75% (95% CI: 66%-86%) and 74% (95% CI: 64%-85%), respectively. By subgroup analysis, no differences in PFS were observed in bortezomib and lenalidomide- naive patients, nor in patients who received a bortezomib-based regimen in first line. Adverse events were consistent with the well-established safety profiles of bortezomib and lenalidomide. INTERPRETATION: Bortezomib and lenalidomide treatments were equally effective in terms of depth of response, PFS, and OS in MM patients at first relapse. Nevertheless, the two drugs have a different safety profile. Clinical Trial Number: This study is registered as EUDRACT 2010- 021557-40. Funding Statement: Associazione Italiana per la Ricerca sul Cancro - AIRC grant IG-10419; Associazione Italiana contro le Leucemie-Linfomi e Mieloma (AIL); Fondazione Adiuvare, Lugano. Declaration of Interests: VM has received honoraria and travel grants from Janssen, Celgene, Bristol-Myers Squibb, Amgen. AC has not competing interests. MG has received honoraria and travel grants from Janssen, Celgene, Bristol-Myers Squibb. IA has not competing interests. SP has not competing interests. CCarniti SP has not competing interests. FP has received honoraria and travel grants from Janssen and Celgene. FG has not competing interests. RZ has not competing interests. SS has not competing interests. MM has not competing interests. AN has not competing interests. CCrippa has not competing interests. AMC has received honoraria and travel grants from Janssen and Celgene. LB has not competing interests. PC has honoraria from advisory board and speaking fees from Celgene, Janssen, Novartis, Roche, Takeda, Sanofi, Abbvie, Amgen, Gilead, and Klowa Kirin. Ethics Approval Statement: The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Ethics committees at each study site reviewed and approved the protocol.

Background The role of up-front consolidation for newly diagnosed, transplant eligible MM (NDMM) patients (pts) has not yet been prospectively addressed in the novel agents era. Methods The EMN02/HO95 trial was designed to randomly (R) compare (R1) 4 cycles of bortezomib-melphalan-prednisone (VMP) vs high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT), either single or double, as intensification therapy after induction with bortezomib-cyclophosphamide-dexamethasone (VCD) (M Cavo et al, ASCO 2016, abstract #8000). A second randomization to consolidation therapy with 2 cycles of VRD vs no consolidation (R2) was performed after intensification, to be followed by lenalidomide maintenance (lenalidomide 10 mg continuously) until progression or toxicity in both arms. (VRD: bortezomib 1.3 mg/m2 intravenously days 1, 4, 8, 11; lenalidomide 25 mg orally days 1 - 21; dexamethasone 20 mg orally days 1, 2, 4, 5, 8, 9, 11, 12 of a 28 days cycle). Primary study end points were progression-free survival (PFS) from R1 and PFS from R2. A first planned interim analysis for R2 was performed in July 2016 when at least 33% (= 172) of the required events for PFS had been observed. Results From February 2011 to April 2014, 1510 pts aged ≤ 65 years with symptomatic MM were enrolled, of whom 1499 were eligible. Of these, 1211 were randomized (stratification by ISS stage) to VMP (505 pts) or HDM (1 or 2 ASCT) (706 pts). For R2 903 eligible patients were randomized to consolidation (459 pts) or no consolidation (444 pts). Median follow up from R2 was 25 months (maximum 53). Response status at time of R2 was ≥ CR (23%), ≥ VGPR (67%), ≥ PR (93%), and will be updated for status at start of maintenance. At the time of analysis, 258 events for PFS after R2 had been reported. 3-year. PFS from R2 was 62% in all patients, i.e., 60% without consolidation and 65% in patients with consolidation, and median PFS had not yet been reached. PFS from R2 with adjustment for R1 was prolonged in pts randomized to VRD (HR=0.78; 95% CI=0.61-1.00; P=0.045), a benefit retained across predefined subgroups with revised ISS stage III (HR=0.67; P=0.26) and in patients randomized in R1 to VMP (HR=0.76; P=0.19) and to HDM (HR=0.79; P=0.13). The benefit of consolidation was observed in patients with low-risk cytogenetics (HR=0.68; P=0.03), but not in patients with high-risk cytogenetics (del(17p) and/or t(4;14) and/or t(14;16); HR=1.03; P=0.91). At 3 years OS from R2 was 86% and 87%, respectively. Toxicity from VRD was limited with 5% CTCAE grade 4, mainly hematological. Conclusions Consolidation treatment with VRD followed by Lenalidomide maintenance until progression or toxicity shows promising results as compared to maintenance alone for younger NDMM pts, but further study follow-up is needed. This trial was registered at www.trialregister.nl as NTR 2528, EudraCT 2009-017903-28 This trial was supported by unrestricted grants from Celgene and Janssen. Disclosures Sonneveld: Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Carella:Millenium: Speakers Bureau; Genentech: Speakers Bureau. Ludwig:Janssen: Speakers Bureau; BMS: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Driessen:janssen: Consultancy; celgene: Consultancy; Mundipharma-EDO: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gay:Celgene: Honoraria; Mundipharma: Other: Advisory Board; Amgen: Honoraria; BMS: Honoraria; Janssen-Cilag: Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board. Mellqvist:Mundipharma: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Zweegman:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Schjesvold:Janssen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Palumbo:Takeda: Employment, Honoraria; Janssen Cilag: Honoraria. Cavo:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria.

Background: Proteasome inhibitor (PI)-based induction and consolidation proved to be effective in newly diagnosed multiple myeloma (NDMM) patients (pts) eligible for melphalan 200 mg/m2-autologous stem cell transplant (MEL200-ASCT). High response rates have been reported with the second-generation PI Carfilzomib in combination with Lenalidomide-dexamethasone (KRd) or Cyclophosphamide-dexamethasone (KCd). Aims: The primary aim was to evaluate the efficacy and safety of KRd induction-ASCT-KRd consolidation (KRd-ASCT-KRd) vs 12 cycles of KRd (KRd12) vs KCd induction-ASCT-KCd consolidation (KCd-ASCT-KCd). Methods: NDMM pts ≤65 years were randomized (1:1:1; stratification ISS and age) to: KRd-ASCT-KRd: 4 28-day cycles with KRd induction (Carfilzomib 20/36 mg/m2 IV days 1,2,8,9,15,16; Lenalidomide 25 mg days 1-21; dexamethasone 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and 4 KRd consolidation cycles; KRd12: 12 KRd cycles; KCd-ASCT-KCd: 4 28-day induction cycles with KCd (Carfilzomib 20/36 mg/m2 IV days 1,2,8,9,15,16; Cyclophosphamide 300 mg/m2 days 1,8,15; dexamethasone 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and 4 KCd consolidation cycles. Thereafter, pts were randomized to maintenance with Lenalidomide alone or plus Carfilzomib. Centralized minimal residual disease (MRD) evaluation - 8-color second generation flow cytometry, sensitivity 10-5 - was performed in pts achieving ≥very good partial response (VGPR). Endpoints were pre-maintenance stringent complete response (sCR) and MRD negativity in intention-to-treat (ITT) analysis. Data cut-off was May 30, 2018. Results: 474 NDMM pts were randomized (KRd-ASCT-KRd, n=158; KRd12, n=157; KCd-ASCT-KCd, n=159) and analyzed. Pts characteristics were well balanced. Median follow-up was 20 months. Depth of response improved during treatment (Figure). By ITT analysis, rates of pre-maintenance sCR was similar between KRd-ASCT-KRd (41%) and KRd12 (42%), and significantly higher than with KCd-ASCT-KCd (30%; P value KRd-ASCT-KRd vs KCd-ASCT-KCd=0.047; P value KRd12 vs KCd-ASCT-KCd=0.028). Similarly, rate of ≥CR was 49% with KRd-ASCT-KRd, 52% with KRd12 and 38% with KCd-ASCT-KCd (P value KRd-ASCT-KRd vs KCd-ASCT-KCd=0.041; P value KRd12 vs KCd-ASCT-KCd=0.014) and rate of ≥CR+unconfirmed CR (missing immunofixation confirmation) raised to 60% vs 63% vs 46% in the 3 groups, respectively; rate of ≥VGPR was 88% with KRd-ASCT-KRd, 86% with KRd12 and 74% with KCd-ASCT-KCd (P value KRd-ASCT-KRd vs KCd-ASCT-KCd=0.002; P value KRd12 vs KCd-ASCT-KCd=0.008). In multivariate analysis, the main factor affecting probability of achieving ≥VGPR, ≥CR or sCR was treatment with KRd-ASCT-KRd or KRd12 vs KCd, with no significant impact of ISS Stage or FISH abnormalities. In ITT analysis (MRD missing [31/395 VGPR pts, 8%] and Conclusions: Rates of MRD negativity, sCR, ≥CR, ≥VGPR were significantly higher with KRd-ASCT-KRd and KRd12 vs KCd. At present, no differences in MRD and overall best response (sCR, ≥CR, ≥VGPR) were noticed between KRd-ASCT-KRd and KRd12; longer follow-up is needed to evaluate survival. Treatment was well tolerated. Updated data will be presented at the meeting. Figure. Figure. Disclosures Gay: Roche: Other: Advisory Board; Seattle Genetics: Other: Advisory Board; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Other: Advisory Board; Amgen: Honoraria; Takeda: Honoraria, Other: Advisory Board. Galli:Sigma-Tau: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Belotti:Celgene: Other: Advisory Board; Amgen: Other: Advisory Board. Zamagni:BMS: 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; 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. Angelucci:Novartis: Honoraria, Other: Chair Steering Committee TELESTO protocol in MDS; Celgene: Honoraria, Other: Chair DMC proptocol BELIEVE 1 and BELIVE 2 in Thalassemia; Vertex Pharmaceuticals Incorporated (MA) and CRISPR Therapeutics AG (CH): Other: Chair DMC CRISPR CAS9 in Hemoglobinopathies; Jazz Pharmaceuticals Italy: Other: Local (national) advisory board on AML; Roche Italia: Other: Local (national) advisory board on biosimilars. Annibali:Celgene; Takeda; Amgen, Janssen Cilag: Honoraria. Offidani:Amgen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board. Palumbo:Takeda: Employment. Musto:Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Cavo: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; Bristol-Myers Squibb: 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; 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, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Bristol-Myers Squibb: Honoraria, Research Funding; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria.

A total of 303 MM patients were retrospectively reviewed to evaluate long-term efficacy and toxicity of thalidomide alone or in combination with steroids. Overall response rate was 57% (CR/VGPR 12%). Median TTP, PFS and OS were 13.4 months, 20.6 months, and 26.2 months, respectively. PFS and OS were significantly different according to response (p < 0.0001), with better outcome in patients achieving CR/VGPR (PFS and OS 35.4 months and 63 months, respectively). PFS and OS of patients achieving SD or PR were overlapping (p = 0.3). The addition of steroids significantly increased the response rate (p = 0.01). The most clinically relevant complications were neuropathy (40%), constipation (26%), thromboembolic events (7%). Thalidomide was reduced for toxicity in 68 patients (24%) and permanently discontinued in 36 (12%). In conclusion, thalidomide produces high response rate in relapsed/refractory MM. The best outcome is observed in patients with good quality response, but even patients with suboptimal response may obtain durable survival.

Preclinical data suggest that all-trans retinoic acid (ATRA) synergizing with granulocyte colony stimulating factor (G-CSF), can improve the effectiveness of chemotherapy in acute myeloid leukemia (AML). Fludarabine 15 mg/m(2) is the minimum dose able to optimize intensification with fludarabine-arabinosylcytosine regimen. In this study 52 patients with relapsed/refractory AML obtained a complete remission (CR) rate of 69.2% after FLAIRG regimen (Fludarabine and arabinosylcytosine twice daily, idarubicin, G-CSF, ATRA). This schedule resulted effective and tolerable enabling 53% of the responding patients to receive transplant procedure. FLAIRG regimen could be proposed as a "bridge" to transplant treatment in this poor risk setting.

Background: Survival rates of multiple myeloma (MM) patients (pts) has improved over the past few years, but patients inevitably relapse and become more resistant to subsequent treatments. Carfilzomib and Pomalidomide were both approved for the treatment of relapsed/refractory MM (RRMM). Combinations including a proteasome inhibitor (PI) plus an immunomodulator (IMiD), such as Bortezomib-Lenalidomide-Dexamethasone (VRD) or Carfilzomib-Lenalidomide-Dexamethasone (CRD), showed a very high response rate with an acceptable toxicity. Moreover, in the CHAMPION1 study (Berenson et al Blood 2016), the weekly infusion of Carfilzomib showed to be as effective as the twice schedule. In this phase I/II study we assessed for the first time weekly Carfilzomib plus Pomalidomide and low dose Dexamethasone (wKPd) for the treatment of RRMM. Here we report preliminary results. Methods: the primary objective of the phase I part of the trial was to determine the maximum tolerated dose (MTD) of wKPd combination. The primary objective of the phase II was to determine the rate of partial response (PR). Patients with RRMM, who received 1-3 prior lines of treatments and were refractory to Lenalidomide were eligible. Treatment consisted of 28-day cycles of oral Pomalidomide at fixed dose of 4 mg on days 1-21 (1 week off), oral or intravenous (iv) Dexamethasone 40 mg on days 1,8,15,22 and iv Carfilzomib at escalating doses on days 1,8,15. Escalation started at the dose of 36 mg/m2 (0 level) and used a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. Treatment was continued until relapse or intolerance. Results: A total of 57 patients were enrolled in 6 Italian centers. Fifty-two patients could be evaluated for this analysis (5 patients did not complete the first cycle yet). The median age was 62 years with a median time from diagnosis of 4 years. 17/39 (44%) of patients were considered high risk according to cytogenetic abnormalities [at least one among t (4;14) t (14;16) and deletion chromosome 17 (del17) detected by FISH]. In the phase I of the trial 15 patients were enrolled. The first 3 patients at the dose level 0 of Carfilzomib did not experience any DLT. In the next cohort with Carfilzomib 20/45 mg/m2 a G3 hypertension and a sudden death occurred. According to the protocol, 3 more patients were enrolled at dose level 0: 1 patient experienced G3 atrial fibrillation, 2 patients ≥ G3 hypertension. Considering the serious adverse events (SAEs) occurred, the trial was temporary stopped to evaluate the benefit of continuing the study. All the DLTs were cardiologic and occurred in patients with a prior history of cardiac disease. As per protocol, they were evaluated with ECG and echocardiogram before the enrolment and were considered eligible for the study. The safety committee established new procedures for the evaluation of cardiac function of potentially eligible patients, including 24 h continuing pressure monitoring before the enrolment and serial measurement of blood pressure during and after Carfilzomib infusions. Six more patients were enrolled at dose level -1 (Carfilzomib 20/27 mg/m2) and none experienced a DLT. The MTD was established at dose level -1 with Carfilzomib 20/27 mg/m2, Pomalidomide 4 mg and Dexamethasone 40 mg. In the phase II portion of the trial, 42 patients were enrolled. Considering both phase I and II portions of the study, the most frequent drug related, grade ≥ 3 AEs were hematologic (65% of neutropenia and 13% of thrombocytopenia) and cardiologic (17%, mainly hypertension). We recorded only 4% of infection and ≥ G3 peripheral neuropathy. The overall response rate (ORR) of phase I/II portions was 58% (30/52) including 25% (13/52) of ≥ very good partial remission (VGPR). The ORR of high risk patients was 44% (7/16) including 19% (3/16) of ≥ VGPR. With a median follow-up of 10 months, median progression free survival (PFS) was 9.5 months and the median overall survival was not reached. Conclusions: This is the first phase I/II trial that combined weekly Carfilzomib with Pomalidomide and Dexamethasone. This combination was highly effective in RRMM. After a median follow-up of 10 months, wKRd showed a double median PFS in comparison with Pomalidomide-low dose dexamethasone (Sanmiguel et al Lancet Oncology 2013): 9.5 vs 4 months respectively, confirming the efficacy of combining a PI with an IMiD. An updated analysis will be presented at the meeting. Disclosures Bringhen: BMS: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Amgen: Other: ADVISORY BOARD; Mundipharma: Other: ADVISORY BOARD; Karyopharm: Other: ADVISORY BOARD. Larocca:Celgene: Honoraria; Janssen-Cilag: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria. Gaidano:Karyopharm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Oliva:Amgen: Honoraria; Celgene: Honoraria; Takeda: Honoraria. Sonneveld:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Boccadoro:Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Abbivie: Honoraria; Mundipharma: Research Funding; SANOFI: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding.

Presented at the 50th Annual American Society of Clinical Oncology Meeting (2014), the 56th American Society of Hematology Annual Meeting (2014), the 20th Congress of the European Hematology Association (2015), the 15th International Myeloma Workshop (2015), and the 57th American Society of Hematology Annual Meeting (2015)., Patients with relapsed and/or refractory multiple myeloma (RRMM) have poor prognosis. The STRATUS study assessed safety and efficacy of pomalidomide plus low-dose dexamethasone in the largest cohort to date of patients with RRMM. Patients who failed treatment with bortezomib and lenalidomide and had adequate prior alkylator therapy were eligible. Pomalidomide 4 mg was given on days 1-21 of 28-day cycles with low-dose dexamethasone 40 mg (20 mg for patients aged >75 years) on days 1, 8, 15, and 22 until progressive disease or unacceptable toxicity. Safety was the primary end point; secondary end points included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Among 682 patients enrolled, median age was 66 years, and median time since diagnosis was 5.3 years. Median number of prior regimens was 5. Most patients were refractory to both lenalidomide and bortezomib (80.2%). Median follow-up was 16.8 months; median duration of treatment was 4.9 months. Most frequent grade 3/4 treatment-emergent adverse events were hematologic (neutropenia [49.7%], anemia [33.0%], and thrombocytopenia [24.1%]). Most common grade 3/4 nonhematologic toxicities were pneumonia (10.9%) and fatigue (5.9%). Grade 3/4 venous thromboembolism and peripheral neuropathy were rare (1.6% each). The ORR was 32.6%, and the median DOR was 7.4 months. Median PFS and OS were 4.6 months and 11.9 months, respectively. We present the largest trial to date evaluating pomalidomide plus low-dose dexamethasone in patients with RRMM, further confirming that this regimen offers clinically meaningful benefit and is generally well tolerated., This study was funded by Celgene Corporation.

Introduction. Bortezomib (Bort) and lenalidomide (Len) are standard treatments for relapsed MM, but, so far, a comparative trial between them has never been conducted. We designed a multicenter, open label, phase III study to compare bortezomib/cyclophosphamide/dexamethasone and lenalidomide/cyclophosphamide/dexamethasone in a fixed duration design protocol. The combination of Bort and Len with chemotherapy was devised to improve efficacy and to allow a fixed duration treatment in patients not heavily pretreated. Methods. The primary endpoint was the achievement of very good partial remission (VGPR) or better at six weeks after 9 cycles. The study enrolled patients at first relapse with measurable disease. Patients could have received Bort or Len in their first line, but they should have obtained at least a PR longer than one year, and previous Bort or Len maintenance was an exclusion criteria. Enrollment started on April 2011, and was ended on April 2015. Patients were assigned 1:1 to sc Bort 1.3 mg/ms on days 1, 8, 15, 22, oral dexamethasone (Dex) 20 mg on days 1-2, 8-9, 15-16, 22-23, iv cyclophosphamide (Cyclo) 500 mg/ms on day 1 and 8 in a 35 days cycle (VCD) or to Len 15 mg from day 1 to 21, oral Dex 20 mg on days 1-2, 8-9, 15-16, 22-23, iv Cyclo 500 mg/ms on day 1 and 8 in a 28 days cycle (RCD). Nine courses of therapy without maintenance were planned. Efficacy and safety were assessed at each cycle using the IMWG response criteria for efficacy assessment (Durie et al. Leukemia 2006), and CTCAE v4.0 for safety. Results. One hundred fifty-seven patients were enrolled, 155 were randomized, 77 were assigned to the VCD, and 80 to the RCD arm, respectively. Both arms were well balanced according to the baseline characteristics. Median age was 65 years (range 41-79), and 63 years (range 46-76) for VCD and RCD, respectively. ISS stage was grade I in 36 and 33, grade II in 20 and 28, and grade III in 16 and 15 patients in the VCD and RCD arms, respectively. Previous treatment included Bort in 35 and 42, Len in 7 and 7, Bort- and Len-free chemotherapy in 32 and 29, thalidomide in 35 and 31, and autologous stem cell transplantation in 58 and 63 patients in the VCD and RCD arms, respectively. The primary endpoint, represented by achievement of VGPR or better at 6 weeks after 9 courses, was met by 12 (16%) and 16 (20%) patients in the VCD and RCD arms, respectively (p=0.70). Median progression-free survival (PFS) was 16.3 (range 13.3 - 22.4) and 20.2 (range 14.7 - 26.8) months (p=0.70), and median overall survival (OS) was 31.1 and 36.2 months (p=0.83), in the VCD and RCD arms, respectively. In subgroup analysis, patients that were Bort and Len naïve at enrollment had a PFS of 20.0 (range 12.2 - 31.8) and 20.2 months (range 12.0 - 29.9) (p=0.44), and a median OS of 31.1, and 22.5 months (p=0.72), for the VCD and RCD arms, respectively. Patients that were Bort exposed, but Len naïve at enrollment, had a PFS of 15.6 (range 9.9 - 22.4) and 19.5 months (range 11.1 - 28.6) (p=0.35), and a median OS of 29.2, and 34.7 months (p=0.62), for the VCD and RCD arms, respectively. Adverse events were consistent with the well-established safety profile of Bort and Len, and grade III and IV toxicities were not significantly different between the 2 arms. Conclusions. This is the first head-to-head study comparing fixed duration therapy of Bort and Len in first relapse patients. We show that both drugs are equally effective, in terms of depth of response, PFS, and OS. Despite drug-specific toxicity profiles, incidence of grade III and IV toxicities were not different between the 2 arms. Disclosures Corradini: Novartis: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Roche: Honoraria; Amgen: Honoraria; Gilead: Honoraria.

Purpose Bisphosphonates (BPs) are currently used to treat bone lesions in patients with multiple myeloma (MM). Osteonecrosis of the jaw (ONJ) has been reported as an adverse event of such treatment, especially after treatment with zoledronic acid (ZA). The aim of this study was to evaluate incidence, risk factors, management, and prevention strategies of ONJ in order to optimize the current standard use of BPs in MM. Patients and Methods We reviewed the medical records of 105 patients with MM treated in 2 hematology departments with monthly pamidronate 90 mg and/or ZA 4 mg and evaluated for ≥ 12 months. Because they are risk factors for ONJ development, we analyzed patient and disease features, previous MM treatments, type and number of BP infusions, and previous history of dental procedures. Results Seventeen patients (16%) with MM treated with BPs developed ONJ after a median number of 43 BP infusions (vs. 28 in patients without ONJ; P = .035). In 11 of 17 patients, ONJ arose after a tooth extraction. Among risk factors, the administered doses of ZA were significantly associated with ONJ, and 12 consecutive doses of ZA proved to double the risk of developing this complication. Regular hard- and soft-tissue oral assessment was of benefit in the prevention of further ONJ occurrence. Conclusion The most important risk factor for ONJ is represented by the number of ZA infusions. Tooth extractions and invasive procedures should be avoided. A multidisciplinary approach including oncohematologists and dental teams proved critical to better identify, prevent, and manage ONJ.

Objective High dose (HD) Ara-C combined with a single HD idarubicin dose (IDA) is an efficient and safe salvage regimen for patients with refractory or relapsed acute lymphoblastic leukemia as indicated by phase II studies. No data are available on the pharmacokinetics of IDA after a rapid HD intravenous infusion. An open phase II pharmacokinetic and clinical study was performed to evaluate antileukemic efficacy, IDA pharmacokinetics and to investigate the presence of IDA and its reduced metabolite idarubicinol (IDAol) in cerebrospinal fluid (CSF) of patients treated with HD-IDA. Patients and methods Twenty-five patients with refractory or relapsed acute lymphoblastic leukemia received Ara-C 3 g/m2 from days 1–5, idarubicin (HD-IDA) 40 mg/m2 as rapid intravenous (i.v.) infusion on day 3 and subcutaneous G-CSF 5 μg/kg from day 7 until PMN recovery. Pharmacokinetics of IDA was evaluated after HD idarubicin administration in nine of these patients. CSF samples were collected in 15 patients at different times. IDA and IDAol concentrations were quantified by a validated HPLC assay described in detail elsewhere. Results Eleven patients (44%, 95% CI: 23–65%) achieved complete remission with median disease free survival for 6 months. After administration of HD-IDA i.v. bolus of 40 mg/m2, plasma level profiles of unchanged drug and IDAol were similar to those previously described after standard dose and measured with the same analytical method. The mean terminal half-life measured for IDA in this group of patients (14.9 h) was not significantly different from the mean value observed after standard dose (13.9 h, P = 0.72). IDAol t 1/2 was also similar after HD-IDA (46.2 h) and standard dose (39.4 h, P = 0.79). Pharmacokinetic data reveal that in our series of patients IDA and IDAol clearances are significantly higher than those observed in patients treated with 12 mg/m2 of IDA but, although the administered dose (mg/m2) of the drug is 3.3 times higher, IDA exposure (measured in terms of AUC) is only 2.3 times and IDAol exposition 2.1 times greater. Furthermore, HD infusion resulted in a ratio between the AUC of parent drug and idarubicinol not different from the value observed with the standard-dose. IDA and IDAol were measurable only in 3 of the 15 cerebrospinal fluid samples collected. Conclusion Responses observed in our series are comparable to those reported with other salvage regimens. The IDA exposure lower than expected may explain the safety of the single i.v. administration of 40 mg/m2 of IDA, combined with HD Ara-C, with a degree of myelosuppression equivalent to that reported with this agent administered in standard doses. Our data do not allow us to clearly attribute this behavior to a pharmacokinetic non-linearity since the baseline creatinine clearance, even within normal values, and patient age are significantly different in the two groups. Cerebrospinal fluid penetration was poor, reaching levels not considered as cytotoxic.

Introduction: For pts with RRMM who have failed or progressed on treatment (Tx) with newer agents, such as lenalidomide (LEN) and bortezomib (BORT), there are few Tx options, and overall survival (OS) is short (Kumar et al, Leukemia, 2012). POM is a distinct immunomodulatory agent with tumoricidal and immunoregulatory effects, and POM + LoDEX is approved in the United States and European Union for the Tx of pts with RRMM who have had ≥ 2 prior Tx, including LEN and BORT. Tx with POM + LoDEX has shown statistically greater survival benefits than high-dose DEX (MM-003; San Miguel et al, Lancet Oncol, 2013) or POM alone (MM-002; Richardson et al, Blood, 2014). POM + LoDEX has also demonstrated high overall response rates in pts with RRMM in the STRATUS trial (MM-010), a single-arm, open-label phase 3b study being conducted in 19 countries across Europe with a primary endpoint of safety (Dimopoulos et al, EHA 2015). Italian pts constituted the largest national subset in MM-010; hence, this subanalysis examines the safety and efficacy of POM + LoDEX in pts from Italy. Patients and Methods: Pts with RRMM (progressive disease [PD] on or within 60 days of last prior Tx) who had experienced Tx failure with BORT and LEN and had received adequate prior alkylator therapy were eligible. Pts received POM 4 mg on days 1-21 of a 28-day cycle in combination with DEX 40 mg (20 mg for pts aged > 75 yrs) on days 1, 8, 15, and 22. Thromboprophylaxis was required for all pts, and Tx was continued until PD or unacceptable toxicity. Results: A total of 219 pts were enrolled in MM-010 in Italy. The median age of this patient population was 67.0 yrs (range, 42-84 yrs), and 54.8% of pts were male. The median time since diagnosis was 5.5 yrs, and 37.0% of pts were International Staging System stage III. Patients were heavily pretreated, with a median of 4 prior anti-myeloma regimens (range, 2-11), and most pts were refractory to LEN (95%), BORT (82.2%), or both LEN and BORT (78.1%). As of May 4, 2015, 2 pts (0.9%) were not treated, 54 pts (24.7%) were still on treatment, and 163 pts (74.4%) had discontinued. After a median follow-up of 11.3 mos, in the intention-to-treat population, the overall response rate was 37.9% (range, 31.4%-44.7%), the median duration of response was 6.8 mos (95% CI, 4.9-10.8 mos), progression-free survival (PFS) was 5.2 mos (95% CI, 4.4-6.4 mos), and OS was 12.0 mos (95% CI, 10.6-15.2 mos). The most frequent grade 3/4 treatment-emergent AEs were neutropenia (56.7%), anemia (25.8%), thrombocytopenia (23.5%), and pneumonia (12.4%). Incidence of grade 3/4 venous thromboembolism (deep vein thrombosis and pulmonary embolism) and peripheral neuropathy were infrequent (2.3% and 0%, respectively). The most common reasons for discontinuation were disease progression (49.8%), death (10.0%), and adverse events (AEs; 5.0%). AEs led to dose reductions or interruptions of POM in 23.0% and 71.0% of pts, respectively, and the median relative dose intensity for POM was 0.90. Conclusions: In line with previous studies, POM + LoDEX was active in Italian pts, a representative subset of the heavily pretreated MM-010 population. PFS and OS were consistent with those seen in previous trials. POM + LoDEX treatment was well tolerated, and discontinuations due to AEs were infrequent, consistent with the well-known toxicity profile and the appropriate drug management. This study confirms that POM + LoDEX is effective in patients with advanced RRMM, including those who have experienced failure of prior Tx with BORT and/or LEN. Disclosures Cavo: Janssen-Cilag, Celgene, Amgen, BMS: Honoraria. Petrini:Novartis: Research Funding; Celgene Corporation: Research Funding; Italfarmaco: Research Funding; Roche: Research Funding. Caravita di Toritto:Celgene Corporation: Honoraria, Research Funding. Offidani:Celgene, Janssen: Honoraria. Petrucci:Celgene Corporation: Honoraria; Janssen-Cilag: Honoraria; Amgen: Honoraria; Mundipharma: Honoraria; BMS: Honoraria. Rodeghiero:Celgene Corporation: Honoraria, Research Funding. Simcock:Celgene Corporation: Employment. Slaughter:Celgene Corporation: Employment, Equity Ownership. Herring:Celgene Corporation: Employment. Peluso:Celgene Corporation: Employment. Palumbo:Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria; Novartis, Sanofi Aventis: Honoraria.

Introduction. High-dose melphalan plus autologous stem-cell transplantation (ASCT) is the standard approach in newly diagnosed, transplant-eligible myeloma patients. We compared consolidation with high-dose melphalan plus ASCT versus cyclophosphamide-lenalidomide-dexamethasone (CRD), and maintenance with lenalidomide-prednisone (RP) versus lenalidomide alone (R). Methods. This is an open-label, randomized, phase 3 study. We enrolled newly diagnosed, transplant-eligible myeloma patients aged ≤65 years. Using a 2-by-2 factorial design, we randomized patients to consolidation with melphalan 200 mg/m2 (MEL200) followed by ASCT or CRD (cyclophosphamide 300 mg/m2 days 1, 8, 15; dexamethasone 40 mg days 1, 8, 15, 22; lenalidomide 25 mg days 1-21); and to maintenance with RP (lenalidomide 10 mg days 1-21; prednisone 50 mg every other day) or R alone. The primary endpoint was progression-free survival (PFS). Results. 389 patients were enrolled between July 6, 2009 and May 6, 2011. Median follow-up was 54.5 months. MEL200 significantly increased PFS (median PFS from the start of consolidation: 43.3 versus 28.6 months; HR 0.40, P Conclusions. MEL200 significantly prolonged PFS and OS compared with CRD, regardless of maintenance. RP maintenance did not significantly improve PFS and OS compared with R alone. Disclosures Gay: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Use off-label of drugs for the dose and/or schedule and/or association. Petrucci:Celgene: Honoraria; Janssen-Cilag: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria. Di Raimondo:Janssen-Cilag, Celgene: Honoraria. Caravita:Celgene: Honoraria. Ria:Italfarmaco: Honoraria; Novartis: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria. Offidani:Janssen-Cilag, Celgene, Sanofi, Amgen, Mundipharma: Honoraria. Bringhen:Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag, Celgene, Novartis: Honoraria; Onyx: Consultancy. Patriarca:Janssen-Cilag, Celgene, Merck Sharp & Dohme: Honoraria. Spencer:Celgene: Honoraria. Hajek:Merck Sharp & Dohme: Consultancy, Honoraria; Janssen-Cilag: Honoraria; Celgene: Consultancy, Honoraria. Boccadoro:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees. Palumbo:Novartis, Sanofi Aventis: Honoraria; Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria.

significant accumulation of the NuRD complex at MYC TSS after IMiDs exposure. Importantly, CHD4 silencing attenuated lenalidomide induced MYC transcriptional repression and cell death. In summary, our studies suggest that IKZF1 drives MYC expression in MM by regulating the activity of the IGH 3’ enhancer and preventing the repositioning of the NURD complex to its promoter. 5. Multiple Myeloma Therapy in Newly Diagnosed Patients excluding Transplantation

Chronic lymphocytic leukemia (CLL) cells could be undetectable by flow cytometry or polymerase chain reaction after sequential treatment with fludarabine and Campath-1H. Concern has been raised regarding the ability to mobilize sufficient peripheral blood progenitor cells (PBPCs) for autografting after purine analogues, and there are few data about PBPC collection after Campath-1H. In all, 16 CLL patients responding to sequential chemo-immunotherapy entered the study. In 10, mobilization regimen consisted of granulocyte colony-stimulating factor (G-CSF) 5-10 microg/kg/die. Patients failing mobilization or not achieving the target of 2.5 x 10(6) CD34+ cells/kg underwent a second attempt using intermediate-dose (ID) Ara-C, 800 mg/m(2) every 12 h for six doses+G-CSF. PBPC collection after G-CSF alone was successful in two out of 10 patients. An adequate number of CD34+ cells were collected after ID Ara-C+G-CSF in eight patients failing the mobilization with G-CSF alone and in five out of six who did not receive G-CSF before. Greater yields of PBPCs were collected with Ara-C+G-CSF compared with G-CSF alone (13.8 vs 3.3). The extrahematologic toxicity was manageable. In conclusion, PBPC collection is feasible in CLL patients treated with sequential therapy including fludarabine and Campath-1H. Excellent yields were obtained in 92.8% of patients primed with ID Ara-C+G-CSF.

Although an increasing number of patients with chronic lymphocytic leukemia (CLL) may achieve complete remission (CR) relapse is almost inevitable, due to re-emergence of the malignant clone. The eradication of minimal residual disease (MRD) is associated with improved remission durability and has great potential in offering the possibility of cure in many lymphoid malignancies. The monoclonal antibody alemtuzumab is the foundation of many eradication-based treatment approaches because of its ability to achieve clinical remissions and to successfully purge MRD. We investigate the use of subcutaneous (sc) alemtuzumab for the eradication of residual disease in the bone marrow of patients in clinical response after fludarabine treatment, as determined by NCI criteria. At least 8 weeks after fludarabine treatment, 35 B-CLL patients (13 female, 22 male; median age 55 [range 39–64] years) received sc alemtuzumab, three times weekly for 6 weeks, at escalating doses up to 10 mg. Residual disease was assessed using a consensus polymerase chain reaction methodology to detect the clonality of IgH sequences. Patients obtaining a successfull peripheral blood stem cell (PBSC) harvest (CD34+ 2.5 x 109/l) after either granulocyte colony-stimulating factor (G-CSF) or intermediate-dose Ara-C (800 mg/m2, every 12 h, for six doses) plus (G-CSF) were considered eligible for autologous PBSC transplant. Pharmacokinetic parameters were estimated in seven patients. Serum samples of alemtuzumab were assayed by indirect immunofluorescence with target cells (HUT-78, a human T cells line) and antibody concentration was calculated by comparison with a standard curve. Post fludarabine responses were: 10 CRs, 11 nodular partial responses (PRn) and 14 partial responses (PR). Post alemtuzumab responses were: 29 CRs, 4 PRn, 2 PR. Overall, 51% of patients converted to polyclonal IgH pattern (MR). Of the patients in CR before alemtuzumab, 7 achieved MR; nine of the patients in PRn before immunotherapy, improved to CR, five achieving MR. Of the fourteen patients in PR before alemtuzumab, twelve improved (two PRn, ten CR) and six achieved MR. Twenty-three out of 25 patients successfully mobilized PBSC. Fourteen patients have been transplanted so far. Subcutaneous alemtuzumab was generally well tolerated; fifteen patients (57%) developed cytomegalovirus (CMV) reactivation, but CMV disease was prevented by prompt treatment with oral ganciclovir. Alemtuzumab serum concentrations measured at second week after the start of therapy, just before the next dose (Ctrough), were relatively stable: Ctrough = 0.79±0.6 mg/ml. Sequential treatment with fludarabine and alemtuzumab is feasible, effective and safe. Overall 83% of patients reached CR according to NCI criteria. Eighty-four percent of patients improved to CR or PRn after alemtuzumab. Residual disease was not detected in 51% of patients. Sequential treatment did not compromise PBSC mobilization, allowing patients to proceed to autologous transplantation.

Background Olaptesed, an L-stereo-isomer RNA aptamer, binds and neutralizes the chemokine CXCL12. By interaction with the chemokine receptors CXCR4 and CXCR7, CXCL12 is responsible for trafficking and homing of normal and malignant blood cells to the bone marrow. Preclinical studies have shown synergistic activity of CXCL12-targeting and anti-myeloma agents, specifically bortezomib (BTZ). Thus, targeting the myeloma niche may increase treatment efficacy. Aims This open label single arm study was conducted to assess the activity and safety of olaptesed when added to the combination of BTZ and dexamethasone (DEX) in patients with relapsed / refractory multiple myeloma (MM). Patients and Methods Twenty-eight relapsed or refractory MM patients (males:females 14:14) were enrolled and treated according to a dose titration design. Olaptesed was administered intravenously at doses increasing from 1 mg/kg to 2 mg/kg and 4 mg/kg in cycles 1, 2 and 3, respectively, at 1 hour prior to bortezomib administration. During cycles 4 to 8, olaptesed was dosed at the highest individually titrated dose. BTZ (1.3 mg/m2) was given on days 1, 4, 8 and 11 as intravenous injection. Oral DEX (20 mg) was added on the day of and on the day after BTZ administration. Response was evaluated based on the uniform IMWG response criteria (Rajkumar SV et. al. Blood 2011; 117: 4691-5). Plasma cell mobilization was studied after a pilot dose of 1 to 4 mg/kg olaptesed administered to the initial 10 patients before start of the regular treatment regimen. Results From Aug 2012 to Feb 2014 we enrolled 28 patients who had received a median of 2 (range 1-6) lines of prior therapy. Pretreatments were lenalidomide (LEN) in 20, BTZ in 14 and carfilzomib in 1 patient. Ten patients had autologous stem cell transplantations prior to entering this study. The patient population enrolled presented predominantly with advanced disease and with adverse outcome predictors. Ten patients had ISS stage III. High-risk cytogenetics were identified in 9 of the 20 patients (45%) with FISH testing available for t(4;14), t(14;16) and/or del17p. Eleven patients were refractory to their last prior treatment, which contained BTZ in 8 cases. After two early withdrawals, 26 patients were available for outcome evaluations. The median number of completed cycles was 8. Progression led to treatment termination in 8 patients. The dose of olaptesed was titrated to 4 mg/kg in all 18 patients treated for 3 or more cycles. The single dose of olaptesed administered to 10 pilot-patients effectively mobilized plasma cells, which increased by approximately 200% for up to 3 days. Based on “best response” of the 26 evaluable patients, the overall response rate was 73%: Two patients (8%) achieved a complete response (CR), 6 patients (23%) a very good partial response (VGPR) and 11 patients (42%) a partial response (PR). Minimal response was recorded in 2 patients (8%), 4 patients (15%) had stable disease and 1 patient (4%) progressive disease. In the 9 evaluable patients with high-risk cytogenetics, the clinical responses were similar. The ORR was 67% with VGPR in 3 (33%) and PR in 3 (33%) patients. Of the 14 patients pre-treated with BTZ, 1 had a CR and 8 a PR (ORR 64%). M-protein decreased rapidly from treatment cycle 1 to cycle 4 with a decrease of ≥50% being observed in 15 of the 26 evaluable patients. Figure 1 shows a waterfall plot of the maximum observed decrease in M-protein. Figure 1: Waterfall Plot of Maximum M-Protein Change Figure 1:. Waterfall Plot of Maximum M-Protein Change Median progression-free survival (PFS) of the evaluable population was 6.5 months. It was also 6.5 months in the 9 patients with high-risk cytogenetics and 6.3 months in the 14 patients pre-treated with BTZ (Figure 2). The median follow-up was 6.3 months. Figure 2: Progression-Free Survival Figure 2:. Progression-Free Survival Treatment with olaptesed in combination with BTZ-DEX was safe and well tolerated without any appreciable increase in adverse events. Conclusions A single dose of olaptesed effectively mobilized plasma cells. Olaptesed in combination with BTZ and DEX resulted in an ORR rate of 73% and PFS of 6.5 months. Response rates and PFS were similar in patients with or without high risk cytogenetic features or with or without previous exposure to BTZ. The combination regimen was well tolerated. These findings merit further exploration of this strategy in randomized trials. Disclosures Weisel: NOXXON Pharma AG: Consultancy. Petrucci:Celgene: Honoraria; Jannsen-Cilag: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria. Leleu:Janssen, Celgene, leopharma, Takeda, Amgen, Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Laurent:Bristol-Myers Squibb: Honoraria. Kruschinski:NOXXON Pharma AG: Employment. Dümmler:NOXXON Pharma AG: Employment. Riecke:NOXXON Pharma AG: Employment. Engelhardt:NOXXON Pharma AG: Consultancy.

Background NOX-A12 is a novel, potent, L-stereoisomer RNA aptamer (Spiegelmer®) that binds and neutralizes CXCL12/SDF-1, a chemokine which attracts and activates immune- and non-immune cells via interaction with its receptors, CXCR4 and CXCR7. CXCL12 plays an important role in homing and trafficking of multiple myeloma (MM) cells to the bone marrow (BM). Here, we evaluate the capacity of NOX-A12 to mobilize plasma cells into the circulation. Furthermore, we analyze a possible therapeutic impact of NOX-A12 which disrupts the interaction of MM cells with the BM stroma resulting in enhanced chemosensitivity to established therapies such as bortezomib and dexamethasone (VD). Methods To date, 21/28 planned patients have been enrolled into a multicenter Phase IIa study of NOX-A12 alone and in combination with VD in relapsed MM patients. Here we report interim data on PK, PD and preliminary efficacy of a pilot group consisting of 3 cohorts of 3 patients each. In the pilot phase, cohorts received single doses of 1, 2 or 4 mg/kg NOX-A12 alone, respectively, two weeks prior to 8 planned cycles of combined treatment with NOX-A12 and VD repeated every 21 days. During combination therapy, NOX-A12 was administered 1-2 hours prior to bortezomib following a dose titration design for all patients: NOX-A12 doses were increased from 1 mg/kg to 2 mg/kg and 4mg/kg at cycles 1, 2 and 3, respectively. During cycles 4-6, doses of NOX-A12 were kept at the highest individually titrated dose. Bortezomib (1.3 mg/m2) was given on days 1, 4, 8 and 11 as intravenous injection. Oral dexamethasone (20 mg) was added on the day of and the day after bortezomib administration. Response was evaluated by applying the uniform response criteria of the IMWG 2011. Results In total, 10 patients were enrolled into the pilot group (one patient was replaced after withdrawal of consent). The median age was 63 years (range 56-78) with 7 women and 3 men being included. Median prior therapies were 2 (range 1-5), with 9 patients having been pretreated with dexamethasone and 3 with bortezomib prior to enrollment. At screening 1, 7 and 2 patients presented with ISS stage I, II and III, respectively. IgG, IgA and LC M-components were present in 6, 3 and 1 patients, respectively. Six patients had cytogenetic aberrations, which were high risk (t(4;14) or del17p) in 2 patients. Plasma profiles of NOX-A12 in the patient population of the pilot group (Figure 1) were similar to healthy volunteers in which a plasma half-life of approximately 38 hours was observed. After single doses of NOX-A12, a dose-linear exposure with peak plasma levels of 2.1, 3.9, and 6.7 µM was found in the corresponding cohorts. Furthermore, an increase of plasma cells in peripheral blood by approximately 200% was detected which lasted throughout the observation period of 3 days (Figure 2). NOX-A12 as single agent was safe and very well tolerated. Of nine evaluable patients who received the combination treatment of NOX-A12 and VD, 2 (22%) achieved a VGPR and 4 (44%) PR, resulting in an ORR (≥ PR) of 67%. In combination with VD, NOX-A12 was equally safe and well tolerated. Conclusion Proof of principle was achieved as single doses of NOX-A12 reached the expected plasma exposure and translated into an effective and prolonged mobilization of plasma cells into the peripheral blood. In addition, responses (PR or better) were noted in 6/9 (67%) patients of this pilot group. Single agent NOX-A12 was not associated with any relevant toxicity and the combination of VD with NOX-A12 was well tolerated and not associated with additional toxicity on top of VD. Provided that these promising findings will be confirmed in the total sample of 28 patients, further development of this novel anti-CXCL12/SDF-1 Spiegelmer® seems warranted. Disclosures: Ludwig: Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Munipharma: Honoraria, Research Funding. Weisel:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Engelhardt:MSD, Janssen-Cilag: Research Funding. Greil:NOXXON Pharma AG: Research Funding. Dümmler:NOXXON Pharma AG: Employment. Zöllner:NOXXON Pharma AG: Employment. Zeitler:NOXXON Pharma AG: Employment. Riecke:NOXXON Pharma AG: Employment. Kruschinski:Noxxon: Employment.

Background High-dose chemotherapy (HDT) with autologous stem cell transplant improves outcome of multiple myeloma (MM) patients in comparison to conventional chemotherapy. The incorporation of new drugs into induction, consolidation and maintenance therapy is changing the treatment paradigm and is questioning the role of HDT in newly diagnosed MM (NDMM) patients Aims To compare in a prospective randomized trial melphalan-prednisone-lenalidomide (MPR) with tandem melphalan (200 mg/m2) (MEL200) both followed by maintenance with lenalidomide or no maintenance in NDMM patients. Methods A 2x2 factorial randomized trial was designed. The induction treatment consisted of four 28-day cycles of lenalidomide (25 mg d 1-21) and low-dose dexamethasone (40 mg d 1,8,15,22) (Rd). As consolidation, patients were randomized to MPR (N=202) [six 28-day cycles of melphalan (0.18 mg/k g d 1-4), prednisone (2 mg/kg d 1-4) and lenalidomide (10 mg d 1-21)] or MEL200 (N=200)[tandem melphalan 200 mg/m2 with stem-cell support]. Patients were further randomized, within each group, to receive lenalidomide maintenance (10 mg, days 1-21, N=198) or no maintenance (N=204). Primary study endpoint was progression free survival (PFS). The secondary study endpoints included response rates, safety and overall survival (OS). Data were analyzed in the intent-to-treat (ITT) population. Results From November 2007 to July 2009, 402 patients with NDMM After a median follow-up of 48 months, the median PFS was 24.2 months in MPR group and 38.6 months in MEL200 group ( P< 0.0001). A multivariate analysis confirms the PFS benefit associated with MEL200 across all subgroups of patients defined by stratification factors and baseline characteristics. The 5-year OS rate was similar between MPR (62%) and MEL200 (71%; P= 0.27). In a landmark analysis, lenalidomide maintenance significantly extended PFS from the start of maintenance (median 42,7 months) compared with no maintenance (median 17.5 months; P During consolidation, the incidence of grade 3-4 adverse events (AEs) between MPR and MEL200 were as follow: neutropenia (50% vs. 90%), thrombocytopenia (8% vs. 89%), infections (1% vs. 15%) and gastrointestinal (0% vs. 18%), with complications being higher with MEL200. During the maintenance phase, grade 3-4 hematologic AEs were reported in 17% of patients receiving lenalidomide (16% neutropenia). For individual group comparisons during maintenance, grade 3-4 hematologic AEs were observed in 20% of patients receiving MPR plus lenalidomide maintenance compared with 15% receiving MEL200 plus lenalidomide maintenance. Second primary malignancies were observed in 11 patients (3%), and were mainly solid tumors. Four solid tumors were observed in the MEL200 group and one in the MPR group in the maintenance arm, while three solid tumors were observed in the MEL200 group and three in the MPR group in no maintenance arm. Conclusion The administration of MPR was significantly inferior to MEL200 in terms of PFS. Toxicities were significantly higher in MEL200 group, but manageable. OS is similar between MPR and MEL200. Lenalidomide maintenance significantly reduced the risk of progression and of death independently from the previous treatment. Disclosures: Gay: Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Cavallo:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Caravita:Celgene: Honoraria, Research Funding. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.

Abstract 1960 Introduction. Lenalidomide (Len) is a highly effective drug against multiple myeloma (MM). It acts through several mechanisms, such as a direct cytotoxic effect, anti-angiogenesis, microenvironment modifications, and immunomodulation. The latter property is particularly interesting in the setting of allogeneic stem cell transplantation (AlloSCT), since Len may interact favourably with the graft-versus-myeloma (GVM) effect. On the other side, the possibility of an over activation of the donor immune system raises some concerns about the safety of this treatment. In order to verify if Len is more effective when given after AlloSCT, we conducted among 7 Italian transplant centers a case-matched analysis comparing Len after autologous SCT (AutoSCT) vs. Len after AlloSCT. The hypothesis is that Len is more active when administered after AlloSCT. A secondary end-point of the study was the safety profile. Methods and results. In this retrospective study, the main matching criterion was represented by the number of treatment lines received before Len. In an attempt to uniform the treatment regimens, an intra-center matching was carried out. We collected data from 40 patients in each group. Baseline characteristics between Auto and Allo patients (pts) were similar, except for age at diagnosis (55 years, range 39–70, in Auto pts; 47 years, range 29 – 62, in Allo pts). The median number of previous lines of treatment was 3 (range 1–6) for both groups. Thirty-one (77%) Auto and 36 (90%) Allo pts received bortezomib. Similarly, 35 (87%) Auto and 21 (52%) Allo pts were previously treated with thalidomide. Twenty-one out of 40 (52%) Allo pts received SCT as a second or subsequent line of therapy. Before Len treatment, 14 (35%) Allo pts had acute graft-versus-host disease (aGVHD) (G1, 3 pts; G2, 8 pts; G3, 2 pts; G4, 1 pts), and 15 (37%) pts had chronic GVHD (cGVHD) (limited, 6 pts; extensive 9 pts). Median time between diagnosis and Len start was 65 months (range 14–162) in Auto, and 72 months(range 19–246) in Allo pts. Median time from transplant to Len start was 50 months (range 7–159) in Auto, and 21 months (range 6–134) in Allo pts. In all cases Len dosage was 25 mg, and it was combined with high or intermediate dose dexamethasone. Best responses for Auto and Allo patients were as follows: 5 vs. 3 CR, 6 vs. 8 VGPR, 12 vs. 13 PR, 9 vs. 8 SD, 8 vs. 8 PD. Time from Len start to the best response was 4 months for both groups. With a median follow-up from Len start of 22 months (range 2–60+), 3-years progression-free survival (PFS) was 13% in the Auto, and 43% in the Allo group (p=0.03). Median PFS was 9 months in Auto, and 16 months in Allo pts. Median OS was 22 months in the Auto group, and was not reached in the Allo group (p=0.05). Hematological toxicities were similar among the 2 groups. Neutropenia was observed in 16 (40%) patients in both the Auto and Allo group, thrombocytopenia in 10 (25%) Auto and 8 (20%) Allo pts, and anemia in 5 (12%) Auto and 2 (5%) Allo pts. Non-hematological toxicities were mild in both groups. In the Allo group one patients developed aGVHD after donor lymphocyte infusion, and 3 pts had a worsening of a pre-existing extensive cGVHD. Conclusions. The comparison between Auto and Allo pts has shown a benefit in terms of PFS and OS in the Allo group. This observation supports the hypothesis that Len may be synergic with the GVM effect. Interestingly, despite the same response rate between the 2 groups, clinical responses in Allo pts were more durable, reinforcing the hypothesis of the immunological control. On the other side, since Len has a potent immunomodulatory effect, this can raise concerns about its use after AlloSCT. The Dutch HOVON 76 trial has shown that the early administration of Len 10 mg after AlloSCT induces aGVHD in a substantial proportion of patients, causing unacceptable toxicity and the premature discontinuation of the study. However, in our retrospective study the median time between AlloSCT and Len administration was 21 months, and we did not observed any increase of GVHD. This suggests that the mechanisms of immune tolerance can mitigate the activation induced by Len, allowing a safe administration. Moreover, since in all cases dexamethasone was given with Len, its immunosuppressive effects may have harnessed the Len-induced immune activation, contributing to the treatment tolerability. In conclusion our case-matched study suggests that Len is more active when given after AlloSCT, still retaining a favorable toxicity profile. Disclosures: No relevant conflicts of interest to declare.

Abstract 1996 Introduction. Lenalidomide (Len) is a highly effective drug against multiple myeloma (MM). It acts through several mechanisms, such as a direct cytotoxic effect, anti-angiogenesis, microenvironment modifications, and immunomodulation. The latter property is particularly interesting in the allogeneic hematopoietic stem cell transplantation (Allo-HSCT) setting, since Len may interact favourably with the graft-versus-myeloma (GVM) effect. Preliminary results from retrospective studies on heterogeneous patient populations have suggested that Len is more effective when given after Allo-HSCT. In order to verify this observation, we have conducted a case-matched analysis comparing Len after autologous stem cell transplantation (Auto-HSCT) vs. Len after Allo-HSCT. The hypothesis is that Len may be more potent when administered after Allo-HSCT. Methods and results. In this retrospective study the matching criteria was represented by the number of treatment lines received before Len. In an attempt to uniform the treatment regimens, an intra-centre matching was recommended. To April 2011 we collected data from 39 patients in each group. Baseline characteristics between Auto and Allo patients were similar, except for age at diagnosis (53 years, range 39–70, in Auto patients; 47 years, range 29 – 61, in Allo patients). The median number of previous lines of treatment was 3 (range 1–6 ) for both groups. Twenty-one out 39 (54%) Allo patients received Allo-HSCT as second or subsequent line of therapy. Thirty-two (82%) Auto and 35 (90%) Allo patients received bortezomib in previous lines. Similarly, 34 (87%) Auto and 12 (54%) Allo patients were previously treated with thalidomide. Len was always combined with dexamethasone. Median time between Auto-HSCT and Len start was 38 months (range 7–159), and for Allo-HSCT 29 months (range 4–215). Best responses were for Auto and Allo patients as follows: 5 vs. 4 CR, 6 vs. 8 VGPR, 11 vs. 12 PR, 6 vs. 8 SD, 11 vs. 7 PD. Time from Len start to the best response was 4 months for both groups. With a median follow-up of 11.5 months (range 1–39), 1 year and 2 year progression-free survival were 41% and 6% for Auto patients, and 52% and 44% for Allo patients (p=0.03), respectively. Two years overall survival was 48% for Auto and 75% for Allo patients (p=0.03). Similar results were observed regardless of previous thalidomide treatment. No unexpected toxicities were reported. Two (10%) patients had worsening of a pre-existent extensive chronic GVHD. Discussion and Conclusion. The comparison between Auto and Allo patients has shown a benefit in terms of PFS and OS in favor of Len administered after AlloHSCT. This observation supports the hypothesis that Len is synergistic with the GVM effect. Since Len has a potent immunomodulatory effect, this can raise concerns about its use after AlloHSCT. A Dutch prospective study showed that the early administration of Len 10 mg daily after non-myeloablative Allo-HSCT induces late onset acute GVHD in a substantial proportion of patients, causing the premature discontinuation of the study. On the contrary, our retrospective study has shown that a later administration is feasible and safe, without an excess of GVHD, suggesting that a more mature immune system can better tolerate Len. Moreover, since in all cases dexamethasone was given in combination with Len, its immunosuppressive effect may have harnessed the Len-induced immune activation. In conclusion our study suggests that Len is particularly active after AlloHSCT, still retaining a favorable toxicity profile. Disclosures: No relevant conflicts of interest to declare.

Abstract 3573 Background: In this randomized study we question the role of HDT, when new drugs are incorporated in the conventional treatment or in the autologous transplant setting in newly diagnosed multiple myeloma (MM) patients. Aims: To compare melphalan, prednisone and lenalidomide (MPR) with tandem melphalan (200 mg/m2) (MEL200) in MM patients younger than 65 years. Methods: The induction treatment consisted of four 28-day cycles of lenalidomide (25 mg d 1–21) and low-dose dexamethasone (40 mg d 1,8,15,22) (Rd). Cyclophosphamide plus G-CSF was used to mobilize stem cells. As consolidation, patients were randomized to MPR (N=202) [six 28-day cycles of melphalan (0.18 mg/k g d 1–4), prednisone (2 mg/kg d 1–4) and lenalidomide (10 mg d 1–21))] or MEL200 (N=200)[tandem melphalan 200 mg/m2 with stem-cell support]. All patients were also randomized to receive either aspirin or low-molecular weight heparin (enoxaparin) as thromboprophylaxis during Rd and MPR. Primary study endpoint was progression free survival (PFS). Data were analyzed in intention-to-treat. Results: From november 2007 to july 2009, 402 patients with newly diagnosed symptomatic MM younger than 65 years of age were recruited and randomized. All patients enrolled were stratified according to International Staging System (ISS) (stages 1 and 2 vs stage 3) and age ( Results: On an intention to treat basis, best responses after Rd induction, were: partial response (PR) rate was 87%, very good partial response (VGPR) rate was 52%, including 13% complete responses (CR). The median yields of stem cells harvested was 8.7 ×106 CD34+ cells/Kg; 91% of patients collected the minimum dose of 4×106/kg CD34+ cells. As of August 10th, 257 patients are evaluable for response after at least 3 cycles of MPR (124) and after the first MEL200 (133); best responses to consolidation: in the MPR group, the VGPR rate was 60% including 20% CR; in the MEL200 group the VGPR rate was 58% including 25% CRs. No differences in responses were reported according to chromosomal abnormalities, such as del13, t(4;14), t(14;16) or del17p. After a median follow-up of 14 months, the projected 2-year PFS and OS were similar in the two groups (table). The achievement of at least VGPR after consolidation was a predictive factor of longer PFS in both groups: in the MEL200 group, the 2-year PFS was 92% for patients with at least VGPR vs 70% for those with PR (p Conclusion: Our study confirms the efficacy and safety of Rd induction. Both MPR and MEL200 improved the quality of response, achieved by Rd induction. At present, PFS and OS are not significantly different in the two groups, but longer follow-up is needed. These data will be updated at the meeting. Disclosures: Palumbo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janseen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavallo:Celgene: Honoraria. Patriarca:Celgene: Honoraria; Roche: Honoraria; Janssen-Cilag: Honoraria; Merck: Membership on an entity's Board of Directors or advisory committees. Caravita:Celgene: Consultancy. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janseen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Introduction: Acquired von Willebrand Disease (AVWD) is a rare bleeding disorder occurring in patients with haematological malignancies, solid tumours, immunological and cardiovascular disorders and monoclonal gammopathy of undetermined significance (MGUS). Several pathogenetic mechanisms have been proposed to explain acquired von Willebrand factor (VWF) defect including autoantibodies. Muco-cutaneous bleeding and laboratory findings are similar to those of the congenital VWD. Several approaches have been attempted to correct haemostatic abnormalities with the aim to control bleeding diathesis or to prevent bleeding during surgery. Desmopressin, plasma-derived FVIII/VWF concentrates, intravenous high dose immunoglobulin (HDIg) are the most commonly used. The efficacy of therapy is not predictable and has to be tested before surgery or invasive procedures. In several cases more than one therapeutic option is required. Case report. The patient was a 64-years-old woman with IgGλ-MGUS. Because of persistent uterine bleeding a neoplasia was suspected. The pre-operative coagulative screening showed a prolonged aPTT with markedly reduced levels of FVIII and VWF-related activities (Table 1). VWF multimeric analysis evidenced loss of high and intermediate molecular weight multimers. Patient’s personal and familial history was negative for bleeding and VWF level was normal in other family members. Desmopressin administration (s.c.0.3 μg/kg) obtained a rapid but transient correction of plasma VWF-related parameters, with a return to baseline levels within 6 hours. HDIg intravenous infusion (1 g/kg/day for two consecutive days) led to stable normalization of VWF:RCo, VWF:Ag and FVIII for at least 7 days (Table 1). A laparoscopic hystero-annessiectomy was performed after two-day HDIg infusion: no bleeding complications were observed in the peri-operative period. Histological diagnosis was endometrial hyperplasia. During the two-months follow-up no haemorrhagic episodes were reported. Comments: In AVWD the correction of laboratory abnormalities is crucial to prevent bleeding in patient undergoing high haemorrhagic risk surgery. The choice among therapeutic options is empirical and depends on underlying disease and clinical setting. The efficacy has to be verified. In our patient HDIg infusion obtained a sustained normalisation of VWF-related parameters and prevented bleeding during surgery and in the post-operative period. Table 1. Patient’s laboratory parameters before and after treatment with HDIg VWF-related parameters Reference interval basal +1* +5* +7* *days after HDIg infusion aPTT (R) 1.73 1.21 1.21 1.27

Contamination of reinfused stem cells with leukemic cells is a major concern affecting outcomes after ASCT in patients with CLL. In fact, outcomes after ASCT strongly correlate with disease status before transplantation. Persistence of minimal residual disease (MRD), as detected by consensus primer PCR, or the switch from a negative to a positive MRD status during follow-up, are both highly predictive of clinical relapse after ASCT. In order to minimize the risk of contaminating the collection with leukemic cells, in our institution patients who undergo an ASCT receive alemtuzumab before peripheral blood stem cell (PBSC) mobilization, to purge in vivo any residual disease. We evaluated the outcome of ASCT in 20 CLL patients who were pretreated with fludarabine (FAMP) containing regimens and subsequently received alemtuzumab SC (10 mg x 3/w for 6 weeks) to purge MRD. A FAMP containing regimen had been administered as first-line treatment in 18 cases and as second-line in 2 cases; median number of FAMP cycles administered was 6 (range, 4–8). All but 1 PBSC patient was mobilized with Ara-C (800mg/m2/12h x 3 d) followed by G-CSF, while the last patient received only G-CSF. Median age at transplant was 56 y (range, 45–65); all patients (pts)were in CR based on the NCI-WG criteria. Of 20 pts who underwent PBSC harvest, polyclonal IgH rearrangement was evident in 13 pts (65%), as assessed by PCR. The conditioning regimen consisted of 12 Gy TBI plus cyclophosphamide 120 mg/kg in 14 pts < 60 yrs, and Melphalan 180 mg/sqm in 6 pts >60 years. Median number of CD34+ cells reinfused was 17.4 x106/kg (range, 3.1–30.4), and in 13 cases the reinfused product was polyclonal for IgH. The median time for PMN (>500/ml) and PLT (>20000/ml) recovery was 9 (range, 8–11) and 11 (range, 9–13) days respectively. During marrow aplasia 13 patients experienced an episode of fever >38°C with a median duration of 2 days (1–8); in 3 pts the fever was of unknown origin, in 8 cases sepsis was due to Staphilococcus epidermidis, and in 1 case it was due to P. aeruginosa. Intravenous antibiotics were administered in 11 cases, and only 1 patient required intravenous antifungal therapy. One patient died due to a pulmonary fungal infection sustained by Aspergillus Terreus. No incidence of grade 3–4 nonhematologic toxicity was observed. During the 3 months post-transplant 2 pts required hospitalization: 1 for a fever, and the other for acute polyneuropathy. No pathogens were isolated in either case. At 11 months post-transplant 1 patient developed thrombocytopenia. None of the pts developed CMV reactivation, even in the 9 cases, which became CMV positive during alemtuzumab treatment. Herpes Zoster was observed in 2 patients at 5 and 10 months after transplant. At a median of 28 months after receiving alemtuzumab (range, 15–48 months), and a median 17 months after PBSC transplantation (range, 1–41 months), 19 pts are in CR. At the 9- and 12-month post-transplant evaluation, performed on 16 and 12 pts respectively, all but 1 patient showed polyclonal IgH rearrangement. ASCT after sequential treatment with FAMP and Campath-1H is feasible with no significant increase in major infections; a substantial number of patients achieved a sustained polyclonal IgH rearrangement after transplant.

Imatinib Mesilate (Glivec) is able to induce a high rate of Complete Cytogenetic Response (CCyR) with low treatment-related toxicity. The long-term duration of this Ph-negative status is, however, still undefined. Therefore, some groups (Drummond et al, Br J Haematol 123:479, 2003; Hui et al, Leukemia 17:821,2003) decided to mobilize and to collect Ph-negative PBSCs in patients reaching CCyR with Glivec. In our experience we studied 12 Ph-negative, FISH-negative patients, median age 50 yrs (26–61). Three of them were also PCR-negative, being the minimal residual disease assessed using RT-PCR. All patients received Imatinib Mesilate at the daily dose of 400 mg. The median duration of treatment with Glivec was 25 months (range 11–35). Eight of 12 pts (67%) were pre-treated with α-interferon (α-IFN) for a median time of 9.5 months (range 3–54). The median duration of CML was 39 months (range: 21–152). We discontinued Imatinib four days (range 3–5) before starting rHu-G-CSF as single agent (5–10 μg/Kg/day), which was maintained until WBC 10/μ L. Eleven of 12 pts (92%) reached the threshold of 10/μ L and started harvesting. The single patient failing collection had been pretreated with IFN and was PCR negative at the time of mobilization. The remaining 11 reached the target of 2.5 x106 CD34+ cells/Kg with a median of two apheresis (range 1–3). The median harvest was 3.14 CD34+ x 106/Kg (range 2.56–4.55). Conventional cytogenetic analysis, RT-PCR and coltural tests were performed in all apheretic samples. All the 11 mobilized patients obtained a Ph-negative harvest, which was also PCR negative in 4/11 (36%). In our experience adequate yields of PBSCs were collected with rHu-G-CSF alone in 11/12 patients achieving CCyR with Glivec, as well as in the majority of those previously treated with α-IFN (7/8). Results of harvesting after rHu-G-CSF alone in 11 CML patients achieving CCyR after Imatinib Mesilate | Patient | N. Apheresis | CD34+ x 10^6/kg | RT-PCR | |:------- | ------------ | --------------- | ------ | | T.M | 2 | 4.55 | pos. | | O.I | 2 | 3.34 | neg. | | V.E. | 1 | 3.33 | neg. | | S.G. | 3 | 3.07 | neg. | | R.R. | 1 | 4.45 | pos. | | M.G. | 3 | 2.56 | pos. | | S.C. | 1 | 3.2 | pos. | | S.C. | 2 | 2.6 | pos. | | C.A. | 1 | 3.75 | pos. | | T.G. | 2 | 3.14 | neg. | | V.M. | 2 | 2.65 | pos.

Background: Monoclonal antibodies directed towards specific cell surface antigens on neoplastic cells have been increasingly used in lymphoid malignancies in the last few years. Alemtuzumab is a humanized monoclonal antibody which binds the CD52 antigen highly expressed on B-CLL cells. Alemtuzumab significantly depletes both B and T lymphocytes increasing the risk of opportunistic infections. Cytomegalovirus (CMV) infection causes significant morbidity and mortality in the setting of immunodeficiency. CMV reactivation has been described in most of the reported series in which alemtuzumab has been administered. Aim: We investigated the incidence and management of CMV reactivation in a population of B-CLL patients treated with FAMP including regimens, followed by Alemtuzumab as consolidation. Methods: 35 B-CLL patients, 22 males and 13 females, median age 55 (range 39–64), responding to FAMP including regimens (32 FAMP alone, 3 FAMP+cyclophosphamide) received subcutaneous Campath-1H three times a week for six weeks in escalating doses up to 10 mg in order to treat residual disease. Monitoring of CMV reactivation by CMV pp65 antigenemia test was weekly performed, starting from the first week of alemtuzumab treatment until 4 weeks after discontinuation. Results: CMV pp65 antigenemia positive test was detected in 20 patients (57%). The median time for reactivation was 43 days (range 23–61) from the beginning of therapy. Among those twenty pts, 11 showed less than 10 positive cells. All the 9 pts (25.7%) showing positive test with more than 10 cells [median positive cells 44.5 (range 12–751) ] received pre-emptive treatment with oral Gancyclovir 1g thrice daily (oGCV). Only three of this group of 9 pts presented mild symptoms (fever and/or epigastric pain). Among the 11 pts presenting with positive antigenemia in less than 10 cells, seven received oGCV as pre-emptive therapy while the remaining four were not treated. Only one of the seven pts given pre-emptive therapy was symptomatic, presenting fever. The four pts not receiving treatment with oGCV showed a negativity at the subsequent test within a week from the first positive detection. Negativity of antigenemia test was obtained in all the pts receiving pre-emptive oGCV treatment. After short-time of discontinuation, alemtuzumab was restarted in all 20 cases tested positive for pp65 antigenemia. Organ involvement was never seen. Conclusion: Our survey shows that pp65 antigenemia is a sensitive test for monitoring CMV reactivation in pts treated with alemtuzumab. We suggest that the combination of FAMP and alemtuzumab is permissive to a higher risk of CMV reactivation in B-CLL pts. Pre-emptive treatment with oGCV is able to prevent the severe manifestations of CMV such as pneumonia and colitis and to permit the completion of the therapeutic program. To improve the cost-effectiveness of this strategy we propose: antigenemia monitoring not before the 4th week of treatment; closely repeating the test in case of positivity less than 10 cells; treating only in case of increase of the number of positive cells.

The efficacy of ASCT in pts with CLL may be compromised by the reinfusion of neoplastic cells with the autograft leading to relapse. For this reason in our Institution pts eligible for an ASCT receive Campath-1H before peripheral blood stem cell (PBSC) mobilization to perform a purging in vivo in order to minimise the contamination of the collection. We evaluate the safety and feasibility of APBSCT in fourteen CLL patients pretreated with Fludarabine (FAMP) containing regimens and subsequent Campath-1H subcutaneusly (10 mg x 3/w for 6 weeks). A FAMP containing regimen had been administered as first line treatment in 12 cases and as second line in 2 cases; median number of FAMP cycles administered was 6 (range 4–8). In all but one pts PBSC were mobilized with Ara-C (800mg/m2/12h x 3 d) followed by G-CSF while the last pt received only G-CSF. Median age at transplant was 57.5 y (range 45–63); all pts were in CR, 9 pts showing a polyclonal rearrangement of the IgH at PCR by consensus primer. Conditioning regimen consisted of 12 Gy TBI plus cyclophosphamide 120 mg/kg in 9 pts aged < 60 y, Melphalan 180 mg/sqm in the 5 pts aged > than 60 y. Median number of CD34+ cells reinfused was 17.1 x106/kg (range3.4–30.4), the reinfused product was polyclonal for the IgH in 9 cases. The median time for PMN (> 500/μl) and PLT (> 20000/μl) recovery was 9 (range 8–10) and 11 (range 9–13) days respectively. During marrow aplasia nine pts experienced an episode of fever > 38°C with a median duration of 2 days (1–8); in three pts the cause of fever remained of unknown origin while in the remaining 6 cases a sepsis due to Staphilococcus Aureus was recorded. Intravenous antibiotics were administered in 7 cases; none of the pts required intravenous antifungal therapy. No grade 3–4 extrahematological toxicity and no treatment related deaths were observed. During the 3 months post transplant period two pts required hospitalisation for fever in one case and for acute polineuropathy in the other case; in both cases no pathogens have been isolated. In none of the pts a CMV reactivation was recorded even in the 6 cases showing a reactivation during Campath-1H treatment. An Herpes Zooster infection was observed in 2 pts after 5 and 10 months from transplant. The recovery of CD4+ and CD8+ cells is illustrated in the followig table. CD4 and CD8 reconstitution after ASCT pre ASCT month +3 month +6 month +12 * * 6 pts CD4/ μl 57 91 86 174 CD8/ μl 171 310 377 540 After a median follow-up of 10 months (3–30) from transplant all pts are in CR. At the three months post-transplant evaluation, performed in 13 cases, all but one pts showed polyclonal IgH rearrangement. ASCT after sequential treatment with FAMP and Campath-1H is feasible with any evidence of increased number of major infections; a substantial number of pts achieved after transplant a polyclonal IgH rearrangement.